GLMN and Glomuvenous Malformation

GLMN (HGNC:14373) is robustly associated with glomuvenous malformation (MONDO_0007672). Multiple case reports and family studies have documented autosomal dominant inheritance with a spectrum of vascular skin lesions. Early reports describe isolated cases in children with complex clinical presentations (PMID:19250411), while subsequent studies have confirmed a consistent link between GLMN mutations and the development of GVM.

Several independent case reports have identified truncating mutations in GLMN that segregate with the disease. Notably, the variant c.108C>A (p.Cys36Ter) has been reported in a familial context, where affected individuals across generations displayed characteristic lesions. Additional affected relatives were noted in these familial cases (PMID:23303036), supporting the observed segregation pattern.

Multi-patient genetic studies further corroborate the association between GLMN and glomuvenous malformation. Investigations have reported mutations in over 43 families, with one large study comprising 162 families documenting a diverse spectrum of variants including recurrent founder mutations (PMID:15689436; PMID:23801931). The genetic evidence is bolstered by the demonstration of locus homogeneity, where nearly all GVM families exhibited a mutation in GLMN.

Functional studies lend additional support to the pathogenic role of GLMN in this disorder. In vitro assays and cellular models have shown that loss-of-function variants lead to disruptions in vascular smooth muscle cell differentiation and aberrant mTOR signaling. Such experiments, including overexpression and knockdown studies, provide mechanistic insights that align well with the clinical phenotype (PMID:31793416; PMID:38489583).

Collectively, the convergent lines of genetic and experimental evidence establish a strong causal relationship between GLMN mutations and glomuvenous malformation. The consistency of the reported variant spectrum, the robust segregation in multiple families, and the supportive functional data render this gene-disease association highly relevant for diagnostic decision‑making and clinical management.

Key take‑home: Comprehensive GLMN genetic analysis is critical for confirming the diagnosis of familial glomuvenous malformation and guiding patient care.

References

• Pediatric Dermatology • 2009 • Glomuvenous malformation in a boy with transposition of the great vessels: a case report and review of literature PMID:19250411
• Journal of cutaneous pathology • 2014 • Glomuvenous malformations with smooth muscle and eccrine glands: unusual histopathologic features in a familial setting PMID:24345188
• Romanian Journal of Morphology and Embryology • 2012 • Multiple disseminated glomuvenous malformations: do we know enough? PMID:23303036
• Journal of Medical Genetics • 2005 • Four common glomulin mutations cause two thirds of glomuvenous malformations PMID:15689436
• Molecular Syndromology • 2013 • Genotypes and phenotypes of 162 families with a glomulin mutation PMID:23801931
• Combinatorial Chemistry & High Throughput Screening • 2019 • Rare Germline GLMN Variants Identified from Blue Rubber Bleb Nevus Syndrome Might Impact mTOR Signaling PMID:31793416
• The British Journal of Dermatology • 2024 • Loss-of-function variants in GLMN are associated with generalized skin hyperpigmentation with or without glomuvenous malformation PMID:38489583

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