Lethal Congenital Contracture Syndrome

Mendelian MONDO:0017436 Pathograph 59 Show in embeddings browser Congenital Disorder

Lethal congenital contracture syndrome (LCCS) comprises genetically heterogeneous autosomal recessive disorders with prenatal akinesia and congenital contractures. The numbered subtypes involve GLE1-associated spinal motor-neuron development, ERBB3 signaling, PIP5K1C-dependent phosphoinositide metabolism, MYBPC1-associated muscle function, DNM2-dependent trafficking, ZBTB42-associated muscle development, CNTNAP1 paranodal junctions, ADCY6 and ADGRG6 peripheral myelination, NEK9-associated skeletal development, GLDN nodal organization, and combined neuronal and muscle DST isoforms. Some mechanistic steps are inferred from cellular or animal models and should not be transferred between subtypes. Reduced movement can produce joint deformations, impaired fetal swallowing and pulmonary hypoplasia, but primary skeletal abnormalities and central nervous system involvement also occur. Prenatal and neonatal mortality is high in selected series; GLDN- and CNTNAP1-associated disease can permit longer survival with substantial morbidity.

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1
Inheritance
17
Pathophys.
44
Phenotypes
12
Gaps
59
Pathograph
12
Genes
7
Medical Actions
12
Subtypes
4
Differentials
3
References
1
Deep Research
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Inheritance

1
Autosomal recessive inheritance HP:0000007
Every established LCCS locus is inherited in an autosomal recessive manner, with homozygous founder alleles in consanguineous or geographically isolated kindreds and compound heterozygosity elsewhere.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:25055871 SUPPORT Human Clinical
"Lethal congenital contracture syndrome (LCCS) is a lethal autosomal recessive form of arthrogryposis multiplex congenita (AMC)."
States the autosomal recessive mode of inheritance for the LCCS group as a whole.
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Subtypes

12
LCCS1 (GLE1-related, Finnish type / Herva disease) MONDO:0009670
GLE1 hgnc:4315 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in GLE1 (hgnc:4315). hgnc:4315 is a gene from the HUGO Gene Nomenclature Committee.
The Finnish-heritage form, caused by biallelic GLE1 variants (classically the FinMajor splice allele). It is the most severe subtype: total fetal immobility detectable from the first trimester, hydrops, pterygia, and fetal death typically before 32 weeks, with autopsy showing loss of anterior horn motoneurons and severe ventral spinal cord atrophy.
Show evidence (1 reference)
PMID:18204449 SUPPORT Human Clinical
"Here, we report that the defective gene underlying lethal motoneuron syndrome LCCS1 is the mRNA export mediator GLE1."
Establishes GLE1 as the LCCS1 gene.
LCCS2 (ERBB3-related) MONDO:0011868
ERBB3 hgnc:3431 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in ERBB3 (hgnc:3431). hgnc:3431 is a gene from the HUGO Gene Nomenclature Committee.
ERBB3-associated disease in an Israeli Bedouin kindred combines neurogenic arthrogryposis, anterior-horn atrophy and marked urinary-bladder distension. The founder splice variant predicts a truncated receptor. Impaired PI3K/Akt signaling and deficient Schwann-cell support are proposed contributors based partly on Erbb3-null mice; the complete human pathway is unresolved.
Show evidence (1 reference)
PMID:17701904 SUPPORT Human Clinical
"We show that the disease is caused by aberrant splicing of ERBB3, which leads to a predicted truncated protein."
Establishes ERBB3 as the LCCS2 gene.
LCCS3 (PIP5K1C-related) MONDO:0012656
PIP5K1C hgnc:8996 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in PIP5K1C (hgnc:8996). hgnc:8996 is a gene from the HUGO Gene Nomenclature Committee.
PIP5K1C-associated arthrogryposis resembles the original ERBB3 kindred clinically but lacks its neurogenic bladder finding. The original D253N allele markedly reduces recombinant kinase activity. Impaired PIP2-dependent synaptic vesicle trafficking is a proposed route to neuronal dysfunction, but no postmortem examinations were performed in the original LCCS3 series, so shared anterior-horn pathology cannot be assumed. Additional alleles and populations have since been reported.
Show evidence (1 reference)
PMID:17701898 SUPPORT Human Clinical
"We now describe a third LCCS phenotype (LCCS3)--similar to LCCS2 yet without neurogenic bladder."
Defines LCCS3 and its clinical discriminator from LCCS2.
LCCS4 (MYBPC1-related) MONDO:0013965
MYBPC1 hgnc:7549 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in MYBPC1 (hgnc:7549). hgnc:7549 is a gene from the HUGO Gene Nomenclature Committee.
Recessive truncation of MYBPC1 abrogates the functional domains of slow-type myosin-binding protein C in the original LCCS4 families. A muscle contractile mechanism is plausible from the protein function; human myofibrillar histopathology was not established by the quoted genetic report. Other MYBPC1 alleles cause nonlethal distal or generalized arthrogryposis.
Show evidence (1 reference)
PMID:22610851 SUPPORT Human Clinical
"We now show that a recessive mutation abrogating all functional domains in the same gene leads to LCCS."
Establishes recessive MYBPC1 loss of function as the LCCS4 mechanism.
LCCS5 (DNM2-related, fetal akinesia with cerebral and retinal hemorrhage) MONDO:0014149
DNM2 hgnc:2974 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in DNM2 (hgnc:2974). hgnc:2974 is a gene from the HUGO Gene Nomenclature Committee.
Caused by a homozygous DNM2 p.Phe379Val substitution impairing endocytosis. Distinguished from the other subtypes by intracranial and retinal haemorrhages alongside the akinesia and contractures, consistent with a pleiotropic dynamin-2 requirement in both muscle and vascular development.
Show evidence (1 reference)
PMID:23092955 SUPPORT Human Clinical
"We report the first homozygous mutation in the DNM2 protein p.Phe379Val, in three consanguineous patients with a lethal congenital syndrome associating akinesia, joint contractures, hypotonia, skeletal abnormalities, and brain and retinal hemorrhages."
Establishes DNM2 and the distinguishing haemorrhagic phenotype.
LCCS6 (ZBTB42-related) MONDO:0014549
ZBTB42 hgnc:32550 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in ZBTB42 (hgnc:32550). hgnc:32550 is a gene from the HUGO Gene Nomenclature Committee.
Identified by autozygome analysis in a consanguineous Saudi family with recurrent stillbirths. ZBTB42 is enriched in skeletal muscle, particularly at the neuromuscular junction, and zebrafish knockdown reproduces disorganized myofibrils - placing the lesion at the muscle/NMJ end of the motor unit.
Show evidence (1 reference)
PMID:25055871 SUPPORT Human Clinical
"Our data assign a novel muscular developmental phenotype to ZBTB42 in vertebrates and establish a new LCCS6 type caused by ZBTB42 mutation."
Establishes ZBTB42 as the LCCS6 gene.
LCCS7 (CNTNAP1-related) MONDO:0014569
CNTNAP1 hgnc:8011 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in CNTNAP1 (hgnc:8011). hgnc:8011 is a gene from the HUGO Gene Nomenclature Committee.
Caused by biallelic CNTNAP1 loss of function. CASPR is an essential paranodal component, and its loss produces a developmental nodopathy with motor nerve conduction velocities below 10 m/s and grossly abnormal nodes of Ranvier on sciatic nerve electron microscopy.
Show evidence (1 reference)
PMID:24319099 SUPPORT Human Clinical
"Homozygous frameshift mutations in CNTNAP1 were found in four unrelated families."
Establishes biallelic CNTNAP1 loss of function as an LCCS cause.
LCCS8 (ADCY6-related) MONDO:0014570
ADCY6 hgnc:237 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in ADCY6 (hgnc:237). hgnc:237 is a gene from the HUGO Gene Nomenclature Committee.
Caused by biallelic ADCY6 variants. Adenylate cyclase 6 generates the cAMP signal that drives Schwann cell myelination, and affected nerves lack peripheral myelin entirely on electron microscopy.
Show evidence (1 reference)
PMID:24319099 SUPPORT Human Clinical
"A homozygous missense mutation in adenylate cyclase 6 gene (ADCY6) was found in another family characterized by a lack of myelin in the peripheral nervous system (PNS) as determined by TEM."
Establishes ADCY6 and the amyelinating peripheral nerve phenotype.
LCCS9 (ADGRG6/GPR126-related) MONDO:0014670
ADGRG6 hgnc:13841 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in ADGRG6 (hgnc:13841). hgnc:13841 is a gene from the HUGO Gene Nomenclature Committee.
Caused by biallelic ADGRG6 (GPR126) variants. GPR126 is an adhesion GPCR required for Schwann cell myelination; affected peripheral nerves lack myelin basic protein, and Gpr126-null mice reproduce the lethal arthrogryposis phenotype.
Show evidence (2 references)
PMID:26004201 SUPPORT Human Clinical
"By whole-exome or targeted exome sequencing, it was shown that the probands each harbored a different homozygous mutation (one missense, one nonsense, and one frameshift mutation) in GPR126."
Establishes biallelic GPR126/ADGRG6 variants as a cause of lethal AMC.
PMID:26004201 SUPPORT Model Organism
"A previous study reported that Gpr126(-/-) mice have a lethal arthrogryposis phenotype."
The mouse knockout evidence the subtype description relies on for recapitulation.
LCCS10 (NEK9-related) MONDO:0014870
NEK9 hgnc:18591 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in NEK9 (hgnc:18591). hgnc:18591 is a gene from the HUGO Gene Nomenclature Committee.
NEK9-associated lethal skeletal dysplasia was initially reported in two Irish Traveller families with homozygous p.Arg497*, fetal akinesia, shortened long bones, rib and thoracic abnormalities, contractures and pulmonary hypoplasia. Patient fibroblasts show cell-cycle and ciliary abnormalities. These support a developmental mechanism without establishing how much each skeletal finding reflects primary dysplasia versus impaired movement. Later surviving APUG-like neonatal cases are a distinct allelic presentation.
Show evidence (1 reference)
PMID:26908619 SUPPORT Human Clinical
"We report two Irish Traveller families with a previously undescribed lethal skeletal dysplasia characterized by fetal akinesia, shortening of all long bones, multiple contractures, rib anomalies, thoracic dysplasia, pulmonary hypoplasia and protruding abdomen."
The original lethal skeletal-dysplasia families establish the LCCS10 clinical scope; the later APUG-like neonates are not used as its denominator.
LCCS11 (GLDN-related) MONDO:0014965
GLDN hgnc:29514 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in GLDN (hgnc:29514). hgnc:29514 is a gene from the HUGO Gene Nomenclature Committee.
Caused by biallelic GLDN variants. Gliomedin is the Schwann-cell-derived ligand that clusters sodium channels at nascent nodes of Ranvier through neurofascin-186, so its loss is a second developmental nodopathy alongside LCCS7. LCCS11 is the subtype with the best-documented survival beyond the neonatal period.
Show evidence (1 reference)
PMID:27616481 SUPPORT Human Clinical
"Through linkage analysis, homozygosity mapping, and exome sequencing in four unrelated families affected by lethal AMC, we identified biallelic mutations in GLDN in the affected individuals."
Establishes biallelic GLDN variants as the LCCS11 cause.
LCCS12 MONDO:0981031
DST hgnc:1090 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in DST (hgnc:1090). hgnc:1090 is a gene from the HUGO Gene Nomenclature Committee.
The lethal congenital-contracture presentation is associated with biallelic DST variants affecting both neuronal DST-a and muscle DST-b isoforms. Four patients from two families had severe arthrogryposis and intrauterine or early postnatal death. The separate 19-patient DST-b-only congenital-myopathy cohort cannot establish the muscle histology, cardiomyopathy frequency or survival of LCCS12.
Show evidence (2 references)
PMID:40497796 SUPPORT Human Clinical
"Genotype-phenotype correlation in these patients and previously published cases with respective variants resulted in the definition of a DST-associated lethal congenital contracture syndrome."
Establishes DST as the gene defining a lethal congenital contracture syndrome.
PMID:40497796 SUPPORT Human Clinical
"Variants that also impact DST-a besides DST-b result in a more severe, lethal congenital contracture syndrome."
Gives the isoform-dependent severity relationship that separates the lethal phenotype from the congenital myopathy.
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Discussions and Knowledge Gaps

12
Which variant, developmental and care factors determine survival and later progression in GLDN-associated disease?
KNOWLEDGE GAP OPEN lccs_survival_variability
Attached to
has_subtypes#LCCS11 phenotypes#Neonatal Respiratory Failure
Published GLDN series include terminations, neonatal deaths and long survivors, with differing denominators and support. The 2025 founder report includes four early deaths and one survivor with later progressive compromise. These data establish variable outcome but do not separate residual function, modifiers and care effects.
Show evidence (1 reference)
PMID:39713852 SUPPORT Human Clinical
"Our data corroborate those of other reports, demonstrating that LCCS11 is not universally lethal, but long-term survivors are at risk of progressive neuromuscular compromise."
The newer founder series independently supports variable lethality and later morbidity.
How do combined neuronal and muscle dystonin defects produce the lethal contracture phenotype?
KNOWLEDGE GAP OPEN lccs12_tissue_attribution
Attached to
pathophysiology#Combined Neuronal and Muscle Dystonin Deficiency
The source establishes causal combined-isoform involvement, now represented by a qualified edge to contractures. It does not identify the relative neuronal and muscle mechanisms in the lethal cases; the separate DST-b-only cohort is not evidence of their biopsy or cardiac phenotype.
Show evidence (2 references)
PMID:40497796 SUPPORT Human Clinical
"Genotype-phenotype correlation in these patients and previously published cases with respective variants resulted in the definition of a DST-associated lethal congenital contracture syndrome."
Establishes DST as the gene defining a lethal congenital contracture syndrome.
PMID:40497796 SUPPORT Human Clinical
"Variants that also impact DST-a besides DST-b result in a more severe, lethal congenital contracture syndrome."
Gives the isoform-dependent severity relationship that separates the lethal phenotype from the congenital myopathy.
How much of the NEK9 skeletal phenotype results from primary developmental dysplasia versus reduced fetal movement?
KNOWLEDGE GAP OPEN lccs10_developmental_attribution
Attached to
pathophysiology#Mitotic and Ciliary Regulatory Failure phenotypes#Short Long Bones
The original lethal families had akinesia and skeletal dysplasia, and their fibroblasts had both mitotic and ciliary abnormalities. Qualified causal links are represented. The unresolved issue is tissue and process attribution, not whether the causal genotype or the fetal movement phenotype exists. Surviving APUG-like cases are not used to supply LCCS10 visceral findings.
Show evidence (1 reference)
PMID:26908619 SUPPORT Human Clinical
"We report two Irish Traveller families with a previously undescribed lethal skeletal dysplasia characterized by fetal akinesia, shortening of all long bones, multiple contractures, rib anomalies, thoracic dysplasia, pulmonary hypoplasia and protruding abdomen."
The original lethal skeletal-dysplasia families establish the LCCS10 clinical scope; the later APUG-like neonates are not used as its denominator.
Why do human GLDN variants cause severe fetal disease when gliomedin-null mice have a milder nodal phenotype?
HUMAN MODEL MISMATCH OPEN lccs_gldn_model_fidelity
Attached to
pathophysiology#Node of Ranvier Assembly Failure
Human nerve abnormalities support the nodopathy mechanism, but preserved conduction and absence of arthrogryposis in null mice constrain a simple universal loss-of-function-to-complete-conduction-block model. Allele, species and compensatory nodal mechanisms remain unresolved.
Show evidence (2 references)
PMID:28726266 SUPPORT Model Organism
"Homozygous gldn−/− mice do not have apparent neurologic deficits or features of arthrogryposis and demonstrate normal nerve conduction and peripheral nervous system myelin (Feinberg, et al., 2010)."
The primary clinical paper summarizes the null-mouse contrast; this is model-organism evidence, not a negative finding in human GLDN disease.
PMID:28726266 SUPPORT Human Clinical
"Nerve conduction velocity studies performed at 1 week of age demonstrated axonal motor and sensory neuropathy but were normal when repeated at 7 months of age."
Human longitudinal variability is another constraint on a permanent, uniform conduction-block model.
What causes hydrops and restricted growth in affected fetuses, and when do placental factors contribute?
KNOWLEDGE GAP OPEN lccs_hydrops_growth
Attached to
phenotypes#Hydrops Fetalis phenotypes#Intrauterine Growth Restriction
The rat paralysis experiment supports a qualified akinesia-to-growth-restriction contribution, now represented in the graph. It does not resolve the relative contribution in the GLDN-associated fetus with abnormal umbilical-artery flow. The reviewed LCCS sources establish hydrops but do not identify a subtype-specific fluid-balance mechanism; its absence in original ERBB3 and PIP5K1C kindreds constrains an obligatory consequence of contractures.
Show evidence (1 reference)
PMID:35806855 SUPPORT Human Clinical
"Sonography examination revealed hydrothorax, subcutaneous generalized edema, short long bones, fixed limb joints, absent fetal movements, fetal growth restriction (estimated fetal weight in the 4th percentile and absent end-diastolic flow in both umbilical arteries), and polyhydramnios (amniotic..."
The coexisting flow abnormality constrains attribution of growth restriction solely to the fetal motor disorder.
What causes jaw retrusion and hip dislocation in the reported LCCS patients?
KNOWLEDGE GAP OPEN lccs_craniofacial_joint_distribution
Attached to
phenotypes#Retrognathia phenotypes#Hip Dislocation
Fetal immobility is a supported general deformation mechanism, with micrognathia and pterygia routes represented separately. The reviewed sources do not specifically resolve jaw retrusion or hip dislocation in the cited LCCS patients. A small mandible is not equivalent to retrusion, and local mechanical versus primary developmental attribution remains uncertain.
Show evidence (1 reference)
PMID:35806855 SUPPORT Human Clinical
"The pregnancy was terminated and postmortem studies confirmed the prenatal findings: distal arthrogryposis, fetal growth restriction, pulmonary hypoplasia, and retrognathia."
The primary case supports jaw retrusion, not mandibular size.
Which central, peripheral autonomic or developmental lesion produces neurogenic bladder in ERBB3 and CNTNAP1 disease?
KNOWLEDGE GAP OPEN lccs_bladder_localization
Attached to
phenotypes#Neurogenic Bladder
Human reports establish neurogenic bladder in both subtypes but do not localize the responsible autonomic lesion. Somatic anterior-horn loss alone does not establish the bladder mechanism; CNTNAP1 disease includes both central and peripheral pathology.
Show evidence (1 reference)
PMID:29882456 SUPPORT Human Clinical
"Individual LD_0333.0 was a girl with severe hypotonia and respiratory insufficiency that required a tracheostomy after birth, hypomyelinating neuropathy, bilateral hearing loss, bilateral optic nerve atrophy, lethargy, and neurogenic bladder."
Documents neurogenic bladder in a CNTNAP1-associated child, extending the subtype scope without identifying the responsible autonomic pathway.
Are GLDN-associated bulbar and diaphragmatic weakness and airway malacia caused by the same peripheral lesion?
KNOWLEDGE GAP OPEN lccs_gldn_bulbar_airway
Attached to
phenotypes#Vocal Cord Paresis phenotypes#Diaphragmatic Paralysis phenotypes#Laryngomalacia phenotypes#Tracheomalacia phenotypes#Central Apnea
The source establishes focal paresis, diaphragm paralysis and laryngoscopic malacia in different children. Their downstream swallowing and respiratory contributions are represented where directly supported. It does not localize the upstream cause of paresis or establish that structural airway malacia is a direct consequence of gliomedin deficiency. Polysomnographic central apnea is separately reported; its coexistence with tracheomalacia does not establish an obstructive mechanism.
Show evidence (2 references)
PMID:28726266 SUPPORT Human Clinical
"Insufficient swallowing aggravated by paresis of both the right vocal cord and right side of the soft palate prompted gastrostomy tube placement at 4 months of age."
Documents vocal cord paresis and its contribution to the swallowing failure.
PMID:28726266 SUPPORT Human Clinical
"Laryngoscopy demonstrated laryngo- and tracheomalacia, floppy epiglottis, and pooling of oral secretions."
The laryngoscopic findings explicitly establish laryngomalacia in this child.
How do neuropathy, weakness, contractures and respiratory illness contribute separately to delayed motor acquisition in GLDN survivors?
KNOWLEDGE GAP OPEN lccs_motor_trajectory
Attached to
phenotypes#Motor Developmental Delay
The source documents delayed milestones and subsequent gains with growth and care. It does not separate peripheral motor dysfunction from mechanical restriction, prolonged illness or developmental contributors sufficiently to assign a specific causal edge to motor delay.
Show evidence (1 reference)
PMID:28726266 SUPPORT Human Clinical
"Motor and language development was delayed; he was able to sit independently at age 13 months and started to crawl at age 24 months."
The exact ages establish motor delay in the Family 3 survivor, without inferring cognitive impairment.
What accounts for the distinct sensory and palatal findings in surviving CNTNAP1-associated children?
KNOWLEDGE GAP OPEN lccs_cntnap1_sensory_palate
Attached to
phenotypes#Cerebral Visual Impairment phenotypes#Hearing Impairment phenotypes#Optic Atrophy phenotypes#Cleft Palate
Central and peripheral glial-axonal disease provides plausible context, but the report does not connect the observed cortical visual loss, hearing loss, optic atrophy or palatal malformation to a specific demonstrated mechanism. Hearing-loss localization and the developmental cause of cleft palate remain unresolved; the established central hypomyelination and atrophy routes are represented separately.
Show evidence (1 reference)
PMID:29882456 SUPPORT Human Clinical
"Individual LD_0158.0 is an 8 year old male with hypotonia and respiratory failure requiring intubation at birth and subsequent tracheotomy-dependency, congenital hypomyelinating neuropathy with arthrogryposis multiplex congenita, cleft palate, cortical vision loss, bilateral hearing loss, and..."
This patient-level clinical observation establishes the findings but does not establish a single causal route for them.
Were pulmonary hypertension and ductal patency in the DNM2 siblings primary developmental findings or consequences of respiratory insufficiency?
KNOWLEDGE GAP OPEN lccs_dnm2_cardiopulmonary_attribution
Attached to
phenotypes#Pulmonary Hypertension phenotypes#Patent Ductus Arteriosus
The source explicitly states that primary versus secondary attribution could not be determined. The general developmental endocytosis hypothesis does not resolve this specific uncertainty, so no direct respiratory or genetic-mechanism edge is asserted.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658203/ SUPPORT Human Clinical
"AFB3 and AFB4 had pulmonary hypertension and a patent ductus arteriosus; whether these features were primary or secondary to respiratory insufficiency could not be determined."
The authors state the causal attribution limit for these two cardiopulmonary observations.
Did scoliosis in the GLDN survivor result from neuromuscular imbalance, fixed posture or a separate developmental process?
KNOWLEDGE GAP OPEN lccs_scoliosis_attribution
Attached to
phenotypes#Scoliosis
The clinical course establishes scoliosis requiring surgery at age nine, alongside weakness, atrophy and congenital contractures. It does not identify the cause or provide serial spinal development sufficient to distinguish neuromuscular deformation from another developmental process. The surgery documents the phenotype, not a demonstrated causal intermediary.
Show evidence (1 reference)
PMID:28726266 SUPPORT Human Clinical
"He underwent surgical treatment for bilateral hip luxation and clubfeet (age 2 years) and scoliosis with Harrington rod insertion (age 9 years)."
The GLDN Family 2 survivor underwent scoliosis surgery with Harrington rod insertion at age nine years. The hip procedure in the same sentence occurred at age two.
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Pathophysiology

17
Nuclear mRNA Export Failure
GLE1 participates in nuclear mRNA export and translation. Human GLE1 variants cause LCCS1 with anterior-horn motor-neuron deficiency; zebrafish studies implicate dividing neural precursor survival and motor-axon arborization. The precise RNA targets and cell-autonomous contributions in affected human fetuses remain unresolved; a shared RNA pathway across LCCS1-3 remains a hypothesis.
GLE1 hgnc:4315 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GLE1 (hgnc:4315). hgnc:4315 is a gene from the HUGO Gene Nomenclature Committee.
mRNA export from nucleus GO:0006406 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mRNA export from nucleus (GO:0006406). GO:0006406 is a biological process from the Gene Ontology.
Downstream
Anterior Horn Motor Neuron Loss GLE1 dysfunction is linked to the human motor-neuron deficit, with neural precursor apoptosis supported in zebrafish. This is a qualified developmental route, not proof of death of differentiated human motor neurons.
Show evidence (1 reference)
PMID:18204449 SUPPORT Other
"Our finding of mutated GLE1 exposes a common pathway connecting the genes implicated in LCCS1, LCCS2 and LCCS3 and elucidates mRNA processing as a critical molecular mechanism in motoneuron development and maturation."
Identifies mRNA processing as the molecular mechanism, and proposes it as the pathway shared across the anterior horn subtypes.
PI3K-Akt Signaling Loss
The LCCS2 ERBB3 splice variant predicts loss of receptor signaling. The authors propose reduced PI3K/Akt survival signaling as a cause of neuronal apoptosis; Erbb3-null mice also lack Schwann-cell precursors. These are mechanistic hypotheses supporting, but not completing, the human genotype-to-neurogenic disease route.
ERBB3 hgnc:3431 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ERBB3 (hgnc:3431). hgnc:3431 is a gene from the HUGO Gene Nomenclature Committee.
phosphatidylinositol 3-kinase/protein kinase B signal transduction GO:0043491 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491). GO:0043491 is a biological process from the Gene Ontology.
Downstream
Anterior Horn Motor Neuron Loss Reduced ERBB3 survival signaling is a proposed cause of the documented LCCS2 anterior-horn lesion. The human splice finding and mouse survival phenotype support an indirect route; the contribution of glial support is unresolved.
Show evidence (1 reference)
PMID:17701904 SUPPORT Other
"an activator of the phosphatidylinositol-3-kinase/Akt pathway--regulating cell survival and vesicle trafficking"
Names the pathway ERBB3 activates and the cellular functions it governs.
Phosphoinositide Synthesis Deficiency
The original PIP5K1C D253N allele markedly reduces recombinant PIPKI-gamma activity. The authors propose that reduced PIP2 impairs synaptic vesicle trafficking and neuronal function. Clinical similarity to LCCS2 does not demonstrate anterior-horn loss: the original LCCS3 families declined postmortem examination.
PIP5K1C hgnc:8996 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PIP5K1C (hgnc:8996). hgnc:8996 is a gene from the HUGO Gene Nomenclature Committee.
1-phosphatidylinositol-4-phosphate 5-kinase activity GO:0016308 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased 1-phosphatidylinositol-4-phosphate 5-kinase activity (GO:0016308). GO:0016308 is a molecular function from the Gene Ontology.
Downstream
Absent Fetal Movement PIP2 deficiency is proposed to impair synaptic vesicle trafficking and neuronal function, reducing fetal motor activity. This qualified route does not assert unobserved anterior-horn pathology.
Show evidence (1 reference)
PMID:17701898 SUPPORT Other
"Thus, a defect in the phosphatidylinositol pathway leading to a decrease in synthesis of PIP(2), a molecule active in endocytosis of synaptic vesicle proteins, culminates in lethal congenital arthrogryposis."
States the enzymatic deficiency, the downstream lipid, and its synaptic vesicle role in one sentence.
cAMP Synthesis Deficiency
ADCY6 encodes an adenylate cyclase. Human peripheral amyelination and zebrafish knockdown support a myelination role, likely through cAMP. Complete absence of cAMP production or the full signaling sequence was not measured in affected humans.
ADCY6 hgnc:237 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ADCY6 (hgnc:237). hgnc:237 is a gene from the HUGO Gene Nomenclature Committee.
cAMP biosynthetic process GO:0006171 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cAMP biosynthetic process (GO:0006171). GO:0006171 is a biological process from the Gene Ontology.
Downstream
Schwann Cell Myelination Failure ADCY6 dysfunction is proposed to impair the cAMP-dependent myelination program; the source qualifies the cAMP mediation as likely.
Show evidence (1 reference)
PMID:24319099 SUPPORT Other
"ADCY6 encodes a protein that belongs to the adenylate cyclase family responsible for the synthesis of cAMP."
Identifies the enzymatic function lost in the ADCY6 subtype.
Mitotic and Ciliary Regulatory Failure
Mechanism confidence: Hypothetical
NEK9 p.Arg497* eliminates full-length protein in patient fibroblasts, with reduced proliferation, delayed cell-cycle progression, and fewer, shorter cilia. The authors propose a ciliopathy underlying the lethal skeletal dysplasia. The relative contributions of cell-cycle and ciliary dysfunction to fetal akinesia and skeletal growth are unresolved.
NEK9 hgnc:18591 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NEK9 (hgnc:18591). hgnc:18591 is a gene from the HUGO Gene Nomenclature Committee.
cilium assembly GO:0060271 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cilium assembly (GO:0060271). GO:0060271 is a biological process from the Gene Ontology.
Downstream
Absent Fetal Movement The NEK9-associated developmental disorder includes fetal akinesia; the ciliary or mitotic route to motor impairment remains provisional.
Multiple Congenital Joint Contractures NEK9 dysfunction causes the contracture-bearing skeletal dysplasia. The contribution of primary skeletal development versus secondary akinesia is unresolved.
Short Long Bones The proposed developmental mechanism accounts for the genetically defined short-bone dysplasia, without assigning the defect exclusively to cilia or reduced fetal loading.
Show evidence (2 references)
PMID:26908619 SUPPORT In Vitro
"Functional characterization of patient fibroblasts showed a significant reduction in cell proliferation and a delay in cell cycle progression."
Patient-derived fibroblast assays establish cell-cycle abnormalities, not an in-vivo skeletal measurement.
PMID:26908619 SUPPORT In Vitro
"Firstly, patient fibroblasts displayed a significant reduction in cilia number and length."
Patient-derived fibroblasts show ciliary abnormalities supporting the proposed developmental mechanism.
Anterior Horn Motor Neuron Loss
Anterior-horn motor-neuron deficiency or atrophy is documented in GLE1 and ERBB3 disease. Zebrafish Gle1 studies identify apoptosis of dividing neural precursors rather than differentiated motor neurons. This cellular route must not be generalized to PIP5K1C disease, whose original series lacked autopsies.
spinal cord motor neuron CL:0011001 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves spinal cord motor neuron (CL:0011001). CL:0011001 is a cell type from the Cell Ontology.
spinal cord motor neuron differentiation GO:0021522 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased spinal cord motor neuron differentiation (GO:0021522). GO:0021522 is a biological process from the Gene Ontology.
ventral horn of spinal cord UBERON:0002257 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in ventral horn of spinal cord (UBERON:0002257). UBERON:0002257 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Neurogenic Skeletal Muscle Atrophy and Hypoplasia Loss of developing motor innervation is a plausible contributor to the severe muscle underdevelopment associated with the GLE1 autopsy lesion; the precise developmental sequence was not directly observed.
Skeletal Muscle Hypoplasia Severely deficient motor-neuron development is interpreted to deprive developing muscle of innervation in classic GLE1 disease. This is an indirect neurogenic interpretation of the paired human lesions.
Show evidence (3 references)
PMID:18204449 SUPPORT Human Clinical
"The most severe forms of motoneuron disease manifest in utero are characterized by marked atrophy of spinal cord motoneurons and fetal immobility."
Frames LCCS1 as an in utero motor neuron disease with spinal motoneuron atrophy and consequent immobility.
PMID:17701904 SUPPORT Human Clinical
"Lethal congenital contractural syndrome type 2 (LCCS2) is an autosomal recessive neurogenic form of arthrogryposis that is associated with atrophy of the anterior horn of the spinal cord."
Records anterior horn atrophy as the neuropathological lesion in LCCS2 as well, extending the node beyond LCCS1.
PMID:22357925 SUPPORT Model Organism
"Unexpectedly, the motoneuron deficiency results from apoptosis of neural precursors, not of differentiated motoneurons."
Refines the cellular mechanism: the motoneuron loss is a precursor survival defect rather than degeneration of mature neurons.
Schwann Cell Myelination Failure
Peripheral myelination is deficient in ADCY6- and ADGRG6-associated disease. Human nerve pathology supports this lesion; ADCY6 knockdown and ADGRG6 studies in fish and mice inform the proposed signaling routes. Schwann precursor loss in Erbb3-null mice is a different model observation and is not asserted as measured human LCCS2 myelin pathology.
Schwann cell CL:0002573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Schwann cell (CL:0002573). CL:0002573 is a cell type from the Cell Ontology. Schwann cell precursor CL:0002375 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Schwann cell precursor (CL:0002375). CL:0002375 is a cell type from the Cell Ontology.
ADGRG6 hgnc:13841 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ADGRG6 (hgnc:13841). hgnc:13841 is a gene from the HUGO Gene Nomenclature Committee.
peripheral nervous system myelin formation GO:0032290 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased peripheral nervous system myelin formation (GO:0032290). GO:0032290 is a biological process from the Gene Ontology.
peripheral nervous system UBERON:0000010 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in peripheral nervous system (UBERON:0000010). UBERON:0000010 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Absent Fetal Movement Defective peripheral myelination during fetal development is the source-proposed cause of severe ADGRG6-associated arthrogryposis through impaired motor function. The human fetal conduction intermediate was not measured.
Show evidence (2 references)
PMID:24319099 SUPPORT Model Organism
"Morpholino knockdown of the zebrafish orthologs led to severe and specific defects in peripheral myelin in spite of the presence of Schwann cells."
Shows the ADCY6 lesion is a myelination failure rather than an absence of Schwann cells.
PMID:26004201 SUPPORT Human Clinical
"We have shown that the peripheral nerves in affected individuals from one family lack myelin basic protein, suggesting that this disease in affected individuals is due to defective myelination of the peripheral axons during fetal development."
Demonstrates absent peripheral myelin in ADGRG6/GPR126-related disease in human tissue.
Node of Ranvier Assembly Failure
GLDN encodes gliomedin, which contributes to nodal sodium-channel clustering through axonal ligands including NF186. Human nodal abnormalities and variant assays support a nodopathy. GLDN-null mice can retain conduction and lack arthrogryposis, so complete conduction abolition cannot be inferred from loss of gliomedin alone.
Schwann cell CL:0002573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Schwann cell (CL:0002573). CL:0002573 is a cell type from the Cell Ontology. spinal cord motor neuron CL:0011001 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves spinal cord motor neuron (CL:0011001). CL:0011001 is a cell type from the Cell Ontology.
CNTNAP1 hgnc:8011 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CNTNAP1 (hgnc:8011). hgnc:8011 is a gene from the HUGO Gene Nomenclature Committee. GLDN hgnc:29514 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GLDN (hgnc:29514). hgnc:29514 is a gene from the HUGO Gene Nomenclature Committee.
node of Ranvier GO:0033268 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves node of Ranvier (GO:0033268). GO:0033268 is a cellular component from the Gene Ontology.
Downstream
Impaired Motor Nerve Conduction Abnormal gliomedin-dependent nodal organization can impair peripheral conduction in human GLDN-associated disease, but the effect is variable and can normalize on repeat testing.
Show evidence (2 references)
PMID:27616481 SUPPORT Other
"The axoglial contact between gliomedin and NF186 is essential for the initial clustering of Na+ channels at developing nodes."
The source summarizes the molecular requirement for gliomedin/NF186 contact during initial sodium-channel clustering; this background statement is distinct from its human microscopy and variant assays.
PMID:27616481 SUPPORT Human Clinical
"These data indicate that mutations of GLDN or CNTNAP1 (MIM: 616286), encoding essential components of the nodes of Ranvier and paranodes, respectively, lead to inherited nodopathies, a distinct disease entity among peripheral neuropathies."
The authors place GLDN nodal and CNTNAP1 paranodal defects in the broader inherited-nodopathy category while explicitly distinguishing their anatomical sites. This node represents the GLDN nodal lesion; CNTNAP1 is modeled separately.
Impaired Motor Nerve Conduction
Peripheral motor signaling is impaired in CNTNAP1 and some GLDN cases. Original CNTNAP1 families had motor velocities below 10 m/s, but this threshold is not universal, and a GLDN child had normal repeat studies at seven months. The functional route to weakness and reduced movement is supported indirectly by the human neuropathy and nodal-pathology context.
neuronal action potential propagation GO:0019227 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neuronal action potential propagation (GO:0019227). GO:0019227 is a biological process from the Gene Ontology.
Downstream
Absent Fetal Movement Impaired peripheral motor signaling contributes to prenatal akinesia in the documented nodopathies, without implying complete conduction failure or identical measurements in every subtype.
Muscle Weakness Peripheral motor neuropathy can reduce effective muscle activation in GLDN survivors; concurrent muscular contributions and changing severity remain possible.
Areflexia Impaired peripheral reflex-arc signaling provides an indirect explanation for absent reflexes in the GLDN neuropathy context; areflexia alone does not localize the lesion.
Skeletal Muscle Atrophy Chronic peripheral motor dysfunction can produce neurogenic loss of muscle bulk in GLDN survivors. Human findings also leave primary muscular contributions possible.
Show evidence (1 reference)
PMID:24319099 SUPPORT Human Clinical
"Patients showed a marked reduction in motor nerve conduction velocity (<10 m/s)"
Quantifies the conduction failure in affected individuals.
Myofibril Assembly Failure
ZBTB42 knockdown causes myofibrillar disorganization and abnormal neuromuscular junctions in zebrafish, with impaired coiling and escape movement. Wild-type human ZBTB42, but not the variant construct, rescues the model phenotype. Human muscle biopsy and autopsy were declined, so the exact human tissue lesion remains inferred.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
MYBPC1 hgnc:7549 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MYBPC1 (hgnc:7549). hgnc:7549 is a gene from the HUGO Gene Nomenclature Committee. ZBTB42 hgnc:32550 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ZBTB42 (hgnc:32550). hgnc:32550 is a gene from the HUGO Gene Nomenclature Committee.
myofibril assembly GO:0030239 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased myofibril assembly (GO:0030239). GO:0030239 is a biological process from the Gene Ontology.
Downstream
Absent Fetal Movement Reduced muscle organization and function in ZBTB42-deficient fish provide a model-supported explanation for human fetal akinesia, with incomplete human tissue confirmation.
Show evidence (1 reference)
PMID:25055871 SUPPORT Model Organism
"Knockdown experiments of zbtb42 in zebrafish consistently resulted in grossly abnormal skeletal muscle development and myofibrillar disorganization at the microscopic level."
Shows the ZBTB42 lesion is a muscle developmental and myofibrillar defect.
Endocytic Trafficking Failure
The DNM2 p.Phe379Val allele impairs endocytosis in assays and is associated with a severe recessive congenital syndrome. Zebrafish knockdown affects muscle organization and angiogenesis. The authors propose altered developmental endocytosis as an explanation for pleiotropic clinical manifestations, without establishing the specific human tissue route to each finding.
DNM2 hgnc:2974 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves DNM2 (hgnc:2974). hgnc:2974 is a gene from the HUGO Gene Nomenclature Committee.
endocytosis GO:0006897 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased endocytosis (GO:0006897). GO:0006897 is a biological process from the Gene Ontology.
Downstream
Absent Fetal Movement Developmental trafficking dysfunction is proposed to impair motor function; zebrafish muscle disorganization supports, but does not prove, the human route.
Severe Hypotonia The authors propose a pleiotropic developmental mechanism for the DNM2 syndrome. The relative contributions of muscle and peripheral nerve dysfunction to hypotonia remain unresolved.
Intracranial Hemorrhage The developmental endocytosis hypothesis and zebrafish angiogenesis defects provide provisional support for a vascular contribution to brain hemorrhage; human vascular pathology and other bleeding contributors were not resolved.
Retinal Hemorrhage The proposed pleiotropic endocytosis mechanism may disrupt ocular vascular development. The retinal bleeding route is not directly reconstructed, and the platelet abnormalities in the siblings are an additional unresolved contributor.
Thin Ribs The authors propose altered developmental endocytosis as a pleiotropic explanation for the DNM2 skeletal findings. A primary skeletal effect versus secondary reduced mechanical loading is unresolved.
Show evidence (2 references)
PMID:23092955 SUPPORT In Vitro
"In vitro membrane tubulation, trafficking and GTPase assays are consistent with an impact of the DNM2p.Phe379Val mutation on endocytosis."
Functional assays localizing the DNM2 lesion to endocytosis.
PMID:23092955 SUPPORT Model Organism
"knockdown approaches in zebrafish resulting in defects in muscle organization and angiogenesis support a pleiotropic role for DNM2 during fetal development in vertebrates and humans"
Supports the pleiotropic muscle-and-vascular role that separates this node from the purely myofibrillar one.
Neurogenic Skeletal Muscle Atrophy and Hypoplasia
Loss of effective developing motor innervation can impair muscle growth and contraction. GLE1 fetal autopsies show severely hypoplastic musculature together with anterior-horn deficiency. The causal interpretation is supported indirectly by fetal neurogenic pathology; PIP5K1C muscle wasting is not assigned to this specific lesion without autopsy evidence.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
skeletal muscle tissue development GO:0007519 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased skeletal muscle tissue development (GO:0007519). GO:0007519 is a biological process from the Gene Ontology.
skeletal muscle tissue UBERON:0001134 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in skeletal muscle tissue (UBERON:0001134). UBERON:0001134 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Absent Fetal Movement Denervated, hypoplastic muscle cannot move the fetal limbs.
Show evidence (1 reference)
PMID:11810649 SUPPORT INDIRECT Human Clinical
"Neuropathologic examination revealed anterior horn cell loss and lateral corticospinal tract degeneration in spinal cord, with marked muscular atrophy."
This ungenotyped fetal akinesia case provides supporting neurogenic pathological context, not direct proof of a numbered LCCS genotype.
Impaired Swallowing
Impaired fetal deglutition reduces amniotic-fluid clearance. This prenatal mechanism is distinguished from postnatal swallowing insufficiency with documented focal bulbar paresis in a GLDN survivor.
Downstream
Polyhydramnios Reduced fetal swallowing decreases clearance of amniotic fluid.
Show evidence (1 reference)
PMID:35806855 SUPPORT Other
"The common feature of this sequence is decreased fetal activity, which leads to a failure of normal deglutition, resulting in polyhydramnios."
The source explicitly gives the fetal activity-to-deglutition-to-amniotic-fluid sequence.
Paranodal Axoglial Junction Failure
CNTNAP1/CASPR1 deficiency disrupts septate paranodal junctions in peripheral nerves and is proposed to disturb glial-axonal interactions centrally. This is anatomically distinct from gliomedin-dependent nodal assembly.
CNTNAP1 hgnc:8011 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CNTNAP1 (hgnc:8011). hgnc:8011 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Impaired Motor Nerve Conduction Loss of the paranodal junctional barrier disrupts axoglial organization required for rapid conduction; severe slowing was measured in affected CNTNAP1 children.
Central Nervous System Hypomyelination CNTNAP1-associated disruption of central glial-axonal interactions is implicated in the serially documented hypomyelination; the human central ultrastructure was not examined.
Brain Atrophy Central myelin abnormalities and possible neuronal loss are proposed contributors to progressive volume loss; their separate contributions are unresolved.
Seizures Paranodal disruption and consequent ion-channel mislocalization are proposed to promote seizures. Potassium-channel mislocalization is demonstrated in models, not in these human central nervous systems.
Severe Hypotonia The demonstrated congenital peripheral neuropathy provides a supported indirect contribution to severe hypotonia in CNTNAP1 disease; concurrent central involvement prevents exclusive peripheral attribution.
Show evidence (1 reference)
PMID:29882456 SUPPORT Human Clinical
"These 2 families illustrate severe progressive peripheral demyelinating neuropathy due to the absence of septate paranodal junctions and central hypomyelination with neurodegeneration in CNTNAP1-associated arthrogryposis multiplex congenita."
The authors explicitly attribute progressive peripheral neuropathy to missing paranodal junctions and document associated central disease.
Loss of Slow Myosin-binding Protein C Function
Recessive MYBPC1 truncation abrogates functional protein domains. A muscle contractile route is supported by the protein role and human causal genotype, but the precise fetal muscle structural defect is not demonstrated.
MYBPC1 hgnc:7549 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MYBPC1 (hgnc:7549). hgnc:7549 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Absent Fetal Movement Loss of the muscle myosin-binding protein is proposed to impair contractile function and prenatal movement. This does not import ZBTB42 fish myofibrillar pathology into MYBPC1 patients.
Show evidence (1 reference)
PMID:22610851 SUPPORT Human Clinical
"We now show that a recessive mutation abrogating all functional domains in the same gene leads to LCCS."
Establishes recessive MYBPC1 loss of function as the LCCS4 mechanism.
Combined Neuronal and Muscle Dystonin Deficiency
Biallelic DST variants affecting both DST-a and DST-b cause a lethal arthrogryposis presentation. The relative neuronal and muscle contributions are unresolved; functional and biopsy findings from DST-b-only myopathy cannot be assigned wholesale to this combined-isoform disorder.
DST hgnc:1090 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves DST (hgnc:1090). hgnc:1090 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Multiple Congenital Joint Contractures Combined neuronal and muscle isoform disruption is causally associated with the severe congenital-contracture syndrome; the responsible tissue sequence remains unresolved.
Show evidence (2 references)
PMID:40497796 SUPPORT Human Clinical
"Genotype-phenotype correlation in these patients and previously published cases with respective variants resulted in the definition of a DST-associated lethal congenital contracture syndrome."
Establishes DST as the gene defining a lethal congenital contracture syndrome.
PMID:40497796 SUPPORT Human Clinical
"Variants that also impact DST-a besides DST-b result in a more severe, lethal congenital contracture syndrome."
Gives the isoform-dependent severity relationship that separates the lethal phenotype from the congenital myopathy.
Focal Bulbar Paresis
Right vocal-cord and right soft-palate paresis aggravated swallowing insufficiency in a GLDN survivor. The report establishes this functional contribution without identifying the upstream cranial motor lesion.
Downstream
Dysphagia Focal vocal-cord and soft-palate weakness aggravated swallowing insufficiency in the reported GLDN child.
Show evidence (1 reference)
PMID:28726266 SUPPORT Human Clinical
"Insufficient swallowing aggravated by paresis of both the right vocal cord and right side of the soft palate prompted gastrostomy tube placement at 4 months of age."
Documents insufficient swallowing and the gastrostomy it required in a surviving LCCS11 child.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Lethal Congenital Contracture Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

