Cenani-Lenz Syndactyly Syndrome

Mendelian MONDO:0008931 Pathograph 35 Show in embeddings browser Limb Development Disorders

Autosomal recessive congenital malformation syndrome of the distal limbs caused by biallelic germline loss-of-function variants in LRP4, a low-density lipoprotein receptor-related protein that antagonizes LRP5/LRP6-mediated canonical Wnt signaling. Complex, usually bilateral syndactyly and oligodactyly of the hands with carpal, metacarpal and phalangeal synostosis and disorganization are the defining features; radioulnar synostosis, mesomelic shortening and toe syndactyly are common, and the feet are less affected than the hands. Renal agenesis or hypoplasia is frequent, and a facial gestalt with prominent forehead, hypertelorism, downslanting palpebral fissures and micrognathia occurs in many patients. Expressivity ranges from isolated hand oligosyndactyly to a prenatally lethal form with limb reduction and bilateral renal agenesis, the severe end being associated with truncating alleles. In mice, loss of Lrp4 disrupts the apical ectodermal ridge of the limb bud and delays ureteric budding, which accounts for the limb and kidney malformations.

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1
Inheritance
7
Pathophys.
22
Phenotypes
35
Pathograph
1
Genes
4
Variants
2
Medical Actions
6
Models
1
Deep Research
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Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE KIDNEY URINARY TRACT
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Inheritance

1
Autosomal Recessive HP:0000007
Autosomal recessive inheritance
Show evidence (2 references)
PMID:20381006 SUPPORT Human Clinical
"Cenani-Lenz syndrome (CLS) is an autosomal-recessive congenital disorder affecting distal limb development."
Recessive inheritance in the gene-identification families.
PMID:31750994 SUPPORT Human Clinical
"Sanger validation confirmed that all affected individuals were homozygous and the obligate carriers were heterozygous for this variant."
Unaffected heterozygous obligate carriers and homozygous affected members.
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Pathophysiology

7
Biallelic LRP4 Loss of Function
Homozygous or compound heterozygous germline LRP4 variants: mostly missense variants in the extracellular beta-propeller and LDL-receptor class B domains, plus splice, nonsense and frameshift alleles. Truncating alleles with no residual function give the most severe, sometimes prenatally lethal, presentations. The extracellular domain binds Wnt ligands; a beta1-propeller patient variant reduced Wnt11 binding.
LRP4 hgnc:6696 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves LRP4 (hgnc:6696). hgnc:6696 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context LRP4 hgnc:6696 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns LRP4 (hgnc:6696). hgnc:6696 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
Wnt-protein binding GO:0017147 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased Wnt-protein binding (GO:0017147). GO:0017147 is a molecular function from the Gene Ontology.
Downstream
Loss of LRP4 Antagonism of Canonical Wnt Signaling
Impaired Agrin-LRP4-MuSK Signaling at the Neuromuscular Junction Shown only for the beta1-propeller allele p.Tyr607Cys; not a general consequence of CLSS alleles.
Show evidence (4 references)
PMID:20381006 SUPPORT Human Clinical
"By sequencing candidate genes, we identified recessive LRP4 mutations in 12 families with CLS."
Gene identification study by homozygosity mapping and sequencing.
PMID:23636941 SUPPORT Human Clinical
"The severity of the phenotype in a patient with absent residual LRP4 function may point to a genotype-phenotype correlation."
A homozygous nonsense allele with no residual function produced a severe phenotype.
PMID:28559208 SUPPORT Human Clinical
"These findings not only further expand the phenotypic variability of CLSS but also indicate that early truncated and loss-of-function mutations in LRP4 lead to a more severe CLSS phenotype."
Early-truncating splice allele in a five-generation family with severe disease.
+ 1 more reference
Loss of LRP4 Antagonism of Canonical Wnt Signaling
LRP4 normally restrains LRP5/LRP6-dependent activation of canonical Wnt/beta-catenin signaling. Patient missense proteins lose this activity in reporter assays, and several fail to reach the plasma membrane normally, consistent with misfolding of the extracellular domain. The result is excess canonical Wnt signaling in tissues where LRP4 acts, including the limb-bud ectoderm and the ureteric bud.
LRP4 hgnc:6696 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves LRP4 (hgnc:6696). hgnc:6696 is a gene from the HUGO Gene Nomenclature Committee. LRP6 hgnc:6698 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves LRP6 (hgnc:6698). hgnc:6698 is a gene from the HUGO Gene Nomenclature Committee.
negative regulation of canonical Wnt signaling pathway GO:0090090 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of canonical Wnt signaling pathway (GO:0090090). GO:0090090 is a biological process from the Gene Ontology. canonical Wnt signaling pathway GO:0060070 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased canonical Wnt signaling pathway (GO:0060070). GO:0060070 is a biological process from the Gene Ontology. protein localization to plasma membrane GO:0072659 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein localization to plasma membrane (GO:0072659). GO:0072659 is a biological process from the Gene Ontology.
inhibition of LRP6-dependent Wnt signaling by LRP4 GO:0030547 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased inhibition of LRP6-dependent Wnt signaling by LRP4, annotated with signaling receptor inhibitor activity (GO:0030547). GO:0030547 is a molecular function from the Gene Ontology.
Experimental models
LRP6-dependent Wnt luciferase reporter assay CELL LINE
Downstream
Abnormal Apical Ectodermal Ridge Signaling Excess Wnt signaling in the limb-bud ectoderm is the proposed link; the step from the receptor defect to the abnormal ridge is inferred from mouse knockouts and has not been observed in human embryos.
Dental Anomalies Inferred from tooth abnormalities in Lrp4-deficient mice; how the receptor defect alters human tooth development is not established.
Delayed Ureteric Bud Formation Constitutively active beta-catenin in the ureteric bud lineage reproduces the kidney agenesis of Lrp4 knockout mice, supporting overactive Wnt signaling as the link; a Gremlin-Bmp4 route was also proposed by the same authors.
Show evidence (2 references)
PMID:34857885 SUPPORT In Vitro
"Wild type LRP4 was able to inhibit LRP6-dependent WNT signaling robustly. The two mutants p.(Asp99His) and p.(Arg545Trp) inhibited WNT signaling less effectively, suggesting they reduced LRP4 function."
Luciferase reporter assay of two further patient missense alleles.
PMID:38013226 SUPPORT BACKGROUND In Vitro
"Proteins encoded by some missense mutations of LRP4 can neither antagonize the canonical WNT signaling pathway nor be transported to the cell membrane normally."
Restates the trafficking and Wnt-antagonism results of the gene-identification study, whose abstract does not describe the trafficking assay.
Abnormal Apical Ectodermal Ridge Signaling
The apical ectodermal ridge at the distal edge of the limb bud is the main site of Lrp4 expression. In Lrp4-deficient mice it forms abnormally from embryonic day 9.5, with ectopic expression and aberrant signaling of Fgf8, Shh, Bmp2, Bmp4 and Wnt7a and of the Wnt- and Bmp-responsive factors Lmx1b and Msx1, reduced apoptosis, and dorsal and ventral expansion of the ridge.
apical ectodermal ridge formation GO:1905139 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal apical ectodermal ridge formation (GO:1905139). GO:1905139 is a biological process from the Gene Ontology. embryonic limb morphogenesis GO:0030326 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal embryonic limb morphogenesis (GO:0030326). GO:0030326 is a biological process from the Gene Ontology.
apical ectodermal ridge UBERON:0004356 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in apical ectodermal ridge (UBERON:0004356). UBERON:0004356 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Lrp4 (Megf7) null mouse Mouse recapitulates
Downstream
Defective Digit Separation and Autopod Skeletal Patterning
Show evidence (2 references)
PMID:16207730 SUPPORT Model Organism
"The reason for this developmental abnormality is apparent as early as embryonic day 9.5 when the apical ectodermal ridge (AER), the principal site of Megf7 expression at the distal edge of the embryonic limb bud, forms abnormally in the absence of Megf7."
Lrp4 (Megf7) knockout mice show an abnormal apical ectodermal ridge from E9.5.
PMID:16207730 SUPPORT Model Organism
"Ectopic expression and aberrant signaling of several molecules involved in limb patterning, including Fgf8, Shh, Bmp2, Bmp4 and Wnt7a, as well as the Wnt- and Bmp-responsive transcription factors Lmx1b and Msx1, result in reduced apoptosis and symmetrical dorsal and ventral expansions of the AER."
Patterning signals from the ridge are mis-expressed.
Defective Digit Separation and Autopod Skeletal Patterning
Reduced interdigital apoptosis and ectopic chondrocyte condensation lead to soft-tissue and bony fusion of digits, reduced or duplicated digital rays and disorganized carpal, metacarpal and phalangeal elements. Mice develop polysyndactyly, whereas human patients mostly show oligosyndactyly; the reason for this species difference is not known.
apoptotic process involved in embryonic digit morphogenesis GO:1902263 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased apoptotic process involved in embryonic digit morphogenesis (GO:1902263). GO:1902263 is a biological process from the Gene Ontology. embryonic digit morphogenesis GO:0042733 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal embryonic digit morphogenesis (GO:0042733). GO:0042733 is a biological process from the Gene Ontology.
autopod region UBERON:0002470 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in autopod region (UBERON:0002470). UBERON:0002470 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Lrp4 dan and mdig mutant mice Mouse partially recapitulates
Bovine mulefoot (syndactyly) Cattle partially recapitulates
Downstream
Complex Finger Syndactyly
Oligodactyly
Metacarpal Synostosis
Carpal Synostosis
Disorganized Metacarpals and Phalanges
Toe Syndactyly
Nail Aplasia or Dysplasia
Radioulnar Synostosis The forearm lesions lie proximal to the autopod; how the LRP4 defect produces them is not established.
Mesomelic Limb Shortening The forearm lesions lie proximal to the autopod; how the LRP4 defect produces them is not established.
Show evidence (1 reference)
PMID:37640745 SUPPORT INDIRECT BACKGROUND Model Organism
"Taken together, these findings can then explain the observed human phenotypes such as brachydactyly due to growth impairment or syndactyly due to defect of interdigital apoptosis."
Authors' interpretation of the mouse ridge findings as the basis of human syndactyly.
Delayed Ureteric Bud Formation
In Lrp4 null mice the ureteric bud forms late, fails to bifurcate or upregulate c-Ret at its tip and does not invade the metanephric mesenchyme in time; Gdnf expression is then lost from the mesenchyme. Pax2 and baseline Ret and Gdnf expression are normal, placing the defect at the timing of budding.
ureteric bud development GO:0001657 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal ureteric bud development (GO:0001657). GO:0001657 is a biological process from the Gene Ontology.
ureteric bud UBERON:0000084 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in ureteric bud (UBERON:0000084). UBERON:0000084 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Lrp4 null mouse (kidney) Mouse recapitulates
Downstream
Failed Induction of the Metanephric Mesenchyme
Show evidence (1 reference)
PMID:20454682 SUPPORT Model Organism
"Lrp4(-/-) mice show a delay in ureteric bud formation that results in unilateral or bilateral kidney agenesis."
Lrp4 null mouse study of kidney development.
Failed Induction of the Metanephric Mesenchyme
The metanephric mesenchyme responds to the ureteric bud only during a narrow window; when the bud arrives late the mesenchyme does not differentiate and is lost, giving unilateral or bilateral kidney agenesis. In 156 postnatal Lrp4 null mice, 51% had bilateral and 22% unilateral agenesis.
metanephros development GO:0001656 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal metanephros development (GO:0001656). GO:0001656 is a biological process from the Gene Ontology.
metanephric mesenchyme UBERON:0003220 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in metanephric mesenchyme (UBERON:0003220). UBERON:0003220 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Renal Agenesis
Renal Hypoplasia Proposed by analogy with the agenesis mechanism; the mouse study notes that the human range from agenesis to hypoplasia suggests additional roles for LRP4 or modifying factors.
Ectopic Kidney Position anomalies of the kidney have not been explained mechanistically.
Horseshoe Kidney Fusion anomalies of the kidney have not been explained mechanistically.
Show evidence (2 references)
PMID:20454682 SUPPORT Model Organism
"These data indicate that ureteric bud formation is delayed in mutants, and that the failure to invade the mesenchyme in time to support normal growth/survival is the cause for the frequent uni- or bilateral kidney agenesis."
Authors' conclusion from the developmental time course.
PMID:20454682 SUPPORT Model Organism
"In the examination of post-partum Lrp4−/− mice (n = 156) we found 51 percent bilateral and 22 percent unilateral kidney agenesis"
Penetrance of kidney agenesis in the null mouse.
Impaired Agrin-LRP4-MuSK Signaling at the Neuromuscular Junction
LRP4 is the muscle receptor for neural agrin and activates MuSK to cluster acetylcholine receptors. The beta1-propeller p.Tyr607Cys protein reaches the plasma membrane and binds MuSK normally, but binds agrin and Wnt11 less, and agrin-induced MuSK phosphorylation is reduced. Patient myotubes formed fewer and smaller agrin- and Wnt11-induced acetylcholine receptor clusters. Most CLSS alleles have not been tested for this function and most patients have no neuromuscular symptoms.
myotube CL:0002372 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves myotube (CL:0002372). CL:0002372 is a cell type from the Cell Ontology.
skeletal muscle acetylcholine-gated channel clustering GO:0071340 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased skeletal muscle acetylcholine-gated channel clustering (GO:0071340). GO:0071340 is a biological process from the Gene Ontology.
Experimental models
Patient-derived myotubes (LRP4 p.Tyr607Cys) PRIMARY CELL CULTURE
Downstream
Fatigable Weakness
Show evidence (1 reference)
PMID:37640745 SUPPORT In Vitro
"Mechanistic expression studies show a significant decrease of AChR aggregation in cultured patient myotubes, as well as altered in vitro binding of agrin and Wnt11 ligands to the mutated β1 propeller domain of LRP4 explaining the dual phenotype characterized clinically and..."
Patient myotube clustering assay and ligand-binding assays.
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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Cenani-Lenz Syndactyly 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

