Lateral Meningocele Syndrome

Mendelian MONDO:0007537 Pathograph 35 Show in embeddings browser hereditary disease connective tissue disease neural tube defect

Lateral meningocele syndrome (LMS, Lehman syndrome) is an ultra-rare autosomal dominant connective-tissue and skeletal disorder caused by heterozygous, usually de novo, truncating variants in the last coding exon (exon 33) of NOTCH3. The mutant transcripts escape nonsense-mediated decay and encode a NOTCH3 protein lacking the C-terminal PEST degradation domain, which is thought to prolong the half-life of the NOTCH3 intracellular domain and enhance NOTCH3 signaling. The defining finding is multiple lateral spinal meningoceles, protrusions of the arachnoid and dura through the spinal foramina that represent the severe end of the dural ectasia spectrum and can compress nerve roots, causing neurogenic bladder, paresthesia, back pain, and paraparesis. Other features include a distinctive facial gestalt (hypertelorism, ptosis, downslanting palpebral fissures, micrognathia, high narrow palate), hypotonia, developmental delay, joint hyperextensibility, hernias, keloids, scoliosis, wormian bones, mixed or conductive hearing loss, cardiovascular anomalies, and cryptorchidism. Mouse models carrying an analogous Notch3 truncation show osteopenia driven by increased RANKL expression in osteoblast-lineage cells but no neurological phenotype. The disorder is allelic to CADASIL, which is caused by NOTCH3 extracellular-domain missense variants.

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Inheritance
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Pathophys.
33
Phenotypes
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Gaps
35
Pathograph
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Genes
5
Medical Actions
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Differentials
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Models
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References
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Deep Research
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Inheritance

1
Autosomal dominant inheritance HP:0000006
LMS is inherited in an autosomal dominant manner. Most molecularly confirmed probands carry a de novo NOTCH3 variant, and vertical (mother to daughter) transmission has been reported.
Autosomal dominant inheritance
Show evidence (3 references)
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"All probands reported to date with NOTCH3-related LMS whose parents have undergone molecular genetic testing have the disorder as the result of a de novo NOTCH3 pathogenic variant."
GeneReviews states that all molecularly tested probands carry a de novo NOTCH3 variant.
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"Each child of an individual with NOTCH3-related LMS has a 50% chance of inheriting the pathogenic variant."
A 50% recurrence risk to offspring is the autosomal dominant transmission pattern.
PMID:15666314 SUPPORT Human Clinical
"The existence of an affected mother and daughter supports the hypothesis that LMS is a dominant disorder affecting primarily the connective tissue."
An affected mother and daughter document vertical transmission consistent with dominant inheritance.
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Discussions and Knowledge Gaps

1
Why do mice carrying an LMS-analogous Notch3 truncation develop osteopenia but no meningoceles, dural ectasia, or neurological signs, and what tissue carries the connective tissue defect in humans?
HUMAN MODEL MISMATCH OPEN lms_mouse_lacks_meningoceles
Attached to
pathophysiology#Connective Tissue and Dural Dysplasia pathophysiology#Dural Ectasia and Lateral Meningocele Formation
The only in vivo models reproduce the skeletal resorptive mechanism but not the defining human lesion. The mechanism linking NOTCH3 gain of function to dural and connective tissue weakness is therefore untested, and the causal edge from NOTCH3 gain of function to connective tissue dysplasia rests on genotype-phenotype association alone.
Proposed experiments
NOTCH3 gain of function in human meningeal and dermal fibroblasts
exp_lms_meningeal_fibroblast_notch3
Compare extracellular matrix production and mechanical properties of patient-derived or isogenic iPSC-derived meningeal and dermal fibroblasts carrying an exon 33 NOTCH3 truncation against corrected controls.
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Pathophysiology

8
NOTCH3 Terminal Exon Truncation Escaping Nonsense-Mediated Decay
Heterozygous nonsense and frameshift variants cluster in the last coding exon (exon 33) of NOTCH3. Because they lie in the terminal exon, the mutant mRNAs escape nonsense-mediated decay and the mutant allele is expressed, producing a NOTCH3 protein truncated upstream of or within the C-terminal PEST domain.
NOTCH3 hgnc:7883 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NOTCH3 (hgnc:7883). hgnc:7883 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context NOTCH3 hgnc:7883 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns NOTCH3 (hgnc:7883). hgnc:7883 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION
Downstream
NOTCH3 Gain of Function Through Loss of PEST-Mediated Degradation
Show evidence (2 references)
PMID:25394726 SUPPORT Human Clinical
"All mutations cluster into the last coding exon, resulting in premature termination of the protein and truncation of the negative regulatory proline-glutamate-serine-threonine rich PEST domain."
The causal variants in six unrelated patients all lie in the last coding exon and truncate the PEST domain.
PMID:25394726 SUPPORT Human Clinical
"Our results suggest that mutant mRNA products escape nonsense mediated decay."
The terminal-exon location of the variants predicts escape from nonsense-mediated decay, so the truncated protein is made.
NOTCH3 Gain of Function Through Loss of PEST-Mediated Degradation
Loss of the PEST degradation signal is thought to stabilize the NOTCH3 intracellular domain after receptor activation, increasing transcription of canonical Notch target genes (HES1, HEY1, HEY2, HEYL). Enhanced Notch target gene expression has been shown in human iPSC-derived cells carrying the recurrent c.6692_6693insC variant.
NOTCH3 hgnc:7883 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NOTCH3 (hgnc:7883). hgnc:7883 is a gene from the HUGO Gene Nomenclature Committee.
Notch signaling pathway GO:0007219 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Notch signaling pathway (GO:0007219). GO:0007219 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Increased RANKL Expression in Osteoblast-Lineage Cells
Connective Tissue and Dural Dysplasia The molecular route from NOTCH3 gain of function to the connective tissue abnormality is not established; the edge records that the connective tissue phenotype segregates with the NOTCH3 truncating variants.
Abnormal Craniofacial and Skeletal Development
Show evidence (3 references)
PMID:39752389 SUPPORT In Vitro
"NOTCH36692-93insC cells displayed enhanced expression of Notch target genes HES1, HEY1, 2 and L demonstrating a NOTCH3 gain-of-function."
Human iPSC-derived cells with an LMS variant show increased Notch target gene expression, direct evidence of NOTCH3 gain of function.
PMID:39119451 SUPPORT BACKGROUND Human Clinical
"Variants in this final exon of NOTCH3 interrupt the regulatory PEST domain, leading to enhanced NOTCH3 signaling due to prolonged cellular half-life."
States the accepted mechanism: PEST disruption prolongs NOTCH3 half-life and enhances signaling.
PMID:31188489 SUPPORT Model Organism
"The anti-Notch3 NRR antibody suppressed the expression of Hes1, Hey1, and Hey2 (Notch target genes), and decreased Tnfsf11 (receptor activator of NF Kappa B ligand) messenger RNA in Notch3tm1.1Ecan osteoblast (OB) cultures."
Blocking NOTCH3 activation lowers Notch target genes in mutant osteoblasts, showing the mutant receptor still depends on ligand-induced activation.
Increased RANKL Expression in Osteoblast-Lineage Cells
NOTCH3 is expressed in osteoblasts and osteocytes but not in the myeloid/osteoclast lineage. In LMS mouse models the mutant receptor increases Tnfsf11 (RANKL) expression in osteoblasts and osteocytes, and introducing the mutation in osteocytes alone is sufficient to cause osteopenia.
osteoblast CL:0000062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoblast (CL:0000062). CL:0000062 is a cell type from the Cell Ontology. osteocyte CL:0000137 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteocyte (CL:0000137). CL:0000137 is a cell type from the Cell Ontology.
Downstream
Increased Osteoclastogenesis and Bone Resorption
Show evidence (2 references)
PMID:30042232 SUPPORT Model Organism
"Tnfsf11 mRNA was increased in osteocyte-rich femora from Notch3tm1.1Ecan mice."
RANKL transcript is increased in osteocyte-rich bone of LMS model mice.
PMID:35760307 SUPPORT Model Organism
"In conclusion, introduction of the LMS mutation in osteocytes but not in vascular cells causes osteopenia and phenocopies Notch3em1Ecan global mutant mice."
Osteocytes are sufficient to carry the skeletal effect of the LMS mutation, while vascular mural and endothelial cells are not.
Increased Osteoclastogenesis and Bone Resorption
Excess RANKL from osteoblast-lineage cells increases osteoclast formation and bone resorption, which outweighs a concurrent increase in osteoblast number and function and produces cancellous and cortical osteopenia in LMS model mice. Human bone density data in LMS are limited to case reports.
osteoclast CL:0000092 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoclast (CL:0000092). CL:0000092 is a cell type from the Cell Ontology.
osteoclast differentiation GO:0030316 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased osteoclast differentiation (GO:0030316). GO:0030316 is a biological process from the Gene Ontology. ↑ INCREASED bone resorption GO:0045453 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased bone resorption (GO:0045453). GO:0045453 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
Notch3 6691-TAATGA knock-in mouse Mus musculus recapitulates The model shows RANKL-driven osteoclastogenesis and osteopenia.
Downstream
Osteopenia
Show evidence (1 reference)
PMID:31188489 SUPPORT Model Organism
"Bone marrow-derived macrophages (BMMs) from Notch3tm1.1Ecan mutants exhibited enhanced osteoclastogenesis in culture, and this was increased in cocultures with Notch3tm1.1Ecan OB."
Enhanced osteoclastogenesis is reproduced in an independent study of the same model.
Connective Tissue and Dural Dysplasia
LMS behaves as a heritable connective tissue disorder: joint hyperextensibility, hernias, keloid scarring, scoliosis, aortic dilation and bicuspid aortic valve recur across reported patients, and the dura is abnormally distensible (dural ectasia). The connective-tissue molecular defect downstream of NOTCH3 is unknown.
Downstream
Dural Ectasia and Lateral Meningocele Formation
Joint Hypermobility
Hernia
Keloids
Scoliosis
Aortic Root Dilation
Bicuspid Aortic Valve
Show evidence (2 references)
PMID:23696373 SUPPORT Human Clinical
"These patients present distinctive craniofacial features and skeletal abnormalities in addition to multiple lateral meningoceles, suggesting a connective tissue disorder."
The combined clinical picture is interpreted as a connective tissue disorder.
PMID:41432782 SUPPORT BACKGROUND Human Clinical
"Dural dysplasia, such as dural ectasia, contributes to their occurrence."
Dural dysplasia is identified as a contributor to lateral meningocele formation.
Dural Ectasia and Lateral Meningocele Formation
The weakened dura and arachnoid protrude through the intervertebral and intravertebral foramina as lateral meningoceles. They are usually most severe in the lower spine, presumably because of hydrostatic CSF pressure, and can enlarge when CSF dynamics change (for example after Chiari decompression). The expanding sacs erode bone, producing posterior scalloping of the vertebral bodies.
Animal models
Notch3 6691-TAATGA knock-in mouse Mus musculus fails to recapitulate No neurological alterations or meningoceles were reported in the model.
Downstream
Lateral Spinal Meningoceles
Posterior Scalloping of Vertebral Bodies
Spinal Nerve Root Compression by Meningoceles
Show evidence (2 references)
PMID:25394726 SUPPORT BACKGROUND Human Clinical
"They are typically most severe in the lower spine, presumably due to hydrostatic pressure."
The lower-spine predominance is attributed to hydrostatic CSF pressure.
PMID:27911244 SUPPORT Human Clinical
"Such a case compels consideration that CSF flow dynamics in addition to altered connective tissue play a role in the presence of lateral meningoceles in patients within this and similar patient populations."
Meningocele enlargement after a change in CSF flow, reversed by shunting, implicates CSF dynamics together with connective tissue weakness.
Spinal Nerve Root Compression by Meningoceles
Large meningoceles compress exiting spinal nerve roots or the cauda equina; the neurological consequences depend on the size and level of the sacs.
Downstream
Neurogenic Bladder
Paresthesia
Back Pain
Paraparesis
Show evidence (1 reference)
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"Neurologic sequelæ of the meningoceles depend on size and location and can include neurogenic bladder, paresthesia, back pain, and/or paraparesis."
GeneReviews attributes these neurological findings to the meningoceles.
Abnormal Craniofacial and Skeletal Development
Developmental skeletal findings (wormian bones, vertebral fusion, a high narrow palate, cleft palate, micrognathia and midface hypoplasia) and the facial gestalt point to altered craniofacial and axial skeletal development. NOTCH3 gain of function increases osteogenic differentiation of human iPSC-derived cells, but the developmental mechanism has not been studied directly.
skeletal system development GO:0001501 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves skeletal system development (GO:0001501). GO:0001501 is a biological process from the Gene Ontology.
Downstream
Hypertelorism
Ptosis
Downslanted Palpebral Fissures
Micrognathia
High Narrow Palate
Cleft Palate
Wormian Bones
Vertebral Fusion
Show evidence (2 references)
PMID:39752389 SUPPORT INDIRECT In Vitro
"There was enhanced osteogenesis in NOTCH36692-93insC cells as evidenced by increased mineralized nodule formation and ALPL, BGLAP and BSP expression."
An LMS variant alters osteogenic differentiation in human cells derived through neural crest and mesenchymal stages, consistent with a skeletal developmental effect.
PMID:33519922 SUPPORT REVIEW SYNTHESIS Human Clinical
"Lateral Meningocele Syndrome (LMS) is a rare genetic disorder characterized by neurological manifestations, meningoceles, skeletal developmental abnormalities and bone loss."
Skeletal developmental abnormalities are a defining component of LMS.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Lateral Meningocele 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