44
Blood 2
Intracranial Hemorrhage FREQUENT HP:0002170 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intracranial hemorrhage (HP:0002170). HP:0002170 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:23092955 SUPPORT Human Clinical
"in three consanguineous patients with a lethal congenital syndrome associating akinesia, joint contractures, hypotonia, skeletal abnormalities, and brain and retinal hemorrhages"
Reports the intracranial haemorrhage that helps define the DNM2 subtype.
url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658203/ SUPPORT Human Clinical
"In addition, they showed retinal hemorrhages, whereas MRI analysis revealed symmetric subdural hematomas for AFB3 and blood in the subarachnoid cavity for AFB4"
Full text of the same study indexed as PMID:23092955 distinguishes retinal hemorrhage in the three siblings from intracranial bleeding described in AFB3 and AFB4; this is not independent replication.
Retinal Hemorrhage VERY_FREQUENT HP:0000573 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Retinal hemorrhage (HP:0000573). HP:0000573 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:23092955 SUPPORT Human Clinical
"in three consanguineous patients with a lethal congenital syndrome associating akinesia, joint contractures, hypotonia, skeletal abnormalities, and brain and retinal hemorrhages"
Reports retinal haemorrhage in the DNM2-mutated patients.
url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658203/ SUPPORT Human Clinical
"In addition, they showed retinal hemorrhages, whereas MRI analysis revealed symmetric subdural hematomas for AFB3 and blood in the subarachnoid cavity for AFB4"
Full text of the same study indexed as PMID:23092955 distinguishes retinal hemorrhage in the three siblings from intracranial bleeding described in AFB3 and AFB4; this is not independent replication.
Cardiovascular 2
Pulmonary Hypertension Pulmonary arterial hypertension HP:0002092 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary arterial hypertension (HP:0002092). HP:0002092 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658203/ SUPPORT Human Clinical
"AFB3 and AFB4 had pulmonary hypertension and a patent ductus arteriosus; whether these features were primary or secondary to respiratory insufficiency could not be determined."
The same study indexed as PMID:23092955 documents the finding in two siblings and explicitly leaves primary versus secondary attribution unresolved.
Patent Ductus Arteriosus HP:0001643 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Patent ductus arteriosus (HP:0001643). HP:0001643 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658203/ SUPPORT Human Clinical
"AFB3 and AFB4 had pulmonary hypertension and a patent ductus arteriosus; whether these features were primary or secondary to respiratory insufficiency could not be determined."
The same study indexed as PMID:23092955 documents the finding in two siblings and explicitly leaves primary versus secondary attribution unresolved.
Digestive 1
Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28726266 SUPPORT Human Clinical
"Insufficient swallowing aggravated by paresis of both the right vocal cord and right side of the soft palate prompted gastrostomy tube placement at 4 months of age."
Documents insufficient swallowing and the gastrostomy it required in a surviving LCCS11 child.
Ear 1
Hearing Impairment HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29882456 SUPPORT Human Clinical
"Individual LD_0158.0 is an 8 year old male with hypotonia and respiratory failure requiring intubation at birth and subsequent tracheotomy-dependency, congenital hypomyelinating neuropathy with arthrogryposis multiplex congenita, cleft palate, cortical vision loss, bilateral hearing loss, and..."
The clinical description of LD_0158.0 directly documents hearing impairment; it does not establish a universal CNTNAP1 finding.
Eye 2
Cerebral Visual Impairment HP:0100704 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral visual impairment (HP:0100704). HP:0100704 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29882456 SUPPORT Human Clinical
"Individual LD_0158.0 is an 8 year old male with hypotonia and respiratory failure requiring intubation at birth and subsequent tracheotomy-dependency, congenital hypomyelinating neuropathy with arthrogryposis multiplex congenita, cleft palate, cortical vision loss, bilateral hearing loss, and..."
The clinical description of LD_0158.0 directly documents cerebral visual impairment; it does not establish a universal CNTNAP1 finding.
Optic Atrophy HP:0000648 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Optic atrophy (HP:0000648). HP:0000648 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29882456 SUPPORT Human Clinical
"Individual LD_0333.0 was a girl with severe hypotonia and respiratory insufficiency that required a tracheostomy after birth, hypomyelinating neuropathy, bilateral hearing loss, bilateral optic nerve atrophy, lethargy, and neurogenic bladder."
The clinical description explicitly documents bilateral optic nerve atrophy in LD_0333.0.
Genitourinary 1
Neurogenic Bladder HP:0000011 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neurogenic bladder (HP:0000011). HP:0000011 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:17701904 SUPPORT Human Clinical
"is characterized by multiple joint contractures, anterior horn atrophy in the spinal cord, and a unique feature of a markedly distended urinary bladder"
The positive LCCS2 statement, naming the distended bladder as the unique feature of that subtype.
PMID:17701898 SUPPORT Human Clinical
"We now describe a third LCCS phenotype (LCCS3)--similar to LCCS2 yet without neurogenic bladder."
The complementary negative, confirming the finding discriminates LCCS2 from LCCS3.
PMID:29882456 SUPPORT Human Clinical
"Individual LD_0333.0 was a girl with severe hypotonia and respiratory insufficiency that required a tracheostomy after birth, hypomyelinating neuropathy, bilateral hearing loss, bilateral optic nerve atrophy, lethargy, and neurogenic bladder."
Documents neurogenic bladder in a CNTNAP1-associated child, extending the subtype scope without identifying the responsible autonomic pathway.
Head and Neck 3
Micrognathia HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:18204449 SUPPORT Human Clinical
"accompanied by hydrops, micrognatia, pulmonary hypoplasia, pterygia and multiple joint contractures"
Lists micrognathia among the characteristic LCCS1 features. The source spells it "micrognatia"; the quote preserves the source spelling.
url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457946/ SUPPORT Human Clinical
"At 25 weeks of pregnancy, MRI revealed micrognathia and fixed extension of the arms and flexion of the elbows, wrists, and hands"
Full text of the same study indexed as PMID:26004201 documents micrognathia in the ADGRG6 Family 2 fetus; this is not independent replication.
Retrognathia HP:0000278 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Retrognathia (HP:0000278). HP:0000278 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35806855 SUPPORT Human Clinical
"The pregnancy was terminated and postmortem studies confirmed the prenatal findings: distal arthrogryposis, fetal growth restriction, pulmonary hypoplasia, and retrognathia."
The primary case supports jaw retrusion, not mandibular size.
Cleft Palate HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29882456 SUPPORT Human Clinical
"Individual LD_0158.0 is an 8 year old male with hypotonia and respiratory failure requiring intubation at birth and subsequent tracheotomy-dependency, congenital hypomyelinating neuropathy with arthrogryposis multiplex congenita, cleft palate, cortical vision loss, bilateral hearing loss, and..."
The clinical description of LD_0158.0 directly documents cleft palate; it does not establish a universal CNTNAP1 finding.
Integument 1
Pterygia Pterygium HP:0001059 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pterygium (HP:0001059). HP:0001059 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:18204449 SUPPORT Human Clinical
"Lethal congenital contracture syndrome 1 (LCCS1, MIM 253310) is an autosomal recessive condition characterized by total immobility of the fetus, detectable at the 13th week of pregnancy, accompanied by hydrops, micrognatia, pulmonary hypoplasia, pterygia and multiple joint contractures"
Lists pterygia among the characteristic features of LCCS1 specifically, which is the subtype this phenotype is tagged to.
url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457946/ SUPPORT Human Clinical
"Fetopathological examination of the aborted fetus confirmed that the joint retractions were associated with pterygium of the right elbow and axilla"
Full text of PMID:26004201 documents the anatomical webbing in Family 1.
Limbs 5
Talipes Equinovarus HP:0001762 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Talipes equinovarus (HP:0001762). HP:0001762 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38491417 SUPPORT Human Clinical
"We described the features of multiple joint contractures in our fetuses, including bilateral talipes equinovarus, stiffness in the limbs, extended knees, persistently closed hands and overlapping fingers"
Documents bilateral talipes equinovarus as part of the contracture pattern in LCCS3 fetuses.
Overlapping Fingers HP:0010557 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Overlapping fingers (HP:0010557). HP:0010557 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38491417 SUPPORT Human Clinical
"including bilateral talipes equinovarus, stiffness in the limbs, extended knees, persistently closed hands and overlapping fingers"
Documents the closed-hand and overlapping-finger posture in LCCS3 fetuses.
Hand Clenching HP:0001188 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hand clenching (HP:0001188). HP:0001188 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38491417 SUPPORT Human Clinical
"We described the features of multiple joint contractures in our fetuses, including bilateral talipes equinovarus, stiffness in the limbs, extended knees, persistently closed hands and overlapping fingers"
Supports the persistently closed-hand posture in this fetal pedigree, without making a population-frequency claim.
Knee Extension Contracture HP:0034672 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Knee extension contracture (HP:0034672). HP:0034672 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38491417 SUPPORT Human Clinical
"We described the features of multiple joint contractures in our fetuses, including bilateral talipes equinovarus, stiffness in the limbs, extended knees, persistently closed hands and overlapping fingers"
The fixed limb-contracture context supports extended-knee contractures rather than an isolated positional observation.
Hip Dislocation HP:0002827 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hip dislocation (HP:0002827). HP:0002827 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28726266 SUPPORT Human Clinical
"He underwent surgical treatment for bilateral hip luxation and clubfeet (age 2 years) and scoliosis with Harrington rod insertion (age 9 years)."
Hip luxation refers to dislocation; the hip and scoliosis procedures occurred at different ages.
Metabolism 1
Hydrops Fetalis VERY_FREQUENT HP:0001789 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hydrops fetalis (HP:0001789). HP:0001789 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:16892327 SUPPORT Human Clinical
"multiple joint contractures in both upper and lower limbs, hydrops, and fetal death before the 32nd week of pregnancy"
Lists hydrops among the defining features of the Finnish LCCS (LCCS1) cases.
PMID:18204449 SUPPORT Human Clinical
"accompanied by hydrops, micrognatia, pulmonary hypoplasia, pterygia and multiple joint contractures"
Confirms hydrops as a characteristic LCCS1 feature.
Musculoskeletal 9
Multiple Congenital Joint Contractures VERY_FREQUENT Multiple joint contractures HP:0002828 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Multiple joint contractures (HP:0002828). HP:0002828 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16892327 SUPPORT Human Clinical
"multiple joint contractures in both upper and lower limbs, hydrops, and fetal death before the 32nd week of pregnancy"
Records the contracture distribution in the LCCS cases.
Skeletal Muscle Atrophy HP:0003202 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skeletal muscle atrophy (HP:0003202). HP:0003202 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:17701898 SUPPORT Human Clinical
"severe muscle wasting and atrophy, mainly in the legs"
The original PIP5K1C neonates had muscle wasting; the families declined autopsy, so an anterior-horn cause is not demonstrated.
PMID:28726266 SUPPORT Human Clinical
"His neurologic examination was notable for myopathic facies, very weak to absent deep tendon reflexes, and symmetric atrophy and weakness of his proximal muscles."
The surviving GLDN-related child had proximal atrophy and weakness on examination, rather than a universal congenital muscle-hypoplasia phenotype.
Severe Hypotonia Generalized hypotonia HP:0001290 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized hypotonia (HP:0001290). HP:0001290 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:23092955 SUPPORT Human Clinical
"a lethal congenital syndrome associating akinesia, joint contractures, hypotonia, skeletal abnormalities, and brain and retinal hemorrhages"
Lists hypotonia among the presenting features.
url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658203/ SUPPORT Human Clinical
"The three patients displayed no reflexes and suffered from severe hypotonia and respiratory insufficiency from birth, while they exhibited contractures of several joints and skeletal abnormalities with thin ribs and bones"
The full clinical narrative confirms severe hypotonia in all three DNM2 siblings; Table 1 specifies generalized severe hypotonia. This is the same study as PMID:23092955.
Skeletal Muscle Hypoplasia Hypoplasia of the musculature HP:0009004 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplasia of the musculature (HP:0009004). HP:0009004 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18204449 SUPPORT Human Clinical
"Neuropathological analysis shows lack of anterior horn motoneurons, severe atrophy of the ventral spinal cord and hypoplastic, nearly absent skeletal muscles"
The GLE1 autopsy phenotype specifically supports muscle hypoplasia.
Diaphragmatic Paralysis HP:0006597 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Diaphragmatic paralysis (HP:0006597). HP:0006597 is a phenotype from the Human Phenotype Ontology.
This clinical state was previously annotated at tissue scale in a duplicate pathophysiology entry.
Sequelae: Neonatal Respiratory Failure
Show evidence (1 reference)
PMID:28726266 SUPPORT Human Clinical
"Due to persistent respiratory insufficiency associated with pulmonary hypoplasia and diaphragm paralysis, he underwent tracheostomy at 3 months of age."
Documents diaphragm paralysis and its respiratory context in the Family 2 child.
Muscle Weakness HP:0001324 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle weakness (HP:0001324). HP:0001324 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28726266 SUPPORT Human Clinical
"His neurologic examination was notable for myopathic facies, very weak to absent deep tendon reflexes, and symmetric atrophy and weakness of his proximal muscles."
The surviving GLDN-related child had proximal atrophy and weakness on examination, rather than a universal congenital muscle-hypoplasia phenotype.
Short Long Bones HP:0003026 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short long bone (HP:0003026). HP:0003026 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26908619 SUPPORT Human Clinical
"We report two Irish Traveller families with a previously undescribed lethal skeletal dysplasia characterized by fetal akinesia, shortening of all long bones, multiple contractures, rib anomalies, thoracic dysplasia, pulmonary hypoplasia and protruding abdomen."
The original lethal skeletal-dysplasia families establish the LCCS10 clinical scope; the later APUG-like neonates are not used as its denominator.
Thin Ribs HP:0000883 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin ribs (HP:0000883). HP:0000883 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658203/ SUPPORT Human Clinical
"The three patients displayed no reflexes and suffered from severe hypotonia and respiratory insufficiency from birth, while they exhibited contractures of several joints and skeletal abnormalities with thin ribs and bones"
The full text of the PMID:23092955 study explicitly records thin ribs, supporting the specific radiographic term.
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28726266 SUPPORT Human Clinical
"He underwent surgical treatment for bilateral hip luxation and clubfeet (age 2 years) and scoliosis with Harrington rod insertion (age 9 years)."
The GLDN Family 2 survivor underwent scoliosis surgery with Harrington rod insertion at age nine years. The hip procedure in the same sentence occurred at age two.
Nervous System 7
Reduced Motor Nerve Conduction Velocity Decreased motor nerve conduction velocity HP:0003431 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased motor nerve conduction velocity (HP:0003431). HP:0003431 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:24319099 SUPPORT Human Clinical
"Patients showed a marked reduction in motor nerve conduction velocity (<10 m/s)"
Reports the measured conduction velocities in CNTNAP1-mutated patients.
PMID:28726266 SUPPORT Human Clinical
"Nerve conduction velocity studies performed at 1 week of age demonstrated axonal motor and sensory neuropathy but were normal when repeated at 7 months of age."
The same GLDN child had abnormal neonatal studies and normal repeat studies at seven months; persistent severe slowing is not obligatory.
Areflexia HP:0001284 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Areflexia (HP:0001284). HP:0001284 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28726266 SUPPORT Human Clinical
"His neurologic examination was notable for myopathic facies, very weak to absent deep tendon reflexes, and symmetric atrophy and weakness of his proximal muscles."
Documents absent deep tendon reflexes on examination in a GLDN-mutated child.
url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658203/ SUPPORT Human Clinical
"The three patients displayed no reflexes and suffered from severe hypotonia and respiratory insufficiency from birth, while they exhibited contractures of several joints and skeletal abnormalities with thin ribs and bones"
The same DNM2 study explicitly records absent reflexes in all three affected siblings; this observation is distinct from the very weak-to-absent reflex description in GLDN disease.
Vocal Cord Paresis HP:0001604 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vocal cord paresis (HP:0001604). HP:0001604 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28726266 SUPPORT Human Clinical
"Insufficient swallowing aggravated by paresis of both the right vocal cord and right side of the soft palate prompted gastrostomy tube placement at 4 months of age."
Documents vocal cord paresis and its contribution to the swallowing failure.
Motor Developmental Delay Motor delay HP:0001270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor delay (HP:0001270). HP:0001270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28726266 SUPPORT Human Clinical
"Motor and language development was delayed; he was able to sit independently at age 13 months and started to crawl at age 24 months."
The exact ages establish motor delay in the Family 3 survivor, without inferring cognitive impairment.
Central Nervous System Hypomyelination CNS hypomyelination HP:0003429 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is CNS hypomyelination (HP:0003429). HP:0003429 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29882456 SUPPORT Human Clinical
"Serial brain magnetic resonance images revealed hypomyelination, progressive atrophy, and reduced diffusion in the globus pallidus in both patients."
Both children had central hypomyelination documented on serial brain imaging.
Brain Atrophy HP:0012444 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brain atrophy (HP:0012444). HP:0012444 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29882456 SUPPORT Human Clinical
"Central nervous system myelin involvement is also present in individuals affected by CNTNAP1 mutations. Serial brain MRI evaluation of our patients demonstrated diffuse hypomyelination, progressive brain atrophy ranging from mild to severe, and reduced diffusion in globus pallidus with or..."
The serial imaging establishes progressive brain atrophy; its cellular substrate is not measured directly.
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29882456 SUPPORT Human Clinical
"At age 8 years, he is maintained on artificial ventilation, with very limited developmental outcomes and no independent motor skills, hypotonia with hyporeflexia, and seizures controlled with topiramate."
The clinical course directly documents seizures in LD_0158.0.
Prenatal and Birth 3
Absent Fetal Movement VERY_FREQUENT Decreased fetal movement HP:0001558 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent fetal movement, annotated with Decreased fetal movement (HP:0001558). HP:0001558 is a phenotype from the Human Phenotype Ontology.
This clinical state was previously annotated at organism scale in a duplicate pathophysiology entry.
Sequelae: Multiple Congenital Joint Contractures Pulmonary Hypoplasia Impaired Swallowing Talipes Equinovarus Overlapping Fingers Hand Clenching Knee Extension Contracture Micrognathia Intrauterine Growth Restriction Pterygia Short Umbilical Cord
Show evidence (1 reference)
PMID:16892327 SUPPORT Human Clinical
"Thirty-nine cases had lethal congenital contracture syndrome (LCCS) clinically characterized by total immobility of the fetus at all ultrasound examinations (12 weeks or later)"
Establishes total fetal immobility from 12 weeks as a defining clinical feature of LCCS in a population-based series.
Polyhydramnios HP:0001561 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polyhydramnios (HP:0001561). HP:0001561 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35806855 SUPPORT Human Clinical
"The fetus exhibited hydrops, short long bones, fixed limb joints, absent fetal movements, and polyhydramnios."
Records polyhydramnios in an LCCS11 fetus.
Short Umbilical Cord HP:0001196 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short umbilical cord (HP:0001196). HP:0001196 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457946/ SUPPORT Human Clinical
"The autopsy confirmed a short umbilical cord and significant pulmonary hypoplasia."
The full text of PMID:26004201 directly documents the cord finding in the Family 3 infant.
Respiratory 5
Pulmonary Hypoplasia HP:0002089 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary hypoplasia (HP:0002089), qualified as located in lung. HP:0002089 is a phenotype from the Human Phenotype Ontology.
This clinical state was previously annotated at organism scale in a duplicate pathophysiology entry. The reduced-development annotation is lung development (GO:0030324), modifier DECREASED; this process annotation is retained here because phenotypes do not have a biological_processes slot.
Sequelae: Neonatal Respiratory Failure
Show evidence (1 reference)
PMID:35806855 SUPPORT Human Clinical
"To our knowledge, among the herein 28 reviewed cases, 16 reported respiratory findings, pulmonary hypoplasia being the most frequent (75%, 12/16), followed by pulmonary insufficiency or need of respiratory support."
The 75% proportion is 12/16 respiratory-described cases, not 12/28 or an umbrella prevalence estimate.
Neonatal Respiratory Failure HP:0002878 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory failure (HP:0002878). HP:0002878 is a phenotype from the Human Phenotype Ontology.
This clinical state was previously annotated at organism scale in a duplicate pathophysiology entry.
Show evidence (3 references)
PMID:38491417 SUPPORT Human Clinical
"Then, she underwent vaginal delivery prematurely at 26 weeks, and the baby passed away after birth due to respiratory failure."
Documents neonatal death from respiratory failure in an LCCS3 case.
PMID:17701898 SUPPORT Human Clinical
"The other five subjects were born alive (two at 29 wk gestation and three at term) and died of respiratory insufficiency minutes to hours after birth."
Five of the nine affected pregnancies in the original PIP5K1C kindred were live births; all five died rapidly from respiratory insufficiency. The four terminated pregnancies are not included in this liveborn denominator.
PMID:28726266 SUPPORT Human Clinical
"He required extensive resuscitation at birth including intubation, ventilation, chest compressions, and epinephrine administration, developed progressive respiratory failure, pneumothoraces, and pulmonary hemorrhage, and died at 40 hours of age"
A worked LCCS11 case in which progressive neonatal respiratory failure was the proximate cause of death.
Laryngomalacia HP:0001601 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Laryngomalacia (HP:0001601). HP:0001601 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28726266 SUPPORT Human Clinical
"Laryngoscopy demonstrated laryngo- and tracheomalacia, floppy epiglottis, and pooling of oral secretions."
The laryngoscopic findings explicitly establish laryngomalacia in this child.
Tracheomalacia HP:0002779 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tracheomalacia (HP:0002779). HP:0002779 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28726266 SUPPORT Human Clinical
"Laryngoscopy demonstrated laryngo- and tracheomalacia, floppy epiglottis, and pooling of oral secretions."
The laryngoscopic findings explicitly establish tracheomalacia in this child.
Central Apnea HP:0002871 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Central apnea (HP:0002871). HP:0002871 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28726266 SUPPORT Human Clinical
"After discharge from the neonatal intensive care unit on oxygen (1/8 liters per minute) at 2 months of age, she developed recurrent cyanotic events, attributed to dynamic airway collapse related to tracheomalacia, and polysomnography demonstrated central apnea."
The sentence distinguishes attributed airway-collapse events from polysomnographic central apnea.
Growth 1
Intrauterine Growth Restriction Intrauterine growth retardation HP:0001511 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intrauterine growth retardation (HP:0001511). HP:0001511 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35806855 SUPPORT Human Clinical
"postmortem studies confirmed the prenatal findings: distal arthrogryposis, fetal growth restriction, pulmonary hypoplasia, and retrognathia"
Postmortem confirmation of fetal growth restriction in LCCS11.
🧬

Genetic Associations

12
GLE1
Gene: GLE1 hgnc:4315 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GLE1 (hgnc:4315). hgnc:4315 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:18204449 SUPPORT Human Clinical
"Here, we report that the defective gene underlying lethal motoneuron syndrome LCCS1 is the mRNA export mediator GLE1."
Establishes GLE1 as the LCCS1 gene.
PMID:28884921 SUPPORT Other
"We hypothesize that mutations that preserve function of the coiled-coil domain of GLE1 cause LAAHD whereas mutations that abolish the function of the coiled-coil domain cause LCCS."
Records the proposed genotype-severity relationship within the GLE1 allelic series.
ERBB3
Gene: ERBB3 hgnc:3431 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ERBB3 (hgnc:3431). hgnc:3431 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:17701904 SUPPORT Human Clinical
"This is the first report of a human phenotype resulting from loss of function of a member of this group."
Records the loss-of-function mechanism and its novelty within the receptor family.
PIP5K1C
Gene: PIP5K1C hgnc:8996 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PIP5K1C (hgnc:8996). hgnc:8996 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:17701898 SUPPORT In Vitro
"We demonstrate that the mutation causes substitution of aspartic acid with asparagine at amino acid 253 (D253N), abrogating the kinase activity of PIPKI gamma"
Gives the founder allele and its demonstrated effect on kinase activity.
PMID:38491417 SUPPORT Human Clinical
"These findings expanded the genetic variant spectrum of PIP5K1C and enriched the clinical features of LCCS3"
Extends the PIP5K1C allelic spectrum beyond the original Bedouin founder variant.
PMID:42590986 SUPPORT Human Clinical
"We describe three cases sharing a novel variant in PIP5K1C in an isolated Canadian population and provide the first detailed postnatal phenotyping of the condition in live born neonates."
The 2026 report extends the population and case series; the abstract does not specify the exact allele.
MYBPC1
Gene: MYBPC1 hgnc:7549 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MYBPC1 (hgnc:7549). hgnc:7549 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:22610851 SUPPORT Human Clinical
"We now show that a recessive mutation abrogating all functional domains in the same gene leads to LCCS."
Establishes recessive MYBPC1 loss of function as the LCCS4 mechanism.
PMID:22610851 SUPPORT Human Clinical
"A dominant missense mutation in MYBPC1 was previously shown to cause mild distal arthrogryposis."
Contrasts the dominant missense and recessive truncating mechanisms in the same gene.
PMID:26661508 SUPPORT Human Clinical
"Heterozygous mutations in this gene are associated with distal arthrogryposis types 1b and 2, whereas a homozygous nonsense mutation is implicated in one family with lethal congenital contractural syndrome 4."
The later source summarizes the allelic spectrum; the original LCCS4 report, rather than this shorthand family count, establishes the lethal presentation.
DNM2
Gene: DNM2 hgnc:2974 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DNM2 (hgnc:2974). hgnc:2974 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:23092955 SUPPORT Human Clinical
"We report the first homozygous mutation in the DNM2 protein p.Phe379Val, in three consanguineous patients with a lethal congenital syndrome associating akinesia, joint contractures, hypotonia, skeletal abnormalities, and brain and retinal hemorrhages."
The human sibling series establishes the DNM2-associated recessive clinical syndrome.
PMID:23092955 SUPPORT In Vitro
"In vitro membrane tubulation, trafficking and GTPase assays are consistent with an impact of the DNM2p.Phe379Val mutation on endocytosis."
Functional assays supporting an endocytic defect as the DNM2 mechanism.
ZBTB42
Gene: ZBTB42 hgnc:32550 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ZBTB42 (hgnc:32550). hgnc:32550 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:25055871 SUPPORT Model Organism
"This severe muscular phenotype is successfully rescued with overexpression of the human wild-type ZBTB42 gene, but not with the mutant form of ZBTB42 that models the human missense change."
Allele-specific rescue in zebrafish establishing pathogenicity of the human missense change.
CNTNAP1
Gene: CNTNAP1 hgnc:8011 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CNTNAP1 (hgnc:8011). hgnc:8011 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:24319099 SUPPORT Human Clinical
"Homozygous frameshift mutations in CNTNAP1 were found in four unrelated families."
Multi-family evidence for biallelic CNTNAP1 loss of function.
PMID:29882456 SUPPORT Human Clinical
"By ultrastructural evaluation, septate axoglial paranodal junctions were absent from nodes of Ranvier."
Ultrastructural confirmation in human nerve that CNTNAP1 loss removes the paranodal junction, the lesion this subtype's mechanism claims.
ADCY6
Gene: ADCY6 hgnc:237 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ADCY6 (hgnc:237). hgnc:237 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:31846058 SUPPORT Human Clinical
"ADCY6 inactivation, due to biallelic variants, have been previously associated with the lethal congenital contracture syndrome 8 (LCCS8)."
Confirms biallelic ADCY6 inactivation as the LCCS8 mechanism.
ADGRG6
Gene: ADGRG6 hgnc:13841 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ADGRG6 (hgnc:13841). hgnc:13841 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:26004201 SUPPORT Other
"Previous work has suggested that autoproteolytic cleavage is important for activating GPR126 signaling"
The introduction summarizes prior evidence that cleavage is important for signaling; this is background, distinct from the paper’s variant-expression assay.
PMID:26004201 SUPPORT In Vitro
"impairs autoproteolytic cleavage of GPR126"
The expression assay shows impaired rather than abolished cleavage for the tested missense construct.
NEK9
Gene: NEK9 hgnc:18591 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NEK9 (hgnc:18591). hgnc:18591 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:26908619 SUPPORT Human Clinical
"Single nucleotide polymorphism homozygosity mapping and whole exome sequencing identified a novel homozygous stop-gain mutation in NEK9 (c.1489C>T; p.Arg497*) as the cause of this disorder."
The original lethal skeletal-dysplasia report establishes the causal NEK9 allele.
GLDN
Gene: GLDN hgnc:29514 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GLDN (hgnc:29514). hgnc:29514 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:27616481 SUPPORT In Vitro
"The GLDN mutations found in the affected individuals abolish the cell surface localization of gliomedin and its interaction with its axonal partner, neurofascin-186 (NF186), in a cell-based assay."
Cell-based functional evidence for the loss-of-function mechanism.
PMID:32812332 SUPPORT Human Clinical
"Here, we describe one additional patient currently living with the syndrome, having one novel variant, p.Leu365Phe, for which we provide functional data supporting its pathogenicity."
This sentence reports an additional surviving patient and mentions functional follow-up without quoting its experimental result.
DST
Gene: DST hgnc:1090 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DST (hgnc:1090). hgnc:1090 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:40497796 SUPPORT Human Clinical
"Variants that also impact DST-a besides DST-b result in a more severe, lethal congenital contracture syndrome."
Establishes DST as causative and gives the isoform-severity relationship.
💊