22
Eye 1
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316), qualified as congenital onset. HP:0000316 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (1 reference)
PMID:30041615 SUPPORT BACKGROUND Human Clinical
"Facial involvement includes a prominent forehead, hypertelorism, downslanting palpebral fissures and micrognathia"
Framing description of the facial gestalt.
Genitourinary 4
Renal Agenesis HP:0000104 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal agenesis (HP:0000104), qualified as congenital onset. HP:0000104 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (2 references)
PMID:20454682 SUPPORT BACKGROUND Human Clinical
"Renal agenesis, in accordance with the murine phenotype, was observed in one-third of the families, another 25% percent presented with ectopic or hypoplastic kidneys."
Family-level frequency in the human CLS series, restated in the mouse study.
PMID:42153583 SUPPORT Human Clinical
"The 2-year-old proband had a horseshoe kidney, whereas his 6-year-old cousin presented with right renal agenesis."
Unilateral renal agenesis in an LRP4-confirmed family.
Renal Hypoplasia HP:0000089 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal hypoplasia (HP:0000089), qualified as congenital onset. HP:0000089 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (2 references)
PMID:23664847 SUPPORT BACKGROUND Human Clinical
"The clinical expression is variable and kidney agenesis/hypoplasia, craniofacial dysmorphism and teeth abnormalities are frequent features as well as lower limb involvement."
Framing description in an LRP4-confirmed family report.
PMID:28559208 SUPPORT Human Clinical
"Here we describe a consanguineous Pakistani kindred with a severe form of CLSS characterized by complete syndactyly and disorganization of fingers, oligo-syndactyly of toes, shortening of limbs, frontal bossing, and hypoplasia/agenesis of left kidney."
Kidney hypoplasia or agenesis in a splice-variant family.
Ectopic Kidney HP:0000086 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ectopic kidney (HP:0000086), qualified as congenital onset. HP:0000086 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (1 reference)
PMID:20454682 SUPPORT BACKGROUND Human Clinical
"Renal agenesis, in accordance with the murine phenotype, was observed in one-third of the families, another 25% percent presented with ectopic or hypoplastic kidneys."
Ectopic kidneys in the human CLS series, restated in the mouse study.
Horseshoe Kidney HP:0000085 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Horseshoe kidney (HP:0000085), qualified as congenital onset. HP:0000085 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (2 references)
PMID:42153583 SUPPORT Human Clinical
"The 2-year-old proband had a horseshoe kidney, whereas his 6-year-old cousin presented with right renal agenesis."
Horseshoe kidney in a p.Arg1277Leu homozygote.
PMID:37640745 SUPPORT Human Clinical
"She was born after normal gestation and delivery, with congenital malformations of the hands and feet characterized by syndactyly and brachydactyly (more severe for the hands), and a renal malformation with a horseshoe-shaped kidney compatible with a CLS"
Horseshoe kidney in a p.Tyr607Cys homozygote.
Head and Neck 5
Prominent Forehead HP:0011220 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prominent forehead (HP:0011220), qualified as congenital onset. HP:0011220 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (2 references)
PMID:30041615 SUPPORT BACKGROUND Human Clinical
"Facial involvement includes a prominent forehead, hypertelorism, downslanting palpebral fissures and micrognathia"
Framing description of the facial gestalt.
PMID:28559208 SUPPORT Human Clinical
"Here we describe a consanguineous Pakistani kindred with a severe form of CLSS characterized by complete syndactyly and disorganization of fingers, oligo-syndactyly of toes, shortening of limbs, frontal bossing, and hypoplasia/agenesis of left kidney."
Frontal bossing in a splice-variant family.
Downslanted Palpebral Fissures HP:0000494 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Downslanted palpebral fissures (HP:0000494), qualified as congenital onset. HP:0000494 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (1 reference)
PMID:30041615 SUPPORT BACKGROUND Human Clinical
"Facial involvement includes a prominent forehead, hypertelorism, downslanting palpebral fissures and micrognathia"
Framing description of the facial gestalt.
Micrognathia HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347), qualified as congenital onset. HP:0000347 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (2 references)
PMID:30041615 SUPPORT BACKGROUND Human Clinical
"Facial involvement includes a prominent forehead, hypertelorism, downslanting palpebral fissures and micrognathia"
Framing description of the facial gestalt.
PMID:38013226 SUPPORT REVIEW SYNTHESIS Human Clinical
"Fetus II‐1 showed a hypoplastic nose, anteverted nares, prominent zygomata, micrognathia, short malformed limbs, and bilateral renal agenesis."
Micrognathia in a fetus compound heterozygous for truncating LRP4 alleles, as summarized in a literature review.
Cleft Lip HP:0410030 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft lip (HP:0410030), qualified as congenital onset. HP:0410030 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (1 reference)
PMID:28559208 SUPPORT Human Clinical
"The affected individuals were additionally presented with short stature, cleft-lip and hypoplastic shoulder joint with restricted upper limb movement."
Cleft lip in the severe splice-variant family.
Dental Anomalies Abnormality of the dentition HP:0000164 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the dentition (HP:0000164), qualified as congenital onset. HP:0000164 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (1 reference)
PMID:23664847 SUPPORT BACKGROUND Human Clinical
"The clinical expression is variable and kidney agenesis/hypoplasia, craniofacial dysmorphism and teeth abnormalities are frequent features as well as lower limb involvement."
Framing description in an LRP4-confirmed family report.
Integument 1
Nail Aplasia or Dysplasia Nail dysplasia HP:0002164 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nail dysplasia (HP:0002164), qualified as congenital onset. HP:0002164 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (2 references)
PMID:38013226 SUPPORT REVIEW SYNTHESIS Human Clinical
"Complete fusion of all fingers, oligodactyly of the right hand, short and hypoplastic nails, disorganized phalanges"
Literature-review table entry for the homozygous p.Tyr384Cys family.
PMID:38013226 SUPPORT REVIEW SYNTHESIS Human Clinical
"Symmetrical malformations of all four limbs, short forearms, symmetrical complicated overlapping syndactyly, adducted thumbs, rudimentary dysplastic fused nails"
Literature-review table entry for the homozygous p.Cys1637Tyr siblings.
Limbs 8
Complex Finger Syndactyly HP:0006101 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Complex finger syndactyly, annotated with Finger syndactyly (HP:0006101), qualified as congenital onset. HP:0006101 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (2 references)
PMID:20381006 SUPPORT Human Clinical
"Cenani-Lenz syndrome (CLS) is an autosomal-recessive congenital disorder affecting distal limb development. It is characterized mainly by syndactyly and/or oligodactyly"
Syndactyly is a principal feature in the gene-identification series.
PMID:28559208 SUPPORT Human Clinical
"Here we describe a consanguineous Pakistani kindred with a severe form of CLSS characterized by complete syndactyly and disorganization of fingers, oligo-syndactyly of toes, shortening of limbs, frontal bossing, and hypoplasia/agenesis of left kidney."
Complete finger syndactyly in an LRP4 splice-variant family.
Oligodactyly HP:0012165 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oligodactyly (HP:0012165), qualified as congenital onset. HP:0012165 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (2 references)
PMID:15710123 SUPPORT REVIEW SYNTHESIS Human Clinical
"According to our research of literature and our clinical findings there seem to exist two grossly different clinical phenotypes: spoon hand type and oligodactyly type."
Literature review plus case describing the oligodactyly type.
PMID:30041615 SUPPORT Human Clinical
"we report here two patients, born to consanguineous Sri Lankan parents, present with bilateral postaxial oligodactyly limited to upper limbs."
Mild end of the spectrum in a homozygous p.Ile450Val family.
Metacarpal Synostosis HP:0009701 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Metacarpal synostosis (HP:0009701), qualified as congenital onset. HP:0009701 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (2 references)
PMID:15710123 SUPPORT REVIEW SYNTHESIS Human Clinical
"Typical constant clinical features such as carpal, metacarpal and digital synostoses, disorganisation of carpal bones, reduction of digital rays and syndactyly of toes are found in the reported cases."
Metacarpal synostosis is constant in the reviewed cases.
PMID:23664847 SUPPORT BACKGROUND Human Clinical
"The disorder is characterized by complete syndactyly with metacarpal fusions and/or oligodactyly sometimes accompanied by radioulnar synostosis."
Background description in an LRP4-confirmed family report.
Carpal Synostosis HP:0009702 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Carpal synostosis (HP:0009702), qualified as congenital onset. HP:0009702 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (2 references)
PMID:15710123 SUPPORT REVIEW SYNTHESIS Human Clinical
"Typical constant clinical features such as carpal, metacarpal and digital synostoses, disorganisation of carpal bones, reduction of digital rays and syndactyly of toes are found in the reported cases."
Carpal synostosis and carpal disorganization are constant in the reviewed cases.
PMID:42153583 SUPPORT BACKGROUND Human Clinical
"Cenani-Lenz syndactyly syndrome (CLSS, OMIM 212780) is a rare autosomal recessive disorder characterized by syndactyly and oligodactyly of the digits, fusion of carpal and tarsal bones, and radioulnar synostosis."
Framing description in an LRP4-confirmed family report.
Disorganized Metacarpals and Phalanges Abnormal metacarpal morphology HP:0005916 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Disorganized metacarpals and phalanges, annotated with Abnormal metacarpal morphology (HP:0005916), qualified as congenital onset. HP:0005916 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (2 references)
PMID:30569497 SUPPORT REVIEW SYNTHESIS Human Clinical
"Cenani-Lenz (C-L) syndrome is characterized by oligosyndactyly, metacarpal synostosis, phalangeal disorganization, and other variable facial and systemic features."
Review of the clinical features.
PMID:42153583 SUPPORT Human Clinical
"All patients presented with bilateral complex syndactyly, characterized by absent phalanges, reduced and disorganized metacarpals, and cutaneous toe syndactyly."
Four affected relatives homozygous for p.Arg1277Leu.
Toe Syndactyly HP:0001770 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Toe syndactyly (HP:0001770), qualified as congenital onset. HP:0001770 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (2 references)
PMID:42153583 SUPPORT Human Clinical
"All patients presented with bilateral complex syndactyly, characterized by absent phalanges, reduced and disorganized metacarpals, and cutaneous toe syndactyly."
Cutaneous toe syndactyly in all four affected relatives.
PMID:15710123 SUPPORT REVIEW SYNTHESIS Human Clinical
"Typical constant clinical features such as carpal, metacarpal and digital synostoses, disorganisation of carpal bones, reduction of digital rays and syndactyly of toes are found in the reported cases."
Toe syndactyly is listed among the constant features.
Radioulnar Synostosis HP:0002974 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Radioulnar synostosis (HP:0002974), qualified as congenital onset. HP:0002974 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (2 references)
PMID:31895055 SUPPORT BACKGROUND Human Clinical
"Cenani-Lenz syndactyly (CLS) is a rare autosomal recessive syndrome characterized by disorganized oligosyndactyly of upper and lower limbs as well as radioulnar synostosis."
Framing description in an LRP4-confirmed case report.
PMID:15710123 SUPPORT REVIEW SYNTHESIS Human Clinical
"Inconstant features such as radio-ulnar synostosis, brachymesomelia, metatarsal synostoses and reduction of metatarsal rays may be present."
Radioulnar synostosis is inconstant in the reviewed cases.
Mesomelic Limb Shortening Mesomelia HP:0003027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mesomelia (HP:0003027), qualified as congenital onset. HP:0003027 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (2 references)
PMID:30041615 SUPPORT BACKGROUND Human Clinical
"radioulnar synostosis and mesomelic shortness of the limbs, with lower limbs usually being much less affected than upper limbs."
Framing description of the syndrome.
PMID:24924585 SUPPORT Human Clinical
"Here we present two sibling fetuses with a prenatal lethal presentation of mesomelic limb reductions, oligosyndactyly, genitourinary malformation and compound heterozygosity for two novel truncating mutations in LRP4."
Severe mesomelic reduction with compound heterozygous truncating alleles.
Musculoskeletal 2
Scoliosis OCCASIONAL 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:28559208 SUPPORT BACKGROUND Human Clinical
"It is occasionally associated with renal hypoplasia, oro-facial defects, scoliosis of the thoracic spine, hearing loss, and genital anomalies."
Framing description stating scoliosis is occasional.
Fatigable Weakness HP:0003473 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatigable weakness (HP:0003473). HP:0003473 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37640745 SUPPORT Human Clinical
"In the French cohort of CMS patients, we identified a novel LRP4 homozygous missense mutation (c.1820A > G; p.Thy607Cys) within the β1 propeller domain in a patient presenting CMS symptoms, including muscle weakness, fluctuating fatigability and a decrement in compound muscle action potential in..."
Single patient with combined CLS and congenital myasthenic syndrome.
Growth 1
Short Stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28559208 SUPPORT Human Clinical
"The affected individuals were additionally presented with short stature, cleft-lip and hypoplastic shoulder joint with restricted upper limb movement."
Short stature in all affected members of one family.
🧬

Genetic Associations

1
LRP4
Gene: LRP4 hgnc:6696 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is LRP4 (hgnc:6696). hgnc:6696 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:20381006 SUPPORT Human Clinical
"We used a homozygosity-mapping approach to map the CLS1 locus to chromosome 11p11.2-q13.1. By sequencing candidate genes, we identified recessive LRP4 mutations in 12 families with CLS."
Identification of LRP4 as the disease gene.
PMID:25676610 SUPPORT BACKGROUND Human Clinical
"LRP4 mutations were identified in most, but not all patients with this syndrome, suggesting the presence of at least one additional locus."
LRP4 explains most but not all clinically diagnosed families.
Variants (4)
c.2858T>C p.Leu953Pro
Homozygous in a consanguineous Pakistani pedigree with nine affected members whose disease was restricted to the limbs and kidneys.
Show evidence (1 reference)
PMID:23664847 SUPPORT Human Clinical
"Genetic analysis using autozygosity mapping and sequencing revealed homozygosity for a novel missense mutation c.2858T > C (p.L953P) in the LRP4 gene."
Segregating homozygous missense variant.
c.316+1G>A
Homozygous canonical splice-donor variant predicted to truncate the protein early; severe CLSS with short stature, cleft lip and kidney hypoplasia or agenesis in a five-generation family.
Show evidence (1 reference)
PMID:28559208 SUPPORT Human Clinical
"A novel splice variant in LRP4 (c.316+1G > A) segregated with the phenotype in a five generations family."
Segregation of the splice variant.
c.295G>C p.Asp99His and c.1633C>T p.Arg545Trp
Two homozygous missense variants in Pakistani families; both reduce LRP4 inhibition of LRP6-dependent Wnt signaling in a reporter assay.
Show evidence (1 reference)
PMID:34857885 SUPPORT In Vitro
"The two mutants p.(Asp99His) and p.(Arg545Trp) inhibited WNT signaling less effectively, suggesting they reduced LRP4 function."
Functional evidence for the two alleles.
c.1820A>G p.Tyr607Cys
Homozygous beta1-propeller variant in a patient with CLS limb and kidney malformations plus congenital myasthenic syndrome; reduces agrin and Wnt11 binding.
Show evidence (1 reference)
PMID:37640745 SUPPORT In Vitro
"In this study, we demonstrated that p.Tyr607Cys mutation in the β1 propeller domain of LRP4 affected its capacity to bind agrin and Wnt11 in vitro."
Ligand-binding effect of the allele.
💊

Medical Actions

2
Digital Ray Individualization and Hand Reconstruction
Action: digital ray individualization surgeryNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is digital ray individualization surgery, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Surgical separation of digital rays with tendon transfers to create a functional grip. Evidence is a single surgical case report; outcomes are limited by the extent of bony fusion and disorganization.
Mechanism Target:
Complex Finger Syndactyly
Show evidence (1 reference)
PMID:15710123 SUPPORT Human Clinical
"In our case, successful bilateral digital ray individualisation and tendon transfers were performed to construct a grip function of the grossly deformed hands."
Single case of successful bilateral reconstruction.
Acetylcholinesterase Inhibitor Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Platform: Small molecule
Tried for the myasthenic weakness in the single patient with combined CLS and congenital myasthenic syndrome (p.Tyr607Cys) without significant improvement.
Mechanism Target:
Impaired Agrin-LRP4-MuSK Signaling at the Neuromuscular Junction
Show evidence (1 reference)
PMID:37640745 REFUTE Human Clinical
"Patient had clinically and electroneuromyographically demonstrated muscle weakness and fatigability associated with congenital malformations of the hands and feet and a horseshoe kidney, with no significant improvement of CMS symptoms with anticholinesterase treatments."
No meaningful response in the one treated patient.
🔬

Diagnosis

4
Hand and Limb Radiography
The diagnosis is clinical and radiographic. Radiographs of the hands and forearms define the synostoses, the number of metacarpals and digital rays and the disorganization of carpal and phalangeal elements; three-dimensional CT has been used to show the limb anomalies in detail. No formal diagnostic criteria have been published.
hand and forearm radiography NCIT:C137876 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:38013226 SUPPORT Human Clinical
"Standard X-ray showed that the both hands have only four metacarpal bones."
Plain radiographs established the metacarpal reduction in a molecularly confirmed patient.
PMID:31895055 SUPPORT Human Clinical
"We present 3D computed tomographic imaging illustrating the limb abnormalities in detail."
CT used to characterize the limb malformations in two siblings.
Prenatal Ultrasound
Severe and lethal presentations with limb reduction (tetraphocomelia) and bilateral renal agenesis can be recognized antenatally.
fetal ultrasound NCIT:C222238 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:33179409 SUPPORT Human Clinical
"in a fetus with lethal Cenani Lenz syndrome with antenatal presentation of tetraphocomelia and symmetrical involvement of hands and feet."
Antenatal detection of the lethal form in an LRP4 frameshift homozygote.
LRP4 Molecular Genetic Testing
Confirmation by identifying biallelic LRP4 variants, either by targeted LRP4 sequencing when the phenotype is typical or by exome sequencing, which the literature recommends as a first-line test for syndactyly phenotypes and for prenatal diagnosis. Segregation testing of parents confirms recessive phase. A negative LRP4 result does not exclude the clinical diagnosis, since APC and GREM1-FMN1 alterations give similar phenotypes.
molecular genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:42153583 SUPPORT Human Clinical
"Based on the clinical suspicion of CLSS, targeted next-generation sequencing of the LRP4 gene was performed."
Targeted LRP4 testing driven by the clinical picture.
PMID:31750994 SUPPORT Human Clinical
"Sanger validation confirmed that all affected individuals were homozygous and the obligate carriers were heterozygous for this variant."
Family segregation testing confirms the recessive genotype.
Exome Sequencing
Exome sequencing has identified LRP4 variants in families where the phenotype overlaps other syndactyly syndromes and in a prenatally diagnosed case, and is proposed as the preferred first-line test for syndactyly phenotypes.
exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:38013226 SUPPORT Human Clinical
"exome sequencing technology is a powerful tool for genetic analysis in prenatal diagnosis and medical research, as a preferred method for the diagnosis of syndactyly and related phenotypes."
Authors' recommendation of exome sequencing for syndactyly diagnosis.
PMID:31750994 SUPPORT Human Clinical
"WES is a powerful tool for genetic analysis in research and can be readily used as a first-line diagnostic test in syndactyly and related phenotypes."
Authors' recommendation of exome sequencing as a first-line test.
🧫

