Expansion of the phenotype of lateral meningocele syndrome

Cappuccio, Gerarda; Apuzzo, Diletta; Alagia, Marianna; Torella, Annalaura; Pinelli, Michele; Bazzoli, Franco; Corrado, Bruno; Giudice, Ennio Del; D’Amico, Alessandra; Nigro, Vincenzo; Tudp,; Brunetti‐Pierri, Nicola

doi:10.1002/ajmg.a.61536

Cited by 8 publications

(3 citation statements)

References 9 publications

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“…This case expands the phenotype for LMS, as all previously reported patients with molecularly confirmed cases had multiple lateral meningoceles before age 8 years, with the average age of identification being approximately 4 years [1,[3][4][5][6][7][8][9][10][11]. However, other expected characteristics of LMS are present in this patient (Fig.…”

Section: Discussionsupporting

confidence: 75%

A Case of Lateral Meningocele Syndrome without Lateral Meningoceles

Rubadeux,

Owens,

Shillington

2024

Mol Syndromol

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Introduction: Lateral meningocele syndrome (LMS), also known as Lehman syndrome, is caused by pathogenic variants in exon 33 of NOTCH3. Variants in this final exon of NOTCH3 interrupt the regulatory PEST domain, leading to enhanced NOTCH3 signaling due to prolonged cellular half-life. Individuals with LMS are expected to have multiple lateral meningoceles, developmental delay, neonatal hypotonia, dysmorphic facial features, and feeding difficulties. Case Presentation: We report an 8-year-old male with a history of autism, feeding difficulties, developmental delay, severe intellectual disability, and self-injurious behavior. Genetic testing revealed a NOTCH3 c.6663C>G (p.Y2221*) pathogenic variant in exon 33, consistent with a diagnosis of LMS. A follow-up spine MRI showed a ventral sacral extradural arachnoid cyst but no lateral meningoceles. This individual’s most recent exam noted multiple dysmorphic features including prominent metopic ridging, broad forehead, downslanting palpebral fissures, high-arched palate, long narrow philtrum, mild pectus excavatum, and wide-based gait. Discussion/Conclusion: This individual shares the dysmorphic facial features, ongoing G-tube dependence, failure to thrive, and developmental delay seen in other individuals with LMS. 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.

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Section: Discussionsupporting

confidence: 75%

A Case of Lateral Meningocele Syndrome without Lateral Meningoceles

Rubadeux,

Owens,

Shillington

2024

Mol Syndromol

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“…LMS, an extremely rare condition, was described for the first time in 1977 and is also known as Lehman syndrome [ 112 ]. Only 14 individuals with LMS have been published in the literature [ 113 ].…”

Section: Pathologic Mutations In Notch Signalingmentioning

confidence: 99%

Relevance of Notch Signaling for Bone Metabolism and Regeneration

Ballhause

Jiang

Baranowsky

et al. 2021

IJMS

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Notch1-4 receptors and their signaling pathways are expressed in almost all organ systems and play a pivotal role in cell fate decision by coordinating cell proliferation, differentiation and apoptosis. Differential expression and activation of Notch signaling pathways has been observed in a variety of organs and tissues under physiological and pathological conditions. Bone tissue represents a dynamic system, which is constantly remodeled throughout life. In bone, Notch receptors have been shown to control remodeling and regeneration. Numerous functions have been assigned to Notch receptors and ligands, including osteoblast differentiation and matrix mineralization, osteoclast recruitment and cell fusion and osteoblast/osteoclast progenitor cell proliferation. The expression and function of Notch1-4 in the skeleton are distinct and closely depend on the temporal expression at different differentiation stages. This review addresses the current knowledge on Notch signaling in adult bone with emphasis on metabolism, bone regeneration and degenerative skeletal disorders, as well as congenital disorders associated with mutant Notch genes. Moreover, the crosstalk between Notch signaling and other important pathways involved in bone turnover, including Wnt/β-catenin, BMP and RANKL/OPG, are outlined.

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“…Pseudo clubbing of the fingers, but not acroosteolysis, is found. Cardiac valve abnormalities can be present and inner ear abnormalities and cystic kidneys were reported in one case (Cappuccio et al, 2020 ). Approximately 20–30 individuals with LMS have been reported.…”

Section: Clinical Aspects Of Lateral Meningocele Syndrome (Lms)mentioning

confidence: 99%

The Skeleton of Lateral Meningocele Syndrome

Canalis

2021

Front. Genet.

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Notch (Notch1 through 4) are transmembrane receptors that determine cell differentiation and function, and are activated following interactions with ligands of the Jagged and Delta-like families. Notch has been established as a signaling pathway that plays a critical role in the differentiation and function of cells of the osteoblast and osteoclast lineages as well as in skeletal development and bone remodeling. Pathogenic variants of Notch receptors and their ligands are associated with a variety of genetic disorders presenting with significant craniofacial and skeletal manifestations. Lateral Meningocele Syndrome (LMS) is a rare genetic disorder characterized by neurological manifestations, meningoceles, skeletal developmental abnormalities and bone loss. LMS is associated with NOTCH3 gain-of-function pathogenic variants. 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. There are no effective therapies for LMS. Antisense oligonucleotides targeting Notch3 and antibodies that prevent the activation of NOTCH3 are being tested in preclinical models of the disease. In conclusion, LMS is a serious genetic disorder associated with NOTCH3 pathogenic variants. Novel experimental models have offered insight on mechanisms responsible and ways to correct the disease.

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Expansion of the phenotype of lateral meningocele syndrome

Cited by 8 publications

References 9 publications

A Case of Lateral Meningocele Syndrome without Lateral Meningoceles

A Case of Lateral Meningocele Syndrome without Lateral Meningoceles

Relevance of Notch Signaling for Bone Metabolism and Regeneration

The Skeleton of Lateral Meningocele Syndrome

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