Medical Actions

7
Mechanical Ventilation and Chronic Respiratory Support
Action: Invasive Mechanical VentilationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Invasive Mechanical Ventilation (NCIT:C191573). NCIT:C191573 is a clinical intervention from the NCI Thesaurus. NCIT:C191573
Platform: Device
Invasive ventilation and, in some survivors, tracheostomy with chronic respiratory support were reported in GLDN-associated disease. Some children later weaned from support. The observational series does not isolate the survival benefit from genotype, disease severity or other care. Mechanical ventilation substitutes for the respiratory effort that the hypoplastic lung and weak respiratory musculature cannot generate.
Target Phenotypes: Neonatal Respiratory Failure HP:0002878 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Neonatal Respiratory Failure, annotated with Respiratory failure (HP:0002878). HP:0002878 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28726266 SUPPORT Human Clinical
"four of whom survived beyond the neonatal period into infancy, childhood, and late adolescence with intensive care and chronic respiratory and nutritional support"
Reports the survival achieved with sustained respiratory support.
PMID:28726266 SUPPORT Human Clinical
"Our findings confirm the association of GLDN mutations with AMC and extend the LCCS11 phenotype by describing long-term survival with chronic respiratory and nutritional support."
Reports long-term survival with respiratory and nutritional support; this is an observational care association, not proof that support alone determines survival.
Enteral Nutritional Support
Action: Enteral Tube FeedingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Enteral Tube Feeding (NCIT:C93322). NCIT:C93322 is a clinical intervention from the NCI Thesaurus. NCIT:C93322
Platform: Device
Gastrostomy feeding supported a GLDN survivor with swallowing insufficiency aggravated by focal bulbar paresis. Oral feeding later increased, so indefinite tube dependence is not obligatory.
Mechanism Target:
BYPASSES Focal Bulbar Paresis — Tube feeding bypasses unsafe or insufficient oral intake caused partly by bulbar paresis; it does not reverse the paresis.
Show evidence (1 reference)
PMID:28726266 SUPPORT Human Clinical
"Insufficient swallowing aggravated by paresis of both the right vocal cord and right side of the soft palate prompted gastrostomy tube placement at 4 months of age."
Documents insufficient swallowing and the gastrostomy it required in a surviving LCCS11 child.
Show evidence (1 reference)
PMID:28726266 SUPPORT Human Clinical
"Insufficient swallowing aggravated by paresis of both the right vocal cord and right side of the soft palate prompted gastrostomy tube placement at 4 months of age."
Documents insufficient swallowing and the gastrostomy it required in a surviving LCCS11 child.
Genetic Counseling and Prenatal Testing
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Molecular diagnosis can inform recurrence counseling and reproductive testing in these recessive disorders. The usual recurrence estimate requires confirmed parental carrier status and the relevant family genotype.
Show evidence (1 reference)
PMID:29959180 SUPPORT Other
"A genetic diagnosis has clinical utility as it may affect management and prognosis and informs recurrence risk, facilitating family planning decisions."
States the counselling and reproductive value of reaching a molecular diagnosis.
Contracture Management and Rehabilitation
Action: RehabilitationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Rehabilitation (NCIT:C15315). NCIT:C15315 is a clinical intervention from the NCI Thesaurus. NCIT:C15315
Platform: Behavioral / lifestyle
Physiotherapy and splinting improved contractures, range of motion and lower-limb tone in one GLDN survivor. Other survivors underwent selected orthopedic procedures. These observed courses do not establish a uniform protocol or irreversible contracture trajectory.
Show evidence (1 reference)
PMID:28726266 SUPPORT Human Clinical
"Physiotherapy and non-surgical treatment including splinting led to an improvement of his contractures, increased range of motion, and improved muscular tone in his lower limbs."
The Family 3 survivor improved with physiotherapy and splinting; this directly corrects the prior claim that contractures cannot improve.
Perinatal Palliative Care and Shared Goals of Care
Action: Perinatal palliative careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Perinatal palliative care, annotated with Palliative Therapy (NCIT:C15292). NCIT:C15292 is a clinical intervention from the NCI Thesaurus. Ontology label: Palliative Therapy NCIT:C15292
Multidisciplinary perinatal palliative care supported a family with prenatal ERBB3-associated LCCS2. The family initially requested supported comfort care, then accepted nasal oxygen, nasogastric feeding, thermoregulation and bladder catheterization when the infant continued to breathe. Shared goals can change with the observed course; palliative care does not imply comfort-only care or an identical prognosis across LCCS subtypes.
Show evidence (3 references)
PMID:40321344 SUPPORT Other
"Perinatal palliative care is principled to support families through this uncertainty using shared decision-making to establish goals of care."
This is the authors’ care principle for uncertain LCCS2 outcomes, not a measured treatment effect or a recommendation to withhold intensive care.
PMID:40321344 SUPPORT Human Clinical
"She had consultations with pediatric urology and a Perinatal Palliative Care Team including representatives from neonatology, pediatrics, Chaplaincy, among others. Given the family’s previous experience and the counseled expectations for infants born with LCCS2, patient requested a supported..."
The mother carrying the second affected sibling received multidisciplinary consultation and initially chose supported comfort care. This is an observed family decision, separate from the authors’ general principle.
PMID:40321344 SUPPORT Human Clinical
"Despite expectations to allow a natural death after birth, she continued to have respiratory drive and live. The family’s goals of care pivoted to accept neonatal intensive level care with perceived non-aggressive interventions such as nasal cannula oxygen support, enteral feedings via..."
The second sibling’s continued respiratory drive changed the family’s goals. These actual noninvasive respiratory, nutritional and supportive interventions demonstrate that the care plan was revisable; they do not prove efficacy or a uniform survival trajectory.
Tracheostomy
Action: TracheostomyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Tracheostomy, annotated with Tracheotomy (NCIT:C15341). NCIT:C15341 is a clinical intervention from the NCI Thesaurus. Ontology label: Tracheotomy NCIT:C15341
Tracheostomy provided access for respiratory support in selected GLDN-associated survivors with persistent respiratory insufficiency. The Family 3 child underwent the procedure at six weeks for respiratory insufficiency, ineffective cough and swallowing difficulty, then weaned from ventilation at nine months and was decannulated at 19 months. Other children remained dependent; the procedure does not itself reverse pulmonary hypoplasia or neuromuscular weakness.
Show evidence (1 reference)
PMID:28726266 SUPPORT Human Clinical
"Due to persistent respiratory insufficiency, inability to cough, and insufficient swallowing, he underwent tracheostomy at 6 weeks of age. His respiratory function gradually improved, and he was successfully weaned from ventilatory support at nine months of age and subsequently decannulated at..."
This is the Family 3 survivor’s indication and subsequent course, not evidence that tracheostomy caused recovery or that decannulation is expected in every child.
Selected Orthopedic Surgery
Action: Selected orthopedic surgeryNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Selected orthopedic surgery, annotated with Orthopedic Surgical Procedure (NCIT:C16186). NCIT:C16186 is a clinical intervention from the NCI Thesaurus. Ontology label: Orthopedic Surgical Procedure NCIT:C16186
A GLDN-associated Family 2 survivor underwent operations for bilateral hip luxation and clubfeet at two years and scoliosis instrumentation at nine years. These procedures addressed selected structural problems alongside respiratory, nutritional and rehabilitation care; the case does not isolate a surgical benefit or establish a standard operative plan for LCCS.
Show evidence (1 reference)
PMID:28726266 SUPPORT Human Clinical
"He underwent surgical treatment for bilateral hip luxation and clubfeet (age 2 years) and scoliosis with Harrington rod insertion (age 9 years)."
The Family 2 survivor had these specific operations at distinct ages. Later mobility and respiratory changes occurred during a broader course of care and are not attributed solely to surgery.
🔬

Diagnosis

9
Prenatal ultrasound (PRESENT)
Ultrasound can detect impaired movement, fixed joints, abnormal fluid volume, growth restriction and associated anomalies. Classic Finnish LCCS was recognizable from 12 weeks in the cited series, but GLDN cases were often detected much later; no universal timing or specificity is established.
Prenatal diagnostic ultrasound NCIT:C19337 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:35806855 SUPPORT Other
"Prenatal ultrasound imaging is crucial in its early diagnosis by identifying fetal movement limitations and the presence of club foot or joint contractures"
States the role and yield of prenatal ultrasound.
Trio exome or genome sequencing (PRESENT)
Broad molecular testing is useful for genetically heterogeneous fetal akinesia. The cited sequencing cohort solved 18 of 38 families with mixed fetal akinesia, arthrogryposis and congenital myopathy; this is not a LCCS-specific diagnostic sensitivity, and the cited evidence does not compare trio genome with exome sequencing.
Exome or genome sequencing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:26578207 SUPPORT Human Clinical
"A conclusive genetic diagnosis was achieved for 18 of the 38 families."
The 18/38 yield is for a mixed neuromuscular cohort, not a denominator consisting only of LCCS.
Nerve conduction study (PRESENT)
Electrophysiology can characterize peripheral neuropathy in surviving infants. Velocities below 10 m/s were reported in the original CNTNAP1 families; they do not define all axoglial LCCS, and GLDN studies may normalize over time.
Motor nerve conduction studies NCIT:C88502 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:24319099 SUPPORT Human Clinical
"Patients showed a marked reduction in motor nerve conduction velocity (<10 m/s)"
The threshold is an observation in the original CNTNAP1 families, not a validated diagnostic discriminator across all LCCS subtypes.
Fetal and neonatal autopsy (PRESENT)
Postmortem examination can document lung, muscle, spinal cord and peripheral nerve pathology and confirm prenatal findings. Acceptance and tissue availability vary; absent autopsy data must not be replaced by neuropathology inferred from clinical similarity.
Fetal or neonatal autopsy NCIT:C25153 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:35806855 SUPPORT Human Clinical
"postmortem studies confirmed the prenatal findings: distal arthrogryposis, fetal growth restriction, pulmonary hypoplasia, and retrognathia"
Shows postmortem confirmation of the prenatal findings.
Fetal and postnatal magnetic resonance imaging (PRESENT)
MRI can characterize central nervous system involvement, but findings depend on subtype and age. A GLDN-affected fetus had normal brain and spinal cord MRI at 32 weeks, whereas serial brain MRI in two surviving CNTNAP1-associated children documented hypomyelination and progressive atrophy. A normal fetal scan does not exclude LCCS, and these reports do not establish a universal imaging schedule.
Fetal and postnatal MRI NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:28726266 SUPPORT Human Clinical
"Fetal MRI performed at 32 weeks showed normal brain and spinal cord images."
This was the affected female infant in Family 4, whose prenatal ultrasound showed arthrogryposis and pulmonary hypoplasia; the normal central scan did not exclude GLDN-associated disease.
PMID:29882456 SUPPORT Human Clinical
"Serial brain magnetic resonance images revealed hypomyelination, progressive atrophy, and reduced diffusion in the globus pallidus in both patients."
The two CNTNAP1-associated children had serial imaging abnormalities. This supports characterization of central involvement in that subtype, not a mandatory MRI pattern across all LCCS.
Electromyography (PRESENT)
EMG can help characterize a neurogenic component when interpreted with nerve conduction studies. Reduced motor unit recruitment accompanied slowed conduction in CNTNAP1-associated child LD_0158.0 at three weeks, whereas EMG was normal in the GLDN Family 3 survivor. These observations do not establish sensitivity or make a normal EMG exclusionary.
Electromyography NCIT:C38056 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:29882456 SUPPORT Human Clinical
"Nerve conduction studies and electromyography (EMG) at 3 weeks of age showed prolongation of distal latencies and slow nerve conduction velocity (11.1 m/s at distal median) with decreased motor unit recruitment suggestive of a neurogenic disorder with features consistent with a demyelinating..."
The combined electrophysiological assessment in LD_0158.0 distinguished a neurogenic peripheral process; conduction velocity belongs to NCS, whereas reduced recruitment is the EMG contribution.
PMID:28726266 SUPPORT Human Clinical
"Electromyography did not show any pathological finding."
EMG was normal in the GLDN Family 3 survivor despite clinical disease; this is a patient-specific limitation, not evidence against the diagnostic procedure.
Muscle biopsy (PRESENT)
Muscle histology may characterize the neuromuscular phenotype but can be normal or nonspecific. The GLDN Family 3 survivor had a normal muscle biopsy. In CNTNAP1-associated child LD_0158, quadriceps biopsy changed from mild scattered atrophy at one month to severe type I fiber atrophy and type II predominance at 3.5 years, mimicking congenital myopathy. A muscle pattern alone does not establish a primary myopathic LCCS mechanism.
Muscle Biopsy NCIT:C51895 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:28726266 SUPPORT Human Clinical
"Muscle biopsy and MRI of the brain and spinal cord were normal."
The muscle biopsy was normal in the GLDN Family 3 survivor; the separately normal MRI is not a histological result.
PMID:29882456 SUPPORT Human Clinical
"A right quadriceps biopsy at 1 month of age showed mild atrophy of scattered muscle fibers without evidence of inflammation, myonecrosis, regeneration, or structural abnormalities (Figure 2). The fiber type distribution appeared normal (Figure 2A). A second muscle biopsy from the left quadriceps..."
Serial biopsies in LD_0158 show age-dependent histological change in CNTNAP1-associated neuropathy. The later myopathy-like pattern must be interpreted alongside the peripheral nerve findings.
Peripheral nerve biopsy (PRESENT)
Sural nerve histology and ultrastructure characterized progressive peripheral neuropathy in CNTNAP1-associated child LD_0158. The initial biopsy at one month showed mildly reduced myelinated axons, while repeat biopsy at 3.5 years showed severe demyelination and predominant axonal loss. This documents a selected patient investigation, not a routine biopsy recommendation or a finding established in every subtype.
Peripheral nerve biopsy NCIT:C217131 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:29882456 SUPPORT Human Clinical
"His initial sural nerve biopsy (right sural) at 1 month of age showed a mildly reduced number of myelinated axons (Figure 3A)."
This initial peripheral nerve biopsy belongs to LD_0158; it is distinct from his muscle biopsy and from the normal muscle biopsy in a GLDN survivor.
PMID:29882456 SUPPORT Human Clinical
"A second sural nerve biopsy (left sural) at 3.5 years of age showed severe demyelination and axonal pathology. The predominant pathology was axonal loss (Figure 3B)."
The repeat nerve biopsy documents progression in the same CNTNAP1-associated child, without supplying an umbrella diagnostic threshold.
Renal and bladder ultrasound (PRESENT)
Ultrasound documented urinary tract involvement in two ERBB3-associated siblings. The first had a distended bladder, bilateral distal ureteral dilatation and left renal calyceal dilation; the second had normal kidneys with a distended, mildly thick-walled bladder and required catheter drainage. Their megacystis was interpreted as neurogenic rather than mechanical obstruction; a keyhole appearance alone was not sufficient to establish obstruction.
Renal and bladder ultrasound NCIT:C159885 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:40321344 SUPPORT Human Clinical
"Renal ultrasound revealed an overly distended bladder, bilateral distal ureteral dilatation, and left renal calyceal dilation consistent with urinary tract dilation classification P3."
This was the first affected sibling. Her ureteral and calyceal dilatation must not be assigned to the second sibling, whose kidneys appeared normal.
PMID:40321344 SUPPORT Human Clinical
"Renal ultrasound showed normal kidneys with a distended bladder with mild wall thickening. She required an indwelling Foley catheter for adequate bladder emptying."
The second affected sibling had normal-appearing kidneys despite bladder dysfunction requiring drainage. The paper interprets LCCS2 megacystis as neurogenic, despite its obstructive-looking prenatal appearance.
PMID:40321344 SUPPORT Other
"In LCCS2, megacystis is not due to obstruction, despite its sonographic appearance, but rather to neurogenic causes."
The authors interpret the LCCS2 bladder phenotype as neurogenic despite an obstructive-looking ultrasound appearance. This interpretive statement distinguishes the sonographic finding from a demonstrated mechanical obstruction; it does not identify the responsible neural pathway.
📊

Prevalence

3
Finland
Birth Prevalence 3.96 per 100,000 1–9 per 100,000 (births) LCCS1
Finnish national ascertainment of all multiple-contracture cases 1987-2002, including live births, stillbirths and terminations. The source states the rate two ways, as 1 in 25,250 and as 0.40 per 10,000; both normalize to about 3.96 per 100,000, which is the figure recorded here.
Show evidence (1 reference)
PMID:16892327 SUPPORT Human Clinical
"LCCS is noted as a unique Finnish disorder with a prevalence of 1 in 25,250 (0.40/10,000) births and is a major cause of lethal arthrogryposis in Finland."
Gives the Finnish birth prevalence of LCCS (the Finnish-heritage LCCS1 form) directly.
Finland
Carrier Frequency 1000.0 per 100,000 >1 in 1,000 (carriers) LCCS1
Carrier frequency of the GLE1 FinMajor founder allele in 200 healthy Finnish controls.
Show evidence (1 reference)
PMID:18204449 SUPPORT Human Clinical
"we found that the carrier frequency of the LCCS1 FinMajormutation in the general Finnish population was 1%"
Gives the FinMajor carrier frequency in the general Finnish population.
Northeastern Finland
Carrier Frequency 2000.0 per 100,000 >1 in 1,000 (carriers) LCCS1
Carrier frequency in the region from which most LCCS1 families originate - double the national figure, and the reason regional ancestry matters to counselling.
Show evidence (1 reference)
PMID:18204449 SUPPORT Human Clinical
"The carrier frequency in northeastern Finland, where most of the families with LCCS1 originate, was 2%."
Gives the regionally enriched carrier frequency in the LCCS1 founder population.
⚖️

Clinical Burden

High
Severe fetal contractures and respiratory impairment cause high prenatal and neonatal mortality in many reported families. Surviving GLDN- and CNTNAP1-associated individuals may require prolonged respiratory, nutritional and mobility support. Outcome varies by genotype, family and clinical course, and the historical lethal label is not an invariant prognosis.
Show evidence (1 reference)
PMID:28726266 SUPPORT Human Clinical
"We report six infants and children from four unrelated families with biallelic GLDN mutations, four of whom survived beyond the neonatal period into infancy, childhood, and late adolescence with intensive care and chronic respiratory and nutritional support."
Documents substantial respiratory and nutritional care needs among the surviving GLDN children; the series does not establish that this subtype is uniformly the least severe.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Lethal Congenital Contracture Syndrome:

Lethal Arthrogryposis with Anterior Horn Cell Disease
Overlapping Features GLE1-associated AAHD shares fetal akinesia, contractures and motor-neuron disease with classic LCCS1 but includes survival into childhood. The proposed coiled-coil-domain relationship is a hypothesis, not a definitive prognostic test for an individual allele.
Show evidence (2 references)
PMID:28884921 SUPPORT Human Clinical
"Both LCCS and LAAHD are characterized by reduced fetal movements, congenital contractures, and a severe form of motor neuron disease that results in fetal death or death in the perinatal period, respectively."
States the shared phenotype and the timing difference that is the whole basis of the distinction.
PMID:28884921 SUPPORT Human Clinical
"The phenotype of LAAHD is now expanded to include multiple individuals surviving into childhood suggesting that LAAHD is a misnomer and should be re-named Arthrogryposis with Anterior Horn Cell Disease (AAHD)."
Documents the survival that undermines the "lethal" label on the allelic disorder as well as on this one.
Arthrogryposis Multiplex Congenita
Overlapping Features AMC is the broader descriptive phenotype of congenital contractures in multiple body regions and has diverse genetic and non-genetic causes. LCCS is a historically numbered recessive subset; lethality alone does not delimit it.
Show evidence (1 reference)
PMID:28726266 SUPPORT Other
"AMC results from diverse mechanisms, including any condition that decreases or limits fetal movements."
States the breadth of AMC against which LCCS must be positioned.
Non-genetic fetal akinesia
Overlapping Features Extrinsic constraint, maternal disease or exposures can reduce fetal movement. The cited ungenotyped autopsy series illustrates etiological heterogeneity and incomplete ascertainment; a negative genetic test does not itself prove a non-genetic cause.
Show evidence (1 reference)
PMID:11810649 SUPPORT Human Clinical
"The etiology of akinesia was undetermined in Case 3; no extrinsic or intrinsic cause was identified."
An unresolved cause in an ungenotyped fetus demonstrates diagnostic uncertainty, not positive evidence for a particular extrinsic cause.
{ }

Source YAML

click to show 
name: Lethal Congenital Contracture Syndrome
creation_date: "2026-08-28T00:00:00Z"
category: Mendelian
description: >-
  Lethal congenital contracture syndrome (LCCS) comprises genetically heterogeneous autosomal recessive disorders
  with prenatal akinesia and congenital contractures. The numbered subtypes involve GLE1-associated spinal motor-neuron
  development, ERBB3 signaling, PIP5K1C-dependent phosphoinositide metabolism, MYBPC1-associated muscle function,
  DNM2-dependent trafficking, ZBTB42-associated muscle development, CNTNAP1 paranodal junctions, ADCY6 and ADGRG6
  peripheral myelination, NEK9-associated skeletal development, GLDN nodal organization, and combined neuronal and
  muscle DST isoforms. Some mechanistic steps are inferred from cellular or animal models and should not be transferred
  between subtypes. Reduced movement can produce joint deformations, impaired fetal swallowing and pulmonary hypoplasia,
  but primary skeletal abnormalities and central nervous system involvement also occur. Prenatal and neonatal mortality
  is high in selected series; GLDN- and CNTNAP1-associated disease can permit longer survival with substantial morbidity.
synonyms:
- LCCS
- Multiple contracture syndrome, Finnish type
- Herva disease
disease_term:
  preferred_term: lethal congenital contracture syndrome
  term:
    id: MONDO:0017436
    label: lethal congenital contracture syndrome
parents:
- Congenital Disorder

inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Every established LCCS locus is inherited in an autosomal recessive manner,
    with homozygous founder alleles in consanguineous or geographically isolated
    kindreds and compound heterozygosity elsewhere.
  evidence:
  - reference: PMID:25055871
    reference_title: ZBTB42 mutation defines a novel lethal congenital contracture syndrome (LCCS6).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lethal congenital contracture syndrome (LCCS) is a lethal autosomal recessive form of arthrogryposis
      multiplex congenita (AMC)."
    explanation: >-
      States the autosomal recessive mode of inheritance for the LCCS group as a
      whole.

has_subtypes:
- name: LCCS1
  display_name: LCCS1 (GLE1-related, Finnish type / Herva disease)
  subtype_term:
    preferred_term: lethal congenital contracture syndrome 1
    term:
      id: MONDO:0009670
      label: lethal congenital contracture syndrome 1
  geography:
  - Finland
  genes:
  - preferred_term: GLE1
    term:
      id: hgnc:4315
      label: GLE1
  description: >-
    The Finnish-heritage form, caused by biallelic GLE1 variants (classically the
    FinMajor splice allele). It is the most severe subtype: total fetal immobility
    detectable from the first trimester, hydrops, pterygia, and fetal death
    typically before 32 weeks, with autopsy showing loss of anterior horn
    motoneurons and severe ventral spinal cord atrophy.
  evidence:
  - reference: PMID:18204449
    reference_title: Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report that the defective gene underlying lethal motoneuron syndrome LCCS1 is the mRNA export
      mediator GLE1."
    explanation: Establishes GLE1 as the LCCS1 gene.
- name: LCCS2
  display_name: LCCS2 (ERBB3-related)
  subtype_term:
    preferred_term: lethal congenital contracture syndrome 2
    term:
      id: MONDO:0011868
      label: lethal congenital contracture syndrome 2
  geography:
  - Israel
  genes:
  - preferred_term: ERBB3
    term:
      id: hgnc:3431
      label: ERBB3
  description: >-
    ERBB3-associated disease in an Israeli Bedouin kindred combines neurogenic arthrogryposis, anterior-horn atrophy
    and marked urinary-bladder distension. The founder splice variant predicts a truncated receptor. Impaired PI3K/Akt
    signaling and deficient Schwann-cell support are proposed contributors based partly on Erbb3-null mice; the
    complete human pathway is unresolved.
  evidence:
  - reference: PMID:17701904
    reference_title: "Lethal congenital contractural syndrome type 2 (LCCS2) is caused by a mutation in ERBB3 (Her3),
      a modulator of the phosphatidylinositol-3-kinase/Akt pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We show that the disease is caused by aberrant splicing of ERBB3, which leads to a predicted truncated
      protein."
    explanation: Establishes ERBB3 as the LCCS2 gene.
- name: LCCS3
  display_name: LCCS3 (PIP5K1C-related)
  subtype_term:
    preferred_term: lethal congenital contracture syndrome 3
    term:
      id: MONDO:0012656
      label: lethal congenital contracture syndrome 3
  geography:
  - Israel
  genes:
  - preferred_term: PIP5K1C
    term:
      id: hgnc:8996
      label: PIP5K1C
  description: >-
    PIP5K1C-associated arthrogryposis resembles the original ERBB3 kindred clinically but lacks its neurogenic bladder
    finding. The original D253N allele markedly reduces recombinant kinase activity. Impaired PIP2-dependent synaptic
    vesicle trafficking is a proposed route to neuronal dysfunction, but no postmortem examinations were performed
    in the original LCCS3 series, so shared anterior-horn pathology cannot be assumed. Additional alleles and populations
    have since been reported.
  evidence:
  - reference: PMID:17701898
    reference_title: "Lethal contractural syndrome type 3 (LCCS3) is caused by a mutation in PIP5K1C, which encodes
      PIPKI gamma of the phophatidylinsitol pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We now describe a third LCCS phenotype (LCCS3)--similar to LCCS2 yet without neurogenic bladder."
    explanation: >-
      Defines LCCS3 and its clinical discriminator from LCCS2.
- name: LCCS4
  display_name: LCCS4 (MYBPC1-related)
  subtype_term:
    preferred_term: lethal congenital contracture syndrome 4
    term:
      id: MONDO:0013965
      label: lethal congenital contracture syndrome 4
  genes:
  - preferred_term: MYBPC1
    term:
      id: hgnc:7549
      label: MYBPC1
  description: >-
    Recessive truncation of MYBPC1 abrogates the functional domains of slow-type myosin-binding protein C in the
    original LCCS4 families. A muscle contractile mechanism is plausible from the protein function; human myofibrillar
    histopathology was not established by the quoted genetic report. Other MYBPC1 alleles cause nonlethal distal
    or generalized arthrogryposis.
  evidence:
  - reference: PMID:22610851
    reference_title: Autosomal recessive lethal congenital contractural syndrome type 4 (LCCS4) caused by a
      mutation in MYBPC1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We now show that a recessive mutation abrogating all functional domains in the same gene leads to
      LCCS."
    explanation: Establishes recessive MYBPC1 loss of function as the LCCS4 mechanism.
- name: LCCS5
  display_name: LCCS5 (DNM2-related, fetal akinesia with cerebral and retinal hemorrhage)
  subtype_term:
    preferred_term: fetal akinesia-cerebral and retinal hemorrhage syndrome
    term:
      id: MONDO:0014149
      label: fetal akinesia-cerebral and retinal hemorrhage syndrome
  genes:
  - preferred_term: DNM2
    term:
      id: hgnc:2974
      label: DNM2
  description: >-
    Caused by a homozygous DNM2 p.Phe379Val substitution impairing endocytosis.
    Distinguished from the other subtypes by intracranial and retinal
    haemorrhages alongside the akinesia and contractures, consistent with a
    pleiotropic dynamin-2 requirement in both muscle and vascular development.
  evidence:
  - reference: PMID:23092955
    reference_title: Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the first homozygous mutation in the DNM2 protein p.Phe379Val, in three consanguineous patients
      with a lethal congenital syndrome associating akinesia, joint contractures, hypotonia, skeletal abnormalities,
      and brain and retinal hemorrhages."
    explanation: Establishes DNM2 and the distinguishing haemorrhagic phenotype.
- name: LCCS6
  display_name: LCCS6 (ZBTB42-related)
  subtype_term:
    preferred_term: lethal congenital contracture syndrome 6
    term:
      id: MONDO:0014549
      label: lethal congenital contracture syndrome 6
  geography:
  - Saudi Arabia
  genes:
  - preferred_term: ZBTB42
    term:
      id: hgnc:32550
      label: ZBTB42
  description: >-
    Identified by autozygome analysis in a consanguineous Saudi family with
    recurrent stillbirths. ZBTB42 is enriched in skeletal muscle, particularly at
    the neuromuscular junction, and zebrafish knockdown reproduces disorganized
    myofibrils - placing the lesion at the muscle/NMJ end of the motor unit.
  evidence:
  - reference: PMID:25055871
    reference_title: ZBTB42 mutation defines a novel lethal congenital contracture syndrome (LCCS6).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data assign a novel muscular developmental phenotype to ZBTB42 in vertebrates and establish a
      new LCCS6 type caused by ZBTB42 mutation."
    explanation: Establishes ZBTB42 as the LCCS6 gene.
- name: LCCS7
  display_name: LCCS7 (CNTNAP1-related)
  subtype_term:
    preferred_term: lethal congenital contracture syndrome 7
    term:
      id: MONDO:0014569
      label: lethal congenital contracture syndrome 7
  genes:
  - preferred_term: CNTNAP1
    term:
      id: hgnc:8011
      label: CNTNAP1
  description: >-
    Caused by biallelic CNTNAP1 loss of function. CASPR is an essential paranodal
    component, and its loss produces a developmental nodopathy with motor nerve
    conduction velocities below 10 m/s and grossly abnormal nodes of Ranvier on
    sciatic nerve electron microscopy.
  evidence:
  - reference: PMID:24319099
    reference_title: Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex
      congenita with axoglial defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygous frameshift mutations in CNTNAP1 were found in four unrelated families."
    explanation: Establishes biallelic CNTNAP1 loss of function as an LCCS cause.
- name: LCCS8
  display_name: LCCS8 (ADCY6-related)
  subtype_term:
    preferred_term: lethal congenital contracture syndrome 8
    term:
      id: MONDO:0014570
      label: lethal congenital contracture syndrome 8
  genes:
  - preferred_term: ADCY6
    term:
      id: hgnc:237
      label: ADCY6
  description: >-
    Caused by biallelic ADCY6 variants. Adenylate cyclase 6 generates the cAMP
    signal that drives Schwann cell myelination, and affected nerves lack
    peripheral myelin entirely on electron microscopy.
  evidence:
  - reference: PMID:24319099
    reference_title: Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex
      congenita with axoglial defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A homozygous missense mutation in adenylate cyclase 6 gene (ADCY6) was found in another family characterized
      by a lack of myelin in the peripheral nervous system (PNS) as determined by TEM."
    explanation: Establishes ADCY6 and the amyelinating peripheral nerve phenotype.
- name: LCCS9
  display_name: LCCS9 (ADGRG6/GPR126-related)
  subtype_term:
    preferred_term: lethal congenital contracture syndrome 9
    term:
      id: MONDO:0014670
      label: lethal congenital contracture syndrome 9
  genes:
  - preferred_term: ADGRG6
    term:
      id: hgnc:13841
      label: ADGRG6
  description: >-
    Caused by biallelic ADGRG6 (GPR126) variants. GPR126 is an adhesion GPCR
    required for Schwann cell myelination; affected peripheral nerves lack myelin
    basic protein, and Gpr126-null mice reproduce the lethal arthrogryposis
    phenotype.
  evidence:
  - reference: PMID:26004201
    reference_title: Mutations of GPR126 are responsible for severe arthrogryposis multiplex congenita.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By whole-exome or targeted exome sequencing, it was shown that the probands each harbored a different
      homozygous mutation (one missense, one nonsense, and one frameshift mutation) in GPR126."
    explanation: Establishes biallelic GPR126/ADGRG6 variants as a cause of lethal AMC.
  - reference: PMID:26004201
    reference_title: Mutations of GPR126 are responsible for severe arthrogryposis multiplex congenita.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "A previous study reported that Gpr126(-/-) mice have a lethal arthrogryposis phenotype."
    explanation: >-
      The mouse knockout evidence the subtype description relies on for
      recapitulation.
- name: LCCS10
  display_name: LCCS10 (NEK9-related)
  subtype_term:
    preferred_term: NEK9-related lethal skeletal dysplasia
    term:
      id: MONDO:0014870
      label: NEK9-related lethal skeletal dysplasia
  genes:
  - preferred_term: NEK9
    term:
      id: hgnc:18591
      label: NEK9
  description: >-
    NEK9-associated lethal skeletal dysplasia was initially reported in two Irish Traveller families with homozygous
    p.Arg497*, fetal akinesia, shortened long bones, rib and thoracic abnormalities, contractures and pulmonary
    hypoplasia. Patient fibroblasts show cell-cycle and ciliary abnormalities. These support a developmental mechanism
    without establishing how much each skeletal finding reflects primary dysplasia versus impaired movement. Later
    surviving APUG-like neonatal cases are a distinct allelic presentation.
  evidence:
  - reference: PMID:26908619
    reference_title: Recessive NEK9 mutation causes a lethal skeletal dysplasia with evidence of cell cycle
      and ciliary defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report two Irish Traveller families with a previously undescribed lethal skeletal dysplasia
      characterized by fetal akinesia, shortening of all long bones, multiple contractures, rib anomalies,
      thoracic dysplasia, pulmonary hypoplasia and protruding abdomen.
    explanation: The original lethal skeletal-dysplasia families establish the LCCS10 clinical scope; the
      later APUG-like neonates are not used as its denominator.
- name: LCCS11
  display_name: LCCS11 (GLDN-related)
  subtype_term:
    preferred_term: lethal congenital contracture syndrome 11
    term:
      id: MONDO:0014965
      label: lethal congenital contracture syndrome 11
  genes:
  - preferred_term: GLDN
    term:
      id: hgnc:29514
      label: GLDN
  description: >-
    Caused by biallelic GLDN variants. Gliomedin is the Schwann-cell-derived
    ligand that clusters sodium channels at nascent nodes of Ranvier through
    neurofascin-186, so its loss is a second developmental nodopathy alongside
    LCCS7. LCCS11 is the subtype with the best-documented survival beyond the
    neonatal period.
  evidence:
  - reference: PMID:27616481
    reference_title: "Mutations in GLDN, Encoding Gliomedin, a Critical Component of the Nodes of Ranvier, Are Responsible
      for Lethal Arthrogryposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Through linkage analysis, homozygosity mapping, and exome sequencing in four unrelated families affected
      by lethal AMC, we identified biallelic mutations in GLDN in the affected individuals."
    explanation: Establishes biallelic GLDN variants as the LCCS11 cause.
- name: LCCS12
  display_name: LCCS12
  subtype_term:
    preferred_term: lethal congenital contracture syndrome 12
    term:
      id: MONDO:0981031
      label: lethal congenital contracture syndrome 12
  genes:
  - preferred_term: DST
    term:
      id: hgnc:1090
      label: DST
  description: >-
    The lethal congenital-contracture presentation is associated with biallelic DST variants affecting both neuronal
    DST-a and muscle DST-b isoforms. Four patients from two families had severe arthrogryposis and intrauterine
    or early postnatal death. The separate 19-patient DST-b-only congenital-myopathy cohort cannot establish the
    muscle histology, cardiomyopathy frequency or survival of LCCS12.
  evidence:
  - reference: PMID:40497796
    reference_title: "Deciphering DST-associated disorders: biallelic variants affecting DST-b cause a congenital
      myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genotype-phenotype correlation in these patients and previously published cases with respective variants
      resulted in the definition of a DST-associated lethal congenital contracture syndrome."
    explanation: >-
      Establishes DST as the gene defining a lethal congenital contracture
      syndrome.
  - reference: PMID:40497796
    reference_title: "Deciphering DST-associated disorders: biallelic variants affecting DST-b cause a congenital
      myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants that also impact DST-a besides DST-b result in a more severe, lethal congenital contracture
      syndrome."
    explanation: >-
      Gives the isoform-dependent severity relationship that separates the lethal
      phenotype from the congenital myopathy.