Experimental Models

2
Patient-derived myotubes (LRP4 p.Tyr607Cys) PRIMARY_CELL_CULTURE
Primary myoblasts from the muscle biopsy of the patient with combined CLS and congenital myasthenic syndrome, differentiated into myotubes and treated with neural agrin or Wnt11.
Publication
PMID:37640745
Pathograph links
Impaired Agrin-LRP4-MuSK Signaling at the Neuromuscular Junction recapitulates fidelity: moderate observes: cellular
Limitations: One patient and one allele; cultured myotubes lack the nerve terminal, so the synapse itself is not modeled.
Show evidence (1 reference)
PMID:37640745 SUPPORT In Vitro
"A decrease of 85% with agrin and 55% with Wnt11 of aggregates was observed in patient-derived myotubes compared with control"
Reduced acetylcholine receptor aggregation in patient cells.
LRP6-dependent Wnt luciferase reporter assay CELL_LINE
Cultured cells co-transfected with LRP6 and wild-type or patient-variant LRP4 and a canonical Wnt reporter.
Publication
PMID:34857885
Pathograph links
Loss of LRP4 Antagonism of Canonical Wnt Signaling measures fidelity: moderate observes: molecular
Limitations: Overexpression in a heterologous cell system; not limb-bud ectoderm or ureteric bud.
Show evidence (1 reference)
PMID:34857885 SUPPORT In Vitro
"Wild type LRP4 was able to inhibit LRP6-dependent WNT signaling robustly. The two mutants p.(Asp99His) and p.(Arg545Trp) inhibited WNT signaling less effectively, suggesting they reduced LRP4 function."
Quantifies loss of Wnt antagonism by patient alleles.
🐁

Animal Models

4
Lrp4 (Megf7) null mouse
Growth-retarded mice with fully penetrant fore- and hindlimb polysyndactyly, partially penetrant tooth abnormalities and an abnormal apical ectodermal ridge from embryonic day 9.5.
Species
Mouse
Genotype
Megf7/Lrp4 targeted null allele, homozygous
Publication
PMID:16207730
Pathograph links
Abnormal Apical Ectodermal Ridge Signaling recapitulates fidelity: moderate observes: tissue
Limitations: Mice develop polysyndactyly with digit duplication, whereas human patients mostly show oligosyndactyly; the ridge defect itself cannot be observed in human embryos.
Show evidence (1 reference)
PMID:16207730 SUPPORT Model Organism
"Homozygous Megf7-deficient mice are growth-retarded, with fully penetrant polysyndactyly in their fore and hind limbs, and partially penetrant abnormalities of tooth development."
Limb phenotype of the knockout.
Lrp4 null mouse (kidney)
Lrp4 null line in which 51% of postnatal animals had bilateral and 22% unilateral kidney agenesis, with delayed ureteric budding.
Species
Mouse
Genotype
Lrp4(-/-)
Publication
PMID:20454682
Pathograph links
Delayed Ureteric Bud Formation recapitulates fidelity: moderate observes: tissue
Limitations: Complete null allele; most human alleles are missense with residual function, and human kidney involvement ranges from agenesis to hypoplasia and ectopia.
Show evidence (1 reference)
PMID:20454682 SUPPORT Model Organism
"Lrp4(-/-) mice show a delay in ureteric bud formation that results in unilateral or bilateral kidney agenesis."
Reproduces the human kidney malformation and shows its developmental basis.
Lrp4 dan and mdig mutant mice
Two spontaneous recessive mouse mutations causing polysyndactyly, positionally cloned to Lrp4.
Species
Mouse
Genotype
Spontaneous recessive Lrp4 alleles dan and mdig, homozygous
Publication
PMID:16517118
Pathograph links
Defective Digit Separation and Autopod Skeletal Patterning partially recapitulates fidelity: moderate observes: tissue
Limitations: Polysyndactyly rather than the oligosyndactyly typical of patients.
Show evidence (1 reference)
PMID:16517118 SUPPORT Model Organism
"Positional cloning of two recessive mutations of the mouse that cause polysyndactyly (dan and mdig-Chr 2) confirmed that the gene encoding MEGF7/LRP4, a member of the low-density lipoprotein receptor family, plays an essential role in the process of digit differentiation."
Independent spontaneous alleles give digit fusion.
Bovine mulefoot (syndactyly)
Naturally occurring autosomal recessive syndactyly (fused digits) of cattle caused by an LRP4 splice variant that predicts a receptor lacking its cytoplasmic domain.
Species
Cattle
Genotype
LRP4 intron 37 splice donor G>A, homozygous
Publication
PMID:16963222
Pathograph links
Defective Digit Separation and Autopod Skeletal Patterning partially recapitulates fidelity: low observes: tissue
Limitations: Artiodactyl distal limb with two main digits; renal and craniofacial involvement are not described in the source.
Show evidence (1 reference)
PMID:16963222 SUPPORT Model Organism
"These findings confirm that autosomal recessive loss-of-function mutations in Megf7/Lrp4 result in phenotypically similar forms of syndactyly in different mammalian species and that such mutations are the cause of MFD in bovines."
Cross-species conservation of LRP4 loss-of-function syndactyly.
{ }