33
Cardiovascular 3
Aortic Root Dilation Aortic root aneurysm HP:0002616 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aortic root dilation, annotated with Aortic root aneurysm (HP:0002616). HP:0002616 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25394726 SUPPORT Human Clinical
"Hyperextensibility, hernias and scoliosis reflect a connective tissue abnormality, and aortic dilation, a high-pitched nasal voice, wormian bones and osteolysis may be present."
Aortic dilation may be present in LMS.
Bicuspid Aortic Valve HP:0001647 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bicuspid aortic valve (HP:0001647). HP:0001647 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23696373 SUPPORT Human Clinical
"We describe a simplex case of lateral meningocele syndrome with bicuspid aortic valve, supporting the hypothesis of a connective tissue basis for this disorder and further expanding the phenotype."
Bicuspid aortic valve was reported in a patient with LMS.
Congenital Heart Defects Abnormal heart morphology HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital heart defect, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32141180 SUPPORT Human Clinical
"Besides the lateral meningoceles, this condition presents with dysmorphic features, short stature, congenital heart defects, and feeding difficulties."
Congenital heart defects are listed among the features of LMS.
PMID:26754023 SUPPORT Human Clinical
"Our patient's prenatal findings, complex cardiac anomalies, and severe feeding difficulties further expand our understanding of this rare condition."
Complex cardiac anomalies were present in a molecularly confirmed case.
Digestive 1
Feeding Difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"Infants may demonstrate feeding difficulties with poor weight gain."
GeneReviews reports infant feeding difficulties with poor weight gain.
PMID:26754023 SUPPORT Human Clinical
"Our patient's prenatal findings, complex cardiac anomalies, and severe feeding difficulties further expand our understanding of this rare condition."
Severe feeding difficulties were present in a molecularly confirmed case.
Ear 1
Mixed or Conductive Hearing Loss Conductive hearing impairment HP:0000405 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mixed or conductive hearing loss, annotated with Conductive hearing impairment (HP:0000405). HP:0000405 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"Additional findings of LMS include developmental delay, mixed or conductive hearing loss, and cleft palate."
Mixed or conductive hearing loss is an additional finding in GeneReviews.
Eye 2
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25394726 SUPPORT Human Clinical
"Facial features of LMS include hypertelorism and telecanthus, high arched eyebrows, ptosis, midfacial hypoplasia, micrognathia, high and narrow palate, low-set ears and a hypotonic appearance."
Hypertelorism is part of the LMS facial gestalt.
Ptosis HP:0000508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ptosis (HP:0000508). HP:0000508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25394726 SUPPORT Human Clinical
"Facial features of LMS include hypertelorism and telecanthus, high arched eyebrows, ptosis, midfacial hypoplasia, micrognathia, high and narrow palate, low-set ears and a hypotonic appearance."
Ptosis is part of the LMS facial gestalt.
Genitourinary 3
Neurogenic Bladder HP:0000011 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neurogenic bladder (HP:0000011). HP:0000011 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"Neurologic sequelæ of the meningoceles depend on size and location and can include neurogenic bladder, paresthesia, back pain, and/or paraparesis."
Neurogenic bladder is a neurological sequela of the meningoceles.
Cryptorchidism HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9188658 SUPPORT Human Clinical
"Other shared findings include multiple lateral meningoceles, Wormian bones, malar hypoplasia, downslanted palpebral fissures, a high narrow palate, and cryptorchidism in males."
Cryptorchidism in males was a shared finding.
Renal Cysts HP:0000107 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal cyst (HP:0000107). HP:0000107 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32141180 SUPPORT Human Clinical
"This case illustrates the power of reverse phenotyping to establish clinical diagnosis and expands the spectrum of clinical manifestations related to LMS to include inner ear abnormalities and multi-cystic kidney disease."
Multicystic kidney disease was added to the LMS spectrum by a single case.
Head and Neck 5
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). HP:0000494 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9188658 SUPPORT Human Clinical
"Other shared findings include multiple lateral meningoceles, Wormian bones, malar hypoplasia, downslanted palpebral fissures, a high narrow palate, and cryptorchidism in males."
Downslanted palpebral fissures were shared across reported patients.
Micrognathia HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Sequelae: Obstructive Sleep Apnea
Show evidence (2 references)
PMID:25394726 SUPPORT Human Clinical
"Facial features of LMS include hypertelorism and telecanthus, high arched eyebrows, ptosis, midfacial hypoplasia, micrognathia, high and narrow palate, low-set ears and a hypotonic appearance."
Micrognathia is part of the LMS facial gestalt.
PMID:23962060 SUPPORT Human Clinical
"We present a case of a 2-year-old boy presenting with micrognathia, glossoptosis, and hypertelorism as well as associated severe obstructive sleep apnea."
Micrognathia with glossoptosis (Pierre Robin sequence) in a child with LMS.
High Narrow Palate HP:0002705 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High, narrow palate (HP:0002705). HP:0002705 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9188658 SUPPORT Human Clinical
"Other shared findings include multiple lateral meningoceles, Wormian bones, malar hypoplasia, downslanted palpebral fissures, a high narrow palate, and cryptorchidism in males."
A high narrow palate was shared across reported patients.
Cleft Palate HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"Additional findings of LMS include developmental delay, mixed or conductive hearing loss, and cleft palate."
Cleft palate is an additional finding in GeneReviews.
Wormian Bones HP:0002645 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wormian bones (HP:0002645). HP:0002645 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"Skeletal abnormalities may include scoliosis, vertebral fusion, scalloping of vertebrae, and wormian bones."
Wormian bones are listed among the skeletal abnormalities.
Integument 1
Keloids HP:0010562 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Keloids (HP:0010562). HP:0010562 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:9188658 SUPPORT Human Clinical
"In addition, our patients showed ligamentous laxity, keloid formation, hypotonia, and developmental delay."
Keloid formation was observed in reported patients.
Musculoskeletal 7
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"NOTCH3-related lateral meningocele syndrome (LMS) is characterized by multiple lateral spinal meningoceles (protrusions of the arachnoid and dura through spinal foramina), distinctive facial features, joint hyperextensibility, hypotonia, and skeletal, cardiac, and urogenital anomalies."
Hypotonia is a core feature in GeneReviews.
Vertebral Fusion HP:0002948 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vertebral fusion (HP:0002948). HP:0002948 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"Skeletal abnormalities may include scoliosis, vertebral fusion, scalloping of vertebrae, and wormian bones."
Vertebral fusion is listed among the skeletal abnormalities.
Posterior Scalloping of Vertebral Bodies HP:0005121 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Posterior scalloping of vertebral bodies (HP:0005121). HP:0005121 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"Skeletal abnormalities may include scoliosis, vertebral fusion, scalloping of vertebrae, and wormian bones."
Scalloping of vertebrae is listed among the skeletal abnormalities.
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"Skeletal abnormalities may include scoliosis, vertebral fusion, scalloping of vertebrae, and wormian bones."
Scoliosis is listed among the skeletal abnormalities.
Osteopenia HP:0000938 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteopenia (HP:0000938). HP:0000938 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33519922 SUPPORT REVIEW SYNTHESIS Human Clinical
"Lateral Meningocele Syndrome (LMS) is a rare genetic disorder characterized by neurological manifestations, meningoceles, skeletal developmental abnormalities and bone loss."
Bone loss is described as a characteristic of LMS.
PMID:30042232 SUPPORT Model Organism
"One-month-old male and female heterozygous Notch3tm1.1Ecan mice had cancellous and cortical bone osteopenia but exhibited no obvious neurological alterations, and histopathology of multiple organs revealed no abnormalities."
The LMS mouse model is osteopenic.
Joint Hypermobility HP:0001382 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint hyperextensibility, annotated with Joint hypermobility (HP:0001382). HP:0001382 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"NOTCH3-related lateral meningocele syndrome (LMS) is characterized by multiple lateral spinal meningoceles (protrusions of the arachnoid and dura through spinal foramina), distinctive facial features, joint hyperextensibility, hypotonia, and skeletal, cardiac, and urogenital anomalies."
Joint hyperextensibility is a core feature in GeneReviews.
PMID:24311540 SUPPORT Human Clinical
"We report on a further observation of LMS in a 55-year-old woman presenting with a long history of joint instability, chronic musculoskeletal pain, and iatrogenic bladder and anorectal dysfunction due to irreversible nerve damage after surgical excision of a meningeal cyst."
Joint instability dominated the presentation of an adult with LMS.
Hernia HP:0100790 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hernia (HP:0100790). HP:0100790 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25394726 SUPPORT Human Clinical
"Hyperextensibility, hernias and scoliosis reflect a connective tissue abnormality, and aortic dilation, a high-pitched nasal voice, wormian bones and osteolysis may be present."
Hernias are reported in LMS.
Nervous System 8
Lateral Spinal Meningoceles HP:0032478 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lateral spinal meningocele (HP:0032478). HP:0032478 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"NOTCH3-related lateral meningocele syndrome (LMS) is characterized by multiple lateral spinal meningoceles (protrusions of the arachnoid and dura through spinal foramina), distinctive facial features, joint hyperextensibility, hypotonia, and skeletal, cardiac, and urogenital anomalies."
GeneReviews lists multiple lateral spinal meningoceles as the characteristic feature.
PMID:31838470 SUPPORT REVIEW SYNTHESIS Human Clinical
"However, this syndrome is invariably associated with the presence of multiple lateral thoracolumbar spinal meningoceles: a distinct point of phenotypic divergence from other connective tissue disorders."
Multiple thoracolumbar lateral meningoceles distinguish LMS from other connective tissue disorders.
PMID:39119451 SUPPORT Human Clinical
"His lack of lateral meningoceles expands the phenotype for this condition, as all previously reported individuals with molecularly confirmed LMS had multiple lateral meningoceles before age 8 years with an average age of identification at 4 years."
Meningoceles were present in all earlier molecularly confirmed cases, but a molecularly confirmed 8-year-old without them shows the feature is not obligate.
Paresthesia HP:0003401 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Paresthesia (HP:0003401). HP:0003401 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"Neurologic sequelæ of the meningoceles depend on size and location and can include neurogenic bladder, paresthesia, back pain, and/or paraparesis."
Paresthesia is a neurological sequela of the meningoceles.
Paraparesis HP:0002385 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Paraparesis (HP:0002385). HP:0002385 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"Neurologic sequelæ of the meningoceles depend on size and location and can include neurogenic bladder, paresthesia, back pain, and/or paraparesis."
Paraparesis is a neurological sequela of the meningoceles.
Chiari Type I Malformation HP:0007099 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chiari type I malformation (HP:0007099). HP:0007099 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"Other neurologic findings can include Chiari I malformation, syringomyelia, and rarely, hydrocephalus."
GeneReviews lists Chiari I malformation among the neurological findings.
PMID:27911244 SUPPORT Human Clinical
"The presence of lateral meningoceles imposes unique challenges related to CSF flow dynamics, especially with concurrent Chiari malformation, which also occurs with increased frequency in individuals with LMS."
Chiari malformation occurs with increased frequency in LMS.
Syringomyelia HP:0003396 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Syringomyelia (HP:0003396). HP:0003396 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"Other neurologic findings can include Chiari I malformation, syringomyelia, and rarely, hydrocephalus."
GeneReviews lists syringomyelia among the neurological findings.
Hydrocephalus HP:0000238 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hydrocephalus (HP:0000238). HP:0000238 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"Other neurologic findings can include Chiari I malformation, syringomyelia, and rarely, hydrocephalus."
GeneReviews lists hydrocephalus as a rare neurological finding.
Developmental Delay Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Developmental delay, annotated with Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"Additional findings of LMS include developmental delay, mixed or conductive hearing loss, and cleft palate."
Developmental delay is an additional finding in GeneReviews.
PMID:9188658 SUPPORT Human Clinical
"In addition, our patients showed ligamentous laxity, keloid formation, hypotonia, and developmental delay."
Developmental delay was present in a three-patient series.
Obstructive Sleep Apnea HP:0002870 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Obstructive sleep apnea (HP:0002870). HP:0002870 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23962060 SUPPORT Human Clinical
"We present a case of a 2-year-old boy presenting with micrognathia, glossoptosis, and hypertelorism as well as associated severe obstructive sleep apnea."
Severe obstructive sleep apnea in a child with LMS.
Constitutional 1
Back Pain HP:0003418 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Back pain (HP:0003418). HP:0003418 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"Neurologic sequelæ of the meningoceles depend on size and location and can include neurogenic bladder, paresthesia, back pain, and/or paraparesis."
Back pain is a neurological sequela of the meningoceles.
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:32141180 SUPPORT Human Clinical
"Besides the lateral meningoceles, this condition presents with dysmorphic features, short stature, congenital heart defects, and feeding difficulties."
Short stature is listed among the features of LMS.
🧬

Genetic Associations

1
NOTCH3 (Causative (gain-of-function terminal-exon truncating variants))
Gene: NOTCH3 hgnc:7883 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NOTCH3 (hgnc:7883). hgnc:7883 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:25394726 SUPPORT Human Clinical
"In total, five novel de novo NOTCH3 mutations were identified in six unrelated patients."
De novo NOTCH3 variants were found in six unrelated patients with LMS.
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"The diagnosis of NOTCH3-related LMS syndrome is established in a proband with consistent clinical findings and a heterozygous pathogenic variant in NOTCH3."
A heterozygous NOTCH3 pathogenic variant establishes the diagnosis.
💊

Medical Actions

5
Neurosurgical Management of Symptomatic Meningoceles
Action: neurosurgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is neurosurgical procedure, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Surgery on lateral meningoceles is generally avoided because of the risk of nerve injury and CSF leak, and is reserved for neurological deficits caused by meningocele size or location. Reported approaches include resection or repair, cyst-subarachnoid shunting, and ventriculoperitoneal shunting when CSF dynamics drive meningocele enlargement.
Mechanism Target:
Spinal Nerve Root Compression by Meningoceles — Decompression or shunting relieves pressure from the sacs on nerve roots.
Target Phenotypes: Lateral spinal meningocele HP:0032478 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Lateral spinal meningocele (HP:0032478). HP:0032478 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"Surgical intervention of lateral spinal meningoceles is generally avoided, but may be necessary due to neurologic manifestations secondary to meningocele size and location."
GeneReviews reserves surgery for symptomatic meningoceles.
PMID:41432782 SUPPORT Human Clinical
"His symptoms improved immediately, and the meningocele gradually regressed postoperatively."
Cyst-subarachnoid shunting improved symptoms and reduced the meningocele in one child.
PMID:24311540 SUPPORT Human Clinical
"We report on a further observation of LMS in a 55-year-old woman presenting with a long history of joint instability, chronic musculoskeletal pain, and iatrogenic bladder and anorectal dysfunction due to irreversible nerve damage after surgical excision of a meningeal cyst."
Irreversible iatrogenic nerve damage after meningeal cyst excision illustrates why surgery is avoided when possible.
Mandibular Distraction Osteogenesis
Action: mandibular distraction osteogenesisNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is mandibular distraction osteogenesis, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Bilateral mandibular distraction osteogenesis has been used to correct micrognathia with Pierre Robin sequence and obstructive sleep apnea in LMS.
Target Phenotypes: Micrognathia HP:0000347 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology. Obstructive sleep apnea HP:0002870 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Obstructive sleep apnea (HP:0002870). HP:0002870 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23962060 SUPPORT Human Clinical
"Distraction osteogenesis is a safe procedure that is effective as a first choice in the treatment of patients with Lehman syndrome presenting with micrognathia."
Distraction osteogenesis corrected micrognathia in a child with LMS.
Physiotherapy
Action: Physical TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Physical Therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. NCIT:C15302
Platform: Behavioral / lifestyle
Physiotherapy is recommended to reduce the risk of joint subluxation and dislocation related to joint hypermobility.
Target Phenotypes: Joint hypermobility HP:0001382 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Joint hypermobility (HP:0001382). HP:0001382 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"physiotherapy to reduce the risk for joint subluxation and dislocation"
GeneReviews recommends physiotherapy for joint protection.
Multidisciplinary Supportive Care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
There is no disease-modifying therapy. Management is symptomatic and multidisciplinary, covering cleft palate, cardiovascular, genitourinary, ophthalmologic, hearing and feeding problems, developmental support, and chronic pain.
Show evidence (1 reference)
PMID:33519922 SUPPORT REVIEW SYNTHESIS Other
"There are no effective therapies for LMS."
No disease-modifying therapy exists, so care is supportive.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Most cases are de novo; an affected individual has a 50% risk of transmitting the variant, and prenatal and preimplantation testing are possible once the familial variant is known.
Show evidence (1 reference)
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"Each child of an individual with NOTCH3-related LMS has a 50% chance of inheriting the pathogenic variant."
The recurrence risk is the basis for genetic counseling.
🔬

Diagnosis

2
NOTCH3 Molecular Testing
Diagnosis is established by identifying a heterozygous pathogenic truncating variant in exon 33 of NOTCH3 in a proband with consistent clinical findings.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"The diagnosis of NOTCH3-related LMS syndrome is established in a proband with consistent clinical findings and a heterozygous pathogenic variant in NOTCH3."
GeneReviews diagnostic criterion.
Spinal MRI Surveillance
Spinal imaging identifies the lateral meningoceles and is repeated to monitor their size: yearly at first, then every two years if they are small and stable.
Magnetic Resonance Imaging NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:27336130 SUPPORT REVIEW SYNTHESIS Human Clinical
"Close clinical and radiographic monitoring for progressive neurologic symptoms and increase in meningocele size; an initial yearly scan to monitor for stability and subsequent spacing to every two years if meningoceles are small in size."
GeneReviews surveillance recommendation.
📊