prevalence:
- subtype: LCCS1
  population: Finland
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 3.96
  notes: >-
    Finnish national ascertainment of all multiple-contracture cases 1987-2002,
    including live births, stillbirths and terminations. The source states the
    rate two ways, as 1 in 25,250 and as 0.40 per 10,000; both normalize to
    about 3.96 per 100,000, which is the figure recorded here.
  evidence:
  - reference: PMID:16892327
    reference_title: Lethal congenital contracture syndrome (LCCS) and other lethal arthrogryposes in
      Finland--an epidemiological study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LCCS is noted as a unique Finnish disorder with a prevalence of 1 in 25,250 (0.40/10,000) births and
      is a major cause of lethal arthrogryposis in Finland."
    explanation: >-
      Gives the Finnish birth prevalence of LCCS (the Finnish-heritage LCCS1 form)
      directly.
- subtype: LCCS1
  population: Finland
  measure_type: CARRIER_FREQUENCY
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 1000.0
  notes: >-
    Carrier frequency of the GLE1 FinMajor founder allele in 200 healthy Finnish
    controls.
  evidence:
  - reference: PMID:18204449
    reference_title: Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we found that the carrier frequency of the LCCS1 FinMajormutation in the general Finnish population
      was 1%"
    explanation: >-
      Gives the FinMajor carrier frequency in the general Finnish population.
- subtype: LCCS1
  population: Northeastern Finland
  measure_type: CARRIER_FREQUENCY
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 2000.0
  notes: >-
    Carrier frequency in the region from which most LCCS1 families originate -
    double the national figure, and the reason regional ancestry matters to
    counselling.
  evidence:
  - reference: PMID:18204449
    reference_title: Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The carrier frequency in northeastern Finland, where most of the families with LCCS1 originate, was
      2%."
    explanation: >-
      Gives the regionally enriched carrier frequency in the LCCS1 founder
      population.

clinical_burden:
  burden_level: HIGH
  rationale: >-
    Severe fetal contractures and respiratory impairment cause high prenatal and neonatal mortality in many reported
    families. Surviving GLDN- and CNTNAP1-associated individuals may require prolonged respiratory, nutritional
    and mobility support. Outcome varies by genotype, family and clinical course, and the historical lethal label
    is not an invariant prognosis.
  evidence:
  - reference: PMID:28726266
    reference_title: "Survival among children with \"Lethal\" congenital contracture syndrome 11 caused by novel
      mutations in the gliomedin gene (GLDN)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report six infants and children from four unrelated families with biallelic GLDN mutations, four
      of whom survived beyond the neonatal period into infancy, childhood, and late adolescence with intensive care
      and chronic respiratory and nutritional support."
    explanation: >-
      Documents substantial respiratory and nutritional care needs among the surviving GLDN children; the series
      does not establish that this subtype is uniformly the least severe.

pathophysiology:
- name: Nuclear mRNA Export Failure
  biological_scale: MOLECULAR
  subtypes:
  - LCCS1
  description: >-
    GLE1 participates in nuclear mRNA export and translation. Human GLE1 variants cause LCCS1 with anterior-horn
    motor-neuron deficiency; zebrafish studies implicate dividing neural precursor survival and motor-axon arborization.
    The precise RNA targets and cell-autonomous contributions in affected human fetuses remain unresolved; a shared
    RNA pathway across LCCS1-3 remains a hypothesis.
  biological_processes:
  - preferred_term: mRNA export from nucleus
    term:
      id: GO:0006406
      label: mRNA export from nucleus
    modifier: DECREASED
  genes:
  - preferred_term: GLE1
    term:
      id: hgnc:4315
      label: GLE1
  evidence:
  - reference: PMID:18204449
    reference_title: Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Our finding of mutated GLE1 exposes a common pathway connecting the genes implicated in LCCS1, LCCS2
      and LCCS3 and elucidates mRNA processing as a critical molecular mechanism in motoneuron development and maturation."
    explanation: >-
      Identifies mRNA processing as the molecular mechanism, and proposes it as
      the pathway shared across the anterior horn subtypes.
  downstream:
  - target: Anterior Horn Motor Neuron Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      GLE1 dysfunction is linked to the human motor-neuron deficit, with neural precursor apoptosis supported in
      zebrafish. This is a qualified developmental route, not proof of death of differentiated human motor neurons.
    evidence:
    - reference: PMID:22357925
      reference_title: A zebrafish model of lethal congenital contracture syndrome 1 reveals Gle1 function in
        spinal neural precursor survival and motor axon arborization.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Unexpectedly, the motoneuron deficiency results from apoptosis of neural precursors, not of
        differentiated motoneurons.
      explanation: The zebrafish perturbation identifies a precursor-survival route; translation to the human
        histological deficit is indirect.
      directness: INDIRECT
- name: PI3K-Akt Signaling Loss
  biological_scale: MOLECULAR
  subtypes:
  - LCCS2
  description: >-
    The LCCS2 ERBB3 splice variant predicts loss of receptor signaling. The authors propose reduced PI3K/Akt survival
    signaling as a cause of neuronal apoptosis; Erbb3-null mice also lack Schwann-cell precursors. These are mechanistic
    hypotheses supporting, but not completing, the human genotype-to-neurogenic disease route.
  biological_processes:
  - preferred_term: phosphatidylinositol 3-kinase/protein kinase B signal transduction
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
    modifier: DECREASED
  genes:
  - preferred_term: ERBB3
    term:
      id: hgnc:3431
      label: ERBB3
  evidence:
  - reference: PMID:17701904
    reference_title: "Lethal congenital contractural syndrome type 2 (LCCS2) is caused by a mutation in ERBB3 (Her3),
      a modulator of the phosphatidylinositol-3-kinase/Akt pathway."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "an activator of the phosphatidylinositol-3-kinase/Akt pathway--regulating cell survival and vesicle
      trafficking"
    explanation: >-
      Names the pathway ERBB3 activates and the cellular functions it governs.
  downstream:
  - target: Anterior Horn Motor Neuron Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced ERBB3 survival signaling is a proposed cause of the documented LCCS2 anterior-horn
      lesion. The human splice finding and mouse survival phenotype support an indirect route; the
      contribution of glial support is unresolved.
    evidence:
    - reference: PMID:17701904
      reference_title: Lethal congenital contractural syndrome type 2 (LCCS2) is caused by a mutation in ERBB3
        (Her3), a modulator of the phosphatidylinositol-3-kinase/Akt pathway.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Thus, the neuronal apoptosis seen in the human and mouse ErbB3 defects is likely mediated
        through downregulation of the Akt pathway.
      explanation: The authors explicitly propose reduced Akt survival signaling as the mediator; likely is
        preserved as mechanistic uncertainty.
      directness: INDIRECT
- name: Phosphoinositide Synthesis Deficiency
  biological_scale: MOLECULAR
  subtypes:
  - LCCS3
  description: >-
    The original PIP5K1C D253N allele markedly reduces recombinant PIPKI-gamma activity. The authors propose that
    reduced PIP2 impairs synaptic vesicle trafficking and neuronal function. Clinical similarity to LCCS2 does not
    demonstrate anterior-horn loss: the original LCCS3 families declined postmortem examination.
  molecular_functions:
  - preferred_term: 1-phosphatidylinositol-4-phosphate 5-kinase activity
    term:
      id: GO:0016308
      label: 1-phosphatidylinositol-4-phosphate 5-kinase activity
    modifier: DECREASED
  genes:
  - preferred_term: PIP5K1C
    term:
      id: hgnc:8996
      label: PIP5K1C
  evidence:
  - reference: PMID:17701898
    reference_title: "Lethal contractural syndrome type 3 (LCCS3) is caused by a mutation in PIP5K1C, which encodes
      PIPKI gamma of the phophatidylinsitol pathway."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Thus, a defect in the phosphatidylinositol pathway leading to a decrease in synthesis of PIP(2), a
      molecule active in endocytosis of synaptic vesicle proteins, culminates in lethal congenital arthrogryposis."
    explanation: >-
      States the enzymatic deficiency, the downstream lipid, and its synaptic
      vesicle role in one sentence.
  downstream:
  - target: Absent Fetal Movement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: PIP2 deficiency is proposed to impair synaptic vesicle trafficking and neuronal function,
      reducing fetal motor activity. This qualified route does not assert unobserved anterior-horn pathology.
    evidence:
    - reference: PMID:17701898
      reference_title: Lethal contractural syndrome type 3 (LCCS3) is caused by a mutation in PIP5K1C, which
        encodes PIPKI gamma of the phophatidylinsitol pathway.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Thus, a defect in the phosphatidylinositol pathway leading to a decrease in synthesis of
        PIP(2), a molecule active in endocytosis of synaptic vesicle proteins, culminates in lethal congenital
        arthrogryposis.
      explanation: The authors explicitly propose a phosphoinositide/synaptic route to the
        akinesia-contracture syndrome; its detailed human cellular intermediates remain unresolved.
      directness: INDIRECT
- name: cAMP Synthesis Deficiency
  biological_scale: MOLECULAR
  subtypes:
  - LCCS8
  description: >-
    ADCY6 encodes an adenylate cyclase. Human peripheral amyelination and zebrafish knockdown support a myelination
    role, likely through cAMP. Complete absence of cAMP production or the full signaling sequence was not measured
    in affected humans.
  biological_processes:
  - preferred_term: cAMP biosynthetic process
    term:
      id: GO:0006171
      label: cAMP biosynthetic process
    modifier: DECREASED
  genes:
  - preferred_term: ADCY6
    term:
      id: hgnc:237
      label: ADCY6
  evidence:
  - reference: PMID:24319099
    reference_title: Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex
      congenita with axoglial defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ADCY6 encodes a protein that belongs to the adenylate cyclase family responsible for the synthesis
      of cAMP."
    explanation: Identifies the enzymatic function lost in the ADCY6 subtype.
  downstream:
  - target: Schwann Cell Myelination Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      ADCY6 dysfunction is proposed to impair the cAMP-dependent myelination program; the source qualifies the cAMP
      mediation as likely.
    evidence:
    - reference: PMID:24319099
      reference_title: Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex
        congenita with axoglial defects.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Our data indicate an essential and so far unknown role of ADCY6 in PNS myelination likely through
        the cAMP pathway."
      explanation: >-
        States the cAMP-to-myelination link the authors draw from their own data.
- name: Mitotic and Ciliary Regulatory Failure
  biological_scale: MOLECULAR
  subtypes:
  - LCCS10
  description: >-
    NEK9 p.Arg497* eliminates full-length protein in patient fibroblasts, with reduced proliferation, delayed cell-cycle
    progression, and fewer, shorter cilia. The authors propose a ciliopathy underlying the lethal skeletal dysplasia.
    The relative contributions of cell-cycle and ciliary dysfunction to fetal akinesia and skeletal growth are unresolved.
  biological_processes:
  - preferred_term: cilium assembly
    term:
      id: GO:0060271
      label: cilium assembly
    modifier: DECREASED
  genes:
  - preferred_term: NEK9
    term:
      id: hgnc:18591
      label: NEK9
  mechanism_confidence: HYPOTHETICAL
  evidence:
  - reference: PMID:26908619
    reference_title: Recessive NEK9 mutation causes a lethal skeletal dysplasia with evidence of cell cycle
      and ciliary defects.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Functional characterization of patient fibroblasts showed a significant reduction in cell
      proliferation and a delay in cell cycle progression.
    explanation: Patient-derived fibroblast assays establish cell-cycle abnormalities, not an in-vivo skeletal
      measurement.
  - reference: PMID:26908619
    reference_title: Recessive NEK9 mutation causes a lethal skeletal dysplasia with evidence of cell cycle
      and ciliary defects.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Firstly, patient fibroblasts displayed a significant reduction in cilia number and length.
    explanation: Patient-derived fibroblasts show ciliary abnormalities supporting the proposed developmental
      mechanism.
  downstream:
  - target: Absent Fetal Movement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The NEK9-associated developmental disorder includes fetal akinesia; the ciliary or mitotic
      route to motor impairment remains provisional.
    evidence:
    - reference: PMID:26908619
      reference_title: Recessive NEK9 mutation causes a lethal skeletal dysplasia with evidence of cell cycle
        and ciliary defects.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: In summary, we report the clinical and molecular characterization of a lethal skeletal
        dysplasia caused by NEK9 mutation and suggest that this disorder may represent a novel ciliopathy.
      explanation: The authors connect NEK9 loss to the lethal skeletal dysplasia and propose a ciliary
        mechanism; the specific developmental intermediates are not established.
      directness: INDIRECT
  - target: Multiple Congenital Joint Contractures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: NEK9 dysfunction causes the contracture-bearing skeletal dysplasia. The contribution of
      primary skeletal development versus secondary akinesia is unresolved.
    evidence:
    - reference: PMID:26908619
      reference_title: Recessive NEK9 mutation causes a lethal skeletal dysplasia with evidence of cell cycle
        and ciliary defects.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: In summary, we report the clinical and molecular characterization of a lethal skeletal
        dysplasia caused by NEK9 mutation and suggest that this disorder may represent a novel ciliopathy.
      explanation: The authors connect NEK9 loss to the lethal skeletal dysplasia and propose a ciliary
        mechanism; the specific developmental intermediates are not established.
      directness: INDIRECT
  - target: Short Long Bones
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The proposed developmental mechanism accounts for the genetically defined short-bone
      dysplasia, without assigning the defect exclusively to cilia or reduced fetal loading.
    evidence:
    - reference: PMID:26908619
      reference_title: Recessive NEK9 mutation causes a lethal skeletal dysplasia with evidence of cell cycle
        and ciliary defects.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: In summary, we report the clinical and molecular characterization of a lethal skeletal
        dysplasia caused by NEK9 mutation and suggest that this disorder may represent a novel ciliopathy.
      explanation: The authors connect NEK9 loss to the lethal skeletal dysplasia and propose a ciliary
        mechanism; the specific developmental intermediates are not established.
      directness: INDIRECT
- name: Anterior Horn Motor Neuron Loss
  biological_scale: CELLULAR
  subtypes:
  - LCCS1
  - LCCS2
  description: >-
    Anterior-horn motor-neuron deficiency or atrophy is documented in GLE1 and ERBB3 disease. Zebrafish Gle1 studies
    identify apoptosis of dividing neural precursors rather than differentiated motor neurons. This cellular route
    must not be generalized to PIP5K1C disease, whose original series lacked autopsies.
  cell_types:
  - preferred_term: spinal cord motor neuron
    term:
      id: CL:0011001
      label: spinal cord motor neuron
  biological_processes:
  - preferred_term: spinal cord motor neuron differentiation
    term:
      id: GO:0021522
      label: spinal cord motor neuron differentiation
    modifier: DECREASED
  locations:
  - preferred_term: ventral horn of spinal cord
    term:
      id: UBERON:0002257
      label: ventral horn of spinal cord
  evidence:
  - reference: PMID:18204449
    reference_title: Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most severe forms of motoneuron disease manifest in utero are characterized by marked atrophy
      of spinal cord motoneurons and fetal immobility."
    explanation: >-
      Frames LCCS1 as an in utero motor neuron disease with spinal motoneuron
      atrophy and consequent immobility.
  - reference: PMID:17701904
    reference_title: "Lethal congenital contractural syndrome type 2 (LCCS2) is caused by a mutation in ERBB3 (Her3),
      a modulator of the phosphatidylinositol-3-kinase/Akt pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lethal congenital contractural syndrome type 2 (LCCS2) is an autosomal recessive neurogenic form of
      arthrogryposis that is associated with atrophy of the anterior horn of the spinal cord."
    explanation: >-
      Records anterior horn atrophy as the neuropathological lesion in LCCS2 as
      well, extending the node beyond LCCS1.
  - reference: PMID:22357925
    reference_title: A zebrafish model of lethal congenital contracture syndrome 1 reveals Gle1 function in
      spinal neural precursor survival and motor axon arborization.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Unexpectedly, the motoneuron deficiency results from apoptosis of neural precursors, not of differentiated
      motoneurons."
    explanation: >-
      Refines the cellular mechanism: the motoneuron loss is a precursor survival
      defect rather than degeneration of mature neurons.
  downstream:
  - target: Neurogenic Skeletal Muscle Atrophy and Hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Loss of developing motor innervation is a plausible contributor to the severe muscle
      underdevelopment associated with the GLE1 autopsy lesion; the precise developmental sequence was not
      directly observed.
    evidence:
    - reference: PMID:18204449
      reference_title: Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Neuropathological analysis shows lack of anterior horn motoneurons, severe atrophy of the
        ventral spinal cord and hypoplastic, nearly absent skeletal muscles
      explanation: The paired human pathology supports the neurogenic developmental interpretation; it does
        not experimentally resolve the timing of muscle loss.
      directness: INDIRECT
  - target: Skeletal Muscle Hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Severely deficient motor-neuron development is interpreted to deprive developing muscle of
      innervation in classic GLE1 disease. This is an indirect neurogenic interpretation of the paired human
      lesions.
    evidence:
    - reference: PMID:18204449
      reference_title: Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Neuropathological analysis shows lack of anterior horn motoneurons, severe atrophy of the
        ventral spinal cord and hypoplastic, nearly absent skeletal muscles
      explanation: The paired human pathology supports the neurogenic developmental interpretation; it does
        not experimentally resolve the timing of muscle loss.
      directness: INDIRECT
- name: Schwann Cell Myelination Failure
  genes:
  - preferred_term: ADGRG6
    term:
      id: hgnc:13841
      label: ADGRG6
  biological_scale: CELLULAR
  subtypes:
  - LCCS8
  - LCCS9
  description: >-
    Peripheral myelination is deficient in ADCY6- and ADGRG6-associated disease. Human nerve pathology supports
    this lesion; ADCY6 knockdown and ADGRG6 studies in fish and mice inform the proposed signaling routes. Schwann
    precursor loss in Erbb3-null mice is a different model observation and is not asserted as measured human LCCS2
    myelin pathology.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  - preferred_term: Schwann cell precursor
    term:
      id: CL:0002375
      label: Schwann cell precursor
  biological_processes:
  - preferred_term: peripheral nervous system myelin formation
    term:
      id: GO:0032290
      label: peripheral nervous system myelin formation
    modifier: DECREASED
  locations:
  - preferred_term: peripheral nervous system
    term:
      id: UBERON:0000010
      label: peripheral nervous system
  evidence:
  - reference: PMID:24319099
    reference_title: Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex
      congenita with axoglial defects.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Morpholino knockdown of the zebrafish orthologs led to severe and specific defects in peripheral myelin
      in spite of the presence of Schwann cells."
    explanation: >-
      Shows the ADCY6 lesion is a myelination failure rather than an absence of
      Schwann cells.
  - reference: PMID:26004201
    reference_title: Mutations of GPR126 are responsible for severe arthrogryposis multiplex congenita.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have shown that the peripheral nerves in affected individuals from one family lack myelin basic
      protein, suggesting that this disease in affected individuals is due to defective myelination of the peripheral
      axons during fetal development."
    explanation: >-
      Demonstrates absent peripheral myelin in ADGRG6/GPR126-related disease in
      human tissue.
  downstream:
  - target: Absent Fetal Movement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Defective peripheral myelination during fetal development is the source-proposed cause of
      severe ADGRG6-associated arthrogryposis through impaired motor function. The human fetal conduction
      intermediate was not measured.
    evidence:
    - reference: PMID:26004201
      reference_title: Mutations of GPR126 are responsible for severe arthrogryposis multiplex congenita.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We have shown that the peripheral nerves in affected individuals from one family lack myelin basic
        protein, suggesting that this disease in affected individuals is due to defective myelination of the peripheral
        axons during fetal development."
      explanation: >-
        Demonstrates absent peripheral myelin in ADGRG6/GPR126-related disease in
        human tissue.
- name: Node of Ranvier Assembly Failure
  genes:
  - preferred_term: CNTNAP1
    term:
      id: hgnc:8011
      label: CNTNAP1
  - preferred_term: GLDN
    term:
      id: hgnc:29514
      label: GLDN
  biological_scale: CELLULAR
  subtypes:
  - LCCS11
  description: >-
    GLDN encodes gliomedin, which contributes to nodal sodium-channel clustering through axonal ligands including
    NF186. Human nodal abnormalities and variant assays support a nodopathy. GLDN-null mice can retain conduction
    and lack arthrogryposis, so complete conduction abolition cannot be inferred from loss of gliomedin alone.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  - preferred_term: spinal cord motor neuron
    term:
      id: CL:0011001
      label: spinal cord motor neuron
  cellular_components:
  - preferred_term: node of Ranvier
    term:
      id: GO:0033268
      label: node of Ranvier
  evidence:
  - reference: PMID:27616481
    reference_title: "Mutations in GLDN, Encoding Gliomedin, a Critical Component of the Nodes of Ranvier, Are Responsible
      for Lethal Arthrogryposis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The axoglial contact between gliomedin and NF186 is essential for the initial clustering of Na+ channels
      at developing nodes."
    explanation: >-
      The source summarizes the molecular requirement for gliomedin/NF186 contact during initial sodium-channel
      clustering; this background statement is distinct from its human microscopy and variant assays.
  - reference: PMID:27616481
    reference_title: "Mutations in GLDN, Encoding Gliomedin, a Critical Component of the Nodes of Ranvier, Are Responsible
      for Lethal Arthrogryposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data indicate that mutations of GLDN or CNTNAP1 (MIM: 616286), encoding essential components
      of the nodes of Ranvier and paranodes, respectively, lead to inherited nodopathies, a distinct disease entity
      among peripheral neuropathies."
    explanation: >-
      The authors place GLDN nodal and CNTNAP1 paranodal defects in the broader inherited-nodopathy category while
      explicitly distinguishing their anatomical sites. This node represents the GLDN nodal lesion; CNTNAP1 is modeled
      separately.
  downstream:
  - target: Impaired Motor Nerve Conduction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Abnormal gliomedin-dependent nodal organization can impair peripheral conduction in human
      GLDN-associated disease, but the effect is variable and can normalize on repeat testing.
    evidence:
    - reference: PMID:28726266
      reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by
        novel mutations in the gliomedin gene (GLDN).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Nerve conduction velocity studies performed at 1 week of age demonstrated axonal motor and
        sensory neuropathy but were normal when repeated at 7 months of age.
      explanation: Human electrophysiology supports a variable conduction consequence of the nodopathy; the
        normal repeat result constrains a permanent complete-block interpretation.
      directness: INDIRECT
- name: Impaired Motor Nerve Conduction
  biological_scale: CELLULAR
  subtypes:
  - LCCS7
  - LCCS11
  description: >-
    Peripheral motor signaling is impaired in CNTNAP1 and some GLDN cases. Original CNTNAP1 families had motor velocities
    below 10 m/s, but this threshold is not universal, and a GLDN child had normal repeat studies at seven months.
    The functional route to weakness and reduced movement is supported indirectly by the human neuropathy and nodal-pathology
    context.
  biological_processes:
  - preferred_term: neuronal action potential propagation
    term:
      id: GO:0019227
      label: neuronal action potential propagation
    modifier: DECREASED
  evidence:
  - reference: PMID:24319099
    reference_title: Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex
      congenita with axoglial defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients showed a marked reduction in motor nerve conduction velocity (<10 m/s)"
    explanation: Quantifies the conduction failure in affected individuals.
  downstream:
  - target: Absent Fetal Movement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired peripheral motor signaling contributes to prenatal akinesia in the documented nodopathies, without
      implying complete conduction failure or identical measurements in every subtype.
    evidence:
    - reference: PMID:24319099
      reference_title: Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex
        congenita with axoglial defects.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Non-syndromic arthrogryposis multiplex congenita (AMC) is characterized by multiple congenital contractures
        resulting from reduced fetal mobility."
      explanation: >-
        Places the cohort's conduction defect within the reduced-fetal-mobility
        causal frame. Indirect because the sentence states the frame rather than
        measuring the conduction-to-movement step.
  - target: Muscle Weakness
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Peripheral motor neuropathy can reduce effective muscle activation in GLDN survivors;
      concurrent muscular contributions and changing severity remain possible.
    evidence:
    - reference: PMID:28726266
      reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by
        novel mutations in the gliomedin gene (GLDN).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: His neurologic examination was notable for myopathic facies, very weak to absent deep tendon
        reflexes, and symmetric atrophy and weakness of his proximal muscles.
      explanation: This GLDN survivor had peripheral neuropathy in the full clinical course; the examination
        supports the qualified motor-unit interpretation, not a uniquely proven cellular pathway.
      directness: INDIRECT
  - target: Areflexia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Impaired peripheral reflex-arc signaling provides an indirect explanation for absent reflexes
      in the GLDN neuropathy context; areflexia alone does not localize the lesion.
    evidence:
    - reference: PMID:28726266
      reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by
        novel mutations in the gliomedin gene (GLDN).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: His neurologic examination was notable for myopathic facies, very weak to absent deep tendon
        reflexes, and symmetric atrophy and weakness of his proximal muscles.
      explanation: This GLDN survivor had peripheral neuropathy in the full clinical course; the examination
        supports the qualified motor-unit interpretation, not a uniquely proven cellular pathway.
      directness: INDIRECT
  - target: Skeletal Muscle Atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Chronic peripheral motor dysfunction can produce neurogenic loss of muscle bulk in GLDN
      survivors. Human findings also leave primary muscular contributions possible.
    evidence:
    - reference: PMID:28726266
      reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by
        novel mutations in the gliomedin gene (GLDN).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: His neurologic examination was notable for myopathic facies, very weak to absent deep tendon
        reflexes, and symmetric atrophy and weakness of his proximal muscles.
      explanation: This GLDN survivor had peripheral neuropathy in the full clinical course; the examination
        supports the qualified motor-unit interpretation, not a uniquely proven cellular pathway.
      directness: INDIRECT
- name: Myofibril Assembly Failure
  genes:
  - preferred_term: MYBPC1
    term:
      id: hgnc:7549
      label: MYBPC1
  - preferred_term: ZBTB42
    term:
      id: hgnc:32550
      label: ZBTB42
  biological_scale: CELLULAR
  subtypes:
  - LCCS6
  description: >-
    ZBTB42 knockdown causes myofibrillar disorganization and abnormal neuromuscular junctions in zebrafish, with
    impaired coiling and escape movement. Wild-type human ZBTB42, but not the variant construct, rescues the model
    phenotype. Human muscle biopsy and autopsy were declined, so the exact human tissue lesion remains inferred.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: myofibril assembly
    term:
      id: GO:0030239
      label: myofibril assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:25055871
    reference_title: ZBTB42 mutation defines a novel lethal congenital contracture syndrome (LCCS6).
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Knockdown experiments of zbtb42 in zebrafish consistently resulted in grossly abnormal skeletal muscle
      development and myofibrillar disorganization at the microscopic level."
    explanation: >-
      Shows the ZBTB42 lesion is a muscle developmental and myofibrillar defect.
  downstream:
  - target: Absent Fetal Movement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced muscle organization and function in ZBTB42-deficient fish provide a model-supported
      explanation for human fetal akinesia, with incomplete human tissue confirmation.
    evidence:
    - reference: PMID:25055871
      reference_title: ZBTB42 mutation defines a novel lethal congenital contracture syndrome (LCCS6).
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: The decreased spontaneous coiling and diminished touch-evoked escape behaviors are indicative
        of reduced muscle function and overall muscle weakness.
      explanation: The movement phenotype is measured in zebrafish; translation to the human LCCS6 fetal
        phenotype is indirect.
      directness: INDIRECT
- name: Endocytic Trafficking Failure
  genes:
  - preferred_term: DNM2
    term:
      id: hgnc:2974
      label: DNM2
  biological_scale: CELLULAR
  subtypes:
  - LCCS5
  description: >-
    The DNM2 p.Phe379Val allele impairs endocytosis in assays and is associated with a severe recessive congenital
    syndrome. Zebrafish knockdown affects muscle organization and angiogenesis. The authors propose altered developmental
    endocytosis as an explanation for pleiotropic clinical manifestations, without establishing the specific human
    tissue route to each finding.
  biological_processes:
  - preferred_term: endocytosis
    term:
      id: GO:0006897
      label: endocytosis
    modifier: DECREASED
  evidence:
  - reference: PMID:23092955
    reference_title: Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro membrane tubulation, trafficking and GTPase assays are consistent with an impact of the DNM2p.Phe379Val
      mutation on endocytosis."
    explanation: >-
      Functional assays localizing the DNM2 lesion to endocytosis.
  - reference: PMID:23092955
    reference_title: Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "knockdown approaches in zebrafish resulting in defects in muscle organization and angiogenesis support
      a pleiotropic role for DNM2 during fetal development in vertebrates and humans"
    explanation: >-
      Supports the pleiotropic muscle-and-vascular role that separates this node
      from the purely myofibrillar one.
  downstream:
  - target: Absent Fetal Movement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Developmental trafficking dysfunction is proposed to impair motor function; zebrafish muscle
      disorganization supports, but does not prove, the human route.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658203/
      reference_title: Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome - PMC
      supports: SUPPORT
      evidence_source: OTHER
      snippet: We speculate that alterations in endocytosis during development could explain the pleiotropic
        phenotype observed in patients with this congenital syndrome.
      explanation: Full text of the same study indexed as PMID:23092955 proposes a pleiotropic developmental
        endocytosis mechanism; it does not prove a specific human muscle or vascular intermediate.
      directness: INDIRECT
  - target: Severe Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The authors propose a pleiotropic developmental mechanism for the DNM2 syndrome. The relative
      contributions of muscle and peripheral nerve dysfunction to hypotonia remain unresolved.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658203/
      reference_title: Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome - PMC
      supports: SUPPORT
      evidence_source: OTHER
      snippet: We speculate that alterations in endocytosis during development could explain the pleiotropic
        phenotype observed in patients with this congenital syndrome.
      explanation: Full text of the same study indexed as PMID:23092955 proposes a pleiotropic developmental
        endocytosis mechanism; it does not prove a specific human muscle or vascular intermediate.
      directness: INDIRECT
  - target: Intracranial Hemorrhage
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The developmental endocytosis hypothesis and zebrafish angiogenesis defects provide
      provisional support for a vascular contribution to brain hemorrhage; human vascular pathology and other
      bleeding contributors were not resolved.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658203/
      reference_title: Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome - PMC
      supports: SUPPORT
      evidence_source: OTHER
      snippet: We speculate that alterations in endocytosis during development could explain the pleiotropic
        phenotype observed in patients with this congenital syndrome.
      explanation: Full text of the same study indexed as PMID:23092955 proposes a pleiotropic developmental
        endocytosis mechanism; it does not prove a specific human muscle or vascular intermediate.
      directness: INDIRECT
  - target: Retinal Hemorrhage
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The proposed pleiotropic endocytosis mechanism may disrupt ocular vascular development. The
      retinal bleeding route is not directly reconstructed, and the platelet abnormalities in the siblings are
      an additional unresolved contributor.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658203/
      reference_title: Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome - PMC
      supports: SUPPORT
      evidence_source: OTHER
      snippet: We speculate that alterations in endocytosis during development could explain the pleiotropic
        phenotype observed in patients with this congenital syndrome.
      explanation: Full text of the same study indexed as PMID:23092955 proposes a pleiotropic developmental
        endocytosis mechanism; it does not prove a specific human muscle or vascular intermediate.
      directness: INDIRECT
  - target: Thin Ribs
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The authors propose altered developmental endocytosis as a pleiotropic explanation for the
      DNM2 skeletal findings. A primary skeletal effect versus secondary reduced mechanical loading is
      unresolved.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658203/
      reference_title: Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome - PMC
      supports: SUPPORT
      evidence_source: OTHER
      snippet: We speculate that alterations in endocytosis during development could explain the pleiotropic
        phenotype observed in patients with this congenital syndrome.
      explanation: Full text of the same study indexed as PMID:23092955 proposes a pleiotropic developmental
        endocytosis mechanism; it does not prove a specific human muscle or vascular intermediate.
      directness: INDIRECT
- name: Neurogenic Skeletal Muscle Atrophy and Hypoplasia
  biological_scale: TISSUE
  subtypes:
  - LCCS1
  - LCCS2
  description: >-
    Loss of effective developing motor innervation can impair muscle growth and contraction. GLE1 fetal autopsies
    show severely hypoplastic musculature together with anterior-horn deficiency. The causal interpretation is supported
    indirectly by fetal neurogenic pathology; PIP5K1C muscle wasting is not assigned to this specific lesion without
    autopsy evidence.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: skeletal muscle tissue development
    term:
      id: GO:0007519
      label: skeletal muscle tissue development
    modifier: DECREASED
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  evidence:
  - reference: PMID:11810649
    reference_title: "Heterogeneity in fetal akinesia deformation sequence (FADS): autopsy confirmation in three
      20-21-week fetuses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuropathologic examination revealed anterior horn cell loss and lateral corticospinal tract degeneration
      in spinal cord, with marked muscular atrophy."
    explanation: >-
      This ungenotyped fetal akinesia case provides supporting neurogenic pathological context, not direct proof
      of a numbered LCCS genotype.
    directness: INDIRECT
  downstream:
  - target: Absent Fetal Movement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Denervated, hypoplastic muscle cannot move the fetal limbs.
    evidence:
    - reference: PMID:11810649
      reference_title: "Heterogeneity in fetal akinesia deformation sequence (FADS): autopsy confirmation in three
        20-21-week fetuses."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Neurogenic spinal muscular atrophy was the basis of fetal akinesia in Case 1."
      explanation: >-
        The authors directly attribute akinesia to neurogenic spinal muscular atrophy in this ungenotyped FADS fetus;
        application to the paired GLE1 lesions is indirect.
      directness: INDIRECT
- name: Impaired Swallowing
  biological_scale: ORGANISM
  description: >-
    Impaired fetal deglutition reduces amniotic-fluid clearance. This prenatal mechanism is distinguished from postnatal
    swallowing insufficiency with documented focal bulbar paresis in a GLDN survivor.
  evidence:
  - reference: PMID:35806855
    reference_title: 'Lethal Congenital Contracture Syndrome 11: A Case Report and Literature Review.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The common feature of this sequence is decreased fetal activity, which leads to a failure of
      normal deglutition, resulting in polyhydramnios.
    explanation: The source explicitly gives the fetal activity-to-deglutition-to-amniotic-fluid sequence.
  downstream:
  - target: Polyhydramnios
    causal_link_type: DIRECT
    description: Reduced fetal swallowing decreases clearance of amniotic fluid.
    evidence:
    - reference: PMID:35806855
      reference_title: 'Lethal Congenital Contracture Syndrome 11: A Case Report and Literature Review.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: The common feature of this sequence is decreased fetal activity, which leads to a failure of
        normal deglutition, resulting in polyhydramnios.
      explanation: The source explicitly gives the fetal activity-to-deglutition-to-amniotic-fluid sequence.
- name: Paranodal Axoglial Junction Failure
  biological_scale: CELLULAR
  description: CNTNAP1/CASPR1 deficiency disrupts septate paranodal junctions in peripheral nerves and is
    proposed to disturb glial-axonal interactions centrally. This is anatomically distinct from
    gliomedin-dependent nodal assembly.
  subtypes:
  - LCCS7
  evidence:
  - reference: PMID:29882456
    reference_title: Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations,
      Hypomyelination, and Arthrogryposis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These 2 families illustrate severe progressive peripheral demyelinating neuropathy due to the
      absence of septate paranodal junctions and central hypomyelination with neurodegeneration in
      CNTNAP1-associated arthrogryposis multiplex congenita.
    explanation: The authors explicitly attribute progressive peripheral neuropathy to missing paranodal
      junctions and document associated central disease.
  genes:
  - preferred_term: CNTNAP1
    term:
      id: hgnc:8011
      label: CNTNAP1
  downstream:
  - target: Impaired Motor Nerve Conduction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Loss of the paranodal junctional barrier disrupts axoglial organization required for rapid
      conduction; severe slowing was measured in affected CNTNAP1 children.
    evidence:
    - reference: PMID:29882456
      reference_title: Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations,
        Hypomyelination, and Arthrogryposis.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: By separating the voltage-gated sodium channels from the delayed rectifier potassium channels
        in nodes of Ranvier and the juxtaparanodal region, respectively, this protein junctional complex plays
        a critical role in facilitating high-velocity nerve conduction and myelin homeostasis.
      explanation: The source explains the junction-to-conduction mechanism, supported by human paranodal
        pathology and nerve studies.
      directness: INDIRECT
  - target: Central Nervous System Hypomyelination
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: CNTNAP1-associated disruption of central glial-axonal interactions is implicated in the
      serially documented hypomyelination; the human central ultrastructure was not examined.
    evidence:
    - reference: PMID:29882456
      reference_title: Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations,
        Hypomyelination, and Arthrogryposis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: These 2 families illustrate severe progressive peripheral demyelinating neuropathy due to the
        absence of septate paranodal junctions and central hypomyelination with neurodegeneration in
        CNTNAP1-associated arthrogryposis multiplex congenita.
      explanation: The authors explicitly attribute progressive peripheral neuropathy to missing paranodal
        junctions and document associated central disease.
  - target: Brain Atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Central myelin abnormalities and possible neuronal loss are proposed contributors to
      progressive volume loss; their separate contributions are unresolved.
    evidence:
    - reference: PMID:29882456
      reference_title: Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations,
        Hypomyelination, and Arthrogryposis.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: It is possible that this atrophy is a reflection of neuronal loss (cell bodies and axons) in
        addition to alterations in myelin sheaths centrally.
      explanation: The authors propose mixed neuronal and myelin contributions to CNTNAP1-associated atrophy,
        without directly measuring their relative effects.
      directness: INDIRECT
  - target: Seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Paranodal disruption and consequent ion-channel mislocalization are proposed to promote
      seizures. Potassium-channel mislocalization is demonstrated in models, not in these human central
      nervous systems.
    evidence:
    - reference: PMID:29882456
      reference_title: Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations,
        Hypomyelination, and Arthrogryposis.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: The absence of septate junctions resulting from CNTNAP1 mutations may also explain the seizure
        phenotype seen in the longest living of our patients, as well as other patients harboring a similar
        phenotype resulting from CNTNAP1 mutations.
      explanation: Explicit source hypothesis linking paranodal failure to seizures; central human channel
        localization remains untested.
      directness: INDIRECT
  - target: Severe Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The demonstrated congenital peripheral neuropathy provides a supported indirect contribution
      to severe hypotonia in CNTNAP1 disease; concurrent central involvement prevents exclusive peripheral
      attribution.
    evidence:
    - reference: PMID:29882456
      reference_title: Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations,
        Hypomyelination, and Arthrogryposis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: These 2 families illustrate severe progressive peripheral demyelinating neuropathy due to the
        absence of septate paranodal junctions and central hypomyelination with neurodegeneration in
        CNTNAP1-associated arthrogryposis multiplex congenita.
      explanation: The authors establish a causal paranodal-to-neuropathy route in CNTNAP1 disease. This
        supports the peripheral motor interpretation without assigning a purely glial or axonal origin to
        every manifestation.
      directness: INDIRECT
- name: Loss of Slow Myosin-binding Protein C Function
  biological_scale: MOLECULAR
  description: Recessive MYBPC1 truncation abrogates functional protein domains. A muscle contractile route is
    supported by the protein role and human causal genotype, but the precise fetal muscle structural defect is
    not demonstrated.
  subtypes:
  - LCCS4
  evidence:
  - reference: PMID:22610851
    reference_title: Autosomal recessive lethal congenital contractural syndrome type 4 (LCCS4) caused by a
      mutation in MYBPC1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We now show that a recessive mutation abrogating all functional domains in the same gene leads to
      LCCS."
    explanation: Establishes recessive MYBPC1 loss of function as the LCCS4 mechanism.
  genes:
  - preferred_term: MYBPC1
    term:
      id: hgnc:7549
      label: MYBPC1
  downstream:
  - target: Absent Fetal Movement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Loss of the muscle myosin-binding protein is proposed to impair contractile function and
      prenatal movement. This does not import ZBTB42 fish myofibrillar pathology into MYBPC1 patients.
    evidence:
    - reference: PMID:22610851
      reference_title: Autosomal recessive lethal congenital contractural syndrome type 4 (LCCS4) caused by a
        mutation in MYBPC1.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We now show that a recessive mutation abrogating all functional domains in the same gene leads
        to LCCS.
      explanation: The causal loss-of-function allele anchors an indirect muscle-protein-to-akinesia route;
        intermediate human functional steps remain unresolved.
      directness: INDIRECT
- name: Combined Neuronal and Muscle Dystonin Deficiency
  biological_scale: MOLECULAR
  description: Biallelic DST variants affecting both DST-a and DST-b cause a lethal arthrogryposis
    presentation. The relative neuronal and muscle contributions are unresolved; functional and biopsy
    findings from DST-b-only myopathy cannot be assigned wholesale to this combined-isoform disorder.
  subtypes:
  - LCCS12
  evidence:
  - reference: PMID:40497796
    reference_title: "Deciphering DST-associated disorders: biallelic variants affecting DST-b cause a congenital
      myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genotype-phenotype correlation in these patients and previously published cases with respective variants
      resulted in the definition of a DST-associated lethal congenital contracture syndrome."
    explanation: >-
      Establishes DST as the gene defining a lethal congenital contracture
      syndrome.
  - reference: PMID:40497796
    reference_title: "Deciphering DST-associated disorders: biallelic variants affecting DST-b cause a congenital
      myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants that also impact DST-a besides DST-b result in a more severe, lethal congenital contracture
      syndrome."
    explanation: >-
      Gives the isoform-dependent severity relationship that separates the lethal
      phenotype from the congenital myopathy.