Source YAML

click to show 
name: Cenani-Lenz Syndactyly Syndrome
description: >-
  Autosomal recessive congenital malformation syndrome of the distal limbs caused by biallelic germline loss-of-function
  variants in LRP4, a low-density lipoprotein receptor-related protein that antagonizes LRP5/LRP6-mediated canonical Wnt
  signaling. Complex, usually bilateral syndactyly and oligodactyly of the hands with carpal, metacarpal and phalangeal
  synostosis and disorganization are the defining features; radioulnar synostosis, mesomelic shortening and toe
  syndactyly are common, and the feet are less affected than the hands. Renal agenesis or hypoplasia is frequent, and a
  facial gestalt with prominent forehead, hypertelorism, downslanting palpebral fissures and micrognathia occurs in many
  patients. Expressivity ranges from isolated hand oligosyndactyly to a prenatally lethal form with limb reduction and
  bilateral renal agenesis, the severe end being associated with truncating alleles. In mice, loss of Lrp4 disrupts the
  apical ectodermal ridge of the limb bud and delays ureteric budding, which accounts for the limb and kidney
  malformations.
category: Mendelian
disease_term:
  preferred_term: Cenani-Lenz syndactyly syndrome
  term:
    id: MONDO:0008931
    label: Cenani-Lenz syndactyly syndrome
synonyms:
- Cenani-Lenz syndrome
- Cenani-Lenz syndactyly
- Cenani syndactyly
- syndactyly type VII
- CLSS
- CLS
creation_date: "2026-10-16T11:33:09Z"
parents:
- Limb Development Disorders
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  - classification_value: KIDNEY_URINARY_TRACT
notes: >-
  Not every family with the clinical picture carries LRP4 variants: LRP4 variants were found in 12 of 14 families in the
  study that identified the gene, and a consanguineous Saudi family with typical features and scoliosis was explained by
  a homozygous APC splice variant instead (PMID:25676610). Genomic rearrangements of the GREM1-FMN1 locus produce
  Cenani-Lenz-like oligosyndactyly, dominant with a 1.7 Mb duplication and recessive with an FMN1 deletion
  (PMID:20610440). These are treated here as differential diagnoses rather than as causes of this LRP4-defined entry.
  Other LRP4 phenotypes are allelic but mechanistically distinct: sclerosteosis 2 (impaired sclerostin facilitation, see
  Sclerosteosis), congenital myasthenic syndrome from third beta-propeller variants, and isolated 3/4 finger syndactyly
  from compound heterozygous fourth beta-propeller variants (PMID:29524275). Recurrent ketotic hypoglycaemia in two
  brothers homozygous for p.Cys1637Tyr (PMID:31895055) has not been reported in other patients and is not listed as a
  phenotype. A Notch-pathway contribution has been proposed from lrp4 knockdown zebrafish and cell assays
  (PMID:30327840) but has not been shown in the mammalian limb or kidney. No population prevalence figure from a primary
  source was used; reported families come mainly from consanguineous pedigrees.
pathophysiology:
- name: Biallelic LRP4 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Homozygous or compound heterozygous germline LRP4 variants: mostly missense variants in the extracellular
    beta-propeller and LDL-receptor class B domains, plus splice, nonsense and frameshift alleles. Truncating alleles
    with no residual function give the most severe, sometimes prenatally lethal, presentations. The extracellular domain
    binds Wnt ligands; a beta1-propeller patient variant reduced Wnt11 binding.
  genes:
  - preferred_term: LRP4
    term:
      id: hgnc:6696
      label: LRP4
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    gene:
      preferred_term: LRP4
      term:
        id: hgnc:6696
        label: LRP4
  molecular_functions:
  - preferred_term: Wnt-protein binding
    modifier: DECREASED
    term:
      id: GO:0017147
      label: Wnt-protein binding
  evidence:
  - reference: PMID:20381006
    reference_title: LRP4 mutations alter Wnt/beta-catenin signaling and cause limb and kidney malformations in Cenani-Lenz syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By sequencing candidate genes, we identified recessive LRP4 mutations in 12 families with CLS.
    explanation: Gene identification study by homozygosity mapping and sequencing.
  - reference: PMID:23636941
    reference_title: Severe Cenani-Lenz syndrome caused by loss of LRP4 function.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The severity of the phenotype in a patient with absent residual LRP4 function may point to a genotype-phenotype
      correlation.
    explanation: A homozygous nonsense allele with no residual function produced a severe phenotype.
  - reference: PMID:28559208
    reference_title: Novel splice mutation in LRP4 causes severe type of Cenani-Lenz syndactyly syndrome with oro-facial and skeletal symptoms.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings not only further expand the phenotypic variability of CLSS but also indicate that early truncated
      and loss-of-function mutations in LRP4 lead to a more severe CLSS phenotype.
    explanation: Early-truncating splice allele in a five-generation family with severe disease.
  - reference: PMID:37640745
    reference_title: New mutation in the β1 propeller domain of LRP4 responsible for congenital myasthenic syndrome associated with Cenani-Lenz syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We observed a significant 45% decrease in Wnt11 binding to mutated LRP4 compared with LRP4 control
    explanation: Co-culture immunoprecipitation shows reduced Wnt11 binding by the p.Tyr607Cys protein; the only CLS allele tested for Wnt binding.
  downstream:
  - target: Loss of LRP4 Antagonism of Canonical Wnt Signaling
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20381006
      reference_title: LRP4 mutations alter Wnt/beta-catenin signaling and cause limb and kidney malformations in Cenani-Lenz syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        LRP4 is known to antagonize LRP6-mediated activation of canonical Wnt signaling, a function that is lost by the
        identified mutations.
      explanation: Patient missense alleles lose LRP4's Wnt-antagonist activity in cell assays.
  - target: Impaired Agrin-LRP4-MuSK Signaling at the Neuromuscular Junction
    causal_link_type: DIRECT
    description: Shown only for the beta1-propeller allele p.Tyr607Cys; not a general consequence of CLSS alleles.
    evidence:
    - reference: PMID:37640745
      reference_title: New mutation in the β1 propeller domain of LRP4 responsible for congenital myasthenic syndrome associated with Cenani-Lenz syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Furthermore, our in vitro results confirm a disruption of agrin/LRP4/MuSK signaling when LRP4 is mutated, with a
        decrease in direct agrin binding leading to a defect of agrin-induced MuSK phosphorylation.
      explanation: Binding and phosphorylation assays with the p.Tyr607Cys protein.
- name: Loss of LRP4 Antagonism of Canonical Wnt Signaling
  biological_scale: MOLECULAR
  description: >-
    LRP4 normally restrains LRP5/LRP6-dependent activation of canonical Wnt/beta-catenin signaling. Patient missense
    proteins lose this activity in reporter assays, and several fail to reach the plasma membrane normally, consistent
    with misfolding of the extracellular domain. The result is excess canonical Wnt signaling in tissues where LRP4 acts,
    including the limb-bud ectoderm and the ureteric bud.
  genes:
  - preferred_term: LRP4
    term:
      id: hgnc:6696
      label: LRP4
  - preferred_term: LRP6
    term:
      id: hgnc:6698
      label: LRP6
  molecular_functions:
  - preferred_term: inhibition of LRP6-dependent Wnt signaling by LRP4
    modifier: DECREASED
    term:
      id: GO:0030547
      label: signaling receptor inhibitor activity
  biological_processes:
  - preferred_term: negative regulation of canonical Wnt signaling pathway
    modifier: DECREASED
    term:
      id: GO:0090090
      label: negative regulation of canonical Wnt signaling pathway
  - preferred_term: canonical Wnt signaling pathway
    modifier: INCREASED
    term:
      id: GO:0060070
      label: canonical Wnt signaling pathway
  - preferred_term: protein localization to plasma membrane
    modifier: DECREASED
    term:
      id: GO:0072659
      label: protein localization to plasma membrane
  evidence:
  - reference: PMID:34857885
    reference_title: Novel variants in the LRP4 underlying Cenani-Lenz Syndactyly syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Wild type LRP4 was able to inhibit LRP6-dependent WNT signaling robustly. The two mutants p.(Asp99His) and
      p.(Arg545Trp) inhibited WNT signaling less effectively, suggesting they reduced LRP4 function.
    explanation: Luciferase reporter assay of two further patient missense alleles.
  - reference: PMID:38013226
    reference_title: A novel homozygous missense variant in LRP4 causing Cenani-Lenz syndactyly syndrome and literature review.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: >-
      Proteins encoded by some missense mutations of LRP4 can neither antagonize the canonical WNT signaling pathway nor
      be transported to the cell membrane normally.
    explanation: Restates the trafficking and Wnt-antagonism results of the gene-identification study, whose abstract does not describe the trafficking assay.
  downstream:
  - target: Abnormal Apical Ectodermal Ridge Signaling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Excess Wnt signaling in the limb-bud ectoderm is the proposed link; the step from the receptor defect to the
      abnormal ridge is inferred from mouse knockouts and has not been observed in human embryos.
    evidence:
    - reference: PMID:24924585
      reference_title: Truncating mutations in LRP4 lead to a prenatal lethal form of Cenani-Lenz syndrome.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: >-
        Loss of LRP4 function leads to excessive Wnt and β-catenin signaling in the limb bud, which causes abnormal limb
        development.
      explanation: Background statement of the mechanism derived from Lrp4-deficient mice, in a human case report.
  - target: Dental Anomalies
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Inferred from tooth abnormalities in Lrp4-deficient mice; how the receptor defect alters human tooth development is
      not established.
    evidence:
    - reference: PMID:16207730
      reference_title: Abnormal development of the apical ectodermal ridge and polysyndactyly in Megf7-deficient mice.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Homozygous Megf7-deficient mice are growth-retarded, with fully penetrant polysyndactyly in their fore and hind
        limbs, and partially penetrant abnormalities of tooth development.
      explanation: Lrp4 loss in mice disturbs tooth development.
  - target: Delayed Ureteric Bud Formation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Constitutively active beta-catenin in the ureteric bud lineage reproduces the kidney agenesis of Lrp4 knockout mice,
      supporting overactive Wnt signaling as the link; a Gremlin-Bmp4 route was also proposed by the same authors.
    evidence:
    - reference: PMID:20454682
      reference_title: Lrp4 regulates initiation of ureteric budding and is crucial for kidney formation--a mouse model for Cenani-Lenz syndrome.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Expression of this transgene under the control of a HoxB7Cre promoter, which is restricted to the ureteric bud
        epithelium indeed resulted in a comparable kidney agenesis phenotype
      explanation: Phenocopy of the Lrp4 knockout kidney phenotype by stabilized beta-catenin in ureteric bud epithelium.
- name: Abnormal Apical Ectodermal Ridge Signaling
  biological_scale: TISSUE
  description: >-
    The apical ectodermal ridge at the distal edge of the limb bud is the main site of Lrp4 expression. In Lrp4-deficient
    mice it forms abnormally from embryonic day 9.5, with ectopic expression and aberrant signaling of Fgf8, Shh, Bmp2,
    Bmp4 and Wnt7a and of the Wnt- and Bmp-responsive factors Lmx1b and Msx1, reduced apoptosis, and dorsal and ventral
    expansion of the ridge.
  locations:
  - preferred_term: apical ectodermal ridge
    term:
      id: UBERON:0004356
      label: apical ectodermal ridge
  biological_processes:
  - preferred_term: apical ectodermal ridge formation
    modifier: ABNORMAL
    term:
      id: GO:1905139
      label: apical ectodermal ridge formation
  - preferred_term: embryonic limb morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0030326
      label: embryonic limb morphogenesis
  evidence:
  - reference: PMID:16207730
    reference_title: Abnormal development of the apical ectodermal ridge and polysyndactyly in Megf7-deficient mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The reason for this developmental abnormality is apparent as early as embryonic day 9.5 when the apical ectodermal
      ridge (AER), the principal site of Megf7 expression at the distal edge of the embryonic limb bud, forms abnormally
      in the absence of Megf7.
    explanation: Lrp4 (Megf7) knockout mice show an abnormal apical ectodermal ridge from E9.5.
  - reference: PMID:16207730
    reference_title: Abnormal development of the apical ectodermal ridge and polysyndactyly in Megf7-deficient mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Ectopic expression and aberrant signaling of several molecules involved in limb patterning, including Fgf8, Shh,
      Bmp2, Bmp4 and Wnt7a, as well as the Wnt- and Bmp-responsive transcription factors Lmx1b and Msx1, result in
      reduced apoptosis and symmetrical dorsal and ventral expansions of the AER.
    explanation: Patterning signals from the ridge are mis-expressed.
  downstream:
  - target: Defective Digit Separation and Autopod Skeletal Patterning
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:16207730
      reference_title: Abnormal development of the apical ectodermal ridge and polysyndactyly in Megf7-deficient mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Abnormal signaling from the AER precedes ectopic chondrocyte condensation and subsequent fusion and duplication
        of digits in the Megf7 knockouts.
      explanation: Temporal order in the knockout places the ridge defect before digit fusion.
- name: Defective Digit Separation and Autopod Skeletal Patterning
  biological_scale: TISSUE
  description: >-
    Reduced interdigital apoptosis and ectopic chondrocyte condensation lead to soft-tissue and bony fusion of digits,
    reduced or duplicated digital rays and disorganized carpal, metacarpal and phalangeal elements. Mice develop
    polysyndactyly, whereas human patients mostly show oligosyndactyly; the reason for this species difference is not
    known.
  locations:
  - preferred_term: autopod region
    term:
      id: UBERON:0002470
      label: autopod region
  biological_processes:
  - preferred_term: apoptotic process involved in embryonic digit morphogenesis
    modifier: DECREASED
    term:
      id: GO:1902263
      label: apoptotic process involved in embryonic digit morphogenesis
  - preferred_term: embryonic digit morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0042733
      label: embryonic digit morphogenesis
  evidence:
  - reference: PMID:37640745
    reference_title: New mutation in the β1 propeller domain of LRP4 responsible for congenital myasthenic syndrome associated with Cenani-Lenz syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: >-
      Taken together, these findings can then explain the observed human phenotypes such as brachydactyly due to growth
      impairment or syndactyly due to defect of interdigital apoptosis.
    explanation: Authors' interpretation of the mouse ridge findings as the basis of human syndactyly.
  downstream:
  - target: Complex Finger Syndactyly
    causal_link_type: DIRECT
  - target: Oligodactyly
    causal_link_type: DIRECT
  - target: Metacarpal Synostosis
    causal_link_type: DIRECT
  - target: Carpal Synostosis
    causal_link_type: DIRECT
  - target: Disorganized Metacarpals and Phalanges
    causal_link_type: DIRECT
  - target: Toe Syndactyly
    causal_link_type: DIRECT
  - target: Nail Aplasia or Dysplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Radioulnar Synostosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The forearm lesions lie proximal to the autopod; how the LRP4 defect produces them is not established.
  - target: Mesomelic Limb Shortening
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The forearm lesions lie proximal to the autopod; how the LRP4 defect produces them is not established.
- name: Delayed Ureteric Bud Formation
  biological_scale: TISSUE
  description: >-
    In Lrp4 null mice the ureteric bud forms late, fails to bifurcate or upregulate c-Ret at its tip and does not invade
    the metanephric mesenchyme in time; Gdnf expression is then lost from the mesenchyme. Pax2 and baseline Ret and Gdnf
    expression are normal, placing the defect at the timing of budding.
  locations:
  - preferred_term: ureteric bud
    term:
      id: UBERON:0000084
      label: ureteric bud
  biological_processes:
  - preferred_term: ureteric bud development
    modifier: ABNORMAL
    term:
      id: GO:0001657
      label: ureteric bud development
  evidence:
  - reference: PMID:20454682
    reference_title: Lrp4 regulates initiation of ureteric budding and is crucial for kidney formation--a mouse model for Cenani-Lenz syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Lrp4(-/-) mice show a delay in ureteric bud formation that results in unilateral or bilateral kidney agenesis.
    explanation: Lrp4 null mouse study of kidney development.
  downstream:
  - target: Failed Induction of the Metanephric Mesenchyme
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20454682
      reference_title: Lrp4 regulates initiation of ureteric budding and is crucial for kidney formation--a mouse model for Cenani-Lenz syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Ureteric budding is delayed with a failure to stimulate the metanephric mesenchyme in a timely manner, resulting
        in failure of cellular differentiation and resulting absence of kidney formation in the mouse
      explanation: Late budding misses the window in which the mesenchyme can respond.
- name: Failed Induction of the Metanephric Mesenchyme
  biological_scale: TISSUE
  description: >-
    The metanephric mesenchyme responds to the ureteric bud only during a narrow window; when the bud arrives late the
    mesenchyme does not differentiate and is lost, giving unilateral or bilateral kidney agenesis. In 156 postnatal Lrp4
    null mice, 51% had bilateral and 22% unilateral agenesis.
  locations:
  - preferred_term: metanephric mesenchyme
    term:
      id: UBERON:0003220
      label: metanephric mesenchyme
  biological_processes:
  - preferred_term: metanephros development
    modifier: ABNORMAL
    term:
      id: GO:0001656
      label: metanephros development
  evidence:
  - reference: PMID:20454682
    reference_title: Lrp4 regulates initiation of ureteric budding and is crucial for kidney formation--a mouse model for Cenani-Lenz syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These data indicate that ureteric bud formation is delayed in mutants, and that the failure to invade the
      mesenchyme in time to support normal growth/survival is the cause for the frequent uni- or bilateral kidney
      agenesis.
    explanation: Authors' conclusion from the developmental time course.
  - reference: PMID:20454682
    reference_title: Lrp4 regulates initiation of ureteric budding and is crucial for kidney formation--a mouse model for Cenani-Lenz syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In the examination of post-partum Lrp4−/− mice (n = 156) we found 51 percent bilateral and 22 percent unilateral
      kidney agenesis
    explanation: Penetrance of kidney agenesis in the null mouse.
  downstream:
  - target: Renal Agenesis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20454682
      reference_title: Lrp4 regulates initiation of ureteric budding and is crucial for kidney formation--a mouse model for Cenani-Lenz syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In mice, complete absence of functional Lrp4 leads to uni- or bilateral kidney agenesis caused by a delay in the
        formation of the ureteric bud.
      explanation: Kidney agenesis follows from the budding delay.
  - target: Renal Hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed by analogy with the agenesis mechanism; the mouse study notes that the human range from agenesis to
      hypoplasia suggests additional roles for LRP4 or modifying factors.
    evidence:
    - reference: PMID:20454682
      reference_title: Lrp4 regulates initiation of ureteric budding and is crucial for kidney formation--a mouse model for Cenani-Lenz syndrome.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        However, the range of phenotypes observed in humans, from complete agenesis to hypoplasia, along with the
        expression of Lrp4 mRNA in multiple cell types of the kidney throughout the embryonic period suggest this
        molecule may have additional roles in kidney development, or that other factors exist, which can modify the
        phenotype.
      explanation: Authors' caveat that hypoplasia may involve more than the budding delay.
  - target: Ectopic Kidney
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Position anomalies of the kidney have not been explained mechanistically.
  - target: Horseshoe Kidney
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Fusion anomalies of the kidney have not been explained mechanistically.
- name: Impaired Agrin-LRP4-MuSK Signaling at the Neuromuscular Junction
  biological_scale: CELLULAR
  description: >-
    LRP4 is the muscle receptor for neural agrin and activates MuSK to cluster acetylcholine receptors. The
    beta1-propeller p.Tyr607Cys protein reaches the plasma membrane and binds MuSK normally, but binds agrin and Wnt11
    less, and agrin-induced MuSK phosphorylation is reduced. Patient myotubes formed fewer and smaller agrin- and
    Wnt11-induced acetylcholine receptor clusters. Most CLSS alleles have not been tested for this function and most
    patients have no neuromuscular symptoms.
  cell_types:
  - preferred_term: myotube
    term:
      id: CL:0002372
      label: myotube
  biological_processes:
  - preferred_term: skeletal muscle acetylcholine-gated channel clustering
    modifier: DECREASED
    term:
      id: GO:0071340
      label: skeletal muscle acetylcholine-gated channel clustering
  evidence:
  - reference: PMID:37640745
    reference_title: New mutation in the β1 propeller domain of LRP4 responsible for congenital myasthenic syndrome associated with Cenani-Lenz syndrome.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mechanistic expression studies show a significant decrease of AChR aggregation in cultured patient myotubes, as
      well as altered in vitro binding of agrin and Wnt11 ligands to the mutated β1 propeller domain of LRP4 explaining
      the dual phenotype characterized clinically and electoneuromyographically in the patient.
    explanation: Patient myotube clustering assay and ligand-binding assays.
  downstream:
  - target: Fatigable Weakness
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37640745
      reference_title: New mutation in the β1 propeller domain of LRP4 responsible for congenital myasthenic syndrome associated with Cenani-Lenz syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our study highlights that a mutation in the β1 propeller domain of LRP4 alters its binding to agrin leading to
        neurotransmission defects whereas mutations described so far in this domain are exclusively reported to be
        responsible for CLS with limb and kidney malformations without neuromuscular defects
      explanation: Links the binding defect to the patient's neuromuscular transmission defect.
phenotypes:
- category: Musculoskeletal
  name: Complex Finger Syndactyly
  description: >-
    Usually bilateral complete osseous and cutaneous fusion of the fingers, classically a spoon- or mitten-shaped hand,
    the defining feature of the syndrome. Hands are more severely affected than feet.
  phenotype_term:
    preferred_term: Complex finger syndactyly
    term:
      id: HP:0006101
      label: Finger syndactyly
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20381006
    reference_title: LRP4 mutations alter Wnt/beta-catenin signaling and cause limb and kidney malformations in Cenani-Lenz syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cenani-Lenz syndrome (CLS) is an autosomal-recessive congenital disorder affecting distal limb development. It is
      characterized mainly by syndactyly and/or oligodactyly
    explanation: Syndactyly is a principal feature in the gene-identification series.
  - reference: PMID:28559208
    reference_title: Novel splice mutation in LRP4 causes severe type of Cenani-Lenz syndactyly syndrome with oro-facial and skeletal symptoms.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe a consanguineous Pakistani kindred with a severe form of CLSS characterized by complete syndactyly
      and disorganization of fingers, oligo-syndactyly of toes, shortening of limbs, frontal bossing, and
      hypoplasia/agenesis of left kidney.
    explanation: Complete finger syndactyly in an LRP4 splice-variant family.
- category: Musculoskeletal
  name: Oligodactyly
  description: >-
    Reduction in the number of digital rays, predominantly in the hands. An oligodactylous form is distinguished from the
    classical spoon-hand form; in one family the phenotype was limited to bilateral postaxial oligodactyly of the hands.
  phenotype_term:
    preferred_term: Oligodactyly
    term:
      id: HP:0012165
      label: Oligodactyly
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:15710123
    reference_title: "A variant of Cenani-Lenz syndactyly (CLS): review of the literature and attempt of classification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      According to our research of literature and our clinical findings there seem to exist two grossly different
      clinical phenotypes: spoon hand type and oligodactyly type.
    explanation: Literature review plus case describing the oligodactyly type.
  - reference: PMID:30041615
    reference_title: Cenani-Lenz syndactyly syndrome - a case report of a family with isolated syndactyly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we report here two patients, born to consanguineous Sri Lankan parents, present with bilateral postaxial
      oligodactyly limited to upper limbs.
    explanation: Mild end of the spectrum in a homozygous p.Ile450Val family.
- category: Musculoskeletal
  name: Metacarpal Synostosis
  description: Fusion of metacarpals, a constant feature in reviewed cases.
  phenotype_term:
    preferred_term: Metacarpal synostosis
    term:
      id: HP:0009701
      label: Metacarpal synostosis
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:15710123
    reference_title: "A variant of Cenani-Lenz syndactyly (CLS): review of the literature and attempt of classification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Typical constant clinical features such as carpal, metacarpal and digital synostoses, disorganisation of carpal
      bones, reduction of digital rays and syndactyly of toes are found in the reported cases.
    explanation: Metacarpal synostosis is constant in the reviewed cases.
  - reference: PMID:23664847
    reference_title: Cenani-Lenz syndrome restricted to limb and kidney anomalies associated with a novel LRP4 missense mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      The disorder is characterized by complete syndactyly with metacarpal fusions and/or oligodactyly sometimes
      accompanied by radioulnar synostosis.
    explanation: Background description in an LRP4-confirmed family report.
- category: Musculoskeletal
  name: Carpal Synostosis
  description: Fusion and disorganization of the carpal bones, a constant feature in reviewed cases.
  phenotype_term:
    preferred_term: Carpal synostosis
    term:
      id: HP:0009702
      label: Carpal synostosis
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:15710123
    reference_title: "A variant of Cenani-Lenz syndactyly (CLS): review of the literature and attempt of classification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Typical constant clinical features such as carpal, metacarpal and digital synostoses, disorganisation of carpal
      bones, reduction of digital rays and syndactyly of toes are found in the reported cases.
    explanation: Carpal synostosis and carpal disorganization are constant in the reviewed cases.
  - reference: PMID:42153583
    reference_title: Targeted Genetic Testing Uncovers a Novel LRP4 Variant in Cenani-Lenz Syndactyly Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Cenani-Lenz syndactyly syndrome (CLSS, OMIM 212780) is a rare autosomal recessive disorder characterized by
      syndactyly and oligodactyly of the digits, fusion of carpal and tarsal bones, and radioulnar synostosis.
    explanation: Framing description in an LRP4-confirmed family report.
- category: Musculoskeletal
  name: Disorganized Metacarpals and Phalanges
  description: Absent, reduced or disorganized metacarpals and phalanges, including absent distal phalanges.
  phenotype_term:
    preferred_term: Disorganized metacarpals and phalanges
    term:
      id: HP:0005916
      label: Abnormal metacarpal morphology
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:30569497
    reference_title: "Cenani-Lenz syndrome and other related syndactyly disorders due to variants in LRP4, GREM1/FMN1, and APC: Insight into the pathogenesis and the relationship to polyposis through the WNT and BMP antagonistic pathways."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Cenani-Lenz (C-L) syndrome is characterized by oligosyndactyly, metacarpal synostosis, phalangeal disorganization,
      and other variable facial and systemic features.
    explanation: Review of the clinical features.
  - reference: PMID:42153583
    reference_title: Targeted Genetic Testing Uncovers a Novel LRP4 Variant in Cenani-Lenz Syndactyly Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients presented with bilateral complex syndactyly, characterized by absent phalanges, reduced and
      disorganized metacarpals, and cutaneous toe syndactyly.
    explanation: Four affected relatives homozygous for p.Arg1277Leu.
- category: Musculoskeletal
  name: Toe Syndactyly
  description: Toe syndactyly, often cutaneous and milder than the hand involvement.
  phenotype_term:
    preferred_term: Toe syndactyly
    term:
      id: HP:0001770
      label: Toe syndactyly
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:42153583
    reference_title: Targeted Genetic Testing Uncovers a Novel LRP4 Variant in Cenani-Lenz Syndactyly Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients presented with bilateral complex syndactyly, characterized by absent phalanges, reduced and
      disorganized metacarpals, and cutaneous toe syndactyly.
    explanation: Cutaneous toe syndactyly in all four affected relatives.
  - reference: PMID:15710123
    reference_title: "A variant of Cenani-Lenz syndactyly (CLS): review of the literature and attempt of classification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Typical constant clinical features such as carpal, metacarpal and digital synostoses, disorganisation of carpal
      bones, reduction of digital rays and syndactyly of toes are found in the reported cases.
    explanation: Toe syndactyly is listed among the constant features.
- category: Dermatologic
  name: Nail Aplasia or Dysplasia
  description: Absent, hypoplastic or fused dysplastic nails on the affected digits.
  phenotype_term:
    preferred_term: Nail dysplasia
    term:
      id: HP:0002164
      label: Nail dysplasia
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:38013226