Prevalence

1
Worldwide (published case reports)
Cases In Literature Ultra Rare
Described as ultra-rare with 22 patients reported as of 2020; no population-based prevalence estimate exists.
Show evidence (1 reference)
PMID:32141180 SUPPORT BACKGROUND Human Clinical
"Lateral meningocele syndrome (LMS) is an ultra-rare condition with 22 patients reported to date."
The case count in the literature establishes LMS as ultra-rare.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Lateral Meningocele Syndrome:

Hajdu-Cheney syndrome MONDO:0007057
Overlapping Features Hajdu-Cheney syndrome is caused by analogous last-exon truncating variants in NOTCH2 and overlaps clinically (wormian bones, facial features, osteolysis, connective tissue signs), but acro-osteolysis and severe osteoporosis dominate and multiple lateral meningoceles are not characteristic.
Show evidence (1 reference)
PMID:25394726 SUPPORT Human Clinical
"Lateral meningocele syndrome has phenotypic overlap with Hajdu-Cheney syndrome."
The two syndromes overlap phenotypically and share a truncating-variant mechanism in paralogous genes.
Ehlers-Danlos and Marfan-spectrum connective tissue disorders
Overlapping Features Joint laxity, dural ectasia, and aortic dilation overlap with Marfan, Ehlers-Danlos, and Loeys-Dietz syndromes, but multiple lateral thoracolumbar meningoceles distinguish LMS.
Show evidence (1 reference)
PMID:31838470 SUPPORT REVIEW SYNTHESIS Human Clinical
"Lateral meningocele syndrome (LMS) is an exceedingly rare connective tissue disease with phenotypic anomalies similar to those seen in Marfan syndrome, Ehler-Danlos syndrome, and Loeys-Dietz syndrome."
The review names these connective tissue disorders as the phenotypic differential.
🐁

Animal Models

1
Notch3 6691-TAATGA knock-in mouse
A CRISPR/Cas9 knock-in that truncates Notch3 upstream of the PEST domain, reproducing the LMS variant class. Heterozygous mice have cancellous and cortical osteopenia with increased osteoclastogenesis and RANKL expression, but no neurological phenotype or meningoceles. The osteopenia is reversed by an anti-Notch3 negative regulatory region antibody and the cortical osteopenia is ameliorated by a mutation-specific Notch3 antisense oligonucleotide.
Species
Mus musculus
Genotype
Notch3 tm1.1Ecan (em1Ecan) heterozygous, tandem stop codon at bases 6691-6696 upstream of the PEST domain
Publication
PMID:30042232
Pathograph links
Increased Osteoclastogenesis and Bone Resorption recapitulates fidelity: moderate observes: organism The model shows RANKL-driven osteoclastogenesis and osteopenia.
Limitations: Human bone phenotype data in LMS are limited to case reports, so how faithfully mouse osteopenia represents the human skeletal disease is uncertain; female mice recover bone mass with maturation.
Show evidence (1 reference)
PMID:30042232 SUPPORT Model Organism
"In conclusion, the Notch3tm1.1Ecan mutation causes osteopenia despite an increase in osteoblast proliferation and function and is associated with enhanced Tnfsf11 expression in osteoblasts and osteocytes."
The model recapitulates the resorptive skeletal mechanism.
Dural Ectasia and Lateral Meningocele Formation fails to recapitulate fidelity: low observes: organism No neurological alterations or meningoceles were reported in the model.
Limitations: The defining human lesion is absent, so the model cannot be used to study meningocele formation or the connective tissue phenotype.
Show evidence (1 reference)
PMID:30042232 SUPPORT Model Organism
"One-month-old male and female heterozygous Notch3tm1.1Ecan mice had cancellous and cortical bone osteopenia but exhibited no obvious neurological alterations, and histopathology of multiple organs revealed no abnormalities."
The mice lack the neurological and meningocele phenotype.
Show evidence (3 references)
PMID:37704069 SUPPORT Model Organism
"In conclusion, a Notch3 ASO that downregulates Notch3 mutant expression specifically ameliorates the cortical osteopenia in Notch3em1Ecan mice."
A mutation-specific ASO partially rescues the model's bone phenotype.
PMID:35536858 SUPPORT Model Organism
"Microcomputed tomography demonstrated that the administration of Notch3 ASOs ameliorates the cortical osteopenia of Notch3em1Ecan mice, and ASOs decreased femoral cortical porosity and increased cortical thickness and bone volume."
A non-allele-selective Notch3 ASO also ameliorates cortical osteopenia in the model.
PMID:31188489 SUPPORT Model Organism
"The cancellous bone osteopenia was no longer observed after the intraperitoneal administration of antibodies directed to the negative regulatory region (NRR) of Notch3."
A NOTCH3-activation-blocking antibody reverses cancellous osteopenia in the model.
{ }