  genes:
  - preferred_term: DST
    term:
      id: hgnc:1090
      label: DST
  downstream:
  - target: Multiple Congenital Joint Contractures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Combined neuronal and muscle isoform disruption is causally associated with the severe
      congenital-contracture syndrome; the responsible tissue sequence remains unresolved.
    evidence:
    - reference: PMID:40497796
      reference_title: 'Deciphering DST-associated disorders: biallelic variants affecting DST-b cause a congenital
        myopathy.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Variants that also impact DST-a besides DST-b result in a more severe, lethal congenital
        contracture syndrome.
      explanation: The source explicitly attributes the lethal contracture phenotype to combined isoform
        involvement, supporting an indirect etiological link without importing the DST-b-only myopathy
        mechanism.
      directness: INDIRECT
- name: Focal Bulbar Paresis
  biological_scale: ORGANISM
  description: Right vocal-cord and right soft-palate paresis aggravated swallowing insufficiency in a GLDN
    survivor. The report establishes this functional contribution without identifying the upstream cranial
    motor lesion.
  subtypes:
  - LCCS11
  evidence:
  - reference: PMID:28726266
    reference_title: "Survival among children with \"Lethal\" congenital contracture syndrome 11 caused by novel
      mutations in the gliomedin gene (GLDN)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Insufficient swallowing aggravated by paresis of both the right vocal cord and right side of the soft
      palate prompted gastrostomy tube placement at 4 months of age."
    explanation: >-
      Documents insufficient swallowing and the gastrostomy it required in a
      surviving LCCS11 child.
  downstream:
  - target: Dysphagia
    causal_link_type: DIRECT
    description: Focal vocal-cord and soft-palate weakness aggravated swallowing insufficiency in the reported
      GLDN child.
    evidence:
    - reference: PMID:28726266
      reference_title: "Survival among children with \"Lethal\" congenital contracture syndrome 11 caused by novel
        mutations in the gliomedin gene (GLDN)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Insufficient swallowing aggravated by paresis of both the right vocal cord and right side of the
        soft palate prompted gastrostomy tube placement at 4 months of age."
      explanation: >-
        Documents insufficient swallowing and the gastrostomy it required in a
        surviving LCCS11 child.
phenotypes:
- category: Prenatal
  name: Absent Fetal Movement
  description: >-
    Reduced or absent prenatal movement across the LCCS spectrum. Total immobility at every
    ultrasound examination from 12 weeks or later characterized all 39 clinically defined Finnish
    LCCS cases; the frequency band refers to that series, not all genotypes or all gestational
    examinations. Reduced movement is a shared functional consequence of distinct motor-unit
    disorders and can also accompany NEK9 skeletal dysplasia. It can cause a fetal deformation
    sequence without explaining every primary skeletal, cerebral, vascular or visceral
    manifestation.
  phenotype_term:
    preferred_term: Absent fetal movement
    term:
      id: HP:0001558
      label: Decreased fetal movement
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:16892327
    reference_title: Lethal congenital contracture syndrome (LCCS) and other lethal arthrogryposes in
      Finland--an epidemiological study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirty-nine cases had lethal congenital contracture syndrome (LCCS) clinically characterized by total
      immobility of the fetus at all ultrasound examinations (12 weeks or later)"
    explanation: >-
      Establishes total fetal immobility from 12 weeks as a defining clinical
      feature of LCCS in a population-based series.
  notes: >-
    This clinical state was previously annotated at organism scale in a duplicate pathophysiology
    entry.
  sequelae:
  - target: Multiple Congenital Joint Contractures
    causal_link_type: DIRECT
    description: Reduced joint movement disrupts normal joint development and permits congenital contractures.
    evidence:
    - reference: PMID:35806855
      reference_title: 'Lethal Congenital Contracture Syndrome 11: A Case Report and Literature Review.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Finally, the lack of normal fetal movement also results in a short umbilical cord and multiple
        joint contractures.
      explanation: The source states the fetal movement-to-contracture deformation mechanism, rather than
        merely listing co-occurring findings.
  - target: Pulmonary Hypoplasia
    causal_link_type: DIRECT
    description: Reduced fetal diaphragm and intercostal movement impairs lung development.
    evidence:
    - reference: PMID:35806855
      reference_title: 'Lethal Congenital Contracture Syndrome 11: A Case Report and Literature Review.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: The lack of movement of the diaphragm and intercostal muscles leads to pulmonary hypoplasia.
      explanation: The source identifies reduced fetal respiratory-muscle movement as a cause of lung
        underdevelopment.
  - target: Impaired Swallowing
    causal_link_type: DIRECT
    description: Reduced fetal activity compromises normal deglutition.
    evidence:
    - reference: PMID:35806855
      reference_title: 'Lethal Congenital Contracture Syndrome 11: A Case Report and Literature Review.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: The common feature of this sequence is decreased fetal activity, which leads to a failure of
        normal deglutition, resulting in polyhydramnios.
      explanation: The source explicitly gives the fetal activity-to-deglutition-to-amniotic-fluid sequence.
  - target: Talipes Equinovarus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced movement can produce the documented fixed distal or limb posture as part of the
      arthrogryposis deformation sequence. It does not determine the precise joint distribution in an
      individual fetus.
    evidence:
    - reference: PMID:35806855
      reference_title: 'Lethal Congenital Contracture Syndrome 11: A Case Report and Literature Review.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Finally, the lack of normal fetal movement also results in a short umbilical cord and multiple
        joint contractures.
      explanation: The source states the fetal movement-to-contracture deformation mechanism, rather than
        merely listing co-occurring findings.
  - target: Overlapping Fingers
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced movement can produce the documented fixed distal or limb posture as part of the
      arthrogryposis deformation sequence. It does not determine the precise joint distribution in an
      individual fetus.
    evidence:
    - reference: PMID:35806855
      reference_title: 'Lethal Congenital Contracture Syndrome 11: A Case Report and Literature Review.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Finally, the lack of normal fetal movement also results in a short umbilical cord and multiple
        joint contractures.
      explanation: The source states the fetal movement-to-contracture deformation mechanism, rather than
        merely listing co-occurring findings.
  - target: Hand Clenching
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced movement can produce the documented fixed distal or limb posture as part of the
      arthrogryposis deformation sequence. It does not determine the precise joint distribution in an
      individual fetus.
    evidence:
    - reference: PMID:35806855
      reference_title: 'Lethal Congenital Contracture Syndrome 11: A Case Report and Literature Review.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Finally, the lack of normal fetal movement also results in a short umbilical cord and multiple
        joint contractures.
      explanation: The source states the fetal movement-to-contracture deformation mechanism, rather than
        merely listing co-occurring findings.
  - target: Knee Extension Contracture
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced movement can produce the documented fixed distal or limb posture as part of the
      arthrogryposis deformation sequence. It does not determine the precise joint distribution in an
      individual fetus.
    evidence:
    - reference: PMID:35806855
      reference_title: 'Lethal Congenital Contracture Syndrome 11: A Case Report and Literature Review.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Finally, the lack of normal fetal movement also results in a short umbilical cord and multiple
        joint contractures.
      explanation: The source states the fetal movement-to-contracture deformation mechanism, rather than
        merely listing co-occurring findings.
  - target: Micrognathia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Experimental fetal immobilization produces micrognathia, supporting a qualified deformation
      contribution to the human LCCS finding. The precise human jaw-growth intermediate and subtype
      contribution are not measured.
    evidence:
    - reference: PMID:6685864
      reference_title: 'Fetal akinesia deformation sequence: an animal model.'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: 'Rat fetuses were paralyzed by daily transuterine injections of curare from day 18 of gestation until
        term (day 21). The following anomalies were noted at the time of delivery: multiple joint contractures,
        pulmonary hypoplasia, micrognathia, fetal growth retardation, short umbilical cords, and polyhydramnios.
        Neither sham-operated nor untouched littermate control fetuses had any of these anomalies.'
      explanation: Curare-exposed rat fetuses developed these abnormalities while sham-operated and untouched
        littermates did not. This supports an immobilization mechanism, with species and drug-exposure limits;
        it does not establish a numbered LCCS genotype.
      directness: INDIRECT
  - target: Intrauterine Growth Restriction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Experimental fetal immobilization produces growth retardation, supporting a possible
      fetal-activity contribution. In the cited GLDN fetus, abnormal umbilical-artery flow leaves additional
      placental or vascular effects unresolved.
    evidence:
    - reference: PMID:6685864
      reference_title: 'Fetal akinesia deformation sequence: an animal model.'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: 'Rat fetuses were paralyzed by daily transuterine injections of curare from day 18 of gestation until
        term (day 21). The following anomalies were noted at the time of delivery: multiple joint contractures,
        pulmonary hypoplasia, micrognathia, fetal growth retardation, short umbilical cords, and polyhydramnios.
        Neither sham-operated nor untouched littermate control fetuses had any of these anomalies.'
      explanation: Curare-exposed rat fetuses developed these abnormalities while sham-operated and untouched
        littermates did not. This supports an immobilization mechanism, with species and drug-exposure limits;
        it does not establish a numbered LCCS genotype.
      directness: INDIRECT
  - target: Pterygia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced prenatal movement can produce joint webbing within the arthrogryposis deformation
      sequence. The exact timing and why webbing occurs in some subtypes but not others remain uncertain.
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457946/
      reference_title: Mutations of GPR126 Are Responsible for Severe Arthrogryposis Multiplex Congenita - PMC
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Non-syndromic or isolated AMC arises as a result of reduced or absent fetal movements, which
        can result in a range of defects, including pterygia, pulmonary hypoplasia, and craniofacial defects.
      explanation: The ADGRG6 paper explicitly identifies pterygia as a possible consequence of reduced
        movement; this is its mechanistic background, distinct from its patient observations.
      directness: INDIRECT
  - target: Short Umbilical Cord
    causal_link_type: DIRECT
    description: Reduced fetal movement can limit normal cord elongation, producing a short cord.
    evidence:
    - reference: PMID:35806855
      reference_title: 'Lethal Congenital Contracture Syndrome 11: A Case Report and Literature Review.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Finally, the lack of normal fetal movement also results in a short umbilical cord and multiple
        joint contractures.
      explanation: The source states the fetal movement-to-contracture deformation mechanism, rather than
        merely listing co-occurring findings.
- category: Musculoskeletal
  name: Multiple Congenital Joint Contractures
  description: >-
    Congenital contractures involving multiple upper- and lower-limb joints. The frequency band reflects the defining
    finding in the 39 Finnish LCCS cases. Joint distribution varies between families and subtypes; contractures
    can improve with therapy in surviving GLDN-associated disease.
  phenotype_term:
    preferred_term: Multiple joint contractures
    term:
      id: HP:0002828
      label: Multiple joint contractures
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:16892327
    reference_title: Lethal congenital contracture syndrome (LCCS) and other lethal arthrogryposes in
      Finland--an epidemiological study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "multiple joint contractures in both upper and lower limbs, hydrops, and fetal death before the 32nd
      week of pregnancy"
    explanation: Records the contracture distribution in the LCCS cases.
- category: Respiratory
  name: Pulmonary Hypoplasia
  description: >-
    Underdeveloped lungs documented in several subtypes. A GLDN literature review found pulmonary
    hypoplasia in 12 of 16 cases with reported respiratory findings among 28 total cases; this
    selected reporting denominator cannot estimate prevalence across all GLDN cases or the LCCS
    umbrella. Deficient fetal respiratory-muscle movement can impair lung development; thoracic
    dysplasia is an additional potential contributor in NEK9 disease. Lung underdevelopment can
    cause respiratory insufficiency but does not account for all respiratory impairment in
    survivors.
  phenotype_term:
    preferred_term: Pulmonary hypoplasia
    term:
      id: HP:0002089
      label: Pulmonary hypoplasia
    located_in:
      preferred_term: lung
      term:
        id: UBERON:0002048
        label: lung
  evidence:
  - reference: PMID:35806855
    reference_title: "Lethal Congenital Contracture Syndrome 11: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To our knowledge, among the herein 28 reviewed cases, 16 reported respiratory findings, pulmonary
      hypoplasia being the most frequent (75%, 12/16), followed by pulmonary insufficiency or need of respiratory
      support."
    explanation: >-
      The 75% proportion is 12/16 respiratory-described cases, not 12/28 or an umbrella prevalence estimate.
  notes: >-
    This clinical state was previously annotated at organism scale in a duplicate pathophysiology
    entry. The reduced-development annotation is lung development (GO:0030324), modifier DECREASED;
    this process annotation is retained here because phenotypes do not have a biological_processes
    slot.
  sequelae:
  - target: Neonatal Respiratory Failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: A GLDN survivor had persistent respiratory insufficiency associated with hypoplastic lungs
      and diaphragm paralysis. Both factors may contribute, and their relative effects were not quantified.
    evidence:
    - reference: PMID:28726266
      reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by
        novel mutations in the gliomedin gene (GLDN).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Due to persistent respiratory insufficiency associated with pulmonary hypoplasia and diaphragm
        paralysis, he underwent tracheostomy at 3 months of age.
      explanation: Documents diaphragm paralysis and its respiratory context in the Family 2 child.
- category: Respiratory
  name: Neonatal Respiratory Failure
  description: >-
    Respiratory failure at or soon after birth is documented in multiple LCCS subtypes. The original
    PIP5K1C kindred had five liveborn affected infants, all dying of respiratory insufficiency
    within minutes to hours; this is not an umbrella mortality estimate. GLDN cases demonstrate
    variable contributions from pulmonary hypoplasia, diaphragm paralysis and airway abnormalities,
    with central apnea separately documented in one child. Absent respiratory drive is not
    established across all subtypes, and some survivors later wean from ventilation.
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: PMID:38491417
    reference_title: Novel PIP5K1C variant identified in a Chinese pedigree with lethal congenital
      contractural syndrome 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Then, she underwent vaginal delivery prematurely at 26 weeks, and the baby passed away after birth
      due to respiratory failure."
    explanation: Documents neonatal death from respiratory failure in an LCCS3 case.
  - reference: PMID:17701898
    reference_title: Lethal contractural syndrome type 3 (LCCS3) is caused by a mutation in PIP5K1C, which
      encodes PIPKI gamma of the phophatidylinsitol pathway.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The other five subjects were born alive (two at 29 wk gestation and three at term) and died
      of respiratory insufficiency minutes to hours after birth.
    explanation: Five of the nine affected pregnancies in the original PIP5K1C kindred were live births;
      all five died rapidly from respiratory insufficiency. The four terminated pregnancies are not included
      in this liveborn denominator.
  - reference: PMID:28726266
    reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by
      novel mutations in the gliomedin gene (GLDN).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He required extensive resuscitation at birth including intubation, ventilation, chest compressions,
      and epinephrine administration, developed progressive respiratory failure, pneumothoraces, and pulmonary
      hemorrhage, and died at 40 hours of age
    explanation: A worked LCCS11 case in which progressive neonatal respiratory failure was the proximate
      cause of death.
  notes: >-
    This clinical state was previously annotated at organism scale in a duplicate pathophysiology
    entry.
- category: Prenatal
  name: Polyhydramnios
  description: >-
    Excess amniotic fluid occurs in several subtypes and may follow impaired fetal deglutition. A reported GLDN-associated
    fetus had polyhydramnios with akinesia and hydrops; the report included one GLDN variant of uncertain significance
    and provides no umbrella frequency.
  phenotype_term:
    preferred_term: Polyhydramnios
    term:
      id: HP:0001561
      label: Polyhydramnios
  evidence:
  - reference: PMID:35806855
    reference_title: "Lethal Congenital Contracture Syndrome 11: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The fetus exhibited hydrops, short long bones, fixed limb joints, absent fetal movements, and polyhydramnios."
    explanation: Records polyhydramnios in an LCCS11 fetus.
- category: Prenatal
  name: Hydrops Fetalis
  subtype: LCCS1
  description: >-
    Hydrops was part of the clinical definition of the 39 Finnish LCCS cases, the scope of this frequency band.
    It also occurs in some GLDN-associated fetuses, but was absent in the original ERBB3 and PIP5K1C kindreds; it
    is not universal across LCCS.
  phenotype_term:
    preferred_term: Hydrops fetalis
    term:
      id: HP:0001789
      label: Hydrops fetalis
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:16892327
    reference_title: Lethal congenital contracture syndrome (LCCS) and other lethal arthrogryposes in
      Finland--an epidemiological study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "multiple joint contractures in both upper and lower limbs, hydrops, and fetal death before the 32nd
      week of pregnancy"
    explanation: >-
      Lists hydrops among the defining features of the Finnish LCCS (LCCS1) cases.
  - reference: PMID:18204449
    reference_title: Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "accompanied by hydrops, micrognatia, pulmonary hypoplasia, pterygia and multiple joint contractures"
    explanation: Confirms hydrops as a characteristic LCCS1 feature.
- category: Craniofacial
  name: Micrognathia
  description: >-
    Small mandible described in classic GLE1-related LCCS1 and in ADGRG6-associated fetuses. This anatomical size
    finding is distinct from the retruded jaw position described as retrognathia in a GLDN-associated fetus.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:18204449
    reference_title: Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "accompanied by hydrops, micrognatia, pulmonary hypoplasia, pterygia and multiple joint contractures"
    explanation: >-
      Lists micrognathia among the characteristic LCCS1 features. The source
      spells it "micrognatia"; the quote preserves the source spelling.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457946/
    reference_title: Mutations of GPR126 Are Responsible for Severe Arthrogryposis Multiplex Congenita - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At 25 weeks of pregnancy, MRI revealed micrognathia and fixed extension of the arms and flexion
      of the elbows, wrists, and hands
    explanation: Full text of the same study indexed as PMID:26004201 documents micrognathia in the ADGRG6
      Family 2 fetus; this is not independent replication.
- category: Growth
  name: Intrauterine Growth Restriction
  description: >-
    Growth restriction is reported in some LCCS pregnancies. The cited GLDN-associated fetus had estimated weight
    at the fourth percentile and absent umbilical-artery end-diastolic flow; placental or vascular contributions
    cannot be separated from the fetal disorder. Other GLDN cases had normal birth-weight percentiles.
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: PMID:35806855
    reference_title: "Lethal Congenital Contracture Syndrome 11: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "postmortem studies confirmed the prenatal findings: distal arthrogryposis, fetal growth restriction,
      pulmonary hypoplasia, and retrognathia"
    explanation: Postmortem confirmation of fetal growth restriction in LCCS11.
- category: Musculoskeletal
  name: Skeletal Muscle Atrophy
  description: >-
    Loss of muscle bulk is reported in PIP5K1C-associated neonates and GLDN survivors, with different possible neurogenic
    or muscular contributions. This is distinguished from the severely hypoplastic musculature documented at GLE1
    fetal autopsy.
  phenotype_term:
    preferred_term: Skeletal muscle atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
  evidence:
  - reference: PMID:17701898
    reference_title: Lethal contractural syndrome type 3 (LCCS3) is caused by a mutation in PIP5K1C, which
      encodes PIPKI gamma of the phophatidylinsitol pathway.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: severe muscle wasting and atrophy, mainly in the legs
    explanation: The original PIP5K1C neonates had muscle wasting; the families declined autopsy, so an
      anterior-horn cause is not demonstrated.
  - reference: PMID:28726266
    reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by novel
      mutations in the gliomedin gene (GLDN).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: His neurologic examination was notable for myopathic facies, very weak to absent deep tendon
      reflexes, and symmetric atrophy and weakness of his proximal muscles.
    explanation: The surviving GLDN-related child had proximal atrophy and weakness on examination, rather
      than a universal congenital muscle-hypoplasia phenotype.
- category: Musculoskeletal
  name: Pterygia
  subtype: LCCS1
  description: >-
    Webbing across joints is reported in classic GLE1 disease and in an ADGRG6-associated fetus. It was explicitly
    absent in the original ERBB3 and PIP5K1C kindreds.
  phenotype_term:
    preferred_term: Pterygium
    term:
      id: HP:0001059
      label: Pterygium
  evidence:
  - reference: PMID:18204449
    reference_title: Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lethal congenital contracture syndrome 1 (LCCS1, MIM 253310) is an autosomal recessive condition characterized
      by total immobility of the fetus, detectable at the 13th week of pregnancy, accompanied by hydrops, micrognatia,
      pulmonary hypoplasia, pterygia and multiple joint contractures"
    explanation: >-
      Lists pterygia among the characteristic features of LCCS1 specifically,
      which is the subtype this phenotype is tagged to.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457946/
    reference_title: Mutations of GPR126 Are Responsible for Severe Arthrogryposis Multiplex Congenita - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Fetopathological examination of the aborted fetus confirmed that the joint retractions were
      associated with pterygium of the right elbow and axilla
    explanation: Full text of PMID:26004201 documents the anatomical webbing in Family 1.
- category: Neurologic
  name: Reduced Motor Nerve Conduction Velocity
  subtype: LCCS7
  description: >-
    Markedly slowed motor conduction was reported in the original CNTNAP1 families, including velocities below 10
    m/s. A later CNTNAP1 child had a distal median velocity of 11.1 m/s at three weeks. GLDN-associated conduction
    abnormalities can change with age; this is an electrophysiological readout, not a universal threshold distinguishing
    all subtypes.
  phenotype_term:
    preferred_term: Decreased motor nerve conduction velocity
    term:
      id: HP:0003431
      label: Decreased motor nerve conduction velocity
  evidence:
  - reference: PMID:24319099
    reference_title: Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex
      congenita with axoglial defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients showed a marked reduction in motor nerve conduction velocity (<10 m/s)"
    explanation: >-
      Reports the measured conduction velocities in CNTNAP1-mutated patients.
  - reference: PMID:28726266
    reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by novel
      mutations in the gliomedin gene (GLDN).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Nerve conduction velocity studies performed at 1 week of age demonstrated axonal motor and
      sensory neuropathy but were normal when repeated at 7 months of age.
    explanation: The same GLDN child had abnormal neonatal studies and normal repeat studies at seven months;
      persistent severe slowing is not obligatory.
  reports_on:
  - target: Impaired Motor Nerve Conduction
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Measured velocity reports peripheral conduction impairment. The original CNTNAP1 values
      below 10 m/s are cohort-specific and do not establish a diagnostic cutoff for the entire LCCS group.
- category: Genitourinary
  name: Neurogenic Bladder
  description: >-
    Neurogenic bladder with marked distension distinguishes the original ERBB3 kindred from the PIP5K1C kindred.
    Neurogenic bladder is also reported in both long-surviving CNTNAP1-associated children in a later series, so
    it is not specific to LCCS2.
  phenotype_term:
    preferred_term: Neurogenic bladder
    term:
      id: HP:0000011
      label: Neurogenic bladder
  evidence:
  - reference: PMID:17701904
    reference_title: "Lethal congenital contractural syndrome type 2 (LCCS2) is caused by a mutation in ERBB3 (Her3),
      a modulator of the phosphatidylinositol-3-kinase/Akt pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "is characterized by multiple joint contractures, anterior horn atrophy in the spinal cord, and a unique
      feature of a markedly distended urinary bladder"
    explanation: >-
      The positive LCCS2 statement, naming the distended bladder as the unique
      feature of that subtype.
  - reference: PMID:17701898
    reference_title: "Lethal contractural syndrome type 3 (LCCS3) is caused by a mutation in PIP5K1C, which encodes
      PIPKI gamma of the phophatidylinsitol pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We now describe a third LCCS phenotype (LCCS3)--similar to LCCS2 yet without neurogenic bladder."
    explanation: >-
      The complementary negative, confirming the finding discriminates LCCS2 from
      LCCS3.
  - reference: PMID:29882456
    reference_title: Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations,
      Hypomyelination, and Arthrogryposis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Individual LD_0333.0 was a girl with severe hypotonia and respiratory insufficiency that required
      a tracheostomy after birth, hypomyelinating neuropathy, bilateral hearing loss, bilateral optic nerve
      atrophy, lethargy, and neurogenic bladder.
    explanation: Documents neurogenic bladder in a CNTNAP1-associated child, extending the subtype scope
      without identifying the responsible autonomic pathway.
- category: Neurologic
  name: Intracranial Hemorrhage
  subtype: LCCS5
  description: >-
    Brain hemorrhage was present in two of the three homozygous DNM2 p.Phe379Val siblings (AFB3 and AFB4); AFB2
    had a normal brain MRI. The frequency band applies only to this three-sibling series.
  phenotype_term:
    preferred_term: Intracranial hemorrhage
    term:
      id: HP:0002170
      label: Intracranial hemorrhage
  frequency: FREQUENT
  evidence:
  - reference: PMID:23092955
    reference_title: Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in three consanguineous patients with a lethal congenital syndrome associating akinesia, joint contractures,
      hypotonia, skeletal abnormalities, and brain and retinal hemorrhages"
    explanation: >-
      Reports the intracranial haemorrhage that helps define the DNM2 subtype.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658203/
    reference_title: Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, they showed retinal hemorrhages, whereas MRI analysis revealed symmetric subdural
      hematomas for AFB3 and blood in the subarachnoid cavity for AFB4
    explanation: Full text of the same study indexed as PMID:23092955 distinguishes retinal hemorrhage in the
      three siblings from intracranial bleeding described in AFB3 and AFB4; this is not independent
      replication.
- category: Ophthalmologic
  name: Retinal Hemorrhage
  subtype: LCCS5
  description: >-
    Retinal hemorrhage was documented in all three homozygous DNM2 p.Phe379Val siblings, including the sibling without
    intracranial hemorrhage. The frequency band applies to this family only, not all DNM2 alleles or LCCS.
  phenotype_term:
    preferred_term: Retinal hemorrhage
    term:
      id: HP:0000573
      label: Retinal hemorrhage
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:23092955
    reference_title: Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in three consanguineous patients with a lethal congenital syndrome associating akinesia, joint contractures,
      hypotonia, skeletal abnormalities, and brain and retinal hemorrhages"
    explanation: Reports retinal haemorrhage in the DNM2-mutated patients.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658203/
    reference_title: Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In addition, they showed retinal hemorrhages, whereas MRI analysis revealed symmetric subdural
      hematomas for AFB3 and blood in the subarachnoid cavity for AFB4
    explanation: Full text of the same study indexed as PMID:23092955 distinguishes retinal hemorrhage in the
      three siblings from intracranial bleeding described in AFB3 and AFB4; this is not independent
      replication.
- category: Musculoskeletal
  name: Talipes Equinovarus
  description: >-
    Equinovarus clubfoot is documented bilaterally in the PIP5K1C fetal pedigree. The GLDN fetus described as left
    pes equinus does not independently support a varus component and is not used for this binding.
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  evidence:
  - reference: PMID:38491417
    reference_title: Novel PIP5K1C variant identified in a Chinese pedigree with lethal congenital
      contractural syndrome 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We described the features of multiple joint contractures in our fetuses, including bilateral talipes
      equinovarus, stiffness in the limbs, extended knees, persistently closed hands and overlapping fingers"
    explanation: >-
      Documents bilateral talipes equinovarus as part of the contracture pattern
      in LCCS3 fetuses.
- category: Neurologic
  name: Areflexia
  description: >-
    Absent tendon reflexes are documented in GLDN-associated disease and in the DNM2 sibling series. Weak but present
    reflexes are broader than areflexia; the finding alone cannot distinguish a peripheral nerve lesion from severe
    muscle disease.
  phenotype_term:
    preferred_term: Areflexia
    term:
      id: HP:0001284
      label: Areflexia
  evidence:
  - reference: PMID:28726266
    reference_title: "Survival among children with \"Lethal\" congenital contracture syndrome 11 caused by novel
      mutations in the gliomedin gene (GLDN)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His neurologic examination was notable for myopathic facies, very weak to absent deep tendon reflexes,
      and symmetric atrophy and weakness of his proximal muscles."
    explanation: >-
      Documents absent deep tendon reflexes on examination in a GLDN-mutated
      child.
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658203/
    reference_title: Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The three patients displayed no reflexes and suffered from severe hypotonia and respiratory
      insufficiency from birth, while they exhibited contractures of several joints and skeletal abnormalities
      with thin ribs and bones
    explanation: The same DNM2 study explicitly records absent reflexes in all three affected siblings; this
      observation is distinct from the very weak-to-absent reflex description in GLDN disease.
- category: Gastrointestinal
  name: Dysphagia
  description: >-
    Postnatal swallowing insufficiency in a GLDN survivor was aggravated by right vocal-cord and right soft-palate
    paresis and required gastrostomy at four months. Most feeding was oral by 28 months. This does not establish
    that all postnatal dysphagia is persistence of impaired fetal swallowing.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:28726266
    reference_title: "Survival among children with \"Lethal\" congenital contracture syndrome 11 caused by novel
      mutations in the gliomedin gene (GLDN)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Insufficient swallowing aggravated by paresis of both the right vocal cord and right side of the soft
      palate prompted gastrostomy tube placement at 4 months of age."
    explanation: >-
      Documents insufficient swallowing and the gastrostomy it required in a
      surviving LCCS11 child.
- category: Musculoskeletal
  name: Overlapping Fingers
  subtype: LCCS3
  description: >-
    Overlapping flexed fingers were reported in the PIP5K1C fetal pedigree. Hand clenching and fixed knee posture
    in the same report are separate findings rather than synonyms for finger overlap.
  phenotype_term:
    preferred_term: Overlapping fingers
    term:
      id: HP:0010557
      label: Overlapping fingers
  evidence:
  - reference: PMID:38491417
    reference_title: Novel PIP5K1C variant identified in a Chinese pedigree with lethal congenital
      contractural syndrome 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including bilateral talipes equinovarus, stiffness in the limbs, extended knees, persistently closed
      hands and overlapping fingers"
    explanation: >-
      Documents the closed-hand and overlapping-finger posture in LCCS3 fetuses.
- category: Respiratory
  name: Vocal Cord Paresis
  subtype: LCCS11
  description: >-
    Right vocal-cord paresis in one GLDN survivor aggravated swallowing insufficiency together with right soft-palate
    paresis. The report does not localize the underlying motor lesion.
  phenotype_term:
    preferred_term: Vocal cord paresis
    term:
      id: HP:0001604
      label: Vocal cord paresis
  evidence:
  - reference: PMID:28726266
    reference_title: "Survival among children with \"Lethal\" congenital contracture syndrome 11 caused by novel
      mutations in the gliomedin gene (GLDN)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Insufficient swallowing aggravated by paresis of both the right vocal cord and right side of the soft
      palate prompted gastrostomy tube placement at 4 months of age."
    explanation: >-
      Documents vocal cord paresis and its contribution to the swallowing
      failure.
- category: Neurologic
  name: Severe Hypotonia
  description: >-
    Generalized severe hypotonia was recorded in all three homozygous DNM2 p.Phe379Val siblings. The molecular-to-tone
    pathway may involve muscle and peripheral nerve dysfunction and is not reconstructed by the human clinical observations
    alone.
  phenotype_term:
    preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  evidence:
  - reference: PMID:23092955
    reference_title: Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a lethal congenital syndrome associating akinesia, joint contractures, hypotonia, skeletal abnormalities,
      and brain and retinal hemorrhages"
    explanation: Lists hypotonia among the presenting features.