    reference_title: A novel homozygous missense variant in LRP4 causing Cenani-Lenz syndactyly syndrome and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Complete fusion of all fingers, oligodactyly of the right hand, short and hypoplastic nails, disorganized phalanges
    explanation: Literature-review table entry for the homozygous p.Tyr384Cys family.
  - reference: PMID:38013226
    reference_title: A novel homozygous missense variant in LRP4 causing Cenani-Lenz syndactyly syndrome and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Symmetrical malformations of all four limbs, short forearms, symmetrical complicated overlapping syndactyly,
      adducted thumbs, rudimentary dysplastic fused nails
    explanation: Literature-review table entry for the homozygous p.Cys1637Tyr siblings.
- category: Musculoskeletal
  name: Radioulnar Synostosis
  description: Fusion of the radius and ulna, present in many but not all patients.
  phenotype_term:
    preferred_term: Radioulnar synostosis
    term:
      id: HP:0002974
      label: Radioulnar synostosis
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:31895055
    reference_title: Cenani-Lenz syndactyly in siblings with a novel homozygous LRP4 mutation and recurrent hypoglycaemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Cenani-Lenz syndactyly (CLS) is a rare autosomal recessive syndrome characterized by disorganized oligosyndactyly
      of upper and lower limbs as well as radioulnar synostosis.
    explanation: Framing description in an LRP4-confirmed case report.
  - reference: PMID:15710123
    reference_title: "A variant of Cenani-Lenz syndactyly (CLS): review of the literature and attempt of classification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Inconstant features such as radio-ulnar synostosis, brachymesomelia, metatarsal synostoses and reduction of
      metatarsal rays may be present.
    explanation: Radioulnar synostosis is inconstant in the reviewed cases.
- category: Musculoskeletal
  name: Mesomelic Limb Shortening
  description: >-
    Shortening of the forearm and leg segments, ranging from mild shortening to severe mesomelic limb reduction in the
    prenatally lethal form.
  phenotype_term:
    preferred_term: Mesomelia
    term:
      id: HP:0003027
      label: Mesomelia
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:30041615
    reference_title: Cenani-Lenz syndactyly syndrome - a case report of a family with isolated syndactyly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      radioulnar synostosis and mesomelic shortness of the limbs, with lower limbs usually being much less affected than
      upper limbs.
    explanation: Framing description of the syndrome.
  - reference: PMID:24924585
    reference_title: Truncating mutations in LRP4 lead to a prenatal lethal form of Cenani-Lenz syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we present two sibling fetuses with a prenatal lethal presentation of mesomelic limb reductions,
      oligosyndactyly, genitourinary malformation and compound heterozygosity for two novel truncating mutations in
      LRP4.
    explanation: Severe mesomelic reduction with compound heterozygous truncating alleles.
- category: Renal
  name: Renal Agenesis
  description: >-
    Unilateral or bilateral absence of the kidney. Bilateral agenesis is part of the prenatally lethal presentation seen
    with truncating alleles. In the gene-identification series renal agenesis was reported in about one-third of
    families.
  phenotype_term:
    preferred_term: Renal agenesis
    term:
      id: HP:0000104
      label: Renal agenesis
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20454682
    reference_title: Lrp4 regulates initiation of ureteric budding and is crucial for kidney formation--a mouse model for Cenani-Lenz syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Renal agenesis, in accordance with the murine phenotype, was observed in one-third of the families, another 25%
      percent presented with ectopic or hypoplastic kidneys.
    explanation: Family-level frequency in the human CLS series, restated in the mouse study.
  - reference: PMID:42153583
    reference_title: Targeted Genetic Testing Uncovers a Novel LRP4 Variant in Cenani-Lenz Syndactyly Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The 2-year-old proband had a horseshoe kidney, whereas his 6-year-old cousin presented with right renal agenesis.
    explanation: Unilateral renal agenesis in an LRP4-confirmed family.
- category: Renal
  name: Renal Hypoplasia
  description: Unilateral or bilateral small kidney.
  phenotype_term:
    preferred_term: Renal hypoplasia
    term:
      id: HP:0000089
      label: Renal hypoplasia
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:23664847
    reference_title: Cenani-Lenz syndrome restricted to limb and kidney anomalies associated with a novel LRP4 missense mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      The clinical expression is variable and kidney agenesis/hypoplasia, craniofacial dysmorphism and teeth
      abnormalities are frequent features as well as lower limb involvement.
    explanation: Framing description in an LRP4-confirmed family report.
  - reference: PMID:28559208
    reference_title: Novel splice mutation in LRP4 causes severe type of Cenani-Lenz syndactyly syndrome with oro-facial and skeletal symptoms.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe a consanguineous Pakistani kindred with a severe form of CLSS characterized by complete syndactyly
      and disorganization of fingers, oligo-syndactyly of toes, shortening of limbs, frontal bossing, and
      hypoplasia/agenesis of left kidney.
    explanation: Kidney hypoplasia or agenesis in a splice-variant family.
- category: Renal
  name: Ectopic Kidney
  phenotype_term:
    preferred_term: Ectopic kidney
    term:
      id: HP:0000086
      label: Ectopic kidney
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:20454682
    reference_title: Lrp4 regulates initiation of ureteric budding and is crucial for kidney formation--a mouse model for Cenani-Lenz syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Renal agenesis, in accordance with the murine phenotype, was observed in one-third of the families, another 25%
      percent presented with ectopic or hypoplastic kidneys.
    explanation: Ectopic kidneys in the human CLS series, restated in the mouse study.
- category: Renal
  name: Horseshoe Kidney
  phenotype_term:
    preferred_term: Horseshoe kidney
    term:
      id: HP:0000085
      label: Horseshoe kidney
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:42153583
    reference_title: Targeted Genetic Testing Uncovers a Novel LRP4 Variant in Cenani-Lenz Syndactyly Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The 2-year-old proband had a horseshoe kidney, whereas his 6-year-old cousin presented with right renal agenesis.
    explanation: Horseshoe kidney in a p.Arg1277Leu homozygote.
  - reference: PMID:37640745
    reference_title: New mutation in the β1 propeller domain of LRP4 responsible for congenital myasthenic syndrome associated with Cenani-Lenz syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She was born after normal gestation and delivery, with congenital malformations of the hands and feet characterized
      by syndactyly and brachydactyly (more severe for the hands), and a renal malformation with a horseshoe-shaped kidney
      compatible with a CLS
    explanation: Horseshoe kidney in a p.Tyr607Cys homozygote.
- category: Craniofacial
  name: Prominent Forehead
  phenotype_term:
    preferred_term: Prominent forehead
    term:
      id: HP:0011220
      label: Prominent forehead
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:30041615
    reference_title: Cenani-Lenz syndactyly syndrome - a case report of a family with isolated syndactyly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Facial involvement includes a prominent forehead, hypertelorism, downslanting palpebral fissures and micrognathia
    explanation: Framing description of the facial gestalt.
  - reference: PMID:28559208
    reference_title: Novel splice mutation in LRP4 causes severe type of Cenani-Lenz syndactyly syndrome with oro-facial and skeletal symptoms.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we describe a consanguineous Pakistani kindred with a severe form of CLSS characterized by complete syndactyly
      and disorganization of fingers, oligo-syndactyly of toes, shortening of limbs, frontal bossing, and
      hypoplasia/agenesis of left kidney.
    explanation: Frontal bossing in a splice-variant family.
- category: Craniofacial
  name: Hypertelorism
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:30041615
    reference_title: Cenani-Lenz syndactyly syndrome - a case report of a family with isolated syndactyly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Facial involvement includes a prominent forehead, hypertelorism, downslanting palpebral fissures and micrognathia
    explanation: Framing description of the facial gestalt.
- category: Craniofacial
  name: Downslanted Palpebral Fissures
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:30041615
    reference_title: Cenani-Lenz syndactyly syndrome - a case report of a family with isolated syndactyly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Facial involvement includes a prominent forehead, hypertelorism, downslanting palpebral fissures and micrognathia
    explanation: Framing description of the facial gestalt.
- category: Craniofacial
  name: Micrognathia
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:30041615
    reference_title: Cenani-Lenz syndactyly syndrome - a case report of a family with isolated syndactyly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Facial involvement includes a prominent forehead, hypertelorism, downslanting palpebral fissures and micrognathia
    explanation: Framing description of the facial gestalt.
  - reference: PMID:38013226
    reference_title: A novel homozygous missense variant in LRP4 causing Cenani-Lenz syndactyly syndrome and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Fetus II‐1 showed a hypoplastic nose, anteverted nares, prominent zygomata, micrognathia, short malformed limbs,
      and bilateral renal agenesis.
    explanation: Micrognathia in a fetus compound heterozygous for truncating LRP4 alleles, as summarized in a literature review.
    quote_role: REVIEW_SYNTHESIS
- category: Craniofacial
  name: Cleft Lip
  description: >-
    Reported in one of three affected members of a family homozygous for the c.316+1G>A splice variant; oro-facial
    defects are an occasional association. No mechanism has been described.
  phenotype_term:
    preferred_term: Cleft lip
    term:
      id: HP:0410030
      label: Cleft lip
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:28559208
    reference_title: Novel splice mutation in LRP4 causes severe type of Cenani-Lenz syndactyly syndrome with oro-facial and skeletal symptoms.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The affected individuals were additionally presented with short stature, cleft-lip and hypoplastic shoulder joint
      with restricted upper limb movement.
    explanation: Cleft lip in the severe splice-variant family.
- category: Dental
  name: Dental Anomalies
  description: Teeth abnormalities are reported as a frequent associated feature; their nature is not specified in the source.
  phenotype_term:
    preferred_term: Abnormality of the dentition
    term:
      id: HP:0000164
      label: Abnormality of the dentition
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:23664847
    reference_title: Cenani-Lenz syndrome restricted to limb and kidney anomalies associated with a novel LRP4 missense mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      The clinical expression is variable and kidney agenesis/hypoplasia, craniofacial dysmorphism and teeth
      abnormalities are frequent features as well as lower limb involvement.
    explanation: Framing description in an LRP4-confirmed family report.
- category: Skeletal
  name: Scoliosis
  description: Thoracic scoliosis is an occasional association.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:28559208
    reference_title: Novel splice mutation in LRP4 causes severe type of Cenani-Lenz syndactyly syndrome with oro-facial and skeletal symptoms.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      It is occasionally associated with renal hypoplasia, oro-facial defects, scoliosis of the thoracic spine, hearing
      loss, and genital anomalies.
    explanation: Framing description stating scoliosis is occasional.
- category: Growth
  name: Short Stature
  description: Reported in the severe splice-variant family.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:28559208
    reference_title: Novel splice mutation in LRP4 causes severe type of Cenani-Lenz syndactyly syndrome with oro-facial and skeletal symptoms.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The affected individuals were additionally presented with short stature, cleft-lip and hypoplastic shoulder joint
      with restricted upper limb movement.
    explanation: Short stature in all affected members of one family.
- category: Neuromuscular
  name: Fatigable Weakness
  description: >-
    Congenital myasthenic syndrome with proximal and axial fatigable weakness and a decremental response on repetitive
    nerve stimulation, beginning at age 19, reported in one patient homozygous for the beta1-propeller variant
    p.Tyr607Cys. Not a general feature of the syndrome.
  phenotype_term:
    preferred_term: Fatigable weakness
    term:
      id: HP:0003473
      label: Fatigable weakness
  evidence:
  - reference: PMID:37640745
    reference_title: New mutation in the β1 propeller domain of LRP4 responsible for congenital myasthenic syndrome associated with Cenani-Lenz syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the French cohort of CMS patients, we identified a novel LRP4 homozygous missense mutation (c.1820A > G;
      p.Thy607Cys) within the β1 propeller domain in a patient presenting CMS symptoms, including muscle weakness,
      fluctuating fatigability and a decrement in compound muscle action potential in spinal accessory nerves, associated
      with congenital agenesis of the hands and feet and renal malformation.
    explanation: Single patient with combined CLS and congenital myasthenic syndrome.
genetic:
- name: LRP4
  gene_term:
    preferred_term: LRP4
    term:
      id: hgnc:6696
      label: LRP4
  relationship_type: CAUSATIVE
  notes: >-
    Biallelic germline variants, homozygous in most reported families (largely consanguineous) and compound heterozygous
    in some. LRP4 variants were found in 12 of 14 families in the gene-identification study. Missense variants in the
    extracellular domain predominate; nonsense, frameshift and early-truncating splice alleles are associated with the
    severe and prenatally lethal end of the spectrum.
  evidence:
  - reference: PMID:20381006
    reference_title: LRP4 mutations alter Wnt/beta-catenin signaling and cause limb and kidney malformations in Cenani-Lenz syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We used a homozygosity-mapping approach to map the CLS1 locus to chromosome 11p11.2-q13.1. By sequencing candidate
      genes, we identified recessive LRP4 mutations in 12 families with CLS.
    explanation: Identification of LRP4 as the disease gene.
  - reference: PMID:25676610
    reference_title: A novel APC mutation defines a second locus for Cenani-Lenz syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      LRP4 mutations were identified in most, but not all patients with this syndrome, suggesting the presence of at
      least one additional locus.
    explanation: LRP4 explains most but not all clinically diagnosed families.
  variants:
  - name: c.2858T>C p.Leu953Pro
    description: >-
      Homozygous in a consanguineous Pakistani pedigree with nine affected members whose disease was restricted to the
      limbs and kidneys.
    evidence:
    - reference: PMID:23664847
      reference_title: Cenani-Lenz syndrome restricted to limb and kidney anomalies associated with a novel LRP4 missense mutation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Genetic analysis using autozygosity mapping and sequencing revealed homozygosity for a novel missense mutation
        c.2858T > C (p.L953P) in the LRP4 gene.
      explanation: Segregating homozygous missense variant.
  - name: c.316+1G>A
    description: >-
      Homozygous canonical splice-donor variant predicted to truncate the protein early; severe CLSS with short stature,
      cleft lip and kidney hypoplasia or agenesis in a five-generation family.
    evidence:
    - reference: PMID:28559208
      reference_title: Novel splice mutation in LRP4 causes severe type of Cenani-Lenz syndactyly syndrome with oro-facial and skeletal symptoms.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A novel splice variant in LRP4 (c.316+1G > A) segregated with the phenotype in a five generations family.
      explanation: Segregation of the splice variant.
  - name: c.295G>C p.Asp99His and c.1633C>T p.Arg545Trp
    description: >-
      Two homozygous missense variants in Pakistani families; both reduce LRP4 inhibition of LRP6-dependent Wnt
      signaling in a reporter assay.
    evidence:
    - reference: PMID:34857885
      reference_title: Novel variants in the LRP4 underlying Cenani-Lenz Syndactyly syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The two mutants p.(Asp99His) and p.(Arg545Trp) inhibited WNT signaling less effectively, suggesting they reduced
        LRP4 function.
      explanation: Functional evidence for the two alleles.
  - name: c.1820A>G p.Tyr607Cys
    description: >-
      Homozygous beta1-propeller variant in a patient with CLS limb and kidney malformations plus congenital myasthenic
      syndrome; reduces agrin and Wnt11 binding.
    evidence:
    - reference: PMID:37640745
      reference_title: New mutation in the β1 propeller domain of LRP4 responsible for congenital myasthenic syndrome associated with Cenani-Lenz syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In this study, we demonstrated that p.Tyr607Cys mutation in the β1 propeller domain of LRP4 affected its capacity
        to bind agrin and Wnt11 in vitro.
      explanation: Ligand-binding effect of the allele.
inheritance:
- name: Autosomal Recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20381006
    reference_title: LRP4 mutations alter Wnt/beta-catenin signaling and cause limb and kidney malformations in Cenani-Lenz syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cenani-Lenz syndrome (CLS) is an autosomal-recessive congenital disorder affecting distal limb development.
    explanation: Recessive inheritance in the gene-identification families.
  - reference: PMID:31750994
    reference_title: Novel missense alteration in LRP4 gene underlies Cenani-Lenz syndactyly syndrome in a consanguineous family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sanger validation confirmed that all affected individuals were homozygous and the obligate carriers were
      heterozygous for this variant.
    explanation: Unaffected heterozygous obligate carriers and homozygous affected members.
diagnosis:
- name: Hand and Limb Radiography
  description: >-
    The diagnosis is clinical and radiographic. Radiographs of the hands and forearms define the synostoses, the number
    of metacarpals and digital rays and the disorganization of carpal and phalangeal elements; three-dimensional CT has
    been used to show the limb anomalies in detail. No formal diagnostic criteria have been published.
  diagnosis_term:
    preferred_term: hand and forearm radiography
    term:
      id: NCIT:C137876
      label: Bone Radiography
  evidence:
  - reference: PMID:38013226
    reference_title: A novel homozygous missense variant in LRP4 causing Cenani-Lenz syndactyly syndrome and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Standard X-ray showed that the both hands have only four metacarpal bones.
    explanation: Plain radiographs established the metacarpal reduction in a molecularly confirmed patient.
  - reference: PMID:31895055
    reference_title: Cenani-Lenz syndactyly in siblings with a novel homozygous LRP4 mutation and recurrent hypoglycaemia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We present 3D computed tomographic imaging illustrating the limb abnormalities in detail.
    explanation: CT used to characterize the limb malformations in two siblings.
- name: Prenatal Ultrasound
  description: >-
    Severe and lethal presentations with limb reduction (tetraphocomelia) and bilateral renal agenesis can be
    recognized antenatally.
  diagnosis_term:
    preferred_term: fetal ultrasound
    term:
      id: NCIT:C222238
      label: Fetal Ultrasound Imaging
  evidence:
  - reference: PMID:33179409
    reference_title: "Lethal Cenani Lenz syndrome in two consecutive pregnancies: Further extension of phenotype from Maldives."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in a fetus with lethal Cenani Lenz syndrome with antenatal presentation of tetraphocomelia and symmetrical
      involvement of hands and feet.
    explanation: Antenatal detection of the lethal form in an LRP4 frameshift homozygote.
- name: LRP4 Molecular Genetic Testing
  description: >-
    Confirmation by identifying biallelic LRP4 variants, either by targeted LRP4 sequencing when the phenotype is
    typical or by exome sequencing, which the literature recommends as a first-line test for syndactyly phenotypes and
    for prenatal diagnosis. Segregation testing of parents confirms recessive phase. A negative LRP4 result does not
    exclude the clinical diagnosis, since APC and GREM1-FMN1 alterations give similar phenotypes.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:42153583
    reference_title: Targeted Genetic Testing Uncovers a Novel LRP4 Variant in Cenani-Lenz Syndactyly Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Based on the clinical suspicion of CLSS, targeted next-generation sequencing of the LRP4 gene was performed.
    explanation: Targeted LRP4 testing driven by the clinical picture.
  - reference: PMID:31750994
    reference_title: Novel missense alteration in LRP4 gene underlies Cenani-Lenz syndactyly syndrome in a consanguineous family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sanger validation confirmed that all affected individuals were homozygous and the obligate carriers were
      heterozygous for this variant.
    explanation: Family segregation testing confirms the recessive genotype.
- name: Exome Sequencing
  description: >-
    Exome sequencing has identified LRP4 variants in families where the phenotype overlaps other syndactyly syndromes and
    in a prenatally diagnosed case, and is proposed as the preferred first-line test for syndactyly phenotypes.
  diagnosis_term:
    preferred_term: exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:38013226
    reference_title: A novel homozygous missense variant in LRP4 causing Cenani-Lenz syndactyly syndrome and literature review.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      exome sequencing technology is a powerful tool for genetic analysis in prenatal diagnosis and medical research, as
      a preferred method for the diagnosis of syndactyly and related phenotypes.
    explanation: Authors' recommendation of exome sequencing for syndactyly diagnosis.
  - reference: PMID:31750994
    reference_title: Novel missense alteration in LRP4 gene underlies Cenani-Lenz syndactyly syndrome in a consanguineous family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WES is a powerful tool for genetic analysis in research and can be readily used as a first-line diagnostic test in
      syndactyly and related phenotypes.
    explanation: Authors' recommendation of exome sequencing as a first-line test.
treatments:
- name: Digital Ray Individualization and Hand Reconstruction
  description: >-
    Surgical separation of digital rays with tendon transfers to create a functional grip. Evidence is a single surgical
    case report; outcomes are limited by the extent of bony fusion and disorganization.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: digital ray individualization surgery
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Complex Finger Syndactyly
  evidence:
  - reference: PMID:15710123
    reference_title: "A variant of Cenani-Lenz syndactyly (CLS): review of the literature and attempt of classification."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In our case, successful bilateral digital ray individualisation and tendon transfers were performed to construct a
      grip function of the grossly deformed hands.
    explanation: Single case of successful bilateral reconstruction.
- name: Acetylcholinesterase Inhibitor Therapy
  description: >-
    Tried for the myasthenic weakness in the single patient with combined CLS and congenital myasthenic syndrome
    (p.Tyr607Cys) without significant improvement.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Impaired Agrin-LRP4-MuSK Signaling at the Neuromuscular Junction
  evidence:
  - reference: PMID:37640745
    reference_title: New mutation in the β1 propeller domain of LRP4 responsible for congenital myasthenic syndrome associated with Cenani-Lenz syndrome.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient had clinically and electroneuromyographically demonstrated muscle weakness and fatigability associated with
      congenital malformations of the hands and feet and a horseshoe kidney, with no significant improvement of CMS
      symptoms with anticholinesterase treatments.
    explanation: No meaningful response in the one treated patient.
animal_models:
- name: Lrp4 (Megf7) null mouse
  species: Mouse
  genotype: Megf7/Lrp4 targeted null allele, homozygous
  publication: PMID:16207730
  description: >-
    Growth-retarded mice with fully penetrant fore- and hindlimb polysyndactyly, partially penetrant tooth abnormalities
    and an abnormal apical ectodermal ridge from embryonic day 9.5.
  modeled_mechanisms:
  - target: Abnormal Apical Ectodermal Ridge Signaling
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    limitations: >-
      Mice develop polysyndactyly with digit duplication, whereas human patients mostly show oligosyndactyly; the ridge
      defect itself cannot be observed in human embryos.
    evidence:
    - reference: PMID:16207730
      reference_title: Abnormal development of the apical ectodermal ridge and polysyndactyly in Megf7-deficient mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Homozygous Megf7-deficient mice are growth-retarded, with fully penetrant polysyndactyly in their fore and hind
        limbs, and partially penetrant abnormalities of tooth development.
      explanation: Limb phenotype of the knockout.
- name: Lrp4 null mouse (kidney)
  species: Mouse
  genotype: Lrp4(-/-)
  publication: PMID:20454682
  description: >-
    Lrp4 null line in which 51% of postnatal animals had bilateral and 22% unilateral kidney agenesis, with delayed
    ureteric budding.
  modeled_mechanisms:
  - target: Delayed Ureteric Bud Formation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    limitations: >-
      Complete null allele; most human alleles are missense with residual function, and human kidney involvement ranges
      from agenesis to hypoplasia and ectopia.
    evidence:
    - reference: PMID:20454682
      reference_title: Lrp4 regulates initiation of ureteric budding and is crucial for kidney formation--a mouse model for Cenani-Lenz syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Lrp4(-/-) mice show a delay in ureteric bud formation that results in unilateral or bilateral kidney agenesis.
      explanation: Reproduces the human kidney malformation and shows its developmental basis.
- name: Lrp4 dan and mdig mutant mice
  species: Mouse
  genotype: Spontaneous recessive Lrp4 alleles dan and mdig, homozygous
  publication: PMID:16517118
  description: Two spontaneous recessive mouse mutations causing polysyndactyly, positionally cloned to Lrp4.
  modeled_mechanisms:
  - target: Defective Digit Separation and Autopod Skeletal Patterning
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    limitations: Polysyndactyly rather than the oligosyndactyly typical of patients.
    evidence:
    - reference: PMID:16517118
      reference_title: Mutations in the gene encoding the low-density lipoprotein receptor LRP4 cause abnormal limb development in the mouse.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Positional cloning of two recessive mutations of the mouse that cause polysyndactyly (dan and mdig-Chr 2)
        confirmed that the gene encoding MEGF7/LRP4, a member of the low-density lipoprotein receptor family, plays an
        essential role in the process of digit differentiation.
      explanation: Independent spontaneous alleles give digit fusion.
- name: Bovine mulefoot (syndactyly)
  species: Cattle
  genotype: LRP4 intron 37 splice donor G>A, homozygous
  publication: PMID:16963222
  description: >-
    Naturally occurring autosomal recessive syndactyly (fused digits) of cattle caused by an LRP4 splice variant that
    predicts a receptor lacking its cytoplasmic domain.
  modeled_mechanisms:
  - target: Defective Digit Separation and Autopod Skeletal Patterning
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    limitations: >-
      Artiodactyl distal limb with two main digits; renal and craniofacial involvement are not described in the source.
    evidence:
    - reference: PMID:16963222
      reference_title: Defective splicing of Megf7/Lrp4, a regulator of distal limb development, in autosomal recessive mulefoot disease.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These findings confirm that autosomal recessive loss-of-function mutations in Megf7/Lrp4 result in phenotypically
        similar forms of syndactyly in different mammalian species and that such mutations are the cause of MFD in
        bovines.
      explanation: Cross-species conservation of LRP4 loss-of-function syndactyly.
experimental_models:
- name: Patient-derived myotubes (LRP4 p.Tyr607Cys)
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Primary myoblasts from the muscle biopsy of the patient with combined CLS and congenital myasthenic syndrome,
    differentiated into myotubes and treated with neural agrin or Wnt11.
  publication: PMID:37640745
  modeled_mechanisms:
  - target: Impaired Agrin-LRP4-MuSK Signaling at the Neuromuscular Junction
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    limitations: >-
      One patient and one allele; cultured myotubes lack the nerve terminal, so the synapse itself is not modeled.
    evidence:
    - reference: PMID:37640745
      reference_title: New mutation in the β1 propeller domain of LRP4 responsible for congenital myasthenic syndrome associated with Cenani-Lenz syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        A decrease of 85% with agrin and 55% with Wnt11 of aggregates was observed in patient-derived myotubes compared
        with control
      explanation: Reduced acetylcholine receptor aggregation in patient cells.
- name: LRP6-dependent Wnt luciferase reporter assay
  experimental_model_type: CELL_LINE
  description: Cultured cells co-transfected with LRP6 and wild-type or patient-variant LRP4 and a canonical Wnt reporter.
  publication: PMID:34857885
  modeled_mechanisms:
  - target: Loss of LRP4 Antagonism of Canonical Wnt Signaling
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: MOLECULAR
    limitations: Overexpression in a heterologous cell system; not limb-bud ectoderm or ureteric bud.
    evidence:
    - reference: PMID:34857885
      reference_title: Novel variants in the LRP4 underlying Cenani-Lenz Syndactyly syndrome.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Wild type LRP4 was able to inhibit LRP6-dependent WNT signaling robustly. The two mutants p.(Asp99His) and
        p.(Arg545Trp) inhibited WNT signaling less effectively, suggesting they reduced LRP4 function.
      explanation: Quantifies loss of Wnt antagonism by patient alleles.
📚