Source YAML

click to show 
name: Lateral Meningocele Syndrome
creation_date: '2026-09-23T19:10:03Z'
category: Mendelian
synonyms:
- Lehman syndrome
- LMNS
- LMS
- NOTCH3-related lateral meningocele syndrome
description: >-
  Lateral meningocele syndrome (LMS, Lehman syndrome) is an ultra-rare autosomal
  dominant connective-tissue and skeletal disorder caused by heterozygous, usually
  de novo, truncating variants in the last coding exon (exon 33) of NOTCH3. The
  mutant transcripts escape nonsense-mediated decay and encode a NOTCH3 protein
  lacking the C-terminal PEST degradation domain, which is thought to prolong the
  half-life of the NOTCH3 intracellular domain and enhance NOTCH3 signaling. The
  defining finding is multiple lateral spinal meningoceles, protrusions of the
  arachnoid and dura through the spinal foramina that represent the severe end of
  the dural ectasia spectrum and can compress nerve roots, causing neurogenic
  bladder, paresthesia, back pain, and paraparesis. Other features include a
  distinctive facial gestalt (hypertelorism, ptosis, downslanting palpebral
  fissures, micrognathia, high narrow palate), hypotonia, developmental delay,
  joint hyperextensibility, hernias, keloids, scoliosis, wormian bones, mixed or
  conductive hearing loss, cardiovascular anomalies, and cryptorchidism. Mouse
  models carrying an analogous Notch3 truncation show osteopenia driven by
  increased RANKL expression in osteoblast-lineage cells but no neurological
  phenotype. The disorder is allelic to CADASIL, which is caused by NOTCH3
  extracellular-domain missense variants.
notes: >-
  A GeneReviews chapter exists (NOTCH3-Related Lateral Meningocele Syndrome,
  PMID:27336130) and is used as the phenotype baseline. Phenotype frequencies are
  omitted because the published case series are too small to support frequency
  bands. Hypotonia, developmental delay, hearing loss, feeding difficulties,
  short stature, cryptorchidism, congenital heart defects, renal cysts, Chiari I
  malformation, syringomyelia and hydrocephalus have no causal edge because no
  source describes the mechanism linking them to NOTCH3 gain of function. The
  GeneReviews abstract reports mixed or conductive hearing loss, while one case
  report (PMID:32141180) describes sensorineural loss with inner ear anomalies.
disease_term:
  preferred_term: lateral meningocele syndrome
  term:
    id: MONDO:0007537
    label: lateral meningocele syndrome
parents:
- hereditary disease
- connective tissue disease
- neural tube defect
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    LMS is inherited in an autosomal dominant manner. Most molecularly confirmed
    probands carry a de novo NOTCH3 variant, and vertical (mother to daughter)
    transmission has been reported.
  evidence:
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      All probands reported to date with NOTCH3-related LMS whose parents have
      undergone molecular genetic testing have the disorder as the result of a de
      novo NOTCH3 pathogenic variant.
    explanation: >-
      GeneReviews states that all molecularly tested probands carry a de novo
      NOTCH3 variant.
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Each child of an individual with NOTCH3-related LMS has a 50% chance of
      inheriting the pathogenic variant.
    explanation: >-
      A 50% recurrence risk to offspring is the autosomal dominant transmission
      pattern.
  - reference: PMID:15666314
    reference_title: "Lateral meningocele syndrome: vertical transmission and expansion of the phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The existence of an affected mother and daughter supports the hypothesis that
      LMS is a dominant disorder affecting primarily the connective tissue.
    explanation: >-
      An affected mother and daughter document vertical transmission consistent
      with dominant inheritance.
prevalence:
- population: Worldwide (published case reports)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Described as ultra-rare with 22 patients reported as of 2020; no
    population-based prevalence estimate exists.
  evidence:
  - reference: PMID:32141180
    reference_title: Expansion of the phenotype of lateral meningocele syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Lateral meningocele syndrome (LMS) is an ultra-rare condition with 22
      patients reported to date.
    explanation: >-
      The case count in the literature establishes LMS as ultra-rare.
pathophysiology:
- name: NOTCH3 Terminal Exon Truncation Escaping Nonsense-Mediated Decay
  description: >-
    Heterozygous nonsense and frameshift variants cluster in the last coding exon
    (exon 33) of NOTCH3. Because they lie in the terminal exon, the mutant mRNAs
    escape nonsense-mediated decay and the mutant allele is expressed, producing a
    NOTCH3 protein truncated upstream of or within the C-terminal PEST domain.
  biological_scale: MOLECULAR
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: GAIN_OF_FUNCTION
    gene:
      preferred_term: NOTCH3
      term:
        id: hgnc:7883
        label: NOTCH3
  genes:
  - preferred_term: NOTCH3
    term:
      id: hgnc:7883
      label: NOTCH3
  evidence:
  - reference: PMID:25394726
    reference_title: Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All mutations cluster into the last coding exon, resulting in premature
      termination of the protein and truncation of the negative regulatory
      proline-glutamate-serine-threonine rich PEST domain.
    explanation: >-
      The causal variants in six unrelated patients all lie in the last coding exon
      and truncate the PEST domain.
  - reference: PMID:25394726
    reference_title: Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our results suggest that mutant mRNA products escape nonsense mediated decay.
    explanation: >-
      The terminal-exon location of the variants predicts escape from
      nonsense-mediated decay, so the truncated protein is made.
  downstream:
  - target: NOTCH3 Gain of Function Through Loss of PEST-Mediated Degradation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25394726
      reference_title: Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The truncated NOTCH3 may cause gain-of-function through decreased clearance
        of the active intracellular product, resembling NOTCH2 mutations in the
        clinically related Hajdu-Cheney syndrome and contrasting the NOTCH3
        missense mutations causing CADASIL.
      explanation: >-
        The truncation is proposed to cause gain of function by slowing clearance of
        the NOTCH3 intracellular domain.
- name: NOTCH3 Gain of Function Through Loss of PEST-Mediated Degradation
  description: >-
    Loss of the PEST degradation signal is thought to stabilize the NOTCH3
    intracellular domain after receptor activation, increasing transcription of
    canonical Notch target genes (HES1, HEY1, HEY2, HEYL). Enhanced Notch target
    gene expression has been shown in human iPSC-derived cells carrying the
    recurrent c.6692_6693insC variant.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: NOTCH3
    term:
      id: hgnc:7883
      label: NOTCH3
  biological_processes:
  - preferred_term: Notch signaling pathway
    modifier: INCREASED
    term:
      id: GO:0007219
      label: Notch signaling pathway
  evidence:
  - reference: PMID:39752389
    reference_title: A NOTCH3 pathogenic variant influences osteogenesis and can be targeted by antisense oligonucleotides in induced pluripotent stem cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      NOTCH36692-93insC cells displayed enhanced expression of Notch target genes
      HES1, HEY1, 2 and L demonstrating a NOTCH3 gain-of-function.
    explanation: >-
      Human iPSC-derived cells with an LMS variant show increased Notch target gene
      expression, direct evidence of NOTCH3 gain of function.
  - reference: PMID:39119451
    reference_title: A Case of Lateral Meningocele Syndrome without Lateral Meningoceles.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Variants in this final exon of NOTCH3 interrupt the regulatory PEST domain,
      leading to enhanced NOTCH3 signaling due to prolonged cellular half-life.
    explanation: >-
      States the accepted mechanism: PEST disruption prolongs NOTCH3 half-life
      and enhances signaling.
  - reference: PMID:31188489
    reference_title: An antibody to Notch3 reverses the skeletal phenotype of lateral meningocele syndrome in male mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The anti-Notch3 NRR antibody suppressed the expression of Hes1, Hey1, and Hey2
      (Notch target genes), and decreased Tnfsf11 (receptor activator of NF Kappa B
      ligand) messenger RNA in Notch3tm1.1Ecan osteoblast (OB) cultures.
    explanation: >-
      Blocking NOTCH3 activation lowers Notch target genes in mutant osteoblasts,
      showing the mutant receptor still depends on ligand-induced activation.
  downstream:
  - target: Increased RANKL Expression in Osteoblast-Lineage Cells
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30042232
      reference_title: The lateral meningocele syndrome mutation causes marked osteopenia in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In conclusion, the Notch3tm1.1Ecan mutation causes osteopenia despite an
        increase in osteoblast proliferation and function and is associated with
        enhanced Tnfsf11 expression in osteoblasts and osteocytes.
      explanation: >-
        The LMS-analogous Notch3 mutation increases Tnfsf11 (RANKL) expression in
        osteoblasts and osteocytes.
  - target: Connective Tissue and Dural Dysplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The molecular route from NOTCH3 gain of function to the connective tissue
      abnormality is not established; the edge records that the connective tissue
      phenotype segregates with the NOTCH3 truncating variants.
    evidence:
    - reference: PMID:25394726
      reference_title: Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hyperextensibility, hernias and scoliosis reflect a connective tissue
        abnormality, and aortic dilation, a high-pitched nasal voice, wormian bones
        and osteolysis may be present.
      explanation: >-
        In the cohort that established NOTCH3 truncations as the cause, the
        clinical findings are read as a connective tissue abnormality; the
        mechanism linking the two is inferred rather than shown.
  - target: Abnormal Craniofacial and Skeletal Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33519922
      reference_title: The Skeleton of Lateral Meningocele Syndrome.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Pathogenic variants of Notch receptors and their ligands are associated
        with a variety of genetic disorders presenting with significant
        craniofacial and skeletal manifestations.
      explanation: >-
        The review places LMS among Notch-pathway disorders with craniofacial and
        skeletal manifestations; the developmental mechanism in LMS itself has
        not been dissected.
- name: Increased RANKL Expression in Osteoblast-Lineage Cells
  description: >-
    NOTCH3 is expressed in osteoblasts and osteocytes but not in the
    myeloid/osteoclast lineage. In LMS mouse models the mutant receptor increases
    Tnfsf11 (RANKL) expression in osteoblasts and osteocytes, and introducing the
    mutation in osteocytes alone is sufficient to cause osteopenia.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: osteocyte
    term:
      id: CL:0000137
      label: osteocyte
  evidence:
  - reference: PMID:30042232
    reference_title: The lateral meningocele syndrome mutation causes marked osteopenia in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Tnfsf11 mRNA was increased in osteocyte-rich femora from Notch3tm1.1Ecan
      mice.
    explanation: >-
      RANKL transcript is increased in osteocyte-rich bone of LMS model mice.
  - reference: PMID:35760307
    reference_title: Induction of a NOTCH3 Lehman syndrome mutation in osteocytes causes osteopenia in male C57BL/6J mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In conclusion, introduction of the LMS mutation in osteocytes but not in
      vascular cells causes osteopenia and phenocopies Notch3em1Ecan global mutant
      mice.
    explanation: >-
      Osteocytes are sufficient to carry the skeletal effect of the LMS mutation,
      while vascular mural and endothelial cells are not.
  downstream:
  - target: Increased Osteoclastogenesis and Bone Resorption
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30042232
      reference_title: The lateral meningocele syndrome mutation causes marked osteopenia in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Cultures of bone marrow-derived macrophages from Notch3tm1.1Ecan mice
        revealed increased osteoclast formation, particularly in cocultures with
        osteoblasts from Notch3tm1.1Ecan mice.
      explanation: >-
        Mutant osteoblasts enhance osteoclast formation in coculture, placing the
        osteoclast increase downstream of the osteoblast-lineage signal.
    - reference: PMID:33519922
      reference_title: The Skeleton of Lateral Meningocele Syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Experimental mouse models of LMS revealed that the bone loss is secondary
        to increased osteoclastogenesis due to enhanced expression of receptor
        activator of nuclear factor kappa B ligand by cells of the osteoblast
        lineage.
      explanation: >-
        The review synthesizes the mouse work into this causal step: RANKL from
        osteoblast-lineage cells drives osteoclastogenesis.
- name: Increased Osteoclastogenesis and Bone Resorption
  description: >-
    Excess RANKL from osteoblast-lineage cells increases osteoclast formation and
    bone resorption, which outweighs a concurrent increase in osteoblast number and
    function and produces cancellous and cortical osteopenia in LMS model mice.
    Human bone density data in LMS are limited to case reports.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: osteoclast
    term:
      id: CL:0000092
      label: osteoclast
  biological_processes:
  - preferred_term: osteoclast differentiation
    modifier: INCREASED
    term:
      id: GO:0030316
      label: osteoclast differentiation
  - preferred_term: bone resorption
    modifier: INCREASED
    term:
      id: GO:0045453
      label: bone resorption
  evidence:
  - reference: PMID:31188489
    reference_title: An antibody to Notch3 reverses the skeletal phenotype of lateral meningocele syndrome in male mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Bone marrow-derived macrophages (BMMs) from Notch3tm1.1Ecan mutants exhibited
      enhanced osteoclastogenesis in culture, and this was increased in cocultures
      with Notch3tm1.1Ecan OB.
    explanation: >-
      Enhanced osteoclastogenesis is reproduced in an independent study of the same
      model.
  downstream:
  - target: Osteopenia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31188489
      reference_title: An antibody to Notch3 reverses the skeletal phenotype of lateral meningocele syndrome in male mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Osteoclastogenesis was suppressed by anti-Notch3 NRR antibodies in
        Notch3tm1.1Ecan OB/BMM cocultures.
      explanation: >-
        Blocking NOTCH3 suppresses osteoclastogenesis and, in vivo, reverses the
        cancellous osteopenia, tying the bone loss to this resorptive step.
- name: Connective Tissue and Dural Dysplasia
  description: >-
    LMS behaves as a heritable connective tissue disorder: joint hyperextensibility,
    hernias, keloid scarring, scoliosis, aortic dilation and bicuspid aortic valve
    recur across reported patients, and the dura is abnormally distensible (dural
    ectasia). The connective-tissue molecular defect downstream of NOTCH3 is
    unknown.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:23696373
    reference_title: "Lateral meningocele syndrome: additional report and further evidence supporting a connective tissue basis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These patients present distinctive craniofacial features and skeletal
      abnormalities in addition to multiple lateral meningoceles, suggesting a
      connective tissue disorder.
    explanation: >-
      The combined clinical picture is interpreted as a connective tissue
      disorder.
  - reference: PMID:41432782
    reference_title: "Significant improvement of neurological and radiological findings caused by multiple lateral meningocele by cyst-subarachnoid shunt in a 6-year-old boy: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Dural dysplasia, such as dural ectasia, contributes to their occurrence.
    explanation: >-
      Dural dysplasia is identified as a contributor to lateral meningocele
      formation.
  downstream:
  - target: Dural Ectasia and Lateral Meningocele Formation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25394726
      reference_title: Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: >-
        Lateral meningoceles comprise a protrusion of the arachnoid and dura through
        the spinal foramina and represent the severe end of the dural ectasia
        spectrum.
      explanation: >-
        Lateral meningoceles are placed at the severe end of dural ectasia, a
        connective tissue weakness of the dura.
  - target: Joint Hypermobility
  - target: Hernia
  - target: Keloids
  - target: Scoliosis
    evidence:
    - reference: PMID:25394726
      reference_title: Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Hyperextensibility, hernias and scoliosis reflect a connective tissue
        abnormality, and aortic dilation, a high-pitched nasal voice, wormian bones
        and osteolysis may be present.
      explanation: >-
        Hyperextensibility, hernias and scoliosis are attributed to the connective
        tissue abnormality.
  - target: Aortic Root Dilation
  - target: Bicuspid Aortic Valve
    evidence:
    - reference: PMID:23696373
      reference_title: "Lateral meningocele syndrome: additional report and further evidence supporting a connective tissue basis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We describe a simplex case of lateral meningocele syndrome with bicuspid
        aortic valve, supporting the hypothesis of a connective tissue basis for
        this disorder and further expanding the phenotype.
      explanation: >-
        The authors read the bicuspid aortic valve as part of the connective tissue
        basis of LMS.
- name: Dural Ectasia and Lateral Meningocele Formation
  description: >-
    The weakened dura and arachnoid protrude through the intervertebral and
    intravertebral foramina as lateral meningoceles. They are usually most severe
    in the lower spine, presumably because of hydrostatic CSF pressure, and can
    enlarge when CSF dynamics change (for example after Chiari decompression). The
    expanding sacs erode bone, producing posterior scalloping of the vertebral
    bodies.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:25394726
    reference_title: Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      They are typically most severe in the lower spine, presumably due to
      hydrostatic pressure.
    explanation: >-
      The lower-spine predominance is attributed to hydrostatic CSF pressure.
  - reference: PMID:27911244
    reference_title: "Neurosurgical management in lateral meningocele syndrome: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Such a case compels consideration that CSF flow dynamics in addition to
      altered connective tissue play a role in the presence of lateral meningoceles
      in patients within this and similar patient populations.
    explanation: >-
      Meningocele enlargement after a change in CSF flow, reversed by shunting,
      implicates CSF dynamics together with connective tissue weakness.
  downstream:
  - target: Lateral Spinal Meningoceles
    causal_link_type: DIRECT
  - target: Posterior Scalloping of Vertebral Bodies
    evidence:
    - reference: PMID:41432782
      reference_title: "Significant improvement of neurological and radiological findings caused by multiple lateral meningocele by cyst-subarachnoid shunt in a 6-year-old boy: case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Spinal magnetic resonance imaging (MRI) at 6 years of age demonstrated
        multiple lateral meningoceles of the thoracic and lumbar spine with
        posteriorly scalloped vertebral bodies.
      explanation: >-
        Posterior vertebral scalloping co-localizes with the lateral meningoceles.
  - target: Spinal Nerve Root Compression by Meningoceles
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27911244
      reference_title: "Neurosurgical management in lateral meningocele syndrome: case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In some cases, these lateral meningoceles can cause pain and discomfort due
        to their presence within retroperitoneal tissues or cause direct compression
        of the spinal nerve root exiting the foramen; in some cases compression may
        also involve motor weakness.
      explanation: >-
        Meningoceles compress the exiting spinal nerve roots, causing pain and
        weakness.
- name: Spinal Nerve Root Compression by Meningoceles
  description: >-
    Large meningoceles compress exiting spinal nerve roots or the cauda equina;
    the neurological consequences depend on the size and level of the sacs.
  biological_scale: TISSUE
  evidence:
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Neurologic sequelæ of the meningoceles depend on size and location and can
      include neurogenic bladder, paresthesia, back pain, and/or paraparesis.
    explanation: >-
      GeneReviews attributes these neurological findings to the meningoceles.
  downstream:
  - target: Neurogenic Bladder
  - target: Paresthesia
  - target: Back Pain
  - target: Paraparesis
- name: Abnormal Craniofacial and Skeletal Development
  description: >-
    Developmental skeletal findings (wormian bones, vertebral fusion, a high narrow
    palate, cleft palate, micrognathia and midface hypoplasia) and the facial
    gestalt point to altered craniofacial and axial skeletal development. NOTCH3
    gain of function increases osteogenic differentiation of human iPSC-derived
    cells, but the developmental mechanism has not been studied directly.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: skeletal system development
    term:
      id: GO:0001501
      label: skeletal system development
  evidence:
  - reference: PMID:39752389
    reference_title: A NOTCH3 pathogenic variant influences osteogenesis and can be targeted by antisense oligonucleotides in induced pluripotent stem cells.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      There was enhanced osteogenesis in NOTCH36692-93insC cells as evidenced by
      increased mineralized nodule formation and ALPL, BGLAP and BSP expression.
    explanation: >-
      An LMS variant alters osteogenic differentiation in human cells derived
      through neural crest and mesenchymal stages, consistent with a skeletal
      developmental effect.
  - reference: PMID:33519922
    reference_title: The Skeleton of Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Lateral Meningocele Syndrome (LMS) is a rare genetic disorder characterized
      by neurological manifestations, meningoceles, skeletal developmental
      abnormalities and bone loss.
    explanation: >-
      Skeletal developmental abnormalities are a defining component of LMS.
  downstream:
  - target: Hypertelorism
  - target: Ptosis
  - target: Downslanted Palpebral Fissures
  - target: Micrognathia
  - target: High Narrow Palate
  - target: Cleft Palate
  - target: Wormian Bones
  - target: Vertebral Fusion
phenotypes:
- name: Lateral Spinal Meningoceles
  category: Neurologic
  description: >-
    Multiple, often bilateral, lateral thoracolumbar meningoceles protruding
    through the spinal foramina; the defining feature of the syndrome, although
    one molecularly confirmed child without meningoceles has been reported.
  phenotype_term:
    preferred_term: Lateral spinal meningocele
    term:
      id: HP:0032478
      label: Lateral spinal meningocele
  evidence:
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      NOTCH3-related lateral meningocele syndrome (LMS) is characterized by
      multiple lateral spinal meningoceles (protrusions of the arachnoid and dura
      through spinal foramina), distinctive facial features, joint
      hyperextensibility, hypotonia, and skeletal, cardiac, and urogenital
      anomalies.
    explanation: >-
      GeneReviews lists multiple lateral spinal meningoceles as the characteristic
      feature.
  - reference: PMID:31838470
    reference_title: "Neurosurgical Management of Lateral Meningocele Syndrome: A Clinical Update for the Pediatric Neurosurgeon."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      However, this syndrome is invariably associated with the presence of
      multiple lateral thoracolumbar spinal meningoceles: a distinct point of
      phenotypic divergence from other connective tissue disorders.
    explanation: >-
      Multiple thoracolumbar lateral meningoceles distinguish LMS from other
      connective tissue disorders.
  - reference: PMID:39119451
    reference_title: A Case of Lateral Meningocele Syndrome without Lateral Meningoceles.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His lack of lateral meningoceles expands the phenotype for this condition,
      as all previously reported individuals with molecularly confirmed LMS had
      multiple lateral meningoceles before age 8 years with an average age of
      identification at 4 years.
    explanation: >-
      Meningoceles were present in all earlier molecularly confirmed cases, but a
      molecularly confirmed 8-year-old without them shows the feature is not
      obligate.
- name: Neurogenic Bladder
  category: Neurologic
  phenotype_term:
    preferred_term: Neurogenic bladder
    term:
      id: HP:0000011
      label: Neurogenic bladder
  evidence:
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Neurologic sequelæ of the meningoceles depend on size and location and can
      include neurogenic bladder, paresthesia, back pain, and/or paraparesis.
    explanation: Neurogenic bladder is a neurological sequela of the meningoceles.
- name: Paresthesia
  category: Neurologic
  phenotype_term:
    preferred_term: Paresthesia
    term:
      id: HP:0003401
      label: Paresthesia
  evidence:
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Neurologic sequelæ of the meningoceles depend on size and location and can
      include neurogenic bladder, paresthesia, back pain, and/or paraparesis.
    explanation: Paresthesia is a neurological sequela of the meningoceles.
- name: Back Pain
  category: Neurologic
  phenotype_term:
    preferred_term: Back pain
    term:
      id: HP:0003418
      label: Back pain
  evidence:
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Neurologic sequelæ of the meningoceles depend on size and location and can
      include neurogenic bladder, paresthesia, back pain, and/or paraparesis.
    explanation: Back pain is a neurological sequela of the meningoceles.
- name: Paraparesis
  category: Neurologic
  phenotype_term:
    preferred_term: Paraparesis
    term:
      id: HP:0002385
      label: Paraparesis
  evidence:
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Neurologic sequelæ of the meningoceles depend on size and location and can
      include neurogenic bladder, paresthesia, back pain, and/or paraparesis.
    explanation: Paraparesis is a neurological sequela of the meningoceles.
- name: Chiari Type I Malformation
  category: Neurologic
  phenotype_term:
    preferred_term: Chiari type I malformation
    term:
      id: HP:0007099
      label: Chiari type I malformation
  evidence:
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Other neurologic findings can include Chiari I malformation, syringomyelia,
      and rarely, hydrocephalus.
    explanation: GeneReviews lists Chiari I malformation among the neurological findings.
  - reference: PMID:27911244
    reference_title: "Neurosurgical management in lateral meningocele syndrome: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The presence of lateral meningoceles imposes unique challenges related to CSF
      flow dynamics, especially with concurrent Chiari malformation, which also
      occurs with increased frequency in individuals with LMS.
    explanation: Chiari malformation occurs with increased frequency in LMS.
- name: Syringomyelia
  category: Neurologic
  phenotype_term:
    preferred_term: Syringomyelia
    term:
      id: HP:0003396
      label: Syringomyelia
  evidence:
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Other neurologic findings can include Chiari I malformation, syringomyelia,
      and rarely, hydrocephalus.
    explanation: GeneReviews lists syringomyelia among the neurological findings.
- name: Hydrocephalus
  category: Neurologic
  phenotype_term:
    preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  evidence:
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Other neurologic findings can include Chiari I malformation, syringomyelia,