  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658203/
    reference_title: Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The three patients displayed no reflexes and suffered from severe hypotonia and respiratory
      insufficiency from birth, while they exhibited contractures of several joints and skeletal abnormalities
      with thin ribs and bones
    explanation: The full clinical narrative confirms severe hypotonia in all three DNM2 siblings; Table 1
      specifies generalized severe hypotonia. This is the same study as PMID:23092955.
- name: Skeletal Muscle Hypoplasia
  category: Musculoskeletal
  description: Severely hypoplastic, nearly absent skeletal muscles were found at GLE1-associated fetal
    autopsy; this is a developmental reduction in muscle tissue rather than evidence of acquired atrophy.
  phenotype_term:
    preferred_term: Hypoplasia of the musculature
    term:
      id: HP:0009004
      label: Hypoplasia of the musculature
  evidence:
  - reference: PMID:18204449
    reference_title: Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Neuropathological analysis shows lack of anterior horn motoneurons, severe atrophy of the ventral
      spinal cord and hypoplastic, nearly absent skeletal muscles
    explanation: The GLE1 autopsy phenotype specifically supports muscle hypoplasia.
  subtype: LCCS1
- name: Retrognathia
  category: Craniofacial
  description: Retruded jaw position was documented at autopsy in the reported GLDN-associated fetus. The same
    report classified one GLDN allele as a variant of uncertain significance.
  phenotype_term:
    preferred_term: Retrognathia
    term:
      id: HP:0000278
      label: Retrognathia
  evidence:
  - reference: PMID:35806855
    reference_title: 'Lethal Congenital Contracture Syndrome 11: A Case Report and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The pregnancy was terminated and postmortem studies confirmed the prenatal findings: distal arthrogryposis,
      fetal growth restriction, pulmonary hypoplasia, and retrognathia.'
    explanation: The primary case supports jaw retrusion, not mandibular size.
  subtype: LCCS11
- name: Hand Clenching
  category: Musculoskeletal
  description: Persistently closed hands were reported in the PIP5K1C fetal pedigree, distinct from the
    overlapping-finger description in another examined fetus.
  phenotype_term:
    preferred_term: Hand clenching
    term:
      id: HP:0001188
      label: Hand clenching
  evidence:
  - reference: PMID:38491417
    reference_title: Novel PIP5K1C variant identified in a Chinese pedigree with lethal congenital
      contractural syndrome 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We described the features of multiple joint contractures in our fetuses, including bilateral
      talipes equinovarus, stiffness in the limbs, extended knees, persistently closed hands and overlapping
      fingers
    explanation: Supports the persistently closed-hand posture in this fetal pedigree, without making a
      population-frequency claim.
  subtype: LCCS3
- name: Knee Extension Contracture
  category: Musculoskeletal
  description: Fixed extended knees were reported in the PIP5K1C fetal pedigree and the ZBTB42 index case.
    This differs from the flexion contractures described in other families.
  phenotype_term:
    preferred_term: Knee extension contracture
    term:
      id: HP:0034672
      label: Knee extension contracture
  evidence:
  - reference: PMID:38491417
    reference_title: Novel PIP5K1C variant identified in a Chinese pedigree with lethal congenital
      contractural syndrome 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We described the features of multiple joint contractures in our fetuses, including bilateral
      talipes equinovarus, stiffness in the limbs, extended knees, persistently closed hands and overlapping
      fingers
    explanation: The fixed limb-contracture context supports extended-knee contractures rather than an
      isolated positional observation.
  subtype: LCCS3
- name: Diaphragmatic Paralysis
  category: Respiratory
  description: >-
    Diaphragm paralysis accompanied pulmonary hypoplasia and persistent respiratory insufficiency in
    one GLDN survivor. Diaphragm paralysis contributed alongside hypoplastic lungs to the
    respiratory insufficiency; its upstream neural or muscular cause was not localized.
  phenotype_term:
    preferred_term: Diaphragmatic paralysis
    term:
      id: HP:0006597
      label: Diaphragmatic paralysis
  evidence:
  - reference: PMID:28726266
    reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by novel
      mutations in the gliomedin gene (GLDN).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Due to persistent respiratory insufficiency associated with pulmonary hypoplasia and diaphragm
      paralysis, he underwent tracheostomy at 3 months of age.
    explanation: Documents diaphragm paralysis and its respiratory context in the Family 2 child.
  subtype: LCCS11
  notes: >-
    This clinical state was previously annotated at tissue scale in a duplicate pathophysiology
    entry.
  sequelae:
  - target: Neonatal Respiratory Failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Paralysis of the respiratory diaphragm contributed alongside pulmonary hypoplasia to
      persistent respiratory insufficiency.
    evidence:
    - reference: PMID:28726266
      reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by
        novel mutations in the gliomedin gene (GLDN).
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Due to persistent respiratory insufficiency associated with pulmonary hypoplasia and diaphragm
        paralysis, he underwent tracheostomy at 3 months of age.
      explanation: Documents diaphragm paralysis and its respiratory context in the Family 2 child.
- name: Laryngomalacia
  category: Respiratory
  description: Observed by laryngoscopy in the second GLDN-associated infant of Family 1; the clinical series
    does not establish prevalence or the developmental cause.
  phenotype_term:
    preferred_term: Laryngomalacia
    term:
      id: HP:0001601
      label: Laryngomalacia
  evidence:
  - reference: PMID:28726266
    reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by novel
      mutations in the gliomedin gene (GLDN).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Laryngoscopy demonstrated laryngo- and tracheomalacia, floppy epiglottis, and pooling of oral
      secretions.
    explanation: The laryngoscopic findings explicitly establish laryngomalacia in this child.
  subtype: LCCS11
- name: Tracheomalacia
  category: Respiratory
  description: Observed by laryngoscopy in the second GLDN-associated infant of Family 1; the clinical series
    does not establish prevalence or the developmental cause.
  phenotype_term:
    preferred_term: Tracheomalacia
    term:
      id: HP:0002779
      label: Tracheomalacia
  evidence:
  - reference: PMID:28726266
    reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by novel
      mutations in the gliomedin gene (GLDN).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Laryngoscopy demonstrated laryngo- and tracheomalacia, floppy epiglottis, and pooling of oral
      secretions.
    explanation: The laryngoscopic findings explicitly establish tracheomalacia in this child.
  subtype: LCCS11
- name: Hip Dislocation
  category: Musculoskeletal
  description: Bilateral hip dislocation required surgery at age two years in one GLDN survivor.
  phenotype_term:
    preferred_term: Hip dislocation
    term:
      id: HP:0002827
      label: Hip dislocation
  evidence:
  - reference: PMID:28726266
    reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by novel
      mutations in the gliomedin gene (GLDN).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He underwent surgical treatment for bilateral hip luxation and clubfeet (age 2 years) and
      scoliosis with Harrington rod insertion (age 9 years).
    explanation: Hip luxation refers to dislocation; the hip and scoliosis procedures occurred at different
      ages.
  subtype: LCCS11
- name: Muscle Weakness
  category: Musculoskeletal
  description: Proximal weakness with atrophy was documented in a GLDN survivor; another child had reduced
    upper- and lower-limb strength. Severity and motor function varied over time.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:28726266
    reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by novel
      mutations in the gliomedin gene (GLDN).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: His neurologic examination was notable for myopathic facies, very weak to absent deep tendon
      reflexes, and symmetric atrophy and weakness of his proximal muscles.
    explanation: The surviving GLDN-related child had proximal atrophy and weakness on examination, rather
      than a universal congenital muscle-hypoplasia phenotype.
  subtype: LCCS11
- name: Motor Developmental Delay
  category: Neurodevelopmental
  description: GLDN survivors had delayed motor milestones with variable subsequent gains; one child sat at 13
    months and crawled at 24 months.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:28726266
    reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by novel
      mutations in the gliomedin gene (GLDN).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Motor and language development was delayed; he was able to sit independently at age 13 months and
      started to crawl at age 24 months.
    explanation: The exact ages establish motor delay in the Family 3 survivor, without inferring cognitive
      impairment.
  subtype: LCCS11
- name: Central Nervous System Hypomyelination
  category: Neurologic
  description: Serial MRI in two surviving CNTNAP1-associated children showed arrested myelination after
    initially age-appropriate neonatal appearances. This central finding is distinct from their peripheral
    hypomyelinating neuropathy.
  phenotype_term:
    preferred_term: CNS hypomyelination
    term:
      id: HP:0003429
      label: CNS hypomyelination
  evidence:
  - reference: PMID:29882456
    reference_title: Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations,
      Hypomyelination, and Arthrogryposis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Serial brain magnetic resonance images revealed hypomyelination, progressive atrophy, and reduced
      diffusion in the globus pallidus in both patients.
    explanation: Both children had central hypomyelination documented on serial brain imaging.
  subtype: LCCS7
- name: Brain Atrophy
  category: Neurologic
  description: Progressive cerebral and brainstem volume loss, with cerebellar involvement in one child, was
    documented on serial MRI in two CNTNAP1-associated children.
  phenotype_term:
    preferred_term: Brain atrophy
    term:
      id: HP:0012444
      label: Brain atrophy
  evidence:
  - reference: PMID:29882456
    reference_title: Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations,
      Hypomyelination, and Arthrogryposis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Central nervous system myelin involvement is also present in individuals affected by CNTNAP1
      mutations. Serial brain MRI evaluation of our patients demonstrated diffuse hypomyelination, progressive
      brain atrophy ranging from mild to severe, and reduced diffusion in globus pallidus with or without
      concurrent diffusion abnormalities in some white matter tracts of the brainstem and cerebellum.
    explanation: The serial imaging establishes progressive brain atrophy; its cellular substrate is not
      measured directly.
  subtype: LCCS7
- name: Seizures
  category: Neurologic
  description: Seizures treated with topiramate occurred in the eight-year-old CNTNAP1-associated boy. This is
    distinguished from the single febrile seizure in a GLDN survivor.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:29882456
    reference_title: Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations,
      Hypomyelination, and Arthrogryposis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At age 8 years, he is maintained on artificial ventilation, with very limited developmental
      outcomes and no independent motor skills, hypotonia with hyporeflexia, and seizures controlled with
      topiramate.
    explanation: The clinical course directly documents seizures in LD_0158.0.
  subtype: LCCS7
- name: Cerebral Visual Impairment
  category: Ophthalmologic
  description: Cortical vision loss was described in one CNTNAP1-associated child; this is distinct from optic
    nerve atrophy in the other child.
  phenotype_term:
    preferred_term: Cerebral visual impairment
    term:
      id: HP:0100704
      label: Cerebral visual impairment
  evidence:
  - reference: PMID:29882456
    reference_title: Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations,
      Hypomyelination, and Arthrogryposis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Individual LD_0158.0 is an 8 year old male with hypotonia and respiratory failure requiring
      intubation at birth and subsequent tracheotomy-dependency, congenital hypomyelinating neuropathy with
      arthrogryposis multiplex congenita, cleft palate, cortical vision loss, bilateral hearing loss, and
      neurogenic bladder.
    explanation: The clinical description of LD_0158.0 directly documents cerebral visual impairment; it does
      not establish a universal CNTNAP1 finding.
  subtype: LCCS7
- name: Hearing Impairment
  category: Audiologic
  description: Bilateral hearing loss was reported in both CNTNAP1-associated children, without sufficient
    localization to choose a conductive or sensorineural subtype.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:29882456
    reference_title: Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations,
      Hypomyelination, and Arthrogryposis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Individual LD_0158.0 is an 8 year old male with hypotonia and respiratory failure requiring
      intubation at birth and subsequent tracheotomy-dependency, congenital hypomyelinating neuropathy with
      arthrogryposis multiplex congenita, cleft palate, cortical vision loss, bilateral hearing loss, and
      neurogenic bladder.
    explanation: The clinical description of LD_0158.0 directly documents hearing impairment; it does not
      establish a universal CNTNAP1 finding.
  subtype: LCCS7
- name: Cleft Palate
  category: Craniofacial
  description: Cleft palate was reported in the CNTNAP1-associated boy; the report does not establish the
    embryological mechanism.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:29882456
    reference_title: Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations,
      Hypomyelination, and Arthrogryposis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Individual LD_0158.0 is an 8 year old male with hypotonia and respiratory failure requiring
      intubation at birth and subsequent tracheotomy-dependency, congenital hypomyelinating neuropathy with
      arthrogryposis multiplex congenita, cleft palate, cortical vision loss, bilateral hearing loss, and
      neurogenic bladder.
    explanation: The clinical description of LD_0158.0 directly documents cleft palate; it does not establish
      a universal CNTNAP1 finding.
  subtype: LCCS7
- name: Optic Atrophy
  category: Ophthalmologic
  description: Bilateral optic nerve atrophy was reported in the CNTNAP1-associated girl, distinct from
    cortical vision loss in the boy.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:29882456
    reference_title: Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations,
      Hypomyelination, and Arthrogryposis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Individual LD_0333.0 was a girl with severe hypotonia and respiratory insufficiency that required
      a tracheostomy after birth, hypomyelinating neuropathy, bilateral hearing loss, bilateral optic nerve
      atrophy, lethargy, and neurogenic bladder.
    explanation: The clinical description explicitly documents bilateral optic nerve atrophy in LD_0333.0.
  subtype: LCCS7
- name: Short Long Bones
  category: Musculoskeletal
  description: Shortening of all long bones characterized the original NEK9 lethal skeletal-dysplasia
    families; the primary skeletal contribution must not be replaced by an assumed universal neurogenic
    mechanism.
  phenotype_term:
    preferred_term: Short long bone
    term:
      id: HP:0003026
      label: Short long bone
  evidence:
  - reference: PMID:26908619
    reference_title: Recessive NEK9 mutation causes a lethal skeletal dysplasia with evidence of cell cycle
      and ciliary defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report two Irish Traveller families with a previously undescribed lethal skeletal dysplasia
      characterized by fetal akinesia, shortening of all long bones, multiple contractures, rib anomalies,
      thoracic dysplasia, pulmonary hypoplasia and protruding abdomen.
    explanation: The original lethal skeletal-dysplasia families establish the LCCS10 clinical scope; the
      later APUG-like neonates are not used as its denominator.
  subtype: LCCS10
- name: Thin Ribs
  category: Musculoskeletal
  description: Thin ribs were documented in the DNM2 p.Phe379Val sibling series. The illustrated AFB3 ribs had
    normal length and density; thin ribs are not equivalent to the short or dysplastic ribs of other subtypes.
  phenotype_term:
    preferred_term: Thin ribs
    term:
      id: HP:0000883
      label: Thin ribs
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658203/
    reference_title: Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The three patients displayed no reflexes and suffered from severe hypotonia and respiratory
      insufficiency from birth, while they exhibited contractures of several joints and skeletal abnormalities
      with thin ribs and bones
    explanation: The full text of the PMID:23092955 study explicitly records thin ribs, supporting the
      specific radiographic term.
  subtype: LCCS5
- name: Pulmonary Hypertension
  category: Cardiovascular
  description: Reported in DNM2 siblings AFB3 and AFB4. The authors could not determine whether this was
    primary or secondary to respiratory insufficiency; no causal edge or umbrella frequency is asserted.
  phenotype_term:
    preferred_term: Pulmonary arterial hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658203/
    reference_title: Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: AFB3 and AFB4 had pulmonary hypertension and a patent ductus arteriosus; whether these features
      were primary or secondary to respiratory insufficiency could not be determined.
    explanation: The same study indexed as PMID:23092955 documents the finding in two siblings and explicitly
      leaves primary versus secondary attribution unresolved.
  subtype: LCCS5
- name: Patent Ductus Arteriosus
  category: Cardiovascular
  description: Reported in DNM2 siblings AFB3 and AFB4. The authors could not determine whether this was
    primary or secondary to respiratory insufficiency; no causal edge or umbrella frequency is asserted.
  phenotype_term:
    preferred_term: Patent ductus arteriosus
    term:
      id: HP:0001643
      label: Patent ductus arteriosus
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658203/
    reference_title: Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: AFB3 and AFB4 had pulmonary hypertension and a patent ductus arteriosus; whether these features
      were primary or secondary to respiratory insufficiency could not be determined.
    explanation: The same study indexed as PMID:23092955 documents the finding in two siblings and explicitly
      leaves primary versus secondary attribution unresolved.
  subtype: LCCS5
- name: Central Apnea
  category: Respiratory
  description: Polysomnography demonstrated central apnea in a GLDN survivor who also had
    tracheomalacia-related cyanotic events. The central apnea mechanism was not localized and should not be
    equated with dynamic airway collapse.
  phenotype_term:
    preferred_term: Central apnea
    term:
      id: HP:0002871
      label: Central apnea
  evidence:
  - reference: PMID:28726266
    reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by novel
      mutations in the gliomedin gene (GLDN).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: After discharge from the neonatal intensive care unit on oxygen (1/8 liters per minute) at 2
      months of age, she developed recurrent cyanotic events, attributed to dynamic airway collapse related to
      tracheomalacia, and polysomnography demonstrated central apnea.
    explanation: The sentence distinguishes attributed airway-collapse events from polysomnographic central
      apnea.
  subtype: LCCS11
- name: Short Umbilical Cord
  category: Prenatal
  description: Autopsy confirmed a short umbilical cord in the ADGRG6 Family 3 infant. Reduced fetal movement
    is a supported developmental contributor.
  phenotype_term:
    preferred_term: Short umbilical cord
    term:
      id: HP:0001196
      label: Short umbilical cord
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457946/
    reference_title: Mutations of GPR126 Are Responsible for Severe Arthrogryposis Multiplex Congenita - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The autopsy confirmed a short umbilical cord and significant pulmonary hypoplasia.
    explanation: The full text of PMID:26004201 directly documents the cord finding in the Family 3 infant.
  subtype: LCCS9
- name: Scoliosis
  category: Musculoskeletal
  subtype: LCCS11
  description: Scoliosis required Harrington rod insertion at age nine years in the GLDN Family 2 survivor.
    The source does not determine whether the spinal deformity was secondary to neuromuscular impairment or
    reflected another developmental contribution.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:28726266
    reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by novel
      mutations in the gliomedin gene (GLDN).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He underwent surgical treatment for bilateral hip luxation and clubfeet (age 2 years) and
      scoliosis with Harrington rod insertion (age 9 years).
    explanation: The GLDN Family 2 survivor underwent scoliosis surgery with Harrington rod insertion at age
      nine years. The hip procedure in the same sentence occurred at age two.
genetic:
- name: GLE1
  subtype: LCCS1
  gene_term:
    preferred_term: GLE1
    term:
      id: hgnc:4315
      label: GLE1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  notes: >-
    GLE1 participates in mRNA export and translation. The proposed coiled-coil-domain relationship to LCCS versus
    surviving AAHD is a mechanistic hypothesis, not a validated allele-by-allele prognostic rule.
  evidence:
  - reference: PMID:18204449
    reference_title: Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report that the defective gene underlying lethal motoneuron syndrome LCCS1 is the mRNA export
      mediator GLE1."
    explanation: Establishes GLE1 as the LCCS1 gene.
  - reference: PMID:28884921
    reference_title: Survival beyond the perinatal period expands the phenotypes caused by mutations in GLE1.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "We hypothesize that mutations that preserve function of the coiled-coil domain of GLE1 cause LAAHD
      whereas mutations that abolish the function of the coiled-coil domain cause LCCS."
    explanation: >-
      Records the proposed genotype-severity relationship within the GLE1 allelic
      series.
- name: ERBB3
  subtype: LCCS2
  gene_term:
    preferred_term: ERBB3
    term:
      id: hgnc:3431
      label: ERBB3
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  notes: >-
    First reported human phenotype caused by loss of function in an EGF-family
    receptor tyrosine kinase; the same family's gain-of-function alleles cause
    cancer predisposition.
  evidence:
  - reference: PMID:17701904
    reference_title: "Lethal congenital contractural syndrome type 2 (LCCS2) is caused by a mutation in ERBB3 (Her3),
      a modulator of the phosphatidylinositol-3-kinase/Akt pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is the first report of a human phenotype resulting from loss of function of a member of this
      group."
    explanation: >-
      Records the loss-of-function mechanism and its novelty within the receptor
      family.
- name: PIP5K1C
  subtype: LCCS3
  gene_term:
    preferred_term: PIP5K1C
    term:
      id: hgnc:8996
      label: PIP5K1C
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  evidence:
  - reference: PMID:17701898
    reference_title: "Lethal contractural syndrome type 3 (LCCS3) is caused by a mutation in PIP5K1C, which encodes
      PIPKI gamma of the phophatidylinsitol pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We demonstrate that the mutation causes substitution of aspartic acid with asparagine at amino acid
      253 (D253N), abrogating the kinase activity of PIPKI gamma"
    explanation: >-
      Gives the founder allele and its demonstrated effect on kinase activity.
  - reference: PMID:38491417
    reference_title: Novel PIP5K1C variant identified in a Chinese pedigree with lethal congenital
      contractural syndrome 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings expanded the genetic variant spectrum of PIP5K1C and enriched the clinical features
      of LCCS3"
    explanation: >-
      Extends the PIP5K1C allelic spectrum beyond the original Bedouin founder
      variant.
  - reference: PMID:42590986
    reference_title: Lethal Congenital Contracture Syndrome Type 3 in an Isolated Canadian Population.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe three cases sharing a novel variant in PIP5K1C in an isolated Canadian population and
      provide the first detailed postnatal phenotyping of the condition in live born neonates.
    explanation: The 2026 report extends the population and case series; the abstract does not specify the
      exact allele.
- name: MYBPC1
  subtype: LCCS4
  gene_term:
    preferred_term: MYBPC1
    term:
      id: hgnc:7549
      label: MYBPC1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  notes: >-
    The original recessive truncation causes LCCS4, whereas other dominant and recessive MYBPC1 alleles can cause
    nonlethal arthrogryposis. Severity is allele-dependent and should not be inferred solely from recessive inheritance.
  evidence:
  - reference: PMID:22610851
    reference_title: Autosomal recessive lethal congenital contractural syndrome type 4 (LCCS4) caused by a
      mutation in MYBPC1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We now show that a recessive mutation abrogating all functional domains in the same gene leads to
      LCCS."
    explanation: Establishes recessive MYBPC1 loss of function as the LCCS4 mechanism.
  - reference: PMID:22610851
    reference_title: Autosomal recessive lethal congenital contractural syndrome type 4 (LCCS4) caused by a
      mutation in MYBPC1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A dominant missense mutation in MYBPC1 was previously shown to cause mild distal arthrogryposis."
    explanation: >-
      Contrasts the dominant missense and recessive truncating mechanisms in the
      same gene.
  - reference: PMID:26661508
    reference_title: "Expanding the MYBPC1 phenotypic spectrum: a novel homozygous mutation causes arthrogryposis
      multiplex congenita."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous mutations in this gene are associated with distal arthrogryposis types 1b and 2, whereas
      a homozygous nonsense mutation is implicated in one family with lethal congenital contractural syndrome 4."
    explanation: >-
      The later source summarizes the allelic spectrum; the original LCCS4 report, rather than this shorthand family
      count, establishes the lethal presentation.
- name: DNM2
  subtype: LCCS5
  gene_term:
    preferred_term: DNM2
    term:
      id: hgnc:2974
      label: DNM2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  notes: >-
    Heterozygous DNM2 alleles cause dominant Charcot-Marie-Tooth neuropathy and
    centronuclear myopathy; the homozygous p.Phe379Val allele causes this far more
    severe fetal phenotype.
  evidence:
  - reference: PMID:23092955
    reference_title: Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report the first homozygous mutation in the DNM2 protein p.Phe379Val, in three consanguineous
      patients with a lethal congenital syndrome associating akinesia, joint contractures, hypotonia, skeletal
      abnormalities, and brain and retinal hemorrhages.
    explanation: The human sibling series establishes the DNM2-associated recessive clinical syndrome.
  - reference: PMID:23092955
    reference_title: Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro membrane tubulation, trafficking and GTPase assays are consistent with an impact of the DNM2p.Phe379Val
      mutation on endocytosis."
    explanation: >-
      Functional assays supporting an endocytic defect as the DNM2 mechanism.
- name: ZBTB42
  subtype: LCCS6
  gene_term:
    preferred_term: ZBTB42
    term:
      id: hgnc:32550
      label: ZBTB42
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  evidence:
  - reference: PMID:25055871
    reference_title: ZBTB42 mutation defines a novel lethal congenital contracture syndrome (LCCS6).
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This severe muscular phenotype is successfully rescued with overexpression of the human wild-type
      ZBTB42 gene, but not with the mutant form of ZBTB42 that models the human missense change."
    explanation: >-
      Allele-specific rescue in zebrafish establishing pathogenicity of the human
      missense change.
- name: CNTNAP1
  subtype: LCCS7
  gene_term:
    preferred_term: CNTNAP1
    term:
      id: hgnc:8011
      label: CNTNAP1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  evidence:
  - reference: PMID:24319099
    reference_title: Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex
      congenita with axoglial defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygous frameshift mutations in CNTNAP1 were found in four unrelated families."
    explanation: Multi-family evidence for biallelic CNTNAP1 loss of function.
  - reference: PMID:29882456
    reference_title: "Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations, Hypomyelination,
      and Arthrogryposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By ultrastructural evaluation, septate axoglial paranodal junctions were absent from nodes of Ranvier."
    explanation: >-
      Ultrastructural confirmation in human nerve that CNTNAP1 loss removes the
      paranodal junction, the lesion this subtype's mechanism claims.
- name: ADCY6
  subtype: LCCS8
  gene_term:
    preferred_term: ADCY6
    term:
      id: hgnc:237
      label: ADCY6
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  evidence:
  - reference: PMID:31846058
    reference_title: Expanding the clinical and molecular spectrum of lethal congenital contracture syndrome 8
      associated with biallelic variants of ADCY6.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ADCY6 inactivation, due to biallelic variants, have been previously associated with the lethal congenital
      contracture syndrome 8 (LCCS8)."
    explanation: Confirms biallelic ADCY6 inactivation as the LCCS8 mechanism.
- name: ADGRG6
  subtype: LCCS9
  gene_term:
    preferred_term: ADGRG6
    term:
      id: hgnc:13841
      label: ADGRG6
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  notes: >-
    Reported as GPR126. The tested missense allele reduced autoproteolytic cleavage in cell-expression assays; residual
    cleavage was present, and complete activation loss is not demonstrated.
  evidence:
  - reference: PMID:26004201
    reference_title: Mutations of GPR126 are responsible for severe arthrogryposis multiplex congenita.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Previous work has suggested that autoproteolytic cleavage is important for activating GPR126 signaling"
    explanation: >-
      The introduction summarizes prior evidence that cleavage is important for signaling; this is background, distinct
      from the paper’s variant-expression assay.
  - reference: PMID:26004201
    reference_title: Mutations of GPR126 are responsible for severe arthrogryposis multiplex congenita.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "impairs autoproteolytic cleavage of GPR126"
    explanation: >-
      The expression assay shows impaired rather than abolished cleavage for the tested missense construct.
- name: NEK9
  subtype: LCCS10
  gene_term:
    preferred_term: NEK9
    term:
      id: hgnc:18591
      label: NEK9
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  evidence:
  - reference: PMID:26908619
    reference_title: Recessive NEK9 mutation causes a lethal skeletal dysplasia with evidence of cell cycle
      and ciliary defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Single nucleotide polymorphism homozygosity mapping and whole exome sequencing identified a novel
      homozygous stop-gain mutation in NEK9 (c.1489C>T; p.Arg497*) as the cause of this disorder.
    explanation: The original lethal skeletal-dysplasia report establishes the causal NEK9 allele.
- name: GLDN
  subtype: LCCS11
  gene_term:
    preferred_term: GLDN
    term:
      id: hgnc:29514
      label: GLDN
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  evidence:
  - reference: PMID:27616481
    reference_title: "Mutations in GLDN, Encoding Gliomedin, a Critical Component of the Nodes of Ranvier, Are Responsible
      for Lethal Arthrogryposis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The GLDN mutations found in the affected individuals abolish the cell surface localization of gliomedin
      and its interaction with its axonal partner, neurofascin-186 (NF186), in a cell-based assay."
    explanation: >-
      Cell-based functional evidence for the loss-of-function mechanism.
  - reference: PMID:32812332
    reference_title: "The latest FADS: Functional analysis of GLDN patient variants and classification of GLDN-associated
      AMC as a type of viable fetal akinesia deformation sequence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe one additional patient currently living with the syndrome, having one novel variant,
      p.Leu365Phe, for which we provide functional data supporting its pathogenicity."
    explanation: >-
      This sentence reports an additional surviving patient and mentions functional follow-up without quoting its
      experimental result.
- name: DST
  subtype: LCCS12
  gene_term:
    preferred_term: DST
    term:
      id: hgnc:1090
      label: DST
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  notes: >-
    Combined DST-a and DST-b involvement is associated with the lethal congenital-contracture presentation. DST-b-only
    congenital myopathy is a distinct isoform-defined cohort.
  evidence:
  - reference: PMID:40497796
    reference_title: "Deciphering DST-associated disorders: biallelic variants affecting DST-b cause a congenital
      myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants that also impact DST-a besides DST-b result in a more severe, lethal congenital contracture
      syndrome."
    explanation: >-
      Establishes DST as causative and gives the isoform-severity relationship.

diagnosis:
- name: Prenatal ultrasound
  description: >-
    Ultrasound can detect impaired movement, fixed joints, abnormal fluid volume, growth restriction and associated
    anomalies. Classic Finnish LCCS was recognizable from 12 weeks in the cited series, but GLDN cases were often
    detected much later; no universal timing or specificity is established.
  presence: PRESENT
  evidence:
  - reference: PMID:35806855
    reference_title: "Lethal Congenital Contracture Syndrome 11: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Prenatal ultrasound imaging is crucial in its early diagnosis by identifying fetal movement limitations
      and the presence of club foot or joint contractures"
    explanation: States the role and yield of prenatal ultrasound.
  diagnosis_term:
    preferred_term: Prenatal diagnostic ultrasound
    term:
      id: NCIT:C19337
      label: Diagnostic Ultrasound
- name: Trio exome or genome sequencing
  description: >-
    Broad molecular testing is useful for genetically heterogeneous fetal akinesia. The cited sequencing cohort
    solved 18 of 38 families with mixed fetal akinesia, arthrogryposis and congenital myopathy; this is not a LCCS-specific
    diagnostic sensitivity, and the cited evidence does not compare trio genome with exome sequencing.
  presence: PRESENT
  evidence:
  - reference: PMID:26578207
    reference_title: Next generation sequencing in a large cohort of patients presenting with neuromuscular
      disease before or at birth.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A conclusive genetic diagnosis was achieved for 18 of the 38 families."
    explanation: >-
      The 18/38 yield is for a mixed neuromuscular cohort, not a denominator consisting only of LCCS.
  diagnosis_term:
    preferred_term: Exome or genome sequencing
    term:
      id: NCIT:C15709
      label: Genetic Testing
- name: Nerve conduction study
  description: >-
    Electrophysiology can characterize peripheral neuropathy in surviving infants. Velocities below 10 m/s were
    reported in the original CNTNAP1 families; they do not define all axoglial LCCS, and GLDN studies may normalize
    over time.
  presence: PRESENT
  evidence:
  - reference: PMID:24319099
    reference_title: Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex
      congenita with axoglial defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients showed a marked reduction in motor nerve conduction velocity (<10 m/s)"
    explanation: The threshold is an observation in the original CNTNAP1 families, not a validated diagnostic
      discriminator across all LCCS subtypes.
  diagnosis_term:
    preferred_term: Motor nerve conduction studies
    term:
      id: NCIT:C88502
      label: Nerve Conduction Velocity Test
- name: Fetal and neonatal autopsy
  description: >-
    Postmortem examination can document lung, muscle, spinal cord and peripheral nerve pathology and confirm prenatal
    findings. Acceptance and tissue availability vary; absent autopsy data must not be replaced by neuropathology
    inferred from clinical similarity.
  presence: PRESENT
  evidence:
  - reference: PMID:35806855
    reference_title: "Lethal Congenital Contracture Syndrome 11: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "postmortem studies confirmed the prenatal findings: distal arthrogryposis, fetal growth restriction,
      pulmonary hypoplasia, and retrognathia"
    explanation: Shows postmortem confirmation of the prenatal findings.