References & Deep Research

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: Cenani-Lenz Syndactyly Syndrome · 2026-10-16T12:20:46Z · View source

New entry for MONDO:0008931 (LRP4). Inputs: one Perplexity deep-research report run at reasoning_effort low, used as a lead only; its numbered citations were not used. The report body named PMIDs 20381006, 38013226, 37640745, 30569497 and 20610440. Added from PubMed searches: 15710123, 16207730, 16517118, 16963222, 20454682, 23636941, 23664847, 24924585, 25676610, 28559208, 29524275, 30041615, 30327840, 31750994, 31895055, 34857885, 42153583. Pathograph: biallelic LRP4 loss of function -> loss of LRP4 antagonism of LRP6 canonical Wnt signaling -> (limb) abnormal apical ectodermal ridge signaling -> defective digit separation -> limb phenotypes; (kidney) delayed ureteric budding -> failed metanephric mesenchyme induction -> renal agenesis/hypoplasia; (one beta1-propeller allele) impaired agrin-LRP4-MuSK signaling -> fatigable weakness. Judgement calls: the Wnt-to-ridge and Wnt-to-ureteric-bud steps rest on mouse evidence and are marked INDIRECT_UNKNOWN_INTERMEDIATES; APC and GREM1-FMN1 Cenani-Lenz-like families are recorded in notes as differentials, not as genetic rows; hypoglycaemia (one sibship) and Notch involvement (zebrafish) kept to notes; facial features, scoliosis and short stature left without a causal edge because no mechanism is published; GO:0030547 signaling receptor inhibitor activity and GO:0017147 Wnt-protein binding bound as LRP4 molecular functions; no prevalence record because Orphanet was not cached and no primary prevalence source was found; no GeneReviews chapter exists. Validation: just validate-disorders passed, 72/72 snippets verified, check-entity-refs, check-causal-targets, check-duplicate-keys, check-gene-activity-grounding OK; 14 of 20 phenotypes causally connected. Review round: added a diagnosis section (hand radiography, prenatal ultrasound, targeted LRP4 testing, exome sequencing) with case-report evidence including PMID:33179409, split carpal from metacarpal synostosis (HP:0009702 and HP:0009701), added cleft lip from PMID:28559208 without a causal edge, and trimmed a mouse-study snippet that also described human malformations; 83/83 snippets verified and all gates pass. A renal-ultrasound row was dropped before push because its only evidence was a case report with normal kidneys.

Perplexity ▸
Cenani–Lenz Syndactyly Syndrome: Disease-Characteristics Research Report
sonar-deep-research 50 citations 2026-10-16T11:56:16.081948

Cenani–Lenz Syndactyly Syndrome: Disease-Characteristics Research Report

Disease: Cenani–Lenz syndactyly syndrome
Preferred abbreviation: CLSS or CLS
MONDO: MONDO:0008931
Disease class: Mendelian congenital-malformation syndrome
Core molecular diagnosis: Biallelic pathogenic variants in LRP4

Scope note. CLSS is exceptionally rare, so most evidence comes from individual families, small case series, functional cell studies, and mouse models—not epidemiologic cohorts or randomized trials. A 2024 publication added a prenatal case and new LRP4 variant, while a 2023 study expanded the phenotype to include congenital myasthenic syndrome in one patient. [PMID: 38013226; PMID: 37640745] [47][59]

1. Disease information

1.1 Definition

Cenani–Lenz syndactyly syndrome is a congenital developmental disorder characterized by severe, usually bilateral complex syndactyly or oligosyndactyly, disorganization and fusion of metacarpal/phalangeal bones, radioulnar abnormalities, and variably renal and craniofacial malformations. The classical hand resembles a “mitten” because of nearly complete digital fusion and synostosis. Lower-limb involvement is common but generally less severe. [16][17]

The molecularly defined classical disorder is an autosomal-recessive LRP4 loss-of-function disorder. Related but nosologically distinct “Cenani–Lenz-like” phenotypes can result from rearrangements involving GREM1–FMN1 or, rarely, APC variants. [PMID: 20381006; PMID: 30569497; PMID: 20610440] [6][136][147]

1.2 Identifiers and terminology

Resource Identifier/name
MONDO MONDO:0008931
OMIM #212780, Cenani-Lenz syndactyly syndrome
Orphanet ORPHA:3258
MedGen/UMLS C1859309
MeSH supplementary concept C538150
GARD 5084
ICD-10 Q78.4; broad osteochondrodysplasia category rather than a highly specific CLSS code
ICD-11 LB79.Y, other specified congenital musculoskeletal anomaly category
Disease Ontology DOID:0090015
Causal-gene OMIM LRP4, OMIM *604270
Common synonyms Cenani-Lenz syndrome; Cenani syndactyly; Cenani-Lenz syndactyly; Cenani syndactylism; syndactyly type VII/type 7; CLSS; CLS

These mappings are reported by Orphanet, OMIM/ClinVar and MedGen. [18][80]

1.3 Evidence granularity

The information is predominantly aggregated disease-level knowledge reconstructed from individual patients and pedigrees. The landmark molecular study examined 14 families and found recessive LRP4 variants in 12; many later publications are single-family or single-patient reports. It is not derived from population-scale EHR analysis. [PMID: 20381006] [6]

2. Etiology

2.1 Causal factors and risk factors

Factor Evidence and interpretation
Biallelic LRP4 variants Established principal cause. Homozygous or compound-heterozygous missense, splice, nonsense, and frameshift variants impair LRP4 function. [PMID: 20381006] [6]
Autosomal-recessive inheritance Parents are usually unaffected heterozygotes; recurrence risk is 25% for each pregnancy when both parents carry the familial variant. [79]
Consanguinity Strong ascertainment/risk factor because it increases homozygosity for rare alleles. Eleven of 12 mutation-positive families in the original study were reported as consanguineous. [PMID: 20381006] [6]
Family history Affected siblings and multiple affected members occur in extended recessive pedigrees.
Founder variants LRP4 p.Asp529Asn was found on a shared Turkish haplotype and p.Asp137Asn on a shared Egyptian haplotype, supporting founder effects. [PMID: 20381006] [6]
Sex No evidence of sex-dependent genetic risk; both sexes can be affected because inheritance is autosomal.
Environmental, infectious, lifestyle factors None demonstrated as causes or modifiers of CLSS.
Maternal age, paternal age, toxins, diet No reproducible association identified.

2.2 Protective factors

No genetic or environmental protective factor has been established. Unaffected heterozygous carriers are protected from classical recessive CLSS by retention of one functional allele, but this is inheritance biology rather than a clinically actionable protective intervention.

2.3 Gene–environment interaction

No CLSS-specific gene–environment interaction has been demonstrated. Embryonic phenotype is driven primarily by altered developmental signaling during tightly constrained windows of limb and renal morphogenesis. Nutritional, toxicologic, infectious, or lifestyle modulation remains unstudied.

2.4 Related genetic phenocopies

A heterozygous 1.7-Mb duplication encompassing GREM1 and FMN1 produced autosomal-dominant, isolated Cenani–Lenz-like oligosyndactyly. Other GREM1–FMN1 rearrangements can cause oligosyndactyly, radioulnar synostosis, hearing loss, and renal defects. These should be treated as differential molecular diagnoses rather than routine causes of classical MONDO:0008931. [PMID: 20610440] [147]

3. Phenotypes

All major abnormalities are congenital, although renal dysfunction, dental consequences, scoliosis, or functional disability may be recognized later. Frequencies below are either qualitative or calculated at the family level from the 12 mutation-positive families in Li et al.; they should not be interpreted as population estimates. [PMID: 20381006] [6]

Phenotype/type Onset, severity, course and frequency Functional/QOL impact Suggested HPO term
Hand syndactyly Congenital; usually bilateral and severe/complex; typical in 10/12 molecular families, partial in two and absent as “typical” in one atypical family Major limitation in grasp, pinch, writing, dressing and self-care; surgery may not restore normal function Syndactyly, HP:0001159; finger syndactyly, HP:0006101
Oligodactyly/digital-ray reduction Congenital; variable from partial absence to severe hand/foot agenesis Reduces manipulative and weight-bearing function Oligodactyly, HP:0012165
Metacarpal/phalangeal disorganization or absence Congenital; reported in all 12 landmark mutation-positive families Limits reconstructive options and explains poor postoperative function Abnormal metacarpal morphology, HP:0001163; absent phalanges
Metacarpal synostosis Congenital; 11/12 families in the landmark series Rigid fused rays, reduced hand span and independent digit motion Metacarpal synostosis, HP:0009701
Radioulnar synostosis Congenital; at least 8/10 assessable families in the landmark series Restricts pronation/supination and activities requiring forearm rotation Radioulnar synostosis, HP:0002974
Short radius/ulna and brachymesomelia Congenital, nonprogressive skeletal malformation; variable Reduced reach and mechanical leverage Hypoplasia of radius, HP:0002984; hypoplasia of ulna, HP:0003022
Foot/toe syndactyly Congenital and common, generally milder than hands Can affect footwear, gait and balance; severity variable Toe syndactyly, HP:0001770
Nail aplasia/hypoplasia Congenital; very common in affected hands and variable in feet Cosmetic impact and reduced protection of distal digits Anonychia, HP:0001798; nail dysplasia, HP:0001597
Renal agenesis Congenital; unilateral or bilateral. Renal agenesis/hypoplasia occurred in over half of reported LRP4-positive families Unilateral disease requires surveillance; bilateral agenesis is lethal prenatally or neonatally Renal agenesis, HP:0000104
Renal hypoplasia Congenital; unilateral or bilateral Risk of reduced renal reserve, hypertension and chronic kidney disease Renal hypoplasia, HP:0000089
Ectopic kidney Congenital, occasional May predispose to obstruction or infection, though CLSS-specific rates are unknown Ectopic kidney, HP:0000086
Prominent/broad forehead Congenital facial morphology; 9/12 landmark families Usually cosmetic, little direct functional effect Prominent forehead, HP:0011220
Hypertelorism Congenital; approximately 7/12 landmark families Usually cosmetic Hypertelorism, HP:0000316
Downslanting palpebral fissures Congenital; minority of families Primarily dysmorphic feature HP:0000494
Malar hypoplasia/flattening Congenital; common but variable Usually cosmetic; can contribute to craniofacial profile Malar flattening, HP:0000272
Micrognathia/retrognathia Congenital; approximately half of landmark families Severe cases could affect feeding or airway, but CLSS-specific outcome data are absent Micrognathia, HP:0000347
Hypodontia/enamel hypoplasia/early tooth loss Congenital dental-development abnormality or later consequence; uncommon/variable Chewing, speech, dental health and cosmetic burden Hypodontia, HP:0000668; enamel hypoplasia, HP:0006297
Vertebral anomalies, scoliosis, hemivertebrae Occasional; congenital structure with possible progression of curvature during growth Pain, posture and mobility effects if severe Hemivertebrae, HP:0002937; scoliosis, HP:0002650
Developmental delay Not core; reported in isolated patients, generally absent in most cases Variable Global developmental delay, HP:0001263
Hearing loss, cataract, pulmonary stenosis, hypothyroidism Isolated case-level associations; causality to CLSS uncertain Feature-dependent Hearing impairment HP:0000365; cataract HP:0000518; pulmonary stenosis HP:0001642
Fluctuating weakness/CMS Newly documented in one 2023 patient with p.Tyr607Cys; not established as a routine CLSS manifestation Fatigability, impaired mobility and neuromuscular disability Muscle weakness HP:0001324; fatigable weakness HP:0003473

MedGen lists the major limb, craniofacial, dental, vertebral, nail and cardiac findings. [91] No validated CLSS-specific EQ-5D, SF-36, PROMIS or quality-of-life cohort has been published.

4. Genetic and molecular information

4.1 Causal gene

Attribute Value
Gene LRP4, LDL receptor-related protein 4
HGNC HGNC:6696
NCBI Gene 4038
Ensembl ENSG00000134569
OMIM gene *604270
UniProt O75096
Location 11p11.2
Protein type Large single-pass type-I membrane receptor with extracellular LDL-A repeats, EGF-like domains and YWTD β-propeller regions
Principal CLSS consequence Partial or complete loss of protein function, commonly through impaired folding/secretory trafficking and failure to reach the cell surface

Gene identifiers are supported by NCBI/HGNC-linked resources. [61][63]

4.2 Representative reported variants

LRP4 variant Type/origin Evidence or reported interpretation
c.409G>A, p.Asp137Asn Homozygous missense; Egyptian founder Impaired surface localization and Wnt-antagonist function
c.479G>A, p.Cys160Tyr Homozygous missense Functionally deficient
c.1345G>A, p.Asp449Asn Homozygous missense Functionally deficient
c.1382A>C, p.Thr461Pro Homozygous missense Disease segregating
c.1417C>T, p.Leu473Phe Homozygous missense Functionally deficient
c.1585G>A, p.Asp529Asn Homozygous missense; Turkish founder Functionally deficient
c.3049T>C, p.Cys1017Arg Homozygous missense Segregated in a large Pakistani family
c.547+1G>A Homozygous canonical splice variant Predicted/observed loss of function
c.200-9G>A and c.4959G>C Compound-heterozygous splice variants Aberrant transcripts and premature truncation
c.289G>T, p.Glu97Ter Homozygous nonsense Severe CLSS; near-complete loss of function
c.2858T>C, p.Leu953Pro Homozygous missense Limb and kidney phenotype
c.316+1G>A Homozygous splice donor Severe CLSS
c.4910G>A, p.Cys1637Tyr Homozygous missense CLSS with recurrent ketotic hypoglycemia in two brothers; hypoglycemia remains an uncertain expansion
c.1820A>G, p.Tyr607Cys Homozygous missense 2023 CLSS/CMS overlap; altered agrin and WNT11 binding and reduced acetylcholine-receptor clustering
c.282C>A, p.Asn94Lys Homozygous missense 2024 prenatal CLSS report; classified as causative by the authors
c.3813del, p.Thr1272Leufs*18 Frameshift Reported likely pathogenic in a 2025 case
c.4910G>A, p.Cys1637Tyr Missense VUS in the 2025 compound-heterozygous case, despite earlier homozygous disease association

The initial variant spectrum and functional assays are from PMID:20381006. [6] The 2024 report states:

“Exome sequencing revealed a novel biallelic c.282C>A variant in… LRP4… causing p.(Asn94Lys).” [PMID: 38013226] [47]

4.3 Variant interpretation and population frequency

  • Classical CLSS variants are germline; no somatic form is recognized.
  • Pathogenic mechanisms include nonsense/frameshift-mediated loss of function, abnormal splicing, and missense-induced folding or trafficking defects.
  • Landmark missense variants were absent from at least 250 controls, but those historical controls are too small to estimate allele frequency. [PMID:20381006] [6]
  • Most credible disease alleles are absent or exceptionally rare in population databases. Exact gnomAD frequencies must be recorded variant by variant and genome build by genome build; no meaningful disease-wide carrier frequency is available.
  • ClinVar assertions can differ by variant and submitter. Classification should be based on the current ClinVar record, segregation, functional evidence, population frequency, and ACMG/AMP criteria rather than assuming that every published variant is pathogenic.

4.4 Modifiers, epigenetics and structural abnormalities

No validated modifier gene or CLSS-specific methylation/epigenetic signature is known. A GREM1–FMN1 duplication is a distinct dominant phenocopy, not an established modifier of biallelic LRP4 disease. No recurrent aneuploidy, translocation, inversion, or mitochondrial variant causes classical CLSS.

5. Environmental information

Category Current evidence
Environmental toxins/radiation/pollution No established causal or modifying exposure
Smoking, alcohol, diet, exercise No demonstrated relationship to occurrence or severity
Occupational exposure Not applicable to a congenital Mendelian developmental disorder
Infectious agent None
Immune trigger None established
Prenatal environment May influence general fetal outcome, but no CLSS-specific interaction has been shown

Therefore, environmental-risk or lifestyle-prevention claims should not be entered into the knowledge base as established associations.

6. Mechanism and pathophysiology

6.1 Ordered causal chain

  1. Biallelic pathogenic germline variation in LRP4 leads to reduced production, abnormal splicing, truncation, misfolding, or defective trafficking of LRP4.
  2. Deficient cell-surface LRP4 leads to loss of its normal integration/antagonism of LRP5/6-mediated canonical WNT signaling and perturbation of WNT–BMP interactions.
  3. Dysregulated WNT/BMP signaling in embryonic limb ectoderm, especially the apical ectodermal ridge, leads to abnormal spatial expression of FGF8, SHH and BMP-family developmental signals; this in-vivo human step is partly inferred from mouse models.
  4. Abnormal limb-bud patterning and impaired interdigital separation/apoptosis lead to syndactyly, abnormal digit number, synostosis and disorganization of metacarpals, metatarsals and phalanges.
  5. Altered skeletal patterning and growth lead to shortened radius/ulna, radioulnar synostosis and brachymesomelia.
  6. In the renal branch, deficient LRP4 signaling leads to delayed or failed ureteric-bud initiation/outgrowth.
  7. Delayed ureteric budding leads to inadequate reciprocal stimulation of metanephric mesenchyme, failed differentiation and, variably, renal hypoplasia, ectopia or unilateral/bilateral agenesis.
  8. In the craniofacial/dental branch, altered WNT/BMP integration leads to abnormal facial-bone and tooth morphogenesis, producing malar hypoplasia, micrognathia, hypodontia, enamel defects or tooth fusion; much of this causal detail is supported by mouse models.
  9. For selected β-propeller variants, impaired agrin–LRP4–MuSK signaling at the neuromuscular junction leads to reduced acetylcholine-receptor clustering and can result in congenital myasthenic weakness; this has been directly demonstrated for p.Tyr607Cys but is not universal in CLSS. [PMID:37640745] [59]

6.2 Molecular and cellular detail

The landmark functional study showed that wild-type LRP4 strongly antagonized WNT1/LRP6-mediated β-catenin reporter activity in HEK293T cells, whereas five CLSS missense proteins lost or markedly reduced that activity. Cell-surface biotinylation showed defective plasma-membrane delivery despite broadly comparable total protein abundance. [PMID:20381006] [6]

Direct abstract evidence states:

“LRP4 is known to antagonize LRP6-mediated activation of canonical Wnt signaling, a function that is lost by the identified mutations.” [PMID:20381006, published May 14, 2010] [6]

Mouse evidence indicates structural abnormalities of the apical ectodermal ridge and disturbed Fgf8, Bmp4 and Shh expression. The precise sequence from excessive canonical WNT activity to each human skeletal lesion remains partly inferred rather than directly measured in human embryos. [37]

6.3 Kidney mechanism and quantitative model evidence

In an Lrp4 null mouse cohort of 156 postnatal animals, 51% had bilateral and 22% unilateral renal agenesis. The investigators observed delayed ureteric budding with failure to stimulate metanephric mesenchyme in time. [109][116]

“Lrp4−/− mice show a delay in ureteric bud formation that results in unilateral or bilateral kidney agenesis.” [PMID associated with the 2010 PLoS One study] [116]

6.4 Neuromuscular-junction branch

LRP4 is an obligate agrin receptor/coreceptor that recruits and activates MuSK, promoting postsynaptic acetylcholine-receptor clustering. Most classical CLSS patients have no overt neuromuscular phenotype. In 2023, however, a homozygous p.Tyr607Cys β-propeller variant caused limb/renal malformations plus weakness, fatigability and an electrophysiologic decrement; patient myotubes had significantly reduced AChR aggregation. [PMID:37640745, August 28, 2023] [59][60]

6.5 Suggested ontology annotations

Mechanistic entity Suggested ontology term
Canonical WNT signaling GO:0060070, canonical Wnt signaling pathway
Negative regulation of canonical WNT GO:0090090
Limb morphogenesis GO:0035108
Embryonic limb morphogenesis GO:0030326
Apoptotic process GO:0006915
Bone development/ossification GO:0060348 / GO:0001503
Kidney development GO:0001822
Ureteric-bud development GO:0001657
Neuromuscular-junction development GO:0007528
Acetylcholine-receptor clustering GO:0095500
Plasma membrane GO:0005886
Cell surface GO:0009986
Limb-bud ectodermal cell CL annotation should use the closest developmental ectoderm/epithelial-cell term; no CLSS-specific cell term
Metanephric mesenchymal cell CL:0002320
Skeletal-muscle cell/myotube CL:0000188 / CL:0002372
Osteoblast CL:0000062
Osteocyte CL:0000137

6.6 Omics and advanced technologies

No disease-specific bulk transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, multi-omic or genome-scale CRISPR study has been established for CLSS patients. Available molecular profiling is chiefly targeted reporter assays, protein trafficking, ligand-binding, splicing, and patient-myotube AChR-clustering experiments.

7. Anatomical structures affected

Level Structures/cells Suggested ontology
Primary organ/system Hands, fingers, carpal/metacarpal/phalangeal skeleton UBERON:0002398 hand; UBERON:0001435 carpal region; UBERON:0002389 digit
Primary organ/system Feet, toes, metatarsals and phalanges UBERON:0002387 foot
Upper limb Radius, ulna, radioulnar articulation and forearm UBERON:0001423 radius; UBERON:0001424 ulna; UBERON:0003403 forearm
Renal Kidney, ureteric bud and metanephric mesenchyme UBERON:0002113 kidney; UBERON:0000084 metanephros
Craniofacial Frontal, orbital, maxillary/malar and mandibular regions UBERON:0001708 jaw; UBERON:0001684 mandible
Dental Tooth primordia, enamel and permanent dentition UBERON:0001091 tooth
Vertebral/thoracic Vertebrae, ribs, sternum UBERON:0002412 vertebral column
Neuromuscular, selected cases Skeletal muscle neuromuscular junction UBERON:0001015 musculature; GO:0031594 neuromuscular junction
Cellular Limb-bud ectoderm/AER cells, chondrogenic and osteogenic precursors, metanephric mesenchyme, ureteric epithelium Developmental epithelial, mesenchymal, chondrocyte and osteoblast CL terms
Subcellular Plasma membrane and secretory pathway; postsynaptic membrane at NMJ GO:0005886; GO:0045211

Hand involvement is generally bilateral and nearly symmetrical, although exact digital anatomy can be asymmetric. Lower limbs are usually bilaterally involved but less severe. Renal agenesis may be unilateral or bilateral. [16][6]

8. Temporal development

  • Biological onset: embryonic, during limb-bud and renal-organogenesis windows.
  • Clinical onset: congenital; detected prenatally by ultrasound in severe cases or at birth.
  • Pattern: not acute, episodic, inflammatory or relapsing. The structural malformations are largely stable, while secondary orthopedic, renal, dental and functional consequences may evolve with growth.
  • Critical periods: limb patterning and interdigital separation in early embryogenesis; ureteric-bud initiation during metanephric kidney development. There is no postnatal therapy capable of reversing these developmental events.
  • Disease duration: lifelong.
  • Remission: not applicable to congenital skeletal malformations. Surgical reconstruction may improve function but is not biologic remission.
  • Lethal end of spectrum: bilateral renal agenesis can cause fetal or neonatal death; the original series included a neonate who died on the first day of life and pregnancies terminated after prenatal diagnosis of bilateral agenesis. [PMID:20381006] [6]

9. Inheritance and population

Characteristic Current evidence
Inheritance Autosomal recessive for classical LRP4-related CLSS
Recurrence 25% affected, 50% carrier and 25% unaffected/noncarrier per pregnancy when both parents are carriers
Penetrance Apparently high for limb abnormalities among biallelic pathogenic genotypes, but organ-specific manifestations—especially kidney and craniofacial anomalies—are incompletely penetrant
Expressivity Markedly variable, from near-isolated hand syndactyly to extensive limb reduction, renal agenesis and multisystem disease
Anticipation Not reported; no repeat-expansion mechanism
Germline mosaicism Not established, although low residual recurrence risk is theoretically possible after an apparently de novo event
Consanguinity Common in reported families and increases recessive risk
Founder effects p.Asp529Asn in Turkish families; p.Asp137Asn in Egyptian families
Carrier frequency Unknown; no population-screening estimate
Sex ratio No established bias
Geographic distribution Cases reported from Turkey, Egypt, Pakistan, Jordan, Iran, Europe, China, Jewish families and, recently, Sudan; this reflects family ascertainment rather than endemicity
Prevalence Orphanet: <1 per 1,000,000
Incidence Not calculated
Historical case count Orphanet stated fewer than 30 described cases; later reports have increased the count, but no current global registry total exists

Orphanet reports prevalence below one per million and notes that most cases occurred in related families. [16]

10. Diagnostics

10.1 Clinical evaluation

The diagnosis should be suspected in a neonate or child with complex bilateral hand syndactyly/oligodactyly plus metacarpal disorganization, radioulnar synostosis, shortened forearms, renal anomaly or the characteristic facial gestalt.

Investigation Purpose
Hand, forearm and foot radiographs Define synostoses, absent/disorganized bones, digital-ray number, radioulnar anatomy and surgical feasibility
Renal ultrasound Mandatory evaluation for agenesis, hypoplasia, ectopia or other structural anomaly
Serum creatinine/eGFR, electrolytes and urinalysis Baseline and longitudinal renal function, especially with a solitary or hypoplastic kidney
Blood pressure Surveillance for renal-associated hypertension
Dental evaluation and panoramic imaging Hypodontia, enamel hypoplasia, abnormal eruption or early tooth loss
Spine/chest radiographs when indicated Hemivertebrae, scoliosis, ribs and pectus abnormality
Echocardiography If murmur or other cardiac signs; pulmonary stenosis is not a universal feature
Audiology and ophthalmology Symptom-directed because hearing loss and cataract are occasional
EMG/repetitive nerve stimulation Only with weakness or fatigability; evaluates possible LRP4-related CMS
Developmental assessment If delay is suspected

Abdominal ultrasound and periodic renal-function testing are specifically recommended by expert review. [79]

10.2 Genetic-testing strategy

  1. First-line: sequence LRP4 with deletion/duplication analysis when the phenotype is classic.
  2. Panel testing: a limb-malformation/syndactyly panel including LRP4, GREM1, FMN1, APC, HOXD13, GJA1, FGF16 and other phenotype-relevant genes is reasonable when the presentation is atypical.
  3. Trio WES: preferred when there are multisystem abnormalities, uncertain clinical classification, negative panel testing, or prenatal disease. The 2024 report explicitly described exome sequencing as powerful and preferred for syndactyly-related phenotypes. [PMID:38013226] [47]
  4. WGS: useful after negative WES/panel testing because it can identify noncoding splice variants, structural variants and rearrangements across GREM1–FMN1.
  5. CMA: appropriate when intellectual disability, multiple congenital anomalies or a suspected GREM1–FMN1 copy-number change is present.
  6. Karyotype/FISH: low yield unless a cytogenetic rearrangement is suspected; not routine for classical disease.
  7. Mitochondrial and repeat-expansion testing: not indicated.
  8. RNA analysis: useful for suspected splice variants to demonstrate aberrant transcripts.
  9. Parental segregation testing: essential for phasing, carrier confirmation and recurrence counseling.

The GTR listed 24 clinical tests for this condition at the time captured by the source. [77]

10.3 Prenatal and preimplantation diagnosis

  • Detailed fetal ultrasound may detect severe oligosyndactyly, abnormal hands/feet, shortened forearms and bilateral renal agenesis, although syndactyly alone can be difficult to visualize.
  • If familial variants are known, targeted chorionic-villus or amniotic-fluid testing provides definitive prenatal diagnosis.
  • Preimplantation genetic testing for monogenic disease is technically feasible.
  • Trio/family WES may diagnose a previously unresolved fetal-malformation phenotype.

10.4 Differential diagnosis

Differential Distinguishing considerations
Carpenter syndrome Craniosynostosis, polysyndactyly and broader craniofacial abnormalities
Apert syndrome Craniosynostosis with characteristic symmetrical “mitten” syndactyly; usually FGFR2, autosomal dominant
Acrocephalopolysyndactyly disorders Craniosynostosis and polydactyly predominate
Greig cephalopolysyndactyly Macrocephaly/hypertelorism and preaxial polydactyly; GLI3
HOXD13-related syndactyly/synpolydactyly Usually dominant, characteristic central digital duplications, typically no renal agenesis
GREM1–FMN1 rearrangement syndrome Can closely resemble CLSS; identify by CNV analysis
APC-associated limb malformation May have a CLSS-like phenotype; assess personal/family polyposis history, although some reported limb cases lacked polyposis
VACTERL association Limb and renal anomalies but requires broader association pattern
Thrombocytopenia-absent radius Absent radii with thumbs present and thrombocytopenia
Sclerosteosis 2 Also LRP4-related but characterized by progressive high bone mass rather than congenital CLSS limb pattern

There are no universally adopted standalone clinical diagnostic criteria; diagnosis is clinical-radiographic and confirmed molecularly.

11. Outcome and prognosis

  • Survival: No 5-year, 10-year or median-survival estimates exist. Survival is expected to be broadly normal in patients without bilateral renal agenesis or severe renal failure, but this has not been demonstrated in a longitudinal cohort.
  • Mortality: Bilateral renal agenesis is the principal known lethal complication. Perinatal respiratory failure in null mice should not be automatically extrapolated to humans.
  • Morbidity: Primarily chronic upper-limb functional impairment, restricted forearm rotation, altered gait/footwear needs, cosmetic burden and possible renal morbidity.
  • Renal prognosis: Depends on nephron mass and whether a functioning contralateral kidney is present. A solitary or hypoplastic kidney requires lifelong monitoring.
  • Neuromuscular prognosis: Unknown because CLSS-associated CMS has been documented only exceptionally.
  • Quality of life: No disease-specific instrument or cohort estimate is available. Severe hand abnormalities can markedly affect independence; published reviews note poor hand function even after surgery. [24]
  • Prognostic factors: extent of metacarpal/phalangeal disorganization, presence of usable thumb/digital rays, radioulnar synostosis, bilateral versus unilateral renal disease, baseline renal function, and—rarely—neuromuscular involvement.
  • Prognostic biomarkers: none validated.

12. Treatment

There is no curative or disease-modifying therapy and no approved drug directed at LRP4/WNT signaling for CLSS.

Intervention Indication and expected outcome Suggested NCIt concept
Multidisciplinary congenital-hand assessment Define anatomy and realistic functional goals, ideally in infancy Clinical evaluation
Syndactyly release/digital reconstruction Create individualized functional rays, improve grasp or hygiene; results may be unsatisfactory when bones are severely fused/disorganized Surgical Procedure, C15329; reconstructive surgery
Orthopedic surgery Selected forearm, foot, hip or spinal abnormalities Orthopedic surgery
Occupational therapy Adaptive grasp, self-care, school/work equipment and postoperative rehabilitation Occupational Therapy, C15309
Physical therapy Mobility, range of motion, strength and gait Physical Therapy, C15311
Orthoses/prosthetic or adaptive devices Improve limb positioning, ambulation or daily function Assistive device
Renal surveillance Blood pressure, urinalysis, creatinine/eGFR and ultrasound follow-up Disease surveillance
Nephrology management Standard management of reduced renal function, hypertension, infection or obstruction Supportive care
Dental treatment Preventive dentistry, restorations, prosthodontics or orthodontics Dental treatment
CMS-directed therapy If physiologically confirmed, management by neuromuscular specialists; no CLSS-specific response rates exist Pharmacologic therapy/supportive care
Genetic counseling Recurrence calculation and reproductive options Genetic Counseling, C15241

Orphanet recommends reconstruction of an individualized digit but warns that syndactyly-release outcomes can be unsatisfactory. [76] Expert review recommends radiographic definition of anatomy and surgical consultation during the first year of life. [79]

Experimental treatment and trials

No CLSS-specific gene therapy, CRISPR, RNA therapy, cell therapy, WNT-targeted drug, immunotherapy or registered interventional trial has established efficacy. Prenatal pathway manipulation would carry major off-target developmental risks and remains theoretical.

13. Prevention

Prevention level Applicable measure
Primary prevention No lifestyle, vaccine, drug or exposure modification prevents a sporadic inherited case. Reproductive carrier testing and PGT-M can prevent an affected pregnancy in known carrier couples.
Secondary prevention Early prenatal molecular diagnosis or fetal ultrasound; prompt neonatal renal imaging and radiographic characterization
Tertiary prevention Early hand/orthopedic assessment, rehabilitation, renal surveillance, dental care and management of scoliosis or CMS to reduce complications
Cascade screening Test adult relatives for the familial variant where reproductive information is desired
Population screening Not justified because prevalence and carrier frequency are extremely low and not established
Newborn screening Not included in biochemical newborn-screening programs; visible congenital findings usually trigger evaluation
Immunization/prophylaxis No disease-specific vaccine or preventive medication
Public-health/environmental intervention Not applicable because there is no demonstrated infectious or environmental cause

Genetic counseling should explain the 25% recurrence risk for carrier couples, variable expressivity, options for prenatal diagnosis, PGT-M, donor gametes and adoption. [79]

14. Other species and naturally occurring disease

Species Taxonomy/model information Natural phenotype and comparative relevance
Domestic cattle, Bos taurus NCBI Taxon 9913; bovine LRP4 ortholog Autosomal-recessive syndactyly or “mulefoot,” OMIA:000963-9913. Independent LRP4 variants occur in Holstein, Angus, Simmental and Simmental–Charolais cattle. The principal phenotype is fused digits/uncloven hooves, generally less multisystemic than human CLSS. [123][130]
House mouse, Mus musculus NCBI Taxon 10090; Lrp4 NCBI Gene 228357, MGI:2442252 Induced and spontaneous alleles cause fully penetrant polysyndactyly, dental abnormalities, growth impairment and variably renal agenesis; severe null alleles can cause neonatal lethality. [106][107]
Fruit fly, Drosophila melanogaster NCBI Taxon 7227; orthologous Lrp4 Regulates synaptic organization; useful for conserved synaptic biology but does not reproduce mammalian limb or renal morphogenesis. [74]

Bovine disease is naturally occurring and economically relevant because fused hooves can impair locomotion and breeding value. It is not zoonotic, infectious or transmissible between species. The shared LRP4 association demonstrates evolutionary conservation of distal-limb developmental function.

15. Model organisms

Model Type/genotype Phenotype recapitulation Applications and limitations
Lrp4 null mouse Targeted knockout replacing exon 1 with a stop/neomycin cassette Polysyndactyly, delayed ureteric budding, unilateral/bilateral renal agenesis, tooth abnormalities and perinatal death Strong model for limb/kidney causality; more severe and often polydactylous compared with human oligodactyly
Hypomorphic/spontaneous Lrp4 mouse Partial-function alleles Viable mice with polysyndactyly, digit fusion and craniofacial/dental abnormalities Useful for dosage and domain studies; exact human variants may behave differently
Domain-specific knock-in mouse Extracellular/intracellular-domain alleles Extracellular-domain disruption produces stronger limb phenotype than many intracellular-domain changes Dissects structural requirements of LRP4
Patient-derived myotubes Human primary in-vitro model, p.Tyr607Cys Reduced acetylcholine-receptor clustering and impaired ligand interactions Direct human evidence for CMS mechanism; represents one variant/patient
HEK293T reporter model Transfected wild-type or mutant LRP4, LRP6, WNT1 Quantifies loss of WNT antagonism and defective membrane localization Mechanistically tractable but not a developing limb or kidney
Bovine mulefoot Naturally occurring large-animal model Digital fusion due to recessive LRP4 variants Valuable comparative limb model; renal and craniofacial phenotypes usually differ from human CLSS
Chick limb-bud manipulation Developmental experimental model, particularly GREM1 overexpression Cenani–Lenz-like digit-reduction patterns Useful for BMP/WNT spatial patterning; not an LRP4-specific whole-disease model

The mouse model quantitatively reproduces renal-organogenesis failure: among 156 null animals, 73% had agenesis—51% bilateral and 22% unilateral. [109] MGI records targeted, spontaneous, ENU-induced and endonuclease-generated Lrp4 alleles and notes polysyndactyly, renal agenesis, abnormal incisors, growth retardation and neonatal respiratory death. [106][107]

Recent developments and evidence assessment

Publication date Development Evidence type
August 28, 2023 Homozygous LRP4 c.1820A>G, p.Tyr607Cys linked CLSS limb/renal abnormalities with congenital myasthenic syndrome; patient-myotube and ligand-binding assays supported impaired agrin–LRP4–MuSK signaling. PMID:37640745; DOI:10.1038/s41598-023-41008-5. [59] Single human case plus in-vitro functional evidence
November 27, 2023 / January 2024 issue Prenatal CLSS diagnosis with homozygous c.282C>A, p.Asn94Lys; expanded the variant spectrum and emphasized WES in fetal syndactyly. PMID:38013226; DOI:10.1002/mgg3.2319. [47][114] Fetal case report and literature review
2021 New LRP4 variants p.Asp99His and p.Arg545Trp showed reduced ability to inhibit WNT signaling. [40] Human families plus reporter assay
2019 Review clarified the mechanistic and nosologic relationship among LRP4, GREM1–FMN1 and APC Cenani–Lenz-like disorders. PMID:30569497. [136] Expert review
2010 landmark Recessive LRP4 variants found in 12/14 families; renal anomalies recognized as common; impaired trafficking and WNT antagonism demonstrated. PMID:20381006; DOI:10.1016/j.ajhg.2010.03.004. [6] Multihousehold human series plus functional assays

Overall evidence conclusion

The strongest disease model is that biallelic germline loss of LRP4 cell-surface function dysregulates embryonic WNT/BMP signaling, disrupting limb and kidney morphogenesis. Limb malformations are highly penetrant, while renal, facial, dental and neuromuscular findings show variable expression. Clinical care remains anatomy- and complication-directed, with genetic diagnosis, renal surveillance, reconstructive assessment, rehabilitation and reproductive counseling as the main current implementations. No disease-modifying therapy, validated biomarker, population-screening program or CLSS-specific natural-history registry outcome has yet been established.

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 23
Resolved 23
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 2
Quoted claims found in source 1
Quoted claims not found in source 1
References weighed for topical relevance 23
On topic 11
Off topic 2

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMID:38013226 (abstract only): "Exome sequencing revealed a novel biallelic c.282C>A variant in… LRP4… causing p.(Asn94Lys)."
  • closest text in source: "Exome sequencing revealed a novel biallelic c.282C⟩Avariant in low-density lipoprotein receptor-related protein 4 (LRP4; OMIM604270; NM_002334.4) causing p"

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:10.1155/2019/9652649 (2 mentions) - A Review of the Genetics and Pathogenesis of Syndactyly in Humans and Experimental Animals: A 3-Step Pathway of Pathogenesis
  • shared terms: syndactyly
  • PMC:PMC6766129 (1 mention) - A Review of the Genetics and Pathogenesis of Syndactyly in Humans and Experimental Animals: A 3-Step Pathway of Pathogenesis.
  • shared terms: syndactyly

Weighed against this report's own most characteristic terms: lrp4, renal, clss, variant, limb, disease, syndactyly, agenesis, congenital, function, abnormalitie, developmental, kidney, phenotype, bilateral, functional, dental, established, severe, loss.

Term Validation

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

Outcome Count
Terms checked 69
Resolved 64
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 4
Terms whose name was checked 16
Terms named correctly 10
Terms named as a different term 4
Terms whose name is worth a second look 2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0008931 (4 mentions) - the report calls it "MONDO"; MONDO calls it Cenani-Lenz syndactyly syndrome
  • DOID:0090015 (1 mention) - the report calls it "Disease Ontology"; DOID calls it Cenani-Lenz syndactyly syndrome
  • HP:0000494 (1 mention) - the report calls it "Primarily dysmorphic feature"; HP calls it Downslanted palpebral fissures
  • CL:0002320 (1 mention) - the report calls it "Metanephric mesenchymal cell"; CL calls it connective tissue cell

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • HP:0001163 (obsolete Abnormality of the metacarpal bones) (1 mention) - replaced by HP:0005916

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:0090090 (1 mention) - the report calls it "Negative regulation of canonical WNT"; GO calls it negative regulation of canonical Wnt signaling pathway
  • GO:0095500 (1 mention) - the report calls it "Acetylcholine-receptor clustering"; GO calls it acetylcholine receptor signaling pathway

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, OMIA, MGI.