ADAMTS2 – Ehlers-Danlos syndrome dermatosparaxis type

Ehlers-Danlos syndrome dermatosparaxis type is a rare autosomal recessive connective tissue disorder caused by deficient procollagen I N-proteinase activity. To date, seven unrelated human patients have been reported, each presenting in infancy with extreme skin fragility, easy bruising, large fontanelles, blue sclerae, puffy eyelids, micrognathia, umbilical hernia, short fingers, and progressive joint hypermobility ([PMID:15389701]). A homozygous truncating variant, c.2384G>A (p.Trp795Ter), in ADAMTS2 has been identified in affected individuals and segregates with disease in familial cases ([PMID:15389701]). The clinical phenotype is highly consistent across unrelated patients, and biochemical analyses demonstrate markedly reduced procollagen I N-proteinase activity in patient-derived fibroblasts, confirming loss of function as the pathogenic mechanism ([PMID:15389701]). No conflicting reports have been described, and animal models lacking Adamts2 replicate key connective tissue defects, supporting the relevance of haploinsufficiency and loss-of-function.

Key Take-home: Biallelic truncating variants in ADAMTS2 cause dermatosparaxis Ehlers-Danlos syndrome via loss of procollagen I N-proteinase activity, enabling definitive molecular diagnosis and carrier testing.

References

• American Journal of Medical Genetics. Part A • 2004 • The natural history, including orofacial features of three patients with Ehlers-Danlos syndrome, dermatosparaxis type (EDS type VIIC). PMID:15389701

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