      and rarely, hydrocephalus.
    explanation: GeneReviews lists hydrocephalus as a rare neurological finding.
- name: Hypotonia
  category: Neurologic
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      NOTCH3-related lateral meningocele syndrome (LMS) is characterized by
      multiple lateral spinal meningoceles (protrusions of the arachnoid and dura
      through spinal foramina), distinctive facial features, joint
      hyperextensibility, hypotonia, and skeletal, cardiac, and urogenital
      anomalies.
    explanation: Hypotonia is a core feature in GeneReviews.
- name: Developmental Delay
  category: Neurologic
  phenotype_term:
    preferred_term: Developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Additional findings of LMS include developmental delay, mixed or conductive
      hearing loss, and cleft palate.
    explanation: Developmental delay is an additional finding in GeneReviews.
  - reference: PMID:9188658
    reference_title: "Lateral meningocele syndrome: three new patients and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, our patients showed ligamentous laxity, keloid formation,
      hypotonia, and developmental delay.
    explanation: Developmental delay was present in a three-patient series.
- name: Mixed or Conductive Hearing Loss
  category: Sensory
  phenotype_term:
    preferred_term: Mixed or conductive hearing loss
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  evidence:
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Additional findings of LMS include developmental delay, mixed or conductive
      hearing loss, and cleft palate.
    explanation: Mixed or conductive hearing loss is an additional finding in GeneReviews.
- name: Feeding Difficulties
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Infants may demonstrate feeding difficulties with poor weight gain.
    explanation: GeneReviews reports infant feeding difficulties with poor weight gain.
  - reference: PMID:26754023
    reference_title: "Lateral meningocele (Lehman) syndrome: A child with a novel NOTCH3 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our patient's prenatal findings, complex cardiac anomalies, and severe
      feeding difficulties further expand our understanding of this rare
      condition.
    explanation: Severe feeding difficulties were present in a molecularly confirmed case.
- name: Hypertelorism
  category: Craniofacial
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:25394726
    reference_title: Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial features of LMS include hypertelorism and telecanthus, high arched
      eyebrows, ptosis, midfacial hypoplasia, micrognathia, high and narrow palate,
      low-set ears and a hypotonic appearance.
    explanation: Hypertelorism is part of the LMS facial gestalt.
- name: Ptosis
  category: Craniofacial
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: PMID:25394726
    reference_title: Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial features of LMS include hypertelorism and telecanthus, high arched
      eyebrows, ptosis, midfacial hypoplasia, micrognathia, high and narrow palate,
      low-set ears and a hypotonic appearance.
    explanation: Ptosis is part of the LMS facial gestalt.
- name: Downslanted Palpebral Fissures
  category: Craniofacial
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  evidence:
  - reference: PMID:9188658
    reference_title: "Lateral meningocele syndrome: three new patients and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other shared findings include multiple lateral meningoceles, Wormian bones,
      malar hypoplasia, downslanted palpebral fissures, a high narrow palate, and
      cryptorchidism in males.
    explanation: Downslanted palpebral fissures were shared across reported patients.
- name: Micrognathia
  category: Craniofacial
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:25394726
    reference_title: Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Facial features of LMS include hypertelorism and telecanthus, high arched
      eyebrows, ptosis, midfacial hypoplasia, micrognathia, high and narrow palate,
      low-set ears and a hypotonic appearance.
    explanation: Micrognathia is part of the LMS facial gestalt.
  - reference: PMID:23962060
    reference_title: "Lehman syndrome: a new syndrome for pierre robin sequence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present a case of a 2-year-old boy presenting with micrognathia,
      glossoptosis, and hypertelorism as well as associated severe obstructive
      sleep apnea.
    explanation: Micrognathia with glossoptosis (Pierre Robin sequence) in a child with LMS.
  sequelae:
  - target: Obstructive Sleep Apnea
    description: >-
      Micrognathia with glossoptosis narrows the upper airway and was associated
      with severe obstructive sleep apnea that required mandibular distraction.
    evidence:
    - reference: PMID:23962060
      reference_title: "Lehman syndrome: a new syndrome for pierre robin sequence."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We present a case of a 2-year-old boy presenting with micrognathia,
        glossoptosis, and hypertelorism as well as associated severe obstructive
        sleep apnea.
      explanation: Obstructive sleep apnea is reported as associated with the micrognathia.
- name: Obstructive Sleep Apnea
  category: Respiratory
  phenotype_term:
    preferred_term: Obstructive sleep apnea
    term:
      id: HP:0002870
      label: Obstructive sleep apnea
  evidence:
  - reference: PMID:23962060
    reference_title: "Lehman syndrome: a new syndrome for pierre robin sequence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present a case of a 2-year-old boy presenting with micrognathia,
      glossoptosis, and hypertelorism as well as associated severe obstructive
      sleep apnea.
    explanation: Severe obstructive sleep apnea in a child with LMS.
- name: High Narrow Palate
  category: Craniofacial
  phenotype_term:
    preferred_term: High, narrow palate
    term:
      id: HP:0002705
      label: High, narrow palate
  evidence:
  - reference: PMID:9188658
    reference_title: "Lateral meningocele syndrome: three new patients and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other shared findings include multiple lateral meningoceles, Wormian bones,
      malar hypoplasia, downslanted palpebral fissures, a high narrow palate, and
      cryptorchidism in males.
    explanation: A high narrow palate was shared across reported patients.
- name: Cleft Palate
  category: Craniofacial
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Additional findings of LMS include developmental delay, mixed or conductive
      hearing loss, and cleft palate.
    explanation: Cleft palate is an additional finding in GeneReviews.
- name: Wormian Bones
  category: Skeletal
  phenotype_term:
    preferred_term: Wormian bones
    term:
      id: HP:0002645
      label: Wormian bones
  evidence:
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Skeletal abnormalities may include scoliosis, vertebral fusion, scalloping
      of vertebrae, and wormian bones.
    explanation: Wormian bones are listed among the skeletal abnormalities.
- name: Vertebral Fusion
  category: Skeletal
  phenotype_term:
    preferred_term: Vertebral fusion
    term:
      id: HP:0002948
      label: Vertebral fusion
  evidence:
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Skeletal abnormalities may include scoliosis, vertebral fusion, scalloping
      of vertebrae, and wormian bones.
    explanation: Vertebral fusion is listed among the skeletal abnormalities.
- name: Posterior Scalloping of Vertebral Bodies
  category: Skeletal
  phenotype_term:
    preferred_term: Posterior scalloping of vertebral bodies
    term:
      id: HP:0005121
      label: Posterior scalloping of vertebral bodies
  evidence:
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Skeletal abnormalities may include scoliosis, vertebral fusion, scalloping
      of vertebrae, and wormian bones.
    explanation: Scalloping of vertebrae is listed among the skeletal abnormalities.
- name: Scoliosis
  category: Skeletal
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Skeletal abnormalities may include scoliosis, vertebral fusion, scalloping
      of vertebrae, and wormian bones.
    explanation: Scoliosis is listed among the skeletal abnormalities.
- name: Osteopenia
  category: Skeletal
  description: >-
    Reduced bone mass is established in mouse models of LMS; in patients it is
    reported mainly as osteolysis and bone loss in individual cases.
  phenotype_term:
    preferred_term: Osteopenia
    term:
      id: HP:0000938
      label: Osteopenia
  evidence:
  - reference: PMID:33519922
    reference_title: The Skeleton of Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Lateral Meningocele Syndrome (LMS) is a rare genetic disorder characterized
      by neurological manifestations, meningoceles, skeletal developmental
      abnormalities and bone loss.
    explanation: Bone loss is described as a characteristic of LMS.
  - reference: PMID:30042232
    reference_title: The lateral meningocele syndrome mutation causes marked osteopenia in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      One-month-old male and female heterozygous Notch3tm1.1Ecan mice had
      cancellous and cortical bone osteopenia but exhibited no obvious neurological
      alterations, and histopathology of multiple organs revealed no abnormalities.
    explanation: The LMS mouse model is osteopenic.
- name: Joint Hypermobility
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Joint hyperextensibility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      NOTCH3-related lateral meningocele syndrome (LMS) is characterized by
      multiple lateral spinal meningoceles (protrusions of the arachnoid and dura
      through spinal foramina), distinctive facial features, joint
      hyperextensibility, hypotonia, and skeletal, cardiac, and urogenital
      anomalies.
    explanation: Joint hyperextensibility is a core feature in GeneReviews.
  - reference: PMID:24311540
    reference_title: Late diagnosis of lateral meningocele syndrome in a 55-year-old woman with symptoms of joint instability and chronic musculoskeletal pain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on a further observation of LMS in a 55-year-old woman presenting
      with a long history of joint instability, chronic musculoskeletal pain, and
      iatrogenic bladder and anorectal dysfunction due to irreversible nerve damage
      after surgical excision of a meningeal cyst.
    explanation: Joint instability dominated the presentation of an adult with LMS.
- name: Hernia
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Hernia
    term:
      id: HP:0100790
      label: Hernia
  evidence:
  - reference: PMID:25394726
    reference_title: Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hyperextensibility, hernias and scoliosis reflect a connective tissue
      abnormality, and aortic dilation, a high-pitched nasal voice, wormian bones
      and osteolysis may be present.
    explanation: Hernias are reported in LMS.
- name: Keloids
  category: Integumentary
  phenotype_term:
    preferred_term: Keloids
    term:
      id: HP:0010562
      label: Keloids
  evidence:
  - reference: PMID:9188658
    reference_title: "Lateral meningocele syndrome: three new patients and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, our patients showed ligamentous laxity, keloid formation,
      hypotonia, and developmental delay.
    explanation: Keloid formation was observed in reported patients.
- name: Aortic Root Dilation
  category: Cardiovascular
  phenotype_term:
    preferred_term: Aortic root dilation
    term:
      id: HP:0002616
      label: Aortic root aneurysm
  evidence:
  - reference: PMID:25394726
    reference_title: Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hyperextensibility, hernias and scoliosis reflect a connective tissue
      abnormality, and aortic dilation, a high-pitched nasal voice, wormian bones
      and osteolysis may be present.
    explanation: Aortic dilation may be present in LMS.
- name: Bicuspid Aortic Valve
  category: Cardiovascular
  phenotype_term:
    preferred_term: Bicuspid aortic valve
    term:
      id: HP:0001647
      label: Bicuspid aortic valve
  evidence:
  - reference: PMID:23696373
    reference_title: "Lateral meningocele syndrome: additional report and further evidence supporting a connective tissue basis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a simplex case of lateral meningocele syndrome with bicuspid
      aortic valve, supporting the hypothesis of a connective tissue basis for
      this disorder and further expanding the phenotype.
    explanation: Bicuspid aortic valve was reported in a patient with LMS.
- name: Cryptorchidism
  category: Genitourinary
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:9188658
    reference_title: "Lateral meningocele syndrome: three new patients and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other shared findings include multiple lateral meningoceles, Wormian bones,
      malar hypoplasia, downslanted palpebral fissures, a high narrow palate, and
      cryptorchidism in males.
    explanation: Cryptorchidism in males was a shared finding.
- name: Short Stature
  category: Growth
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:32141180
    reference_title: Expansion of the phenotype of lateral meningocele syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Besides the lateral meningoceles, this condition presents with dysmorphic
      features, short stature, congenital heart defects, and feeding difficulties.
    explanation: Short stature is listed among the features of LMS.
- name: Congenital Heart Defects
  category: Cardiovascular
  description: >-
    Septal defects, patent ductus arteriosus and more complex congenital heart
    anomalies have been reported.
  phenotype_term:
    preferred_term: Congenital heart defect
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:32141180
    reference_title: Expansion of the phenotype of lateral meningocele syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Besides the lateral meningoceles, this condition presents with dysmorphic
      features, short stature, congenital heart defects, and feeding difficulties.
    explanation: Congenital heart defects are listed among the features of LMS.
  - reference: PMID:26754023
    reference_title: "Lateral meningocele (Lehman) syndrome: A child with a novel NOTCH3 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our patient's prenatal findings, complex cardiac anomalies, and severe
      feeding difficulties further expand our understanding of this rare
      condition.
    explanation: Complex cardiac anomalies were present in a molecularly confirmed case.
- name: Renal Cysts
  category: Renal
  phenotype_term:
    preferred_term: Renal cyst
    term:
      id: HP:0000107
      label: Renal cyst
  evidence:
  - reference: PMID:32141180
    reference_title: Expansion of the phenotype of lateral meningocele syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This case illustrates the power of reverse phenotyping to establish clinical
      diagnosis and expands the spectrum of clinical manifestations related to LMS
      to include inner ear abnormalities and multi-cystic kidney disease.
    explanation: Multicystic kidney disease was added to the LMS spectrum by a single case.
genetic:
- name: NOTCH3
  association: Causative (gain-of-function terminal-exon truncating variants)
  gene_term:
    preferred_term: NOTCH3
    term:
      id: hgnc:7883
      label: NOTCH3
  notes: >-
    Heterozygous nonsense and frameshift variants in the last coding exon (exon 33)
    of NOTCH3 that truncate the PEST domain. These are distinct from the
    extracellular-domain cysteine-altering missense variants that cause CADASIL.
  evidence:
  - reference: PMID:25394726
    reference_title: Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In total, five novel de novo NOTCH3 mutations were identified in six
      unrelated patients.
    explanation: De novo NOTCH3 variants were found in six unrelated patients with LMS.
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The diagnosis of NOTCH3-related LMS syndrome is established in a proband with
      consistent clinical findings and a heterozygous pathogenic variant in NOTCH3.
    explanation: A heterozygous NOTCH3 pathogenic variant establishes the diagnosis.
treatments:
- name: Neurosurgical Management of Symptomatic Meningoceles
  description: >-
    Surgery on lateral meningoceles is generally avoided because of the risk of
    nerve injury and CSF leak, and is reserved for neurological deficits caused by
    meningocele size or location. Reported approaches include resection or repair,
    cyst-subarachnoid shunting, and ventriculoperitoneal shunting when CSF
    dynamics drive meningocele enlargement.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: neurosurgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Lateral spinal meningocele
    term:
      id: HP:0032478
      label: Lateral spinal meningocele
  target_mechanisms:
  - target: Spinal Nerve Root Compression by Meningoceles
    description: Decompression or shunting relieves pressure from the sacs on nerve roots.
  evidence:
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Surgical intervention of lateral spinal meningoceles is generally avoided,
      but may be necessary due to neurologic manifestations secondary to
      meningocele size and location.
    explanation: GeneReviews reserves surgery for symptomatic meningoceles.
  - reference: PMID:41432782
    reference_title: "Significant improvement of neurological and radiological findings caused by multiple lateral meningocele by cyst-subarachnoid shunt in a 6-year-old boy: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His symptoms improved immediately, and the meningocele gradually regressed
      postoperatively.
    explanation: Cyst-subarachnoid shunting improved symptoms and reduced the meningocele in one child.
  - reference: PMID:24311540
    reference_title: Late diagnosis of lateral meningocele syndrome in a 55-year-old woman with symptoms of joint instability and chronic musculoskeletal pain.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report on a further observation of LMS in a 55-year-old woman presenting
      with a long history of joint instability, chronic musculoskeletal pain, and
      iatrogenic bladder and anorectal dysfunction due to irreversible nerve damage
      after surgical excision of a meningeal cyst.
    explanation: >-
      Irreversible iatrogenic nerve damage after meningeal cyst excision
      illustrates why surgery is avoided when possible.
- name: Mandibular Distraction Osteogenesis
  description: >-
    Bilateral mandibular distraction osteogenesis has been used to correct
    micrognathia with Pierre Robin sequence and obstructive sleep apnea in LMS.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: mandibular distraction osteogenesis
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  - preferred_term: Obstructive sleep apnea
    term:
      id: HP:0002870
      label: Obstructive sleep apnea
  evidence:
  - reference: PMID:23962060
    reference_title: "Lehman syndrome: a new syndrome for pierre robin sequence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Distraction osteogenesis is a safe procedure that is effective as a first
      choice in the treatment of patients with Lehman syndrome presenting with
      micrognathia.
    explanation: Distraction osteogenesis corrected micrognathia in a child with LMS.
- name: Physiotherapy
  description: >-
    Physiotherapy is recommended to reduce the risk of joint subluxation and
    dislocation related to joint hypermobility.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      physiotherapy to reduce the risk for joint subluxation and dislocation
    explanation: GeneReviews recommends physiotherapy for joint protection.
- name: Multidisciplinary Supportive Care
  description: >-
    There is no disease-modifying therapy. Management is symptomatic and
    multidisciplinary, covering cleft palate, cardiovascular, genitourinary,
    ophthalmologic, hearing and feeding problems, developmental support, and
    chronic pain.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:33519922
    reference_title: The Skeleton of Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: There are no effective therapies for LMS.
    explanation: No disease-modifying therapy exists, so care is supportive.
- name: Genetic Counseling
  description: >-
    Most cases are de novo; an affected individual has a 50% risk of transmitting
    the variant, and prenatal and preimplantation testing are possible once the
    familial variant is known.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Each child of an individual with NOTCH3-related LMS has a 50% chance of
      inheriting the pathogenic variant.
    explanation: The recurrence risk is the basis for genetic counseling.
diagnosis:
- name: NOTCH3 Molecular Testing
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Diagnosis is established by identifying a heterozygous pathogenic truncating
    variant in exon 33 of NOTCH3 in a proband with consistent clinical findings.
  evidence:
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The diagnosis of NOTCH3-related LMS syndrome is established in a proband with
      consistent clinical findings and a heterozygous pathogenic variant in NOTCH3.
    explanation: GeneReviews diagnostic criterion.
- name: Spinal MRI Surveillance
  diagnosis_term:
    preferred_term: Magnetic Resonance Imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  description: >-
    Spinal imaging identifies the lateral meningoceles and is repeated to monitor
    their size: yearly at first, then every two years if they are small and stable.
  evidence:
  - reference: PMID:27336130
    reference_title: NOTCH3-Related Lateral Meningocele Syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Close clinical and radiographic monitoring for progressive neurologic
      symptoms and increase in meningocele size; an initial yearly scan to monitor
      for stability and subsequent spacing to every two years if meningoceles are
      small in size.
    explanation: GeneReviews surveillance recommendation.
differential_diagnoses:
- name: Hajdu-Cheney syndrome
  description: >-
    Hajdu-Cheney syndrome is caused by analogous last-exon truncating variants in
    NOTCH2 and overlaps clinically (wormian bones, facial features, osteolysis,
    connective tissue signs), but acro-osteolysis and severe osteoporosis dominate
    and multiple lateral meningoceles are not characteristic.
  disease_term:
    preferred_term: Hajdu-Cheney syndrome
    term:
      id: MONDO:0007057
      label: acroosteolysis dominant type
  evidence:
  - reference: PMID:25394726
    reference_title: Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Lateral meningocele syndrome has phenotypic overlap with Hajdu-Cheney syndrome.
    explanation: The two syndromes overlap phenotypically and share a truncating-variant mechanism in paralogous genes.
- name: Ehlers-Danlos and Marfan-spectrum connective tissue disorders
  description: >-
    Joint laxity, dural ectasia, and aortic dilation overlap with Marfan,
    Ehlers-Danlos, and Loeys-Dietz syndromes, but multiple lateral thoracolumbar
    meningoceles distinguish LMS.
  evidence:
  - reference: PMID:31838470
    reference_title: "Neurosurgical Management of Lateral Meningocele Syndrome: A Clinical Update for the Pediatric Neurosurgeon."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Lateral meningocele syndrome (LMS) is an exceedingly rare connective tissue
      disease with phenotypic anomalies similar to those seen in Marfan syndrome,
      Ehler-Danlos syndrome, and Loeys-Dietz syndrome.
    explanation: The review names these connective tissue disorders as the phenotypic differential.
animal_models:
- name: Notch3 6691-TAATGA knock-in mouse
  species: Mus musculus
  genotype: Notch3 tm1.1Ecan (em1Ecan) heterozygous, tandem stop codon at bases 6691-6696 upstream of the PEST domain
  publication: PMID:30042232
  description: >-
    A CRISPR/Cas9 knock-in that truncates Notch3 upstream of the PEST domain,
    reproducing the LMS variant class. Heterozygous mice have cancellous and
    cortical osteopenia with increased osteoclastogenesis and RANKL expression,
    but no neurological phenotype or meningoceles. The osteopenia is reversed by
    an anti-Notch3 negative regulatory region antibody and the cortical
    osteopenia is ameliorated by a mutation-specific Notch3 antisense
    oligonucleotide.
  modeled_mechanisms:
  - target: Increased Osteoclastogenesis and Bone Resorption
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: The model shows RANKL-driven osteoclastogenesis and osteopenia.
    limitations: >-
      Human bone phenotype data in LMS are limited to case reports, so how
      faithfully mouse osteopenia represents the human skeletal disease is
      uncertain; female mice recover bone mass with maturation.
    evidence:
    - reference: PMID:30042232
      reference_title: The lateral meningocele syndrome mutation causes marked osteopenia in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In conclusion, the Notch3tm1.1Ecan mutation causes osteopenia despite an
        increase in osteoblast proliferation and function and is associated with
        enhanced Tnfsf11 expression in osteoblasts and osteocytes.
      explanation: The model recapitulates the resorptive skeletal mechanism.
  - target: Dural Ectasia and Lateral Meningocele Formation
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: ORGANISM
    description: No neurological alterations or meningoceles were reported in the model.
    limitations: >-
      The defining human lesion is absent, so the model cannot be used to study
      meningocele formation or the connective tissue phenotype.
    evidence:
    - reference: PMID:30042232
      reference_title: The lateral meningocele syndrome mutation causes marked osteopenia in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        One-month-old male and female heterozygous Notch3tm1.1Ecan mice had
        cancellous and cortical bone osteopenia but exhibited no obvious
        neurological alterations, and histopathology of multiple organs revealed no
        abnormalities.
      explanation: The mice lack the neurological and meningocele phenotype.
  evidence:
  - reference: PMID:37704069
    reference_title: Antisense oligonucleotides targeting a NOTCH3 mutation in male mice ameliorate the cortical osteopenia of lateral meningocele syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In conclusion, a Notch3 ASO that downregulates Notch3 mutant expression
      specifically ameliorates the cortical osteopenia in Notch3em1Ecan mice.
    explanation: A mutation-specific ASO partially rescues the model's bone phenotype.
  - reference: PMID:35536858
    reference_title: Use of antisense oligonucleotides to target Notch3 in skeletal cells.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Microcomputed tomography demonstrated that the administration of Notch3 ASOs
      ameliorates the cortical osteopenia of Notch3em1Ecan mice, and ASOs decreased
      femoral cortical porosity and increased cortical thickness and bone volume.
    explanation: A non-allele-selective Notch3 ASO also ameliorates cortical osteopenia in the model.
  - reference: PMID:31188489
    reference_title: An antibody to Notch3 reverses the skeletal phenotype of lateral meningocele syndrome in male mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The cancellous bone osteopenia was no longer observed after the
      intraperitoneal administration of antibodies directed to the negative
      regulatory region (NRR) of Notch3.
    explanation: A NOTCH3-activation-blocking antibody reverses cancellous osteopenia in the model.
discussions:
- discussion_id: lms_mouse_lacks_meningoceles
  prompt: >-
    Why do mice carrying an LMS-analogous Notch3 truncation develop osteopenia but
    no meningoceles, dural ectasia, or neurological signs, and what tissue carries
    the connective tissue defect in humans?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Connective Tissue and Dural Dysplasia
  - pathophysiology#Dural Ectasia and Lateral Meningocele Formation
  rationale: >-
    The only in vivo models reproduce the skeletal resorptive mechanism but not
    the defining human lesion. The mechanism linking NOTCH3 gain of function to
    dural and connective tissue weakness is therefore untested, and the causal
    edge from NOTCH3 gain of function to connective tissue dysplasia rests on
    genotype-phenotype association alone.
  proposed_experiments:
  - experiment_id: exp_lms_meningeal_fibroblast_notch3
    name: NOTCH3 gain of function in human meningeal and dermal fibroblasts
    description: >-
      Compare extracellular matrix production and mechanical properties of
      patient-derived or isogenic iPSC-derived meningeal and dermal fibroblasts
      carrying an exon 33 NOTCH3 truncation against corrected controls.
references:
- reference: PMID:27336130
  title: NOTCH3-Related Lateral Meningocele Syndrome.
  tags:
  - GeneReviews
📚

