NOTCH3 – Lateral Meningocele Syndrome

Lateral meningocele syndrome (LMS), or Lehman syndrome, is a rare connective tissue disorder characterized by multiple lateral spinal meningoceles, craniofacial dysmorphism, joint hypermobility, hypotonia, and anomalies of the skeletal, cardiac, and genitourinary systems. Pathogenic heterozygous truncating mutations in the terminal exon of NOTCH3 have been firmly implicated in LMS.

Initial exome sequencing in six unrelated LMS patients identified de novo truncating NOTCH3 variants clustering in exon 33 (PMID:25394726), and subsequent reports described four additional de novo probands: one with an 80 bp deletion in exon 33 (PMID:26754023), one with a novel frameshift loss-of-function variant (PMID:32141180), one diagnosed by early genomic analysis in infancy (PMID:34121137), and one without lateral meningoceles but carrying a PEST domain stop codon (PMID:39119451).

All ten probands harbored heterozygous de novo LoF variants that escape nonsense-mediated decay, consistent with an autosomal dominant, gain-of-function mechanism. No multiplex family segregation has been observed, underscoring the de novo nature of LMS.

The prototypical variant c.6663C>G (p.Tyr2221Ter) truncates the PEST domain, impairing NOTCH3 degradation, prolonging receptor half-life, and enhancing downstream signaling in cell models, thereby recapitulating key LMS features (PMID:39119451).

Phenotypic spectrum includes skeletal anomalies (HP:0000924), genitourinary malformations (HP:0000119), congenital heart defects (HP:0001627), multiple renal cysts (HP:0005562), skin hyperextensibility (HP:0000974), feeding difficulties (HP:0011968), and developmental delay. MRI surveillance for dural ectasia is recommended even in presymptomatic cases.

Early molecular diagnosis of NOTCH3-associated LMS informs neurosurgical planning, guides monitoring of systemic manifestations, and enables accurate genetic counseling.

References

• American journal of medical genetics. Part A • 2015 • Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome. PMID:25394726
• American journal of medical genetics. Part A • 2016 • Lateral meningocele (Lehman) syndrome: A child with a novel NOTCH3 mutation. PMID:26754023
• American journal of medical genetics. Part A • 2020 • Expansion of the phenotype of lateral meningocele syndrome. PMID:32141180
• Child's nervous system : ChNS • 2022 • Early diagnosis of lateral meningocele syndrome in an infant without neurological symptoms based on genomic analysis. PMID:34121137
• Molecular syndromology • 2024 • A Case of Lateral Meningocele Syndrome without Lateral Meningoceles. PMID:39119451

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