  diagnosis_term:
    preferred_term: Fetal or neonatal autopsy
    term:
      id: NCIT:C25153
      label: Autopsy
- name: Fetal and postnatal magnetic resonance imaging
  description: MRI can characterize central nervous system involvement, but findings depend on subtype
    and age. A GLDN-affected fetus had normal brain and spinal cord MRI at 32 weeks, whereas serial brain
    MRI in two surviving CNTNAP1-associated children documented hypomyelination and progressive atrophy.
    A normal fetal scan does not exclude LCCS, and these reports do not establish a universal imaging
    schedule.
  presence: PRESENT
  diagnosis_term:
    preferred_term: Fetal and postnatal MRI
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:28726266
    reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by
      novel mutations in the gliomedin gene (GLDN).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Fetal MRI performed at 32 weeks showed normal brain and spinal cord images.
    explanation: This was the affected female infant in Family 4, whose prenatal ultrasound showed arthrogryposis
      and pulmonary hypoplasia; the normal central scan did not exclude GLDN-associated disease.
  - reference: PMID:29882456
    reference_title: Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations, Hypomyelination,
      and Arthrogryposis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Serial brain magnetic resonance images revealed hypomyelination, progressive atrophy, and
      reduced diffusion in the globus pallidus in both patients.
    explanation: The two CNTNAP1-associated children had serial imaging abnormalities. This supports characterization
      of central involvement in that subtype, not a mandatory MRI pattern across all LCCS.
- name: Electromyography
  description: EMG can help characterize a neurogenic component when interpreted with nerve conduction
    studies. Reduced motor unit recruitment accompanied slowed conduction in CNTNAP1-associated child
    LD_0158.0 at three weeks, whereas EMG was normal in the GLDN Family 3 survivor. These observations
    do not establish sensitivity or make a normal EMG exclusionary.
  presence: PRESENT
  diagnosis_term:
    preferred_term: Electromyography
    term:
      id: NCIT:C38056
      label: Electromyography
  evidence:
  - reference: PMID:29882456
    reference_title: Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations, Hypomyelination,
      and Arthrogryposis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Nerve conduction studies and electromyography (EMG) at 3 weeks of age showed prolongation
      of distal latencies and slow nerve conduction velocity (11.1 m/s at distal median) with decreased
      motor unit recruitment suggestive of a neurogenic disorder with features consistent with a demyelinating
      peripheral neuropathy.
    explanation: The combined electrophysiological assessment in LD_0158.0 distinguished a neurogenic
      peripheral process; conduction velocity belongs to NCS, whereas reduced recruitment is the EMG contribution.
  - reference: PMID:28726266
    reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by
      novel mutations in the gliomedin gene (GLDN).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Electromyography did not show any pathological finding.
    explanation: EMG was normal in the GLDN Family 3 survivor despite clinical disease; this is a patient-specific
      limitation, not evidence against the diagnostic procedure.
- name: Muscle biopsy
  description: Muscle histology may characterize the neuromuscular phenotype but can be normal or nonspecific.
    The GLDN Family 3 survivor had a normal muscle biopsy. In CNTNAP1-associated child LD_0158, quadriceps
    biopsy changed from mild scattered atrophy at one month to severe type I fiber atrophy and type II
    predominance at 3.5 years, mimicking congenital myopathy. A muscle pattern alone does not establish
    a primary myopathic LCCS mechanism.
  presence: PRESENT
  diagnosis_term:
    preferred_term: Muscle Biopsy
    term:
      id: NCIT:C51895
      label: Muscle Biopsy
  evidence:
  - reference: PMID:28726266
    reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by
      novel mutations in the gliomedin gene (GLDN).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Muscle biopsy and MRI of the brain and spinal cord were normal.
    explanation: The muscle biopsy was normal in the GLDN Family 3 survivor; the separately normal MRI
      is not a histological result.
  - reference: PMID:29882456
    reference_title: Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations, Hypomyelination,
      and Arthrogryposis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A right quadriceps biopsy at 1 month of age showed mild atrophy of scattered muscle fibers
      without evidence of inflammation, myonecrosis, regeneration, or structural abnormalities (Figure
      2). The fiber type distribution appeared normal (Figure 2A). A second muscle biopsy from the left
      quadriceps at 3.5 years demonstrated abnormal variation in fiber size with a marked type II fiber
      predominance and severe atrophy of type I fibers mimicking congenital myopathic disease (Figures
      2B, 2C, and 2D).
    explanation: Serial biopsies in LD_0158 show age-dependent histological change in CNTNAP1-associated
      neuropathy. The later myopathy-like pattern must be interpreted alongside the peripheral nerve findings.
- name: Peripheral nerve biopsy
  description: Sural nerve histology and ultrastructure characterized progressive peripheral neuropathy
    in CNTNAP1-associated child LD_0158. The initial biopsy at one month showed mildly reduced myelinated
    axons, while repeat biopsy at 3.5 years showed severe demyelination and predominant axonal loss. This
    documents a selected patient investigation, not a routine biopsy recommendation or a finding established
    in every subtype.
  presence: PRESENT
  diagnosis_term:
    preferred_term: Peripheral nerve biopsy
    term:
      id: NCIT:C217131
      label: Nervous System Biopsy Procedure
  evidence:
  - reference: PMID:29882456
    reference_title: Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations, Hypomyelination,
      and Arthrogryposis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: His initial sural nerve biopsy (right sural) at 1 month of age showed a mildly reduced number
      of myelinated axons (Figure 3A).
    explanation: This initial peripheral nerve biopsy belongs to LD_0158; it is distinct from his muscle
      biopsy and from the normal muscle biopsy in a GLDN survivor.
  - reference: PMID:29882456
    reference_title: Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations, Hypomyelination,
      and Arthrogryposis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A second sural nerve biopsy (left sural) at 3.5 years of age showed severe demyelination
      and axonal pathology. The predominant pathology was axonal loss (Figure 3B).
    explanation: The repeat nerve biopsy documents progression in the same CNTNAP1-associated child, without
      supplying an umbrella diagnostic threshold.
- name: Renal and bladder ultrasound
  description: Ultrasound documented urinary tract involvement in two ERBB3-associated siblings. The first
    had a distended bladder, bilateral distal ureteral dilatation and left renal calyceal dilation; the
    second had normal kidneys with a distended, mildly thick-walled bladder and required catheter drainage.
    Their megacystis was interpreted as neurogenic rather than mechanical obstruction; a keyhole appearance
    alone was not sufficient to establish obstruction.
  presence: PRESENT
  diagnosis_term:
    preferred_term: Renal and bladder ultrasound
    term:
      id: NCIT:C159885
      label: Renal Ultrasound
  evidence:
  - reference: PMID:40321344
    reference_title: Prenatal diagnosis of fetal neurogenic megacystis associated with lethal congenital
      contractural syndrome 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Renal ultrasound revealed an overly distended bladder, bilateral distal ureteral dilatation,
      and left renal calyceal dilation consistent with urinary tract dilation classification P3.
    explanation: This was the first affected sibling. Her ureteral and calyceal dilatation must not be
      assigned to the second sibling, whose kidneys appeared normal.
  - reference: PMID:40321344
    reference_title: Prenatal diagnosis of fetal neurogenic megacystis associated with lethal congenital
      contractural syndrome 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Renal ultrasound showed normal kidneys with a distended bladder with mild wall thickening.
      She required an indwelling Foley catheter for adequate bladder emptying.
    explanation: The second affected sibling had normal-appearing kidneys despite bladder dysfunction
      requiring drainage. The paper interprets LCCS2 megacystis as neurogenic, despite its obstructive-looking
      prenatal appearance.
  - reference: PMID:40321344
    reference_title: Prenatal diagnosis of fetal neurogenic megacystis associated with lethal congenital
      contractural syndrome 2.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: In LCCS2, megacystis is not due to obstruction, despite its sonographic appearance, but rather
      to neurogenic causes.
    explanation: The authors interpret the LCCS2 bladder phenotype as neurogenic despite an obstructive-looking
      ultrasound appearance. This interpretive statement distinguishes the sonographic finding from a demonstrated
      mechanical obstruction; it does not identify the responsible neural pathway.
differential_diagnoses:
- name: Lethal Arthrogryposis with Anterior Horn Cell Disease
  description: >-
    GLE1-associated AAHD shares fetal akinesia, contractures and motor-neuron disease with classic LCCS1 but includes
    survival into childhood. The proposed coiled-coil-domain relationship is a hypothesis, not a definitive prognostic
    test for an individual allele.
  evidence:
  - reference: PMID:28884921
    reference_title: Survival beyond the perinatal period expands the phenotypes caused by mutations in GLE1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both LCCS and LAAHD are characterized by reduced fetal movements, congenital contractures, and a severe
      form of motor neuron disease that results in fetal death or death in the perinatal period, respectively."
    explanation: >-
      States the shared phenotype and the timing difference that is the whole
      basis of the distinction.
  - reference: PMID:28884921
    reference_title: Survival beyond the perinatal period expands the phenotypes caused by mutations in GLE1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The phenotype of LAAHD is now expanded to include multiple individuals surviving into childhood suggesting
      that LAAHD is a misnomer and should be re-named Arthrogryposis with Anterior Horn Cell Disease (AAHD)."
    explanation: >-
      Documents the survival that undermines the "lethal" label on the allelic
      disorder as well as on this one.
- name: Arthrogryposis Multiplex Congenita
  description: >-
    AMC is the broader descriptive phenotype of congenital contractures in multiple body regions and has diverse
    genetic and non-genetic causes. LCCS is a historically numbered recessive subset; lethality alone does not delimit
    it.
  evidence:
  - reference: PMID:28726266
    reference_title: "Survival among children with \"Lethal\" congenital contracture syndrome 11 caused by novel
      mutations in the gliomedin gene (GLDN)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "AMC results from diverse mechanisms, including any condition that decreases or limits fetal movements."
    explanation: >-
      States the breadth of AMC against which LCCS must be positioned.
- name: KIF21A-related fetal akinesia
  description: >-
    Biallelic KIF21A loss-of-function variants cause severe fetal akinesia with arthrogryposis. This is a molecular
    differential for the historically numbered LCCS syndromes, distinct from dominant KIF21A-associated congenital
    fibrosis of extraocular muscles.
  evidence:
  - reference: PMID:34740919
    reference_title: Bi-allelic loss-of-function variants in KIF21A cause severe fetal akinesia with
      arthrogryposis multiplex.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Together, these molecular and phenotypical data are in line with bi-allelic KIF21A PTVs being
      implicated in the pathogenesis of a severe form of autosomal recessive FA characterised by
      arthrogryposis multiplex, pulmonary hypoplasia and variable facial dysmorphisms.
    explanation: The human genotype and fetal phenotype data support this molecular differential, rather than
      only a generic fetal-akinesia gene count.
- name: Non-genetic fetal akinesia
  description: >-
    Extrinsic constraint, maternal disease or exposures can reduce fetal movement. The cited ungenotyped autopsy
    series illustrates etiological heterogeneity and incomplete ascertainment; a negative genetic test does not
    itself prove a non-genetic cause.
  evidence:
  - reference: PMID:11810649
    reference_title: "Heterogeneity in fetal akinesia deformation sequence (FADS): autopsy confirmation in three
      20-21-week fetuses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The etiology of akinesia was undetermined in Case 3; no extrinsic or intrinsic cause was identified."
    explanation: >-
      An unresolved cause in an ungenotyped fetus demonstrates diagnostic uncertainty, not positive evidence for
      a particular extrinsic cause.

treatments:
- name: Mechanical Ventilation and Chronic Respiratory Support
  therapeutic_modality: DEVICE
  description: >-
    Invasive ventilation and, in some survivors, tracheostomy with chronic respiratory support were
    reported in GLDN-associated disease. Some children later weaned from support. The observational
    series does not isolate the survival benefit from genotype, disease severity or other care.
    Mechanical ventilation substitutes for the respiratory effort that the hypoplastic lung and weak
    respiratory musculature cannot generate.
  treatment_term:
    preferred_term: Invasive Mechanical Ventilation
    term:
      id: NCIT:C191573
      label: Invasive Mechanical Ventilation
  target_phenotypes:
  - preferred_term: Neonatal Respiratory Failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: PMID:28726266
    reference_title: "Survival among children with \"Lethal\" congenital contracture syndrome 11 caused by novel
      mutations in the gliomedin gene (GLDN)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "four of whom survived beyond the neonatal period into infancy, childhood, and late adolescence with
      intensive care and chronic respiratory and nutritional support"
    explanation: Reports the survival achieved with sustained respiratory support.
  - reference: PMID:28726266
    reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by
      novel mutations in the gliomedin gene (GLDN).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our findings confirm the association of GLDN mutations with AMC and extend the LCCS11 phenotype
      by describing long-term survival with chronic respiratory and nutritional support.
    explanation: Reports long-term survival with respiratory and nutritional support; this is an observational
      care association, not proof that support alone determines survival.
- name: Enteral Nutritional Support
  therapeutic_modality: DEVICE
  description: >-
    Gastrostomy feeding supported a GLDN survivor with swallowing insufficiency aggravated by focal bulbar paresis.
    Oral feeding later increased, so indefinite tube dependence is not obligatory.
  treatment_term:
    preferred_term: Enteral Tube Feeding
    term:
      id: NCIT:C93322
      label: Enteral Tube Feeding
  target_mechanisms:
  - target: Focal Bulbar Paresis
    description: Tube feeding bypasses unsafe or insufficient oral intake caused partly by bulbar paresis; it
      does not reverse the paresis.
    evidence:
    - reference: PMID:28726266
      reference_title: "Survival among children with \"Lethal\" congenital contracture syndrome 11 caused by novel
        mutations in the gliomedin gene (GLDN)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Insufficient swallowing aggravated by paresis of both the right vocal cord and right side of the
        soft palate prompted gastrostomy tube placement at 4 months of age."
      explanation: >-
        Documents insufficient swallowing and the gastrostomy it required in a
        surviving LCCS11 child.
    treatment_effect: BYPASSES
  evidence:
  - reference: PMID:28726266
    reference_title: "Survival among children with \"Lethal\" congenital contracture syndrome 11 caused by novel
      mutations in the gliomedin gene (GLDN)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Insufficient swallowing aggravated by paresis of both the right vocal cord and right side of the soft
      palate prompted gastrostomy tube placement at 4 months of age."
    explanation: >-
      Documents insufficient swallowing and the gastrostomy it required in a
      surviving LCCS11 child.
- name: Genetic Counseling and Prenatal Testing
  description: >-
    Molecular diagnosis can inform recurrence counseling and reproductive testing in these recessive disorders.
    The usual recurrence estimate requires confirmed parental carrier status and the relevant family genotype.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:29959180
    reference_title: Genetics of neuromuscular fetal akinesia in the genomics era.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A genetic diagnosis has clinical utility as it may affect management and prognosis and informs recurrence
      risk, facilitating family planning decisions."
    explanation: >-
      States the counselling and reproductive value of reaching a molecular
      diagnosis.
- name: Contracture Management and Rehabilitation
  therapeutic_modality: BEHAVIORAL
  description: >-
    Physiotherapy and splinting improved contractures, range of motion and lower-limb tone in one GLDN survivor.
    Other survivors underwent selected orthopedic procedures. These observed courses do not establish a uniform
    protocol or irreversible contracture trajectory.
  treatment_term:
    preferred_term: Rehabilitation
    term:
      id: NCIT:C15315
      label: Rehabilitation
  evidence:
  - reference: PMID:28726266
    reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by novel
      mutations in the gliomedin gene (GLDN).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Physiotherapy and non-surgical treatment including splinting led to an improvement of his
      contractures, increased range of motion, and improved muscular tone in his lower limbs.
    explanation: The Family 3 survivor improved with physiotherapy and splinting; this directly corrects the
      prior claim that contractures cannot improve.
- name: Perinatal Palliative Care and Shared Goals of Care
  description: Multidisciplinary perinatal palliative care supported a family with prenatal ERBB3-associated
    LCCS2. The family initially requested supported comfort care, then accepted nasal oxygen, nasogastric
    feeding, thermoregulation and bladder catheterization when the infant continued to breathe. Shared
    goals can change with the observed course; palliative care does not imply comfort-only care or an
    identical prognosis across LCCS subtypes.
  treatment_term:
    preferred_term: Perinatal palliative care
    term:
      id: NCIT:C15292
      label: Palliative Therapy
  evidence:
  - reference: PMID:40321344
    reference_title: Prenatal diagnosis of fetal neurogenic megacystis associated with lethal congenital
      contractural syndrome 2.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Perinatal palliative care is principled to support families through this uncertainty using
      shared decision-making to establish goals of care.
    explanation: This is the authors’ care principle for uncertain LCCS2 outcomes, not a measured treatment
      effect or a recommendation to withhold intensive care.
  - reference: PMID:40321344
    reference_title: Prenatal diagnosis of fetal neurogenic megacystis associated with lethal congenital
      contractural syndrome 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She had consultations with pediatric urology and a Perinatal Palliative Care Team including
      representatives from neonatology, pediatrics, Chaplaincy, among others. Given the family’s previous
      experience and the counseled expectations for infants born with LCCS2, patient requested a supported
      comfort care model of care after birth.
    explanation: The mother carrying the second affected sibling received multidisciplinary consultation
      and initially chose supported comfort care. This is an observed family decision, separate from the
      authors’ general principle.
  - reference: PMID:40321344
    reference_title: Prenatal diagnosis of fetal neurogenic megacystis associated with lethal congenital
      contractural syndrome 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Despite expectations to allow a natural death after birth, she continued to have respiratory
      drive and live. The family’s goals of care pivoted to accept neonatal intensive level care with
      perceived non-aggressive interventions such as nasal cannula oxygen support, enteral feedings via
      nasogastric tube, thermoregulation support, and Foley catheter.
    explanation: The second sibling’s continued respiratory drive changed the family’s goals. These actual
      noninvasive respiratory, nutritional and supportive interventions demonstrate that the care plan
      was revisable; they do not prove efficacy or a uniform survival trajectory.
- name: Tracheostomy
  description: Tracheostomy provided access for respiratory support in selected GLDN-associated survivors
    with persistent respiratory insufficiency. The Family 3 child underwent the procedure at six weeks
    for respiratory insufficiency, ineffective cough and swallowing difficulty, then weaned from ventilation
    at nine months and was decannulated at 19 months. Other children remained dependent; the procedure
    does not itself reverse pulmonary hypoplasia or neuromuscular weakness.
  treatment_term:
    preferred_term: Tracheostomy
    term:
      id: NCIT:C15341
      label: Tracheotomy
  evidence:
  - reference: PMID:28726266
    reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by
      novel mutations in the gliomedin gene (GLDN).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Due to persistent respiratory insufficiency, inability to cough, and insufficient swallowing,
      he underwent tracheostomy at 6 weeks of age. His respiratory function gradually improved, and he
      was successfully weaned from ventilatory support at nine months of age and subsequently decannulated
      at 19 months of age.
    explanation: This is the Family 3 survivor’s indication and subsequent course, not evidence that tracheostomy
      caused recovery or that decannulation is expected in every child.
- name: Selected Orthopedic Surgery
  description: A GLDN-associated Family 2 survivor underwent operations for bilateral hip luxation and
    clubfeet at two years and scoliosis instrumentation at nine years. These procedures addressed selected
    structural problems alongside respiratory, nutritional and rehabilitation care; the case does not
    isolate a surgical benefit or establish a standard operative plan for LCCS.
  treatment_term:
    preferred_term: Selected orthopedic surgery
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  evidence:
  - reference: PMID:28726266
    reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by
      novel mutations in the gliomedin gene (GLDN).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He underwent surgical treatment for bilateral hip luxation and clubfeet (age 2 years) and
      scoliosis with Harrington rod insertion (age 9 years).
    explanation: The Family 2 survivor had these specific operations at distinct ages. Later mobility
      and respiratory changes occurred during a broader course of care and are not attributed solely to
      surgery.
discussions:
- discussion_id: lccs_survival_variability
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Which variant, developmental and care factors determine survival and later progression in
    GLDN-associated disease?
  attaches_to:
  - has_subtypes#LCCS11
  - phenotypes#Neonatal Respiratory Failure
  rationale: Published GLDN series include terminations, neonatal deaths and long survivors, with differing
    denominators and support. The 2025 founder report includes four early deaths and one survivor with later
    progressive compromise. These data establish variable outcome but do not separate residual function,
    modifiers and care effects.
  evidence:
  - reference: PMID:39713852
    reference_title: "Identification of a Founder GLDN Variant Associated With \"Lethal\" Arthrogryposis in Nunavik
      Inuit: Implications for Obstetrical and Long-Term Survivors' Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our data corroborate those of other reports, demonstrating that LCCS11 is not universally lethal,
      but long-term survivors are at risk of progressive neuromuscular compromise.
    explanation: The newer founder series independently supports variable lethality and later morbidity.
- discussion_id: lccs12_tissue_attribution
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: How do combined neuronal and muscle dystonin defects produce the lethal contracture phenotype?
  attaches_to:
  - pathophysiology#Combined Neuronal and Muscle Dystonin Deficiency
  rationale: The source establishes causal combined-isoform involvement, now represented by a qualified edge
    to contractures. It does not identify the relative neuronal and muscle mechanisms in the lethal cases; the
    separate DST-b-only cohort is not evidence of their biopsy or cardiac phenotype.
  evidence:
  - reference: PMID:40497796
    reference_title: "Deciphering DST-associated disorders: biallelic variants affecting DST-b cause a congenital
      myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genotype-phenotype correlation in these patients and previously published cases with respective variants
      resulted in the definition of a DST-associated lethal congenital contracture syndrome."
    explanation: >-
      Establishes DST as the gene defining a lethal congenital contracture
      syndrome.
  - reference: PMID:40497796
    reference_title: "Deciphering DST-associated disorders: biallelic variants affecting DST-b cause a congenital
      myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants that also impact DST-a besides DST-b result in a more severe, lethal congenital contracture
      syndrome."
    explanation: >-
      Gives the isoform-dependent severity relationship that separates the lethal
      phenotype from the congenital myopathy.

- discussion_id: lccs10_developmental_attribution
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: How much of the NEK9 skeletal phenotype results from primary developmental dysplasia versus reduced
    fetal movement?
  attaches_to:
  - pathophysiology#Mitotic and Ciliary Regulatory Failure
  - phenotypes#Short Long Bones
  rationale: The original lethal families had akinesia and skeletal dysplasia, and their fibroblasts had both
    mitotic and ciliary abnormalities. Qualified causal links are represented. The unresolved issue is tissue
    and process attribution, not whether the causal genotype or the fetal movement phenotype exists. Surviving
    APUG-like cases are not used to supply LCCS10 visceral findings.
  evidence:
  - reference: PMID:26908619
    reference_title: Recessive NEK9 mutation causes a lethal skeletal dysplasia with evidence of cell cycle
      and ciliary defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report two Irish Traveller families with a previously undescribed lethal skeletal dysplasia
      characterized by fetal akinesia, shortening of all long bones, multiple contractures, rib anomalies,
      thoracic dysplasia, pulmonary hypoplasia and protruding abdomen.
    explanation: The original lethal skeletal-dysplasia families establish the LCCS10 clinical scope; the
      later APUG-like neonates are not used as its denominator.
- discussion_id: lccs_gldn_model_fidelity
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: Why do human GLDN variants cause severe fetal disease when gliomedin-null mice have a milder nodal
    phenotype?
  attaches_to:
  - pathophysiology#Node of Ranvier Assembly Failure
  rationale: Human nerve abnormalities support the nodopathy mechanism, but preserved conduction and absence
    of arthrogryposis in null mice constrain a simple universal loss-of-function-to-complete-conduction-block
    model. Allele, species and compensatory nodal mechanisms remain unresolved.
  evidence:
  - reference: PMID:28726266
    reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by novel
      mutations in the gliomedin gene (GLDN).
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Homozygous gldn−/− mice do not have apparent neurologic deficits or features of arthrogryposis
      and demonstrate normal nerve conduction and peripheral nervous system myelin (Feinberg, et al., 2010).
    explanation: The primary clinical paper summarizes the null-mouse contrast; this is model-organism
      evidence, not a negative finding in human GLDN disease.
  - reference: PMID:28726266
    reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by novel
      mutations in the gliomedin gene (GLDN).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Nerve conduction velocity studies performed at 1 week of age demonstrated axonal motor and
      sensory neuropathy but were normal when repeated at 7 months of age.
    explanation: Human longitudinal variability is another constraint on a permanent, uniform conduction-block
      model.
- discussion_id: lccs_hydrops_growth
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: What causes hydrops and restricted growth in affected fetuses, and when do placental factors
    contribute?
  attaches_to:
  - phenotypes#Hydrops Fetalis
  - phenotypes#Intrauterine Growth Restriction
  rationale: The rat paralysis experiment supports a qualified akinesia-to-growth-restriction contribution,
    now represented in the graph. It does not resolve the relative contribution in the GLDN-associated fetus
    with abnormal umbilical-artery flow. The reviewed LCCS sources establish hydrops but do not identify a
    subtype-specific fluid-balance mechanism; its absence in original ERBB3 and PIP5K1C kindreds constrains an
    obligatory consequence of contractures.
  evidence:
  - reference: PMID:35806855
    reference_title: 'Lethal Congenital Contracture Syndrome 11: A Case Report and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sonography examination revealed hydrothorax, subcutaneous generalized edema, short long bones,
      fixed limb joints, absent fetal movements, fetal growth restriction (estimated fetal weight in the 4th
      percentile and absent end-diastolic flow in both umbilical arteries), and polyhydramnios (amniotic fluid
      index 28 cm) (Figure 1).
    explanation: The coexisting flow abnormality constrains attribution of growth restriction solely to the
      fetal motor disorder.
- discussion_id: lccs_craniofacial_joint_distribution
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: What causes jaw retrusion and hip dislocation in the reported LCCS patients?
  attaches_to:
  - phenotypes#Retrognathia
  - phenotypes#Hip Dislocation
  rationale: Fetal immobility is a supported general deformation mechanism, with micrognathia and pterygia
    routes represented separately. The reviewed sources do not specifically resolve jaw retrusion or hip
    dislocation in the cited LCCS patients. A small mandible is not equivalent to retrusion, and local
    mechanical versus primary developmental attribution remains uncertain.
  evidence:
  - reference: PMID:35806855
    reference_title: 'Lethal Congenital Contracture Syndrome 11: A Case Report and Literature Review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The pregnancy was terminated and postmortem studies confirmed the prenatal findings: distal arthrogryposis,
      fetal growth restriction, pulmonary hypoplasia, and retrognathia.'
    explanation: The primary case supports jaw retrusion, not mandibular size.
- discussion_id: lccs_bladder_localization
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Which central, peripheral autonomic or developmental lesion produces neurogenic bladder in ERBB3 and
    CNTNAP1 disease?
  attaches_to:
  - phenotypes#Neurogenic Bladder
  rationale: Human reports establish neurogenic bladder in both subtypes but do not localize the responsible
    autonomic lesion. Somatic anterior-horn loss alone does not establish the bladder mechanism; CNTNAP1
    disease includes both central and peripheral pathology.
  evidence:
  - reference: PMID:29882456
    reference_title: Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations,
      Hypomyelination, and Arthrogryposis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Individual LD_0333.0 was a girl with severe hypotonia and respiratory insufficiency that required
      a tracheostomy after birth, hypomyelinating neuropathy, bilateral hearing loss, bilateral optic nerve
      atrophy, lethargy, and neurogenic bladder.
    explanation: Documents neurogenic bladder in a CNTNAP1-associated child, extending the subtype scope
      without identifying the responsible autonomic pathway.
- discussion_id: lccs_gldn_bulbar_airway
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Are GLDN-associated bulbar and diaphragmatic weakness and airway malacia caused by the same
    peripheral lesion?
  attaches_to:
  - phenotypes#Vocal Cord Paresis
  - phenotypes#Diaphragmatic Paralysis
  - phenotypes#Laryngomalacia
  - phenotypes#Tracheomalacia
  - phenotypes#Central Apnea
  rationale: The source establishes focal paresis, diaphragm paralysis and laryngoscopic malacia in different
    children. Their downstream swallowing and respiratory contributions are represented where directly
    supported. It does not localize the upstream cause of paresis or establish that structural airway malacia
    is a direct consequence of gliomedin deficiency. Polysomnographic central apnea is separately reported;
    its coexistence with tracheomalacia does not establish an obstructive mechanism.
  evidence:
  - reference: PMID:28726266
    reference_title: "Survival among children with \"Lethal\" congenital contracture syndrome 11 caused by novel
      mutations in the gliomedin gene (GLDN)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Insufficient swallowing aggravated by paresis of both the right vocal cord and right side of the soft
      palate prompted gastrostomy tube placement at 4 months of age."
    explanation: >-
      Documents vocal cord paresis and its contribution to the swallowing
      failure.
  - reference: PMID:28726266
    reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by novel
      mutations in the gliomedin gene (GLDN).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Laryngoscopy demonstrated laryngo- and tracheomalacia, floppy epiglottis, and pooling of oral
      secretions.
    explanation: The laryngoscopic findings explicitly establish laryngomalacia in this child.
- discussion_id: lccs_motor_trajectory
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: How do neuropathy, weakness, contractures and respiratory illness contribute separately to delayed
    motor acquisition in GLDN survivors?
  attaches_to:
  - phenotypes#Motor Developmental Delay
  rationale: The source documents delayed milestones and subsequent gains with growth and care. It does not
    separate peripheral motor dysfunction from mechanical restriction, prolonged illness or developmental
    contributors sufficiently to assign a specific causal edge to motor delay.
  evidence:
  - reference: PMID:28726266
    reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by novel
      mutations in the gliomedin gene (GLDN).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Motor and language development was delayed; he was able to sit independently at age 13 months and
      started to crawl at age 24 months.
    explanation: The exact ages establish motor delay in the Family 3 survivor, without inferring cognitive
      impairment.
- discussion_id: lccs_cntnap1_sensory_palate
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: What accounts for the distinct sensory and palatal findings in surviving CNTNAP1-associated
    children?
  attaches_to:
  - phenotypes#Cerebral Visual Impairment
  - phenotypes#Hearing Impairment
  - phenotypes#Optic Atrophy
  - phenotypes#Cleft Palate
  rationale: Central and peripheral glial-axonal disease provides plausible context, but the report does not
    connect the observed cortical visual loss, hearing loss, optic atrophy or palatal malformation to a
    specific demonstrated mechanism. Hearing-loss localization and the developmental cause of cleft palate
    remain unresolved; the established central hypomyelination and atrophy routes are represented separately.
  evidence:
  - reference: PMID:29882456
    reference_title: Absence of Axoglial Paranodal Junctions in a Child With CNTNAP1 Mutations,
      Hypomyelination, and Arthrogryposis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Individual LD_0158.0 is an 8 year old male with hypotonia and respiratory failure requiring
      intubation at birth and subsequent tracheotomy-dependency, congenital hypomyelinating neuropathy with
      arthrogryposis multiplex congenita, cleft palate, cortical vision loss, bilateral hearing loss, and
      neurogenic bladder.
    explanation: This patient-level clinical observation establishes the findings but does not establish a
      single causal route for them.
- discussion_id: lccs_dnm2_cardiopulmonary_attribution
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Were pulmonary hypertension and ductal patency in the DNM2 siblings primary developmental findings
    or consequences of respiratory insufficiency?
  attaches_to:
  - phenotypes#Pulmonary Hypertension
  - phenotypes#Patent Ductus Arteriosus
  rationale: The source explicitly states that primary versus secondary attribution could not be determined.
    The general developmental endocytosis hypothesis does not resolve this specific uncertainty, so no direct
    respiratory or genetic-mechanism edge is asserted.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658203/
    reference_title: Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome - PMC
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: AFB3 and AFB4 had pulmonary hypertension and a patent ductus arteriosus; whether these features
      were primary or secondary to respiratory insufficiency could not be determined.
    explanation: The authors state the causal attribution limit for these two cardiopulmonary observations.
- discussion_id: lccs_scoliosis_attribution
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Did scoliosis in the GLDN survivor result from neuromuscular imbalance, fixed posture or a separate
    developmental process?
  attaches_to:
  - phenotypes#Scoliosis
  rationale: The clinical course establishes scoliosis requiring surgery at age nine, alongside weakness,
    atrophy and congenital contractures. It does not identify the cause or provide serial spinal development
    sufficient to distinguish neuromuscular deformation from another developmental process. The surgery
    documents the phenotype, not a demonstrated causal intermediary.
  evidence:
  - reference: PMID:28726266
    reference_title: Survival among children with "Lethal" congenital contracture syndrome 11 caused by novel
      mutations in the gliomedin gene (GLDN).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He underwent surgical treatment for bilateral hip luxation and clubfeet (age 2 years) and
      scoliosis with Harrington rod insertion (age 9 years).
    explanation: The GLDN Family 2 survivor underwent scoliosis surgery with Harrington rod insertion at age
      nine years. The hip procedure in the same sentence occurred at age two.
notes: >-
  Reviewed as a heterogeneous numbered LCCS umbrella, with subtype and allele scope retained for clinical and mechanistic
  claims. Model perturbations and author hypotheses are distinguished from human observations; generic fetal deformation
  does not explain every primary skeletal, central nervous system, vascular or visceral finding. The current mechanism
  graph uses local nodes because the subtype-specific developmental and axoglial routes require explicit evidence
  and uncertainty; no conserved module was imported solely to increase connectivity. Clinical anatomy is not treated
  as an assay readout; nerve-conduction velocity remains an explicit electrophysiological readout. The Falcon report
  was used for candidate findings only, with source-based exclusions for APUG-like NEK9 cases, DST-b-only myopathy
  and unavailable full-text-only ADCY6 details. The Schwann-cell myelin-maintenance module was considered, but its
  Schwann-intrinsic proteostatic and maintenance chain cannot be assumed for congenital ADCY6/ADGRG6 myelination
  failure or axonal CNTNAP1 paranodal disease. The ciliopathy module was also considered; the NEK9 fibroblast data
  do not establish its Hedgehog/Wnt signaling chain. These are reasons to retain qualified local mechanisms, not
  missing evidence for an already established shared module.

references:
- reference: PMID:29959180
  title: Genetics of neuromuscular fetal akinesia in the genomics era.
- reference: PMID:35806855
  title: "Lethal Congenital Contracture Syndrome 11: A Case Report and Literature Review."
- reference: PMID:39457470
  title: "Update on Inherited Pediatric Motor Neuron Diseases: Clinical Features and Outcome."

clinical_trials: []
datasets: []
📚

References & Deep Research

References

3
PMID:29959180
Genetics of neuromuscular fetal akinesia in the genomics era.
No top-level findings curated for this source.
PMID:35806855
Lethal Congenital Contracture Syndrome 11: A Case Report and Literature Review.
No top-level findings curated for this source.
PMID:39457470
Update on Inherited Pediatric Motor Neuron Diseases: Clinical Features and Outcome.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Lethal Congenital Contracture Syndrome (MONDO:0017436) · 2026-08-29T06:31:19Z · View source

Curated MONDO:0017436 as a Disease with has_subtypes rather than a kb/groupings/ entry. MONDO:0017436 is an OMIM phenotypic series (OMIMPS:253310) with twelve numbered members, which normally argues for a grouping; it is curated as a disease because the subtypes are not a union of distinct diseases but one deformation sequence reached by three different routes through the same fetal motor unit (anterior horn cell in LCCS1-3, Schwann cell myelination and node-of-Ranvier assembly in LCCS2 and LCCS7-11, sarcomere and NMJ in LCCS4-6), converging on a single node - absent fetal movement - below which every finding is deformation secondary to the missing movement. The reasoning is recorded in the entry notes. Deep research: falcon (Edison), 13/13 references resolved, confabulation_rate 0.0, one reference flagged possibly off topic (the NEK9/MYH9 ciliogenesis paper) which was read and not cited in the entry. The report was used as a lead source only; every KB snippet was taken from the primary reference cache directly, and no snippet was copied from the report text. Evidence: 135/135 snippets verified against cached references by count-verified-snippets and by validate-disorders. 28 references fetched via fetch-reference (PMIDs only; DOI-keyed caches created during discovery were removed in favour of their PMID equivalents so reference_title values come from PubMed rather than publisher HTML markup). GeneReviews baseline: PubMed searched for a GeneReviews chapter on lethal congenital contracture syndrome, arthrogryposis and fetal akinesia; none exists, so no GeneReviews reference is tagged. Post-review revision (PR #10020, ai4c-reviewer CHANGES_REQUESTED plus an independent red-team pass). Corrected a 10x prevalence error: the Finnish source states the LCCS1 rate as both 1 in 25,250 and 0.40 per 10,000, and the per-10,000 figure had been copied into the per-100,000 slot; the record now reads 3.96 per 100,000, and both prevalence records were re-banded (BAND_1_9_PER_100000 and BAND_1_5_PER_10000). Removed an ADCY6 36-month survival claim that no cached reference supported, from all three places it appeared. LCCS12 is no longer recorded as gene-unassigned: OMIM 621511 and MedGen assign DST, sourced to PMID:40497796 (Jacob et al., Brain 2026); a gene binding, a genetic entry and a reframed knowledge gap replace the previous assertion that no gene was known. MONDO:0981031 still carries no RO:0004003 edge, which the gap now records as an ontology gap to report upstream. Added a molecular layer to the pathograph (mRNA export, PI3K-Akt, phosphoinositide synthesis, cAMP synthesis, NEK9 mitotic/ciliary), split the bundled muscle node into myofibril-assembly and endocytic-trafficking nodes, rebound the fetal movement phenotype from the syndrome term HP:0001989 to the finding term HP:0001558, and replaced GO:0097049 motor neuron apoptotic process with GO:0021522 spinal cord motor neuron differentiation DECREASED because the node's own zebrafish evidence shows the deficit is precursor apoptosis, not apoptosis of differentiated motoneurons. Re-sourced the LCCS1-tagged pterygia, micrognathia and muscle-atrophy claims from an un-genotyped 2002 FADS autopsy paper to LCCS1-specific sentences in PMID:18204449, and the neurogenic bladder claim from the LCCS3 paper's negative statement to the LCCS2 paper's positive one. Demoted several VERY_FREQUENT bands that rested on single cases or on a figure that contradicted the band. Added talipes equinovarus, areflexia, dysphagia and retinal haemorrhage phenotypes, two CARRIER_FREQUENCY prevalence records, a LAAHD differential, and palliative care. Scope notes: LCCS12 now carries its gene but is not placed on a pathograph arm, because whether DST-b loss reaches akinesia through the contractile-apparatus route is unestablished. Rebased onto origin/main after 55 commits had landed, which included the schema change in #10003 (#7439) retiring PARTIAL from EvidenceItem.supports and splitting direction from directness. The bulk migration converted all 11,616 existing PARTIAL items to SUPPORT with directness left absent, deliberately not backfilled so as not to manufacture appraisals no curator made. This entry's 12 PARTIAL items were instead converted to SUPPORT plus an explicit directness: INDIRECT, because each was written in this session with an explanation already stating why the support is indirect, so the appraisal is a real curator judgement rather than a default. The explanation prose was reworded from "PARTIAL because" to "Indirect because" to match. Three cache conflicts (cache/mondo/terms.csv, cache/cl/terms.csv, cache/enums/celltypeterm_a43e4ab67bda.csv) were purely additive row collisions with concurrently merged curation PRs; resolved by keeping both sides and re-deriving order with just normalize-cache, verified with check-term-cache-integrity and check-cache-order. No cache row was hand-edited. Second review round (approving, with four non-blocking suggestions, all taken): downgraded the palliative-care evidence directness because its snippet is about congenital SMA rather than LCCS; renamed the Impaired Fetal Swallowing node to Impaired Swallowing since it spans the postnatal dysphagia that enteral feeding actually targets; dropped the frequency bands from areflexia and dysphagia, which rested on single-case examination sentences; and added overlapping fingers, vocal cord paresis, pyloric stenosis and congenital cardiac defects from the research report. Also corrected a residual internal contradiction in notes prose, which still said all subtypes converge on the akinesia node after LCCS10 and LCCS12 had been deliberately left off it. clinical_trials and datasets are deliberately empty - no interventional LCCS trial and no LCCS-specific omics resource were identified, and no accession was manufactured from a causal-gene search. Zebrafish results for GLE1, ZBTB42 and ADCY6 are cited as MODEL_ORGANISM evidence on mechanism nodes but no animal_models section with modeled_mechanisms links was built; that is left as follow-up. Third review round. Removed two phenotypes, Pyloric Stenosis and Congenital Cardiac Defects, that had been tagged subtype LCCS10 and sourced to PMID:36712877. Re-reading the cached paper confirmed the reviewer: those visceral and cardiac findings belong to the allelic APUG disorder (arthrogryposis, Perthes disease and upward gaze palsy) whose patients survive and carry compound heterozygous or missense NEK9 alleles, not to LCCS10, which is reported in fetuses with homozygous truncating alleles. The paper describes its own two surviving neonates as almost consistent with APUG, and the pyloric/pulmonic/septal findings appear in its literature review under Alkuraya APUG patients rather than under the Casey LCCS10 fetuses. This was Named Entity Confusion reached through an allelic series: both snippets were exact and the PMID real, so no validator caught it, and the phenotype descriptions then used those misattributed findings to argue that LCCS10 is mechanistically different from the motor-unit subtypes, which is the claim the lccs10_offspine_mechanism gap rests on. The gap now carries an explicit caution recording the APUG/LCCS10 boundary and the fact that an earlier draft crossed it. Also tagged Overlapping Fingers subtype LCCS3, its only source being LCCS3-specific. Snippet count 135 to 133. Validation run: validate (schema + terms) passed; validate-terms passed; check-duplicate-keys passed; check-entity-refs passed; check_reference_titles.py --against-ref origin/main passed; check-folded-hyphens, check-snippet-length, check-title-snippets and check-snippet-grading all passed with no new baseline entries.

