ESAM Loss of Function and Congenital Neurovascular Injury: Strengthening the Case for a Recognizable Clinical Phenotype.

ESAM LOF deficiency: disruption of endothelial junctional cohesion and transcytotic transport

Two unrelated Turkish families with ESAM loss-of-function haploinsufficiency carry distinct variants (c.451+