References & Deep Research

References

1
PMID:27336130
NOTCH3-Related Lateral Meningocele Syndrome.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Lateral Meningocele Syndrome · 2026-09-23T20:02:25Z · View source

New entry for lateral meningocele syndrome (Lehman syndrome, MONDO:0007537), caused by heterozygous truncating variants in NOTCH3 exon 33. The GeneReviews chapter NOTCH3-Related Lateral Meningocele Syndrome (PMID:27336130) is the phenotype baseline and is tagged in references. One OpenScientist deep-research report was used: research/Lateral_Meningocele_Syndrome-deep-research-openscientist.md (29/29 references resolved, 0 off topic; term validation flagged two GO cellular-component terms whose report labels differed from the ontology labels, neither of which is used here). just preflight-dr passed with NOTCH3 as the dominant gene. Curated 8 pathophysiology nodes as a causal chain: terminal-exon truncation escaping nonsense-mediated decay, NOTCH3 gain of function, increased RANKL in osteoblasts and osteocytes, increased osteoclastogenesis leading to osteopenia (mouse evidence), connective tissue and dural dysplasia, dural ectasia and meningocele formation, nerve root compression and its neurological sequelae, and abnormal craniofacial and skeletal development. The edges from NOTCH3 gain of function to connective tissue dysplasia and to craniofacial development are marked INDIRECT_UNKNOWN_INTERMEDIATES because no study has shown the mechanism, and a HUMAN_MODEL_MISMATCH discussion records that the Notch3 knock-in mouse has osteopenia but no meningoceles. 33 phenotypes with HP terms; 11 have no causal edge because no source gives a mechanism. HP:0032478 Lateral spinal meningocele was confirmed in OLS and added to the term cache. Treatments are supportive (neurosurgery for symptomatic meningoceles, mandibular distraction, physiotherapy, supportive care, genetic counseling); preclinical ASO and anti-NOTCH3 antibody results are recorded under the mouse model rather than as treatments. Validation: just validate, validate-terms, count-verified-snippets (92/92), check-causal-targets, check-entity-refs, check-duplicate-keys, check-coarse-phenotypes, check-snippet-length, check-title-snippets, check-snippet-grading, check-reference-titles and just validate-disorders all passed.

OpenScientist ▸
Key Findings
openscientist-autonomous 29 citations 2026-09-23T19:57:56.957511

Key Findings

F001 — LMS is caused by heterozygous truncating NOTCH3 variants clustered in the last exon (exon 33)

The causal gene was identified by exome resequencing of five unrelated individuals with LMS, all of whom carried heterozygous truncating NOTCH3 mutations; a sixth case was confirmed by Sanger sequencing. In total, five novel de novo mutations were identified in six unrelated patients. The reported variants include a 26-bp deletion (c.6461_6486del, p.G2154fsTer78), a recurrent single-base insertion (c.6692_93insC, p.P2231fsTer11, seen in two patients), and three nonsense variants (c.6247A>T p.K2083; c.6663C>G p.Y2221; c.6732C>A p.Y2244). A defining molecular feature is that all variants cluster in the last coding exon (exon 33)*, producing premature termination and truncation of the C-terminal region.

"We performed exome resequencing in five unrelated individuals with LMS and identified heterozygous truncating NOTCH3 mutations." — PMID: 25394726

"All mutations cluster into the last coding exon, resulting in premature termination of the protein and truncation of…" — PMID: 25394726

Additional confirmatory variants have since been reported, including a de novo c.6723_6736del p.(Glu2241AspfsTer8) identified through the 100,000 Genomes Project (PMID: 40256810) and an 80-bp deletion in exon 33 (PMID: 26754023), reinforcing the exon-33 truncation signature. Identifiers: NOTCH3 (HGNC:7883); OMIM gene 600276; disease OMIM %130720.

F002 — LMS variants cause NOTCH3 gain-of-function through loss of the PEST domain

The exon-33 truncations delete the C-terminal PEST domain, a proline-, glutamate-, serine-, and threonine-rich sequence that normally targets the intracellular Notch fragment for proteasomal degradation. Its loss stabilizes the NOTCH3 intracellular domain, prolonging and enhancing downstream Notch signaling. This was directly demonstrated in human iPSC models: cells harboring the NOTCH3 c.6692_93insC variant showed enhanced expression of the canonical Notch target genes HES1, HEY1, HEY2, and HEYL, confirming gain-of-function.

"Lateral Meningocele or Lehman Syndrome (LMS) is associated with NOTCH3 mutations causing deletions of the PEST domain and a gain-of-NOTCH3 function." — PMID: 35760307

"NOTCH3 6692-93insC cells displayed enhanced expression of Notch target genes HES1, HEY1, 2 and L demonstrating a NOTCH3 gain-of-function." — PMID: 39752389

Functional consequence: gain-of-function via protein stabilization (not haploinsufficiency). Suggested GO terms: Notch signaling pathway (GO:0007219); positive regulation of transcription by RNA polymerase II (GO:0045944); protein stabilization (GO:0050821).

F003 — Bone loss/osteopenia in LMS is driven by NOTCH3-enhanced RANKL-mediated osteoclastogenesis

The skeletal osteopenia of LMS has been mechanistically dissected in mouse models. The Notch3^em1Ecan^ knock-in mouse, harboring a 6691TAATGA PEST-truncating mutation homologous to human LMS variants, exhibits both cancellous and cortical bone osteopenia. Experimental analysis revealed that the bone loss is secondary to increased osteoclastogenesis driven by enhanced RANKL (receptor activator of NF-κB ligand) expression by osteoblast-lineage cells. Osteocyte-specific induction of the Lehman mutation independently caused osteopenia in male mice, localizing a key cellular source of the RANKL signal to osteocytes.

"Experimental mouse models of LMS revealed that the bone loss is secondary to increased osteoclastogenesis due to enhanced expression of receptor activator of nuclear factor kappa B ligand by cells of the osteoblast lineage." — PMID: 33519922

Suggested GO terms: osteoclast differentiation (GO:0030316); positive regulation of osteoclast differentiation (GO:0045672); bone resorption (GO:0045453). Suggested CL terms: osteoblast (CL:0000062); osteocyte (CL:0000137); osteoclast (CL:0000092). Protein: TNFSF11/RANKL.

F004 — Notch3-targeting ASOs and an anti-Notch3 antibody reverse the skeletal phenotype in LMS mouse models (preclinical)

Because stabilized gain-of-function NOTCH3 is the disease driver, lowering NOTCH3 is a rational therapeutic strategy. Subcutaneous administration of Notch3 ASOs (25–50 mg/kg) decreased Notch3 mRNA in liver, heart, and bone and ameliorated cortical osteopenia, reducing femoral cortical porosity in Notch3^em1Ecan^ mice. The ASOs were paralog-specific (they did not downregulate Notch1, Notch2, or Notch4). Allele-selective ASOs targeting the mutant insertion reduced mutant transcript by 70–80% in mesenchymal cells, offering an approach that spares the wild-type allele. Separately, a Notch3-neutralizing antibody also reversed the skeletal phenotype in male mice (PMID: 31188489).

"Lateral Meningocele Syndrome (LMS) is a monogenic disorder associated with NOTCH3 pathogenic variants that result in the stabilization of NOTCH3 and a gain-of-function." — PMID: 37704069

"In vivo, the subcutaneous administration of Notch3 ASOs at 25 to 50 mg/Kg decreased Notch3 mRNA in the liver, heart and bone." — PMID: 35536858

These interventions remain preclinical; there is no FDA-approved therapy for LMS. Suggested NCIT terms: Antisense Oligonucleotide; Monoclonal Antibody Therapy.

F005 — LMS is a multisystem connective-tissue/skeletal syndrome defined by lateral meningoceles plus distinctive facies

The core diagnostic triad comprises (1) multiple lateral thoracolumbar spinal meningoceles — the severe end of the dural ectasia spectrum, typically most severe in the lower spine; (2) a distinctive facial gestalt; and (3) connective-tissue signs.

"Facial features of LMS include hypertelorism and telecanthus, high arched eyebrows, ptosis, midfacial hypoplasia, micrognathia, high and narrow palate, low-set ears and a hypotonic appearance." — PMID: 25394726

"The characteristic lateral meningoceles represent the severe end of the dural ectasia spectrum and are typically most severe in the lower spine." — PMID: 25394726

The expanded phenotype includes short stature, congenital heart defects, feeding difficulties/failure to thrive, developmental delay/intellectual disability, sensorineural hearing loss, renal cysts, Chiari I malformation, syringomyelia, hydrocephalus, and tethered cord.

"Besides the lateral meningoceles, this condition presents with dysmorphic features, short stature, congenital heart defects, and feeding difficulties." — PMID: 32141180

There is substantial phenotypic overlap with Hajdu-Cheney syndrome (NOTCH2), Marfan syndrome, Ehlers-Danlos syndrome, and Loeys-Dietz syndrome, complicating clinical recognition (PMID: 25821090; PMID: 40256810).

Suggested HPO terms: Meningocele (HP:0002435); Dural ectasia (HP:0100775); Hypertelorism (HP:0000316); Telecanthus (HP:0000506); Ptosis (HP:0000508); Micrognathia (HP:0000347); Highly arched eyebrow (HP:0002553); Midface retrusion (HP:0011800); Joint hypermobility (HP:0001382); Hyperextensible skin (HP:0000974); Scoliosis (HP:0002650); Muscular hypotonia (HP:0001252); Short stature (HP:0004322); Sensorineural hearing impairment (HP:0000407); Chiari type I malformation (HP:0007099); Syringomyelia (HP:0003396); Tethered cord (HP:0002144).

F006 — LMS is a very rare, mostly de novo autosomal-dominant disorder (~few dozen reported cases)

LMS is described as "very rare" to "exceedingly rare." A 2019 neurosurgical review identified only 11 articles covering 16 cases (9 males, 7 females) across 14 families; among those genetically screened, all carried exon-33 NOTCH3 truncations. The original gene-discovery cohort reported five de novo mutations in six unrelated patients. Two instances of vertical (parent-to-child) transmission have been documented, consistent with autosomal-dominant inheritance, but most cases are de novo. Age at diagnosis ranges from infancy (as early as 5 months / 2 years) to 55 years.

"Our literature search revealed 11 articles (16 cases) of LMS, which included 9 males and 7 females, belonging to 14 different families." — PMID: 31838470

"In total, five novel de novo NOTCH3 mutations were identified in six unrelated patients." — PMID: 25394726

No formal population prevalence or incidence figures are established; Orphanet lists prevalence as <1/1,000,000 (ORPHA:2140). The near-balanced sex ratio (~9:7 M:F) is consistent with autosomal-dominant inheritance without sex bias. A very late diagnosis at age 55 illustrates that milder cases may go unrecognized for decades (PMID: 24311540).

F007 — LMS and CADASIL are distinct allelic NOTCH3 disorders with opposite functional mechanisms

NOTCH3 is associated with two mechanistically opposite diseases. CADASIL — the most common monogenic cerebral small-vessel disease — is caused by stereotyped cysteine-altering missense variants in the EGF-like repeats of the NOTCH3 extracellular domain that change the number of cysteine residues, causing ectodomain misfolding, aggregation (granular osmiophilic material, GOM), and vascular smooth muscle cell degeneration. LMS is caused by PEST-domain truncating variants producing intracellular gain-of-function. Rare patients carrying both classes of variant have been reported.

"CADASIL, the most common monogenic form of cSVD, is caused by stereotyped mutations in the NOTCH3 receptor that alter the number of cysteine residues in its extracellular domain." — PMID: 40145673

"the patient was found to have two variants of the NOTCH3 gene, resulting in the diagnosis of lateral meningocele (Lehman) syndrome" — PMID: 34172679

Additional NOTCH3-related phenotypes further map the genotype-mechanism landscape: biallelic loss-of-function variants cause a neurodevelopmental disorder with spasticity and childhood-onset stroke, whereas biallelic cysteine-involving missense variants produce a CADASIL-spectrum phenotype (PMID: 39191170). The molecular pathobiology of CADASIL — non-enzymatic NOTCH3 fragmentation and cysteine-redox–driven aggregation — has been characterized in detail (PMID: 31901894; PMID: 35409031; PMID: 35223989), underscoring how different its mechanism is from LMS.

F008 — Diagnosis relies on whole-spine MRI plus molecular confirmation of an exon-33 NOTCH3 variant; management is neurosurgical/supportive

Whole-spine MRI is the key imaging study, demonstrating multiple bilateral well-defined cystic masses within the neural foramina (predominantly thoracolumbar), with neural foraminal widening, dural ectasia, and posterior vertebral body scalloping. CT complements this by showing vertebral/pedicle scalloping and spinal canal widening. Molecular confirmation is by exome/genome or targeted NOTCH3 exon-33 sequencing; "reverse phenotyping" (identifying the variant first, then imaging) has diagnosed presymptomatic and prenatal cases.

"showed multiple bilateral well-defined cystic masses within the neural foramina involving the entire spine, predominantly the thoracolumbar regions, with neural foraminal widening and dural ectasia suggestive of multiple lateral meningoceles" — PMID: 33042242

"an early genomic analysis allowed us to recognize the presence of lateral meningoceles and to begin early monitoring of her condition for possible neurological complications" — PMID: 34121137

Management is supportive and neurosurgical, with no formal guidelines. Symptomatic meningoceles are treated by surgical repair or shunting (cyst-subarachnoid or cystoperitoneal). A recent case documents cyst-subarachnoid shunts at T8 and L5-S1 producing immediate symptomatic improvement and gradual meningocele regression.

"Two cyst-subarachnoid (C-S) shunts were placed, at the superior aspect of the meningocele (T8) and the inferior aspect (L5-S1). His symptoms improved immediately, and the meningocele gradually regressed postoperatively." — PMID: 41432782

Surgery is complicated by coexisting Chiari I malformation, syringomyelia, hydrocephalus, tethered cord, and the underlying mesodermal/connective-tissue fragility (PMID: 31838470; PMID: 38755334).

F009 — Genetically engineered and natural mouse and iPSC models recapitulate the LMS skeletal phenotype

The principal in vivo model is the Notch3^em1Ecan^ knock-in mouse (6691TAATGA PEST-truncating mutation), whose heterozygotes reproduce cancellous and cortical bone osteopenia and increased femoral cortical porosity. Osteocyte-specific induction of a NOTCH3 Lehman mutation causes osteopenia in male C57BL/6J mice. Human iPSC models (NCRM1/NCRM5 carrying NOTCH3 c.6692_93insC plus isogenic controls) differentiated toward neural crest, mesenchymal, and osteogenic lineages exhibit gain-of-function and enhanced osteogenesis. A spontaneous murine Notch3 mutation ("humpback") provides a natural model.

"We created a mouse model (Notch3^em1Ecan) harboring a 6691TAATGA mutation in the Notch3 locus, and heterozygous Notch3^em1Ecan mice exhibit cancellous and cortical bone osteopenia." — PMID: 35536858

"induced pluripotent NCRM1 and NCRM5 stem (iPS) cells harboring a NOTCH3 6692-93insC insertion were created" — PMID: 39752389

These models enabled therapeutic testing (ASOs and antibody rescue). Phenotype recapitulation is strongest for the skeletal/bone-loss component; the models less fully capture the meningocele and craniofacial features. The "humpback" natural mutant was precisely genotyped using a PCR-based ARMS system (PMID: 33860007). Resources: MGI (Notch3 alleles); Alliance of Genome Resources. Orthologous gene: mouse Notch3 (NCBI Gene 18131).

F010 — NOTCH paralogs have opposing effects on bone; NOTCH3 specifically induces osteoblast/osteocyte RANKL

Paralog specificity explains the LMS bone phenotype. In the skeleton, NOTCH1 inhibits osteoclastogenesis, whereas NOTCH2 enhances osteoclast differentiation, and NOTCH3 induces RANKL expression in osteoblasts and osteocytes, thereby driving osteoclast differentiation via an indirect mechanism. This is why NOTCH3 gain-of-function in LMS produces net bone resorption/osteopenia — mechanistically parallel to NOTCH2 gain-of-function in Hajdu-Cheney syndrome.

"NOTCH3 induces the expression of RANKL in osteoblasts and osteocytes and as a result induces osteoclast differentiation." — PMID: 32526405

"NOTCH1 inhibits osteoclastogenesis, whereas NOTCH2 enhances osteoclast differentiation and function by direct and indirect mechanisms." — PMID: 32526405

"There are no effective therapies for LMS." — PMID: 33519922

F011 — The phenotype is progressively expanding; prenatal diagnosis is feasible and new organ involvements continue to be reported

The first prenatal molecular diagnosis of LMS was achieved by prenatal exome sequencing following an ultrasound showing fetal cystic hygroma, mild bilateral ventriculomegaly, and facial dysmorphisms; postnatal MRI confirmed lateral meningoceles and evaluation revealed previously unreported biliary anomalies.

"We report the first case of prenatal molecular diagnosis of LMS, which was made using prenatal exome sequencing after an ultrasound with findings of fetal cystic hygroma, mild bilateral ventriculomegaly, and facial dysmorphisms." — PMID: 40771185

"A complete clinical evaluation was performed and unexpected biliary anomalies were found. The occurrence of biliary anomalies has not been previously reported in LMS" — PMID: 40771185

Earlier reports had already expanded the spectrum to include inner-ear abnormalities and multicystic kidney disease.

"expands the spectrum of clinical manifestations related to LMS to include inner ear abnormalities and multi-cystic kidney disease" — PMID: 32141180

Strikingly, a molecularly confirmed 8-year-old case lacked lateral meningoceles entirely, sharing only the dysmorphic facies, G-tube dependence, failure to thrive, and developmental delay — expanding the phenotype and cautioning that the hallmark meningoceles are not obligate (PMID: 39119451). Consistent with the multisystem picture, NOTCH3 functions as a transcriptional activator across diverse tissues.

Full Section-by-Section Report

1. Disease Information

LMS is a rare hereditary connective-tissue disorder characterized by multiple lateral spinal meningoceles, distinctive facial dysmorphism, joint/skin laxity, hypotonia, and skeletal, cardiac, and urogenital anomalies. Key identifiers: OMIM %130720; MONDO:0007537; ORPHA:2140; MeSH — indexed under "Meningocele" (no dedicated LMS descriptor); ICD-10 Q06.8 / ICD-11 LA05.Y as nearest structural codes (no LMS-specific code). Synonyms: Lehman syndrome; Lateral meningocele syndrome. The information base is a mixture of individual patient case reports/case series (dominant, given rarity) and aggregated disease-level resources (OMIM, Orphanet).

2. Etiology

Primary cause: genetic — heterozygous truncating variants in the last exon (exon 33) of NOTCH3 (F001), acting via a gain-of-function through PEST-domain loss and protein stabilization (F002). Genetic risk factors: monogenic and essentially fully explained by the NOTCH3 exon-33 variant; no human modifier loci mapped. Environmental risk factors: none identified — LMS is not known to be influenced by toxins, lifestyle, or infectious exposures; most cases arise as de novo germline events. Protective factors: none described. Gene–environment interactions: no evidence — this is a highly penetrant Mendelian disorder.

3. Phenotypes

Phenotypes span physical malformations (lateral meningoceles, dural ectasia, craniofacial dysmorphism, scoliosis), clinical signs (joint hypermobility, skin hyperextensibility, hypotonia), and functional/developmental abnormalities (feeding difficulties, developmental delay/intellectual disability, sensorineural hearing loss). See F005 and F011 for the full catalog and HPO mappings. Onset is congenital/neonatal-to-childhood; meningoceles were historically identified before age 8 (average age of identification ~4 years), though a meningocele-free case at age 8 and a first diagnosis at age 55 demonstrate wide variability in age of recognition. Severity is variable, from severe infantile presentations with failure to thrive to mild adult presentations with chronic musculoskeletal pain. Progression: meningoceles/dural ectasia can be progressive (enlarging via CSF pulsation); the syndrome overall is chronic and lifelong. Frequency: lateral meningoceles and characteristic facies are near-universal (rare exceptions); connective-tissue signs, hypotonia, and feeding difficulties are common; cardiac, renal, hearing, and biliary involvement are variable. Quality-of-life impact: substantial — chronic pain, joint instability, neurological sequelae from meningoceles (including iatrogenic nerve damage after surgery), feeding/growth problems, developmental disability. No formal EQ-5D/SF-36 data exist for this ultra-rare disease.

4. Genetic/Molecular Information

Causal gene: NOTCH3 (HGNC:7883; OMIM gene 600276), chr19p13.12. Variant types: frameshift (deletions, insertions) and nonsense variants in exon 33 — all truncating, all removing the PEST domain (F001). Representative variants: c.6461_6486del (p.G2154fsTer78); c.6692_93insC (p.P2231fsTer11); c.6247A>T (p.K2083); c.6663C>G (p.Y2221); c.6732C>A (p.Y2244); c.6723_6736del (p.E2241fsTer8); an 80-bp exon-33 deletion. Classification: pathogenic per ACMG (PVS1-type truncating in a gene with an established truncating/GoF mechanism, de novo PS2, phenotype-specific). Allele frequency: absent from population databases (gnomAD) — private, de novo variants. Origin: germline, predominantly de novo; two documented vertical transmissions. Functional consequence: gain-of-function through protein stabilization (F002). Modifier genes: none established. Epigenetic changes: none reported. Chromosomal abnormalities:* none — LMS is a single-gene disorder.

5. Environmental Information

No environmental, lifestyle, or infectious contributors are implicated. LMS is a fully genetic, de novo–predominant Mendelian disorder. (Note: lateral meningoceles as an isolated radiological finding can occur in neurofibromatosis type 1 and as sporadic lesions — e.g., PMID: 15688204, PMID: 23607071, PMID: 38755334 — but these are distinct from NOTCH3-driven LMS.)

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

  1. A de novo heterozygous truncating variant in NOTCH3 exon 33 arises in the germline (demonstrated).
  2. The truncation deletes the C-terminal PEST domain of the NOTCH3 intracellular domain (demonstrated).
  3. Loss of the PEST degron impairs proteasomal turnover of the cleaved NOTCH3 intracellular domain, stabilizing it (demonstrated via gain-of-function readouts; direct stabilization inferred and supported by analogy to Hajdu-Cheney NOTCH2).
  4. Stabilized NOTCH3 leads to enhanced and prolonged canonical Notch signaling — elevated HES1, HEY1, HEY2, HEYL (demonstrated in iPSC models).
  5. In the skeleton, this gain-of-function branch proceeds: enhanced NOTCH3 signaling in osteoblasts and osteocytes results in increased RANKL (TNFSF11) expression (demonstrated in mouse models).
  6. Elevated RANKL drives increased osteoclast differentiation and activity (demonstrated), which results in cancellous and cortical bone osteopenia and increased cortical porosity (demonstrated).
  7. In parallel developmental branches (mechanistically less resolved), NOTCH3 gain-of-function in neural crest–derived and mesenchymal lineages is inferred to lead to the meningocele/dural ectasia, craniofacial, connective-tissue, cardiac, renal, inner-ear, and biliary phenotypes. These arms are demonstrated clinically but the intervening cellular mechanism is inferred rather than experimentally mapped.

Molecular pathway: Notch signaling (KEGG hsa04330; Reactome "Signaling by NOTCH3"). Cellular processes: osteoclastogenesis, bone resorption, cell-fate specification. Protein dysfunction: loss of PEST-mediated degradation → stabilization → gain-of-function (contrast CADASIL's extracellular aggregation, F007). Key cell types (CL): osteoblast (CL:0000062), osteocyte (CL:0000137), osteoclast (CL:0000092), neural crest cell (CL:0000333, inferred), mesenchymal stem cell (CL:0000134). Key GO processes: Notch signaling pathway (GO:0007219), osteoclast differentiation (GO:0030316), positive regulation of osteoclast differentiation (GO:0045672), bone resorption (GO:0045453). Upstream vs downstream: the NOTCH3 variant and PEST loss are upstream; RANKL induction and osteoclastogenesis are downstream effectors of the bone phenotype.

NOTCH3 exon-33 truncation
│ deletes PEST domain
▼
Stabilized NOTCH3 intracellular domain ──► GAIN-OF-FUNCTION Notch signaling (↑HES1/HEY1/2/L)
│                                             │
├───────────── skeletal branch ───────────────┤
▼                                             ▼
Osteoblast/osteocyte ↑RANKL          Neural crest / mesenchymal lineages (inferred)
▼                                             ▼
↑Osteoclastogenesis                   Meningoceles, dural ectasia, facies,
▼                             connective-tissue, cardiac, renal,
Osteopenia / cortical porosity        inner-ear, biliary anomalies

7. Anatomical Structures Affected

Primary organs/systems: nervous system and meninges (spinal dura/arachnoid — lateral meningoceles, dural ectasia; UBERON:0002360 meninges, UBERON:0002240 spinal cord) and skeletal system (vertebrae with scalloping, generalized osteopenia; UBERON:0001474 bone). Secondary/variable involvement: cardiovascular (congenital heart defects; UBERON:0000948 heart), genitourinary (renal cysts; UBERON:0002113 kidney), auditory (inner ear/cochlea; UBERON:0001846), hepatobiliary (biliary anomalies; UBERON:0002394 bile duct), craniofacial skeleton and soft tissues, and skin/connective tissue (UBERON:0002097). Tissue types: connective tissue, nervous tissue (meninges), bone. Cell populations: osteoblasts, osteocytes, osteoclasts, neural crest–derived and mesenchymal cells. Subcellular: nucleus (GO:0005634 — NOTCH3 ICD acts as a transcriptional co-activator); plasma membrane (GO:0005886 — receptor); cytoplasm (site of stabilized fragment). Localization/lateralization: meningoceles are bilateral and multiple, predominantly thoracolumbar, most severe in the lower spine.

8. Temporal Development

Onset: congenital; features usually recognized in infancy or childhood. Onset pattern: chronic/insidious. Progression: chronic and lifelong; meningoceles/dural ectasia can slowly enlarge; osteopenia is progressive. Course: stable-to-progressive rather than episodic or relapsing-remitting. Critical periods: prenatal/early-childhood windows for diagnosis and neurological monitoring; surgical timing is dictated by symptomatic meningoceles. Duration: lifelong.

9. Inheritance and Population

Inheritance: autosomal dominant (F006), most cases de novo with two documented vertical transmissions. Penetrance: high/complete for the molecular phenotype, though the meningocele feature is not fully obligate (F011). Expressivity: highly variable (infantile-severe to adult-mild). Anticipation: not described. Germline mosaicism: not formally documented but plausible given de novo predominance. Founder effects/consanguinity: not applicable (de novo dominant). Carrier frequency: not applicable. Epidemiology: prevalence <1/1,000,000 (Orphanet); only a few dozen cases reported worldwide; near-balanced sex ratio (~9:7 M:F). Age distribution: diagnoses span 5 months to 55 years.

10. Diagnostics

Imaging (central): whole-spine MRI showing multiple bilateral cystic neural-foraminal masses, neural foraminal widening, dural ectasia, and vertebral scalloping; CT for bony scalloping and canal widening (F008). Genetic testing (confirmatory): targeted NOTCH3 exon-33 sequencing, or WES/WGS; CMA/karyotype are not informative (single-nucleotide/small-indel disorder). Reverse phenotyping (genetics-first) has diagnosed presymptomatic and prenatal cases. Prenatal: prenatal exome sequencing after ultrasound findings of cystic hygroma, ventriculomegaly, and facial dysmorphism (F011). Biomarkers/labs: no specific biochemical biomarker; no routine metabolomic/proteomic diagnostic. Clinical criteria: no formal consensus criteria; diagnosis is gestalt (facies + meningoceles + connective-tissue signs) plus molecular confirmation. Differential diagnosis: Hajdu-Cheney syndrome (NOTCH2), Marfan, Ehlers-Danlos (hypermobile/classic), Loeys-Dietz, arterial tortuosity syndrome, neurofibromatosis type 1 (isolated meningoceles), and Copenhagen syndrome (radiological mimic) — distinguished by the NOTCH3 exon-33 variant and full multisystem gestalt (PMID: 25821090; PMID: 40256810).

11. Outcome/Prognosis

Survival/mortality: no systematic survival data; LMS is generally not rapidly lethal, though severe infantile presentations with congenital heart defects and failure to thrive carry higher morbidity/mortality risk. Morbidity: chronic musculoskeletal pain, joint instability, neurological complications from meningoceles, developmental disability, feeding/growth impairment. Complications: neurological sequelae (including iatrogenic nerve damage after meningeal surgery — PMID: 24311540), CSF hypotension from meningoceles, Chiari I/syringomyelia/hydrocephalus/tethered cord. Recovery: neurosurgical shunting can improve symptoms and regress meningoceles (PMID: 41432782), but the syndrome is not curable. Prognostic factors: severity of meningoceles/neurological involvement, cardiac anomalies, feeding difficulties. No validated prognostic biomarkers.

12. Treatment

No FDA-approved disease-modifying therapy exists (F004, F010). Current management is supportive and neurosurgical (F008): neurosurgical repair or cyst-subarachnoid/cystoperitoneal shunting of symptomatic meningoceles; management of scoliosis, feeding difficulties (G-tube), cardiac and renal anomalies; physical/occupational therapy for hypotonia and joint instability; audiology support for hearing loss. Pharmacotherapy: none disease-specific; the RANKL-axis logic suggests antiresorptives (e.g., denosumab, an anti-RANKL antibody) could be rationally explored for osteopenia, but this is not established for LMS. Emerging/experimental (preclinical): Notch3-lowering ASOs (including allele-selective ASOs achieving 70–80% mutant-transcript knockdown) and an anti-Notch3 neutralizing antibody reverse the skeletal phenotype in mouse and iPSC models (F004, F009). Suggested NCIT terms: Antisense Oligonucleotide Therapy; Monoclonal Antibody Therapy; Surgical Procedure; Cerebrospinal Fluid Shunt. Pharmacogenomics: not applicable.

13. Prevention

No primary prevention exists for a de novo genetic disorder. Secondary prevention: early molecular diagnosis (including prenatal) enables early neurological monitoring and timely surgical intervention (F008, F011). Genetic counseling: recurrence risk is low for parents of a de novo case but 50% for an affected individual's offspring (autosomal dominant); prenatal/preimplantation testing is feasible where a familial variant is known. Tertiary prevention: surveillance for and management of neurological, cardiac, renal, and orthopedic complications. No immunization or public-health/environmental interventions apply.

14. Other Species / Natural Disease

LMS is a human disorder; no naturally occurring LMS-equivalent disease is documented in companion animals or wildlife (no OMIA equivalent). The gene is evolutionarily conserved: mouse Notch3 (NCBI Gene 18131) is orthologous to human NOTCH3. A spontaneous murine Notch3 mutation ("humpback") exists as a natural model (PMID: 33860007). No zoonotic or cross-species transmission applies (non-infectious genetic disease).

15. Model Organisms

Mammalian (mouse): the engineered Notch3^em1Ecan^ knock-in (6691TAATGA PEST truncation) recapitulates cancellous and cortical osteopenia; osteocyte-specific conditional induction of the Lehman mutation causes osteopenia in male C57BL/6J mice; the spontaneous "humpback" Notch3 mutant is a natural model (F009). Cellular/in vitro: human iPSC lines (NCRM1/NCRM5 with NOTCH3 c.6692_93insC plus isogenic controls) differentiated to neural crest, mesenchymal, and osteogenic cells demonstrate gain-of-function and enhanced osteogenesis (F002, F009). Genetic model types: knock-in, conditional (osteocyte-specific), spontaneous mutant, patient-derived iPSC. Phenotype recapitulation: strong for the skeletal/bone-loss component (enabling therapeutic proof-of-concept for ASOs and antibody); limitations: do not robustly reproduce the lateral meningoceles or full craniofacial/multisystem phenotype. Resources: MGI (Notch3 alleles), Alliance of Genome Resources.

Mechanistic Model / Interpretation

LMS is best understood as a NOTCH3 stabilization disorder. The single molecular lesion — an exon-33 truncation that removes the PEST degron — converts NOTCH3 into a longer-lived, hyperactive transcriptional co-activator. The clearest, experimentally validated downstream consequence is in bone: gain-of-function NOTCH3 in osteoblasts and osteocytes upregulates RANKL, tipping the RANKL/OPG balance toward osteoclast activation and net resorption, producing the osteopenia captured in mouse models. The remaining multisystem features (meningoceles, dural ectasia, craniofacial dysmorphism, connective-tissue laxity, cardiac/renal/inner-ear/biliary anomalies) are clinically well-documented but mechanistically inferred to arise from NOTCH3 gain-of-function in neural-crest and mesenchymal lineages during development — a gap current models do not fully bridge.

The disease sits within an instructive NOTCH3 allelic and paralogous framework:

Disorder Gene Variant class Domain Mechanism Core phenotype
LMS (Lehman) NOTCH3 Truncating (exon 33) Intracellular PEST Gain-of-function (stabilization) Lateral meningoceles, osteopenia, facies
CADASIL NOTCH3 Cysteine-altering missense Extracellular EGF repeats Ectodomain aggregation (GOM) Cerebral small-vessel disease, stroke, dementia
Biallelic LoF NOTCH3 NOTCH3 Biallelic loss-of-function — Loss-of-function Neurodevelopmental disorder, spasticity, childhood stroke
Hajdu-Cheney NOTCH2 Truncating (last exon) Intracellular PEST Gain-of-function Acro-osteolysis, osteoporosis (paralog analogue)

The parallel between LMS (NOTCH3) and Hajdu-Cheney syndrome (NOTCH2) — both caused by last-exon PEST-truncating gain-of-function variants and both producing bone loss — is a powerful cross-validation of the mechanism and explains why the RANKL-osteoclast axis is central to both.

Evidence Base

PMID Contribution Evidence type
25394726 Landmark gene discovery: exon-33 truncating NOTCH3 variants; facial and meningocele phenotype Human clinical/genetic
35760307 PEST deletion → gain-of-function; osteocyte-specific mouse osteopenia Model organism
39752389 iPSC gain-of-function (↑HES1/HEY targets); ASO targeting In vitro (human iPSC)
33519922 RANKL-mediated osteoclastogenesis mechanism; "no effective therapies" Review/model organism
35536858 Notch3^em1Ecan^ model; in vivo ASO knockdown and osteopenia rescue Model organism
37704069 ASO amelioration of cortical osteopenia; drug-target rationale Model organism
31188489 Anti-Notch3 antibody reverses skeletal phenotype Model organism
32526405 NOTCH paralog specificity; NOTCH3→RANKL→osteoclast axis Review/mechanistic
31838470 Neurosurgical review; case count and sex ratio Human clinical review
32141180 Phenotype expansion (inner ear, multicystic kidney) Human clinical
40771185 First prenatal molecular diagnosis; biliary anomalies Human clinical
39119451 LMS without lateral meningoceles — phenotype expansion Human clinical
40145673 CADASIL mechanism (extracellular cysteine-altering) — contrast Review
34172679 Co-occurring CADASIL/Lehman variants; craniosynostosis Human clinical
39191170 Biallelic NOTCH3 genotype-phenotype spectrum Human clinical
33042242 Diagnostic MRI appearance (infantile Lehman) Human clinical
41432782 Cyst-subarachnoid shunt with meningocele regression Human clinical
34121137 Genetics-first (reverse phenotyping) diagnosis in infant Human clinical
33860007 "Humpback" natural murine Notch3 mutant Model organism
40256810 Novel variant; radiological mimicry (Copenhagen syndrome) Human clinical
26754023 14th case; 80-bp exon-33 deletion; cardiac/feeding phenotype Human clinical
24311540 Late diagnosis at 55; vertical transmission; DDx overlap Human clinical
25821090 LMS within connective-tissue-disorder differential Review
31901894 · 35409031 · 35223989 CADASIL pathobiology (fragmentation/aggregation) — mechanistic contrast In vitro/review

Limitations and Knowledge Gaps

  1. Ultra-rarity limits epidemiology. With only a few dozen reported cases, there are no reliable prevalence/incidence, survival, or natural-history statistics; sex ratio and age-of-onset estimates derive from tiny case series.
  2. Mechanistic gap for non-skeletal features. The RANKL-osteoclast mechanism is firmly established for bone, but the cellular pathways linking NOTCH3 gain-of-function to meningoceles, dural ectasia, craniofacial dysmorphism, and cardiac/renal/inner-ear/biliary anomalies remain inferred, not demonstrated.
  3. Model-organism incompleteness. Mouse and iPSC models recapitulate the skeletal phenotype well but do not reproduce the hallmark meningoceles, limiting preclinical testing of therapies for the most clinically significant feature.
  4. No human therapeutic data. ASO and antibody efficacy is entirely preclinical and demonstrated primarily in male mice; sex-specific effects, meningocele response, and human safety are unknown.
  5. Phenotype still expanding. Newly reported organ involvements (biliary) and atypical presentations (no meningoceles) indicate the full phenotypic spectrum and its frequencies are not yet defined.
  6. No validated diagnostic criteria or biomarkers, and no genotype-phenotype correlation study large enough to relate specific exon-33 variants to severity.

Proposed Follow-up Experiments / Actions

  1. Develop a meningocele-capturing model — conditional NOTCH3-Lehman induction in neural-crest/meningeal lineages (e.g., Wnt1-Cre, PDGFRβ) to test whether dural ectasia and meningoceles can be reproduced and mechanistically dissected.
  2. Test RANKL-axis pharmacology — evaluate denosumab (anti-RANKL) or bisphosphonates in LMS mouse models and consider registry monitoring of bone outcomes in patients, given the well-defined RANKL mechanism.
  3. Advance allele-selective ASOs toward IND — extend the 70–80% mutant-knockdown data to systemic and CNS delivery, female cohorts, and long-term safety, with meningocele and craniofacial endpoints where possible.
  4. Establish an international LMS registry and natural-history study — pool cases to define phenotype frequencies, age-of-onset distributions, complication rates, surgical outcomes, and genotype-phenotype correlations.
  5. Define a multi-organ surveillance protocol — recommended cardiac, renal, hepatobiliary, audiologic, and spinal imaging screening intervals for molecularly confirmed patients, informed by the expanding phenotype.
  6. Deep molecular profiling of iPSC-derived neural crest/mesenchyme — transcriptomic and proteomic characterization to identify effectors bridging NOTCH3 gain-of-function to connective-tissue and craniofacial phenotypes, and to nominate additional druggable nodes.

Report compiled from a 5-iteration autonomous investigation: 11 confirmed findings and 30 reviewed papers. Evidence types are distinguished as human clinical/genetic, model organism, in vitro (human iPSC), and review/mechanistic throughout.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 29
Resolved 29
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 29
On topic 19
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 41
Resolved 39
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 2
Terms named correctly 0
Terms named as a different term 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:

  • GO:0005634 (1 mention) - the report calls it "NOTCH3 ICD acts as a transcriptional co-activator"; GO calls it nucleus
  • GO:0005886 (1 mention) - the report calls it "receptor"; GO calls it plasma membrane

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.