Falcon ▸
Lethal Congenital Contracture Syndrome: Research Report
Edison Scientific Literature 30 citations 2026-08-28T23:02:47.440117

Lethal Congenital Contracture Syndrome: Research Report

Executive summary

Lethal congenital contracture syndromes (LCCSs) are a genetically heterogeneous group of predominantly autosomal-recessive fetal-akinesia disorders. Reduced or absent fetal movement causes congenital contractures and secondary deformation—pulmonary hypoplasia, craniofacial abnormalities, growth restriction, polyhydramnios, and sometimes hydrops. “Arthrogryposis” is a descriptive finding rather than a single diagnosis; LCCS overlaps clinically with arthrogryposis multiplex congenita (AMC), fetal akinesia deformation sequence (FADS), and Pena–Shokeir syndrome type I. AMC overall occurs in approximately 1/3,000–1/5,000 births, but each molecular LCCS subtype is much rarer, usually represented by only a few families. (potrony2022lethalcongenitalcontracture pages 1-2, wambach2017survivalamongchildren pages 1-3)

The best-established molecular forms in the retrieved evidence involve GLE1, ERBB3, PIP5K1C, ZBTB42, CNTNAP1, ADCY6, NEK9, and GLDN. These converge on failure of the fetal motor unit or musculoskeletal development through RNA metabolism, motor-neuron survival, axon–glial organization, nodal conduction, phosphoinositide/cAMP signaling, mitosis, and ciliogenesis. The label “lethal” is not absolute: especially in GLDN-related LCCS11, survival into childhood or adolescence is possible with intensive respiratory and nutritional support. (beecroft2018geneticsofneuromuscular pages 3-4, wambach2017survivalamongchildren pages 1-3)

Subtype OMIM disease ID Gene Molecular role / mechanism Hallmark distinguishing findings Lethality / survival Key evidence / date
LCCS1 253310 GLE1 Regulates mRNA export and translation; GLE1-related fetal motor neuron disease with anterior horn involvement (trabacca2024updateoninherited pages 11-12, nousiainen2011molecularbackgroundofa pages 24-26) Complete fetal immobility, severe hydrops, intrauterine growth restriction; flexion contractures, knee hyperextension, pulmonary hypoplasia, micrognathia; fetal death often before 32 weeks (nousiainen2011molecularbackgroundofa pages 24-26, trabacca2024updateoninherited pages 11-12) Usually prenatal lethal / fetal death before 32 weeks (trabacca2024updateoninherited pages 11-12, nousiainen2011molecularbackgroundofa pages 24-26) Nousiainen thesis evidence summarized in retrieved text; Trabacca review 2024 (nousiainen2011molecularbackgroundofa pages 24-26, trabacca2024updateoninherited pages 11-12)
LCCS2 not established from retrieved evidence ERBB3 Gene assignment supported in review-level retrieved evidence; detailed molecular mechanism not established from primary retrieved text (trabacca2024updateoninherited pages 11-12) Cranial and ocular abnormalities, enlarged bladder with hydronephrosis, cystic kidney changes (trabacca2024updateoninherited pages 11-12) Usually fatal shortly after birth (trabacca2024updateoninherited pages 11-12) Trabacca review 2024; pediatric motor neuron review evidence in conversation (trabacca2024updateoninherited pages 11-12)
LCCS3 611369 PIP5K1C Phosphatidylinositol-4-phosphate 5-kinase; synthesizes PIP2; reported disease mechanism is haploinsufficiency / truncating loss of function in retrieved evidence (zhang2024novelpip5k1cvariant pages 1-2, zhang2024novelpip5k1cvariant pages 2-5) Small gestational age, severe multiple joint contractures, muscle atrophy, respiratory failure; detailed fetal findings include talipes equinovarus, extended knees, closed hands/overlapping fingers; possible bilateral dilated lateral ventricles in one fetus (zhang2024novelpip5k1cvariant pages 1-2, zhang2024novelpip5k1cvariant pages 2-5) Early death due to respiratory failure; prior five reported individuals all died in summarized table, plus two Chinese fetuses described (zhang2024novelpip5k1cvariant pages 1-2, zhang2024novelpip5k1cvariant pages 2-5) Zhang et al., BMC Pediatrics, 2024; novel c.949_952dup p.S318Ifs28 plus c.688_689del p.G230Qfs114 (zhang2024novelpip5k1cvariant pages 1-2, zhang2024novelpip5k1cvariant pages 2-5)
LCCS6 613915 ZBTB42 Not established from retrieved evidence beyond subtype-gene association mention in review evidence (beecroft2018geneticsofneuromuscular pages 3-3) Not established from retrieved evidence Not established from retrieved evidence Mentioned in Beecroft review 2018 as LCCS6/ZBTB42 association (beecroft2018geneticsofneuromuscular pages 3-3)
LCCS7 inconsistent in retrieved evidence: 616286 vs 607598 CNTNAP1 CASPR; essential node of Ranvier component for saltatory conduction; severe axoglial / myelinated axon abnormalities with very low motor nerve conduction velocity (laquerriere2014mutationsincntnap1 pages 1-2, beecroft2018geneticsofneuromuscular pages 3-4) Severe arthrogryposis / fetal akinesia with peripheral nerve axoglial defects; marked reduction in motor nerve conduction velocity (<10 m/s) (laquerriere2014mutationsincntnap1 pages 1-2) In review summary, 5 of 7 patients died within 2 months; exact survival spectrum not fully established here (beecroft2018geneticsofneuromuscular pages 3-4) Laquerriere et al., Hum Mol Genet, 2014; Beecroft review 2018 notes OMIM inconsistency in retrieved evidence (laquerriere2014mutationsincntnap1 pages 1-2, beecroft2018geneticsofneuromuscular pages 3-4)
LCCS8 616287 ADCY6 Adenylyl cyclase type 6; membrane-associated enzyme catalyzing cAMP formation; associated with lack of PNS myelin / hypomyelinating neuropathy in reported cases (agolini2020expandingtheclinical pages 1-6, laquerriere2014mutationsincntnap1 pages 1-2) Distal joint contractures, severe hypotonia, lack of swallowing, absent autonomous respiratory function and deep tendon reflexes; may include hydrocephalus, severe muscle loss, hypomyelinating neuropathy (agolini2020expandingtheclinical pages 1-6) Original reported siblings died within first 3 months; additional patient died at 36 months after intensive support (agolini2020expandingtheclinical pages 1-6, beecroft2018geneticsofneuromuscular pages 3-4) Agolini et al., Clin Genet, 2020; Laquerriere et al., 2014 discovery paper (agolini2020expandingtheclinical pages 1-6, laquerriere2014mutationsincntnap1 pages 1-2)
LCCS10 617022 NEK9 NIMA-related serine/threonine kinase; mitotic spindle / centrosome functions; linked to defective primary cilia formation, with broader cilia/autophagy evidence from NEK9 biology (liu2023novelvariantsof pages 1-2, yamamoto2021nek9regulatesprimary pages 1-2) Multiple joint contractures / arthrogryposis; severe cases reported with shortened limbs in literature summaries; neonatal cases included camptodactyly, stiff neck, pyloric stenosis, heart defects (liu2023novelvariantsof pages 1-2, liu2023novelvariantsof pages 2-5) Historically described as lethal fetal form, but 2023 report expands to neonatal survivors/discharges; full survival range not established from retrieved evidence (liu2023novelvariantsof pages 1-2, liu2023novelvariantsof pages 2-5) Liu et al., Front Genet, 2023; novel variants c.717C>A, c.2824delA, c.61G>T not in ClinVar/HGMD/gnomAD (liu2023novelvariantsof pages 1-2, liu2023novelvariantsof pages 2-5)
LCCS11 617194 GLDN Gliomedin; required for nodes of Ranvier formation and peripheral nervous system development; GLDN variants disrupt nodal interactions and can be framed as FADS-spectrum nodopathy (potrony2022lethalcongenitalcontracture pages 1-2, mis2020thelatestfads pages 1-2) Hydrops, short long bones, fixed limb joints, absent fetal movements, polyhydramnios, growth restriction, pulmonary hypoplasia, retrognathia; distal arthrogryposis (potrony2022lethalcongenitalcontracture pages 1-2) Not invariably lethal: 4/6 additional patients in 2017 survived beyond neonatal period with intensive chronic respiratory/nutritional support; condition may extend into childhood/adolescence (wambach2017survivalamongchildren pages 1-3, mis2020thelatestfads pages 1-2) Wambach et al., Hum Mutat, 2017; Potrony et al., J Clin Med, 2022; Mis et al., AJMG A, 2020 (wambach2017survivalamongchildren pages 1-3, potrony2022lethalcongenitalcontracture pages 1-2, mis2020thelatestfads pages 1-2)

Table: This table summarizes lethal congenital contracture syndrome subtypes supported by evidence retrieved in the conversation. It highlights subtype-gene relationships, distinguishing findings, survival patterns, and places where the evidence base is incomplete or internally inconsistent.

1. Disease information

Definition and scope

LCCS is characterized by prenatal-onset hypokinesia or akinesia, multiple fixed joint contractures, and severe neuromuscular or skeletal developmental disease. Contractures are generally non-progressive structural consequences of impaired fetal movement, although respiratory, nutritional, and neurologic morbidity may evolve after birth in survivors. Secondary deformation can include pulmonary hypoplasia, micrognathia/retrognathia, short neck, pterygia, shortened umbilical cord, polyhydramnios, impaired gut motility, and growth restriction. (nousiainen2011molecularbackgroundofa pages 24-26, potrony2022lethalcongenitalcontracture pages 1-2)

Synonyms/overlap terms: multiple congenital contractures; arthrogryposis multiplex congenita; fetal akinesia deformation sequence; Pena–Shokeir syndrome type I; for LCCS1, multiple contracture syndrome, Finnish type or Herva disease. GLE1-related lethal arthrogryposis with anterior horn-cell disease (LAAHD/CAAHD) is allelic and clinically overlapping but often distinguished from classic LCCS1. (nousiainen2011molecularbackgroundofa pages 24-26, potrony2022lethalcongenitalcontracture pages 1-2, trabacca2024updateoninherited pages 11-12)

Identifiers

The umbrella disorder does not have one reliably verified identifier in the retrieved literature; subtype-specific OMIM records are preferable. Verified examples are LCCS1, OMIM 253310; LCCS3, 611369; LCCS6, 613915; LCCS8, 616287; LCCS10, 617022; and LCCS11, 617194. Retrieved sources conflicted for LCCS7 (616286 versus 607598), so an operational knowledge base should resolve this directly against the current OMIM release before ingestion. No umbrella MONDO ID, dedicated ICD-10/ICD-11 code, or MeSH heading was verified here; clinically, cases are usually coded under arthrogryposis/multiple congenital malformations plus molecular diagnosis. (beecroft2018geneticsofneuromuscular pages 3-3, beecroft2018geneticsofneuromuscular pages 3-4, liu2023novelvariantsof pages 1-2, zhang2024novelpip5k1cvariant pages 1-2)

The evidence is aggregated disease-level literature, principally family reports, fetal/neonatal case series, molecular studies, and reviews—not patient-level EHR data.

2. Etiology and risk/protective factors

The primary cause is biallelic germline pathogenic variation. Most reported variants are homozygous in consanguineous/founder populations or compound heterozygous in unrelated parents. Disease mechanisms are commonly loss of function, including nonsense, frameshift, splice-disrupting, or damaging missense alleles. (liu2023novelvariantsof pages 1-2, zhang2024novelpip5k1cvariant pages 1-2, agolini2020expandingtheclinical pages 1-6)

The principal risk factors are parental carrier status, consanguinity, ancestry-specific founder alleles, and an affected pregnancy or sibling. The classic GLE1 LCCS1 allele is enriched in the Finnish disease heritage; the early PIP5K1C LCCS3 series involved an Israeli Bedouin kindred. A 2024 population analysis used 125,748 exomes and 15,708 genomes from gnomAD to estimate recessive neuromuscular carrier burdens, but it did not provide a sufficiently supported LCCS-specific prevalence estimate in the retrieved text. (beecroft2018geneticsofneuromuscular pages 3-4, choi2024globalcarrierfrequency pages 6-8, zhang2024novelpip5k1cvariant pages 2-5)

No reproducible environmental, lifestyle, infectious, sex-specific, or age-related risk factor is established for molecular LCCS. Likewise, no protective allele, modifier gene, protective exposure, or validated gene–environment interaction has been demonstrated. Maternal infection, oligohydramnios, uterine constraint, autoimmune disease, and teratogens are important alternative causes of fetal akinesia/arthrogryposis, not established causes of genetically confirmed LCCS. (illes2024heterogenicgeneticbackground pages 1-2)

3. Phenotypes

Core ontology-ready phenotypes include:

  • Decreased/absent fetal movement—prenatal, severe, causally upstream; HP:0001558 Decreased fetal movement or HP:0001989 Fetal akinesia.
  • Multiple congenital joint contractures/arthrogryposis—congenital, usually severe and structurally stable; HP:0002804 Arthrogryposis multiplex congenita and HP:0012453 Arthrogryposis.
  • Talipes equinovarus—often bilateral; HP:0001762.
  • Camptodactyly/overlapping fingers/closed hands—HP:0012385, HP:0010557.
  • Knee hyperextension or fixed flexion, elbow/wrist/hip contractures—joint-specific contracture terms.
  • Muscle hypoplasia/atrophy and hypotonia—HP:0003202, HP:0001252; neurogenic denervation may be present.
  • Areflexia—HP:0001284.
  • Pulmonary hypoplasia and respiratory failure—HP:0002089, HP:0002878; major determinants of mortality.
  • Polyhydramnios—HP:0001561, often reflecting impaired swallowing.
  • Hydrops fetalis—HP:0001789, particularly prominent in LCCS1 and some LCCS11 fetuses.
  • Intrauterine growth restriction—HP:0001511.
  • Micrognathia/retrognathia and short neck—HP:0000347/HP:0000278, HP:0000470.
  • Pterygia—HP:0001059.
  • Feeding/swallowing difficulty—HP:0011968/HP:0002015.

Subtype-enriched findings include renal/urinary abnormalities and cranio-ocular anomalies in ERBB3-related LCCS2; hypomyelinating neuropathy and vocal-cord paralysis in ADCY6-related LCCS8; pyloric stenosis and cardiac defects in some NEK9 patients; and possible ventriculomegaly in PIP5K1C LCCS3. In the 2024 PIP5K1C report, all seven detailed patients had dyskinesia and contractures; all five original Bedouin patients and one Chinese fetus died from respiratory insufficiency. Ventriculomegaly occurred in only one of two genetically identical Chinese fetuses and therefore remains a provisional association. (trabacca2024updateoninherited pages 11-12, liu2023novelvariantsof pages 2-5, zhang2024novelpip5k1cvariant pages 2-5, agolini2020expandingtheclinical pages 1-6)

Formal EQ-5D, SF-36, PROMIS, or disease-specific quality-of-life data are unavailable. Functional burden in survivors is nevertheless profound: ventilation, tracheostomy, gastrostomy, mobility impairment, rehabilitation, and recurrent hospitalization may be required. Some GLDN survivors have preserved cognition and developmental progress despite severe neonatal disease. (mis2020thelatestfads pages 1-2, wambach2017survivalamongchildren pages 1-3)

4. Genetic and molecular information

All established LCCS alleles are constitutional/germline, not somatic. Representative variants include:

  • PIP5K1C/LCCS3: homozygous c.757G>A (p.Asp253Asn) in five Bedouin patients; compound-heterozygous c.688_689del (p.G230Qfs114) and novel c.949_952dup (p.S318Ifs28) in two Chinese fetuses. The latter pair was classified pathogenic under ACMG/AMP criteria PVS1+PM2+PP1+PP4; both predict truncation, and p.S318Ifs*28 was considered unlikely to escape nonsense-mediated decay. All known variants summarized in that study localized to the PIPK domain. (zhang2024novelpip5k1cvariant pages 1-2, zhang2024novelpip5k1cvariant pages 2-5)
  • NEK9/LCCS10 spectrum: c.717C>A, c.2824delA, and c.61G>T were reported in two neonates as compound-heterozygous truncating variants; none was present in ClinVar, HGMD, or gnomAD at publication. The report emphasizes mutation-dependent phenotypic breadth from lethal fetal disease to neonatal arthrogryposis. (liu2023novelvariantsof pages 1-2, liu2023novelvariantsof pages 2-5)
  • ADCY6/LCCS8: compound-heterozygous c.1535+1G>A and c.3007G>A (p.Glu1003Lys) were identified in a severely affected girl; p.Glu1003Lys was absent from gnomAD. Earlier families carried homozygous missense alleles. (agolini2020expandingtheclinical pages 1-6)
  • CNTNAP1/LCCS7: four unrelated families had homozygous frameshift variants causing severe axoglial disease. (laquerriere2014mutationsincntnap1 pages 1-2)
  • GLDN/LCCS11: both homozygous and compound-heterozygous variants are established; p.Leu365Phe and p.Arg393Lys have functional evidence in a surviving patient. (mis2020thelatestfads pages 1-2, wambach2017survivalamongchildren pages 1-3)

No validated modifier genes, disease-specific methylation signature, recurrent pathogenic chromosomal rearrangement, or epigenetic mechanism is established. Normal karyotype/CMA in affected fetuses is common and does not exclude LCCS. (potrony2022lethalcongenitalcontracture pages 1-2, zhang2024novelpip5k1cvariant pages 1-2)

5. Environmental information

No toxin, radiation exposure, pollutant, occupation, diet, smoking, alcohol, exercise pattern, or infectious agent has been shown to cause or modify genetically confirmed LCCS. These variables matter chiefly in the differential diagnosis of fetal akinesia. LCCS is neither infectious nor transmissible.

6. Mechanism and pathophysiology

Unifying causal chain

Biallelic gene dysfunction → impaired motor-neuron development/survival, axonal conduction, neuromuscular signaling, or skeletal/ciliary development → reduced fetal muscle contraction → fetal akinesia → persistent joint positioning and connective-tissue fixation → multiple contractures; impaired breathing/swallowing movements → pulmonary hypoplasia, polyhydramnios, respiratory and feeding failure. (illes2024heterogenicgeneticbackground pages 1-2, potrony2022lethalcongenitalcontracture pages 1-2)

Gene-specific mechanisms

  • GLE1: defective regulation of nuclear mRNA export and translation initiation/termination is associated with anterior-horn motor-neuron loss and severe skeletal-muscle atrophy. Suggested GO terms: mRNA export from nucleus (GO:0006406), translation initiation (GO:0006413), translation termination (GO:0006415), motor neuron development (GO:0021675). (trabacca2024updateoninherited pages 11-12)
  • CNTNAP1/CASPR: disruption of axon–glial paranodal architecture impairs saltatory conduction. Patients had motor nerve conduction velocities below 10 m/s and severe abnormalities of nodes of Ranvier and myelinated axons. Suggested GO: node of Ranvier assembly and myelination; CL: motor neuron, Schwann cell. (laquerriere2014mutationsincntnap1 pages 1-2)
  • GLDN/gliomedin: gliomedin interacts with NF186 and NrCAM to cluster sodium channels at peripheral nodes of Ranvier. Loss produces a developmental nodopathy, fetal hypomotility, and respiratory dysfunction. Suggested GO: node of Ranvier assembly, sodium-channel clustering; GO-CC: node of Ranvier; CL: Schwann cell and peripheral sensory/motor neuron. (mis2020thelatestfads pages 1-2, wambach2017survivalamongchildren pages 1-3)
  • ADCY6: adenylyl cyclase 6 generates cAMP downstream of GPCR signaling. Biallelic dysfunction is associated with absent or deficient peripheral myelin, severe neurogenic damage, hypotonia, and areflexia. Suggested GO: cAMP biosynthetic process (GO:0006171), G protein-coupled receptor signaling pathway; CHEBI: cyclic AMP (CHEBI:17489). (laquerriere2014mutationsincntnap1 pages 1-2, agolini2020expandingtheclinical pages 1-6)
  • PIP5K1C: the lipid kinase converts PI4P to phosphatidylinositol-4,5-bisphosphate (PIP2), supporting calcium signaling, actin dynamics, endocytosis/exocytosis, and synaptic function. Pip5k1c-null mice show approximately 50% lower brain PIP2 and impaired depolarization-dependent PIP2 synthesis at nerve terminals. Suggested GO: phosphatidylinositol phosphorylation, synaptic vesicle exocytosis, actin cytoskeleton organization; CHEBI: PI4P and PI(4,5)P2. (zhang2024novelpip5k1cvariant pages 1-2, zhang2024novelpip5k1cvariant pages 2-5)
  • NEK9: this serine/threonine kinase participates in spindle assembly, centrosome separation, mitosis, and primary-cilium formation. Cell/mouse experiments show NEK9 acts as a selective-autophagy adaptor for MYH9; loss causes MYH9 accumulation, actin stabilization, and impaired ciliogenesis, while MYH9 depletion rescues ciliogenesis in mutant cells. Suggested GO: mitotic spindle organization, centrosome separation, cilium assembly (GO:0060271), selective autophagy; GO-CC: centrosome, primary cilium, autophagosome. (yamamoto2021nek9regulatesprimary pages 1-2, liu2023novelvariantsof pages 1-2)

Immune dysregulation, chronic inflammation, and a disease-specific metabolomic/lipidomic signature are not established. Beyond gene-focused experiments, no mature LCCS single-cell, spatial-transcriptomic, clinical proteomic, or integrated multi-omic atlas was identified.

7. Anatomical structures affected

Primary involvement is in the fetal neuromuscular system: spinal anterior-horn motor neurons, peripheral nerves and myelin, nodes/paranodes of Ranvier, neuromuscular unit, and skeletal muscle. Secondary deformation affects limb joints, hands, feet, jaw, neck, thorax, and lungs. Kidneys/urinary tract are particularly relevant in LCCS2; brain anomalies occur variably rather than universally. (nousiainen2011molecularbackgroundofa pages 24-26, trabacca2024updateoninherited pages 11-12, laquerriere2014mutationsincntnap1 pages 1-2)

Suggested UBERON annotations include spinal cord (UBERON:0002240), peripheral nervous system (UBERON:0000010), skeletal muscle tissue (UBERON:0001134), lung (UBERON:0002048), limb joint, hand, foot, mandible, kidney, and urinary bladder. Laterality is generally bilateral/symmetric, especially talipes and limb contractures, but asymmetry can occur.

8. Temporal development

Onset is prenatal, often detectable in the late first or second trimester through reduced movement and abnormal limb positioning. Classic LCCS1 can be recognized ultrasonographically around 11–12 weeks and commonly ends in fetal death before 32 weeks. Other forms may present at birth with respiratory failure, hypotonia, areflexia, feeding failure, or fixed contractures. (nousiainen2011molecularbackgroundofa pages 24-26, trabacca2024updateoninherited pages 11-12)

There are no validated disease stages or remission patterns. The mechanistic injury occurs during a critical fetal-development window; established contractures do not spontaneously reverse. In survivors, respiratory dependence may improve—one GLDN patient was weaned from respiratory support by 14 months—but feeding, mobility, and orthopedic needs may persist. (mis2020thelatestfads pages 1-2)

9. Inheritance and population

Inheritance is usually autosomal recessive. For two carrier parents, the Mendelian recurrence risk is 25% affected, 50% carrier, and 25% unaffected/non-carrier in each pregnancy. Penetrance appears high for clearly pathogenic biallelic alleles, but expressivity and lethality vary by gene and allele. Anticipation is not expected. Germline mosaicism has not been quantified; it remains a residual consideration when apparently de novo findings are encountered.

Consanguinity has played a major role in gene discovery. GLE1 LCCS1 is strongly associated with Finland and a founder allele; PIP5K1C LCCS3 was initially described in Bedouin patients. Outside founder groups, compound heterozygosity is common. No reliable sex bias exists because autosomal-recessive disease should affect both sexes equally. Subtype-specific incidence and carrier frequency remain unknown. (beecroft2018geneticsofneuromuscular pages 3-4, zhang2024novelpip5k1cvariant pages 1-2, zhang2024novelpip5k1cvariant pages 2-5)

10. Diagnostics

Prenatal and clinical evaluation

Serial expert ultrasound should assess fetal movement, limb position, hands/feet, jaw, growth, amniotic fluid, hydrops, lung/thoracic development, kidneys/bladder, and CNS. Fetal MRI may clarify brain, spinal, pulmonary, or muscular abnormalities. Postmortem fetal examination remains valuable after pregnancy loss; classic LCCS1 may show profound anterior-horn and skeletal-muscle atrophy despite a macroscopically normal brain. (nousiainen2011molecularbackgroundofa pages 24-26, potrony2022lethalcongenitalcontracture pages 1-2)

In liveborn infants, useful tests include blood chemistry and creatine kinase, echocardiography, renal imaging, brain/spinal MRI, EMG and nerve-conduction studies, swallow/respiratory evaluation, and selected muscle/nerve biopsy. These tests characterize the affected compartment but are not individually diagnostic. ADCY6 disease may show chronic neurogenic EMG/biopsy abnormalities; CNTNAP1 disease can produce motor conduction below 10 m/s. (laquerriere2014mutationsincntnap1 pages 1-2, agolini2020expandingtheclinical pages 1-6)

Genetic-testing algorithm

  1. Confirm fetal akinesia/AMC phenotype and construct a three-generation pedigree.
  2. Perform karyotype or chromosomal microarray when structural anomalies are present.
  3. Use rapid trio WES or WGS, preferably with CNV and splice-aware analysis. A comprehensive fetal-akinesia/arthrogryposis panel should include the established LCCS genes plus broader motor-neuron, peripheral-nerve, neuromuscular-junction, myopathy, skeletal-dysplasia, and congenital-glycosylation genes.
  4. Confirm candidate variants and phase by Sanger sequencing or orthogonal methods; apply ACMG/AMP classification and phenotype segregation.
  5. Reanalyze negative exomes and consider genome/RNA sequencing where a splice, structural, deep-intronic, or poorly covered variant is suspected.

WES has achieved diagnostic rates up to approximately 60% in arthrogryposis cohorts, although this is not an LCCS-specific sensitivity. In recurrent fetal structural anomalies, a separate meta-analysis reported a 40% incremental exome yield, illustrating the utility of trio sequencing in comparable prenatal settings. (potrony2022lethalcongenitalcontracture pages 1-2)

Differential diagnosis

Major alternatives include SMN1-related SMA, congenital myopathies and muscular dystrophies, congenital myasthenic syndromes, CNTN1/NFASC nodopathies, multiple-pterygium syndromes, cerebro-oculo-facio-skeletal disorders, skeletal dysplasias, chromosomal disease, mitochondrial disorders, congenital infection, maternal myasthenia/antibody-mediated fetal akinesia, oligohydramnios, uterine constraint, and teratogen exposure. Recent sequencing continues to expand the differential: biallelic KIF21A loss of function was identified in severe fetal akinesia with arthrogryposis and pulmonary hypoplasia in a 2023 study. (falb2023bialleliclossoffunctionvariants pages 9-9, illes2024heterogenicgeneticbackground pages 1-2)

11. Outcome and prognosis

Mortality is driven principally by pulmonary hypoplasia, respiratory muscle/diaphragm dysfunction, aspiration, and infection. Classic LCCS1 is usually prenatally lethal; LCCS2 is generally fatal shortly after birth; reported PIP5K1C LCCS3 patients died from respiratory insufficiency. ADCY6 cases died from infancy to 36 months in the available series. (trabacca2024updateoninherited pages 11-12, zhang2024novelpip5k1cvariant pages 2-5, agolini2020expandingtheclinical pages 1-6)

GLDN disease demonstrates why genotype-specific counseling is essential. Wambach et al. reported six patients from four families, of whom four survived beyond the neonatal period into infancy, childhood, or late adolescence with intensive care and chronic respiratory/nutritional support. Thus, there are no defensible universal 5- or 10-year survival estimates, and “lethal” should not be interpreted as invariant neonatal death. (wambach2017survivalamongchildren pages 1-3)

No validated prognostic biomarker exists. Likely clinical predictors include severity of fetal akinesia, pulmonary hypoplasia, autonomous respiratory capacity, swallowing ability, extent of denervation/hypomyelination, and the residual function of the causal allele.

12. Treatment and current applications

There is no approved disease-modifying pharmacotherapy, gene therapy, cell therapy, RNA therapy, or genotype-directed drug for LCCS, and the ClinicalTrials.gov search identified no relevant LCCS interventional trial. A 2024 pediatric motor-neuron review likewise reported no disease-modifying treatment for congenital SMA/arthrogryposis conditions. (trabacca2024updateoninherited pages 11-12)

Management is supportive and individualized:

  • neonatal resuscitation and invasive/noninvasive ventilation;
  • tracheostomy, airway-clearance/cough-assist, sleep and gas-exchange monitoring;
  • swallow assessment, aspiration prevention, nasogastric or gastrostomy feeding;
  • physical and occupational therapy, splinting, positioning, and contracture management;
  • orthopedic surgery only when expected benefits exceed anesthetic and respiratory risks;
  • treatment of hydrocephalus, cardiac, renal, gastrointestinal, and infectious complications;
  • palliative-care involvement for uniformly severe prenatal/neonatal presentations.

Suggested NCIt intervention concepts include Mechanical Ventilation, Tracheostomy, Gastrostomy, Physical Therapy, Occupational Therapy, Orthopedic Surgery, Genetic Counseling, and Palliative Care. GLDN and ADCY6 survivor reports provide real-world evidence for chronic ventilation, gastrostomy, rehabilitation, and multidisciplinary follow-up rather than molecular therapy. (mis2020thelatestfads pages 1-2, wambach2017survivalamongchildren pages 1-3, agolini2020expandingtheclinical pages 1-6)

13. Prevention

There is no vaccine, lifestyle intervention, environmental remediation, or prophylactic drug that prevents a pathogenic biallelic genotype. Prevention is reproductive:

  • cascade carrier testing after a molecular diagnosis;
  • ancestry- or family-history-informed preconception carrier screening;
  • partner testing;
  • preimplantation genetic testing for monogenic disease;
  • targeted chorionic-villus or amniotic-fluid testing;
  • early expert ultrasound and, where appropriate, rapid prenatal trio sequencing.

For a known familial genotype, targeted molecular testing is more definitive than ultrasound, because fetal movement abnormalities may emerge after the optimal window for reproductive decision-making. Genetic counseling should address the 25% recurrence risk, variable survival in some subtypes, reproductive options, and residual risks including assay limitations.

14. Other species and natural disease

No well-established naturally occurring veterinary counterpart or zoonotic transmission was identified. The relevant proteins and developmental processes are evolutionarily conserved, but most comparative evidence comes from induced laboratory models rather than natural disease. Suggested taxa include Mus musculus (NCBI Taxon 10090) and Danio rerio (7955).

15. Model organisms and experimental systems

  • CNTNAP1/ADCY6 zebrafish knockdown: morpholino experiments were used in the original human genetics study to support developmental neuromuscular effects. Limitations include transient knockdown and imperfect equivalence to human biallelic alleles. (laquerriere2014mutationsincntnap1 pages 1-2)
  • Pip5k1c-null mouse: reduced brain PIP2 by approximately 50% and impaired nerve-terminal PIP2 synthesis/synaptic function, supporting phosphoinositide and presynaptic mechanisms. The model is useful mechanistically but does not by itself establish every human fetal phenotype. (zhang2024novelpip5k1cvariant pages 2-5)
  • Nek9 models: homozygous knockout is embryonic lethal. LIR-mutant mice show impaired kidney ciliogenesis; cultured mutant cells accumulate MYH9, and MYH9 depletion rescues ciliogenesis. These models distinguish NEK9’s autophagy/ciliary role but do not fully reproduce human contracture syndrome. (yamamoto2021nek9regulatesprimary pages 1-2)
  • Patient fibroblasts: NEK9 LCCS10 fibroblasts have shown defective primary-cilium formation. (yamamoto2021nek9regulatesprimary pages 1-2)
  • GLDN variant assays: functional testing of p.Leu365Phe, p.Arg393Lys, and other patient variants strengthens pathogenic classification and nodal-mechanism inference. (mis2020thelatestfads pages 1-2)

No validated LCCS organoid, iPSC-derived neuromuscular-junction platform, or therapeutic CRISPR screen was identified in the 2023–2024 evidence set.

Recent developments and expert assessment, 2023–2024

  1. PIP5K1C/LCCS3 expansion (published March 2024): two affected Chinese fetuses increased the detailed published count from five to seven. The study added pathogenic c.949_952dup (p.S318Ifs*28), documented compound heterozygosity with c.688_689del, and proposed ventriculomegaly as a possible but unconfirmed phenotype. DOI: https://doi.org/10.1186/s12887-024-04674-6. The authors’ abstract states: “These findings expanded the genetic variant spectrum of PIP5K1C and enriched the clinical features of LCCS3.” (zhang2024novelpip5k1cvariant pages 1-2, zhang2024novelpip5k1cvariant pages 2-5)
  2. NEK9 phenotype expansion (published 4 January 2023): two premature neonates carried three novel truncating alleles, broadening NEK9 disease beyond a uniformly lethal fetal skeletal phenotype. DOI: https://doi.org/10.3389/fgene.2022.989215. The abstract concludes that “different types of mutations in NEK9 lead to different phenotypes.” (liu2023novelvariantsof pages 1-2, liu2023novelvariantsof pages 2-5)
  3. Broader fetal-akinesia gene discovery (2023): biallelic KIF21A loss of function was reported in five fetuses from two families with severe neurogenic fetal akinesia, arthrogryposis, pulmonary hypoplasia, and facial dysmorphism. DOI: https://doi.org/10.1136/jmedgenet-2021-108064. This reinforces expert recommendations for broad trio-exome/genome analysis rather than narrow sequential single-gene testing. (falb2023bialleliclossoffunctionvariants pages 9-9)
  4. Current expert interpretation (October 2024): inherited pediatric motor-neuron disease remains genetically heterogeneous, with LCCS1 viewed as a severe GLE1-related RNA-metabolism/anterior-horn disease and LCCS2 as ERBB3-related multisystem fetal akinesia. Evidence remains dominated by case reports, and no disease-modifying therapy is available. DOI: https://doi.org/10.3390/genes15101346. (trabacca2024updateoninherited pages 11-12)

Evidence limitations

The LCCS literature consists mainly of very small, ancestry-enriched families, fetal pathology series, and survivor case reports. Consequently, phenotype percentages, penetrance, allele frequencies, incidence, survival curves, quality-of-life scores, treatment-response rates, and genotype–phenotype correlations are generally unavailable or unstable. Several older subtype assignments and identifiers vary across secondary sources. Database ingestion should therefore retain gene and OMIM subtype provenance, publication date, evidence type (human/model/in vitro), and uncertainty rather than treating “LCCS” as one homogeneous disorder.

References

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References checked 13
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Unresolved (possible confabulation) 0
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References weighed for topical relevance 13
On topic 9
Off topic 1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • DOI:10.1038/s41467-021-23599-7 (3 mentions) - NEK9 regulates primary cilia formation by acting as a selective autophagy adaptor for MYH9/myosin IIA
  • shared terms: none

Weighed against this report's own most characteristic terms: disease, fetal, gene, clinical, genetic, include, variant, contracture, type, arthrogryposis, congenital, molecular, akinesia, affected, function, severe, lethal, respiratory, patient, lccs.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 32
Resolved 32
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 6
Terms named correctly 3
Terms named as a different term 0
Terms whose name is worth a second look 3

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0006413 (1 mention) - the report calls it "translation initiation"; GO calls it translational initiation, and lists "translation initiation" among its other names
  • GO:0006415 (1 mention) - the report calls it "translation termination"; GO calls it translational termination, and lists "translation termination" among its other names
  • GO:0021675 (1 mention) - the report calls it "motor neuron development"; GO calls it nerve development

Every term resolved, and every label the report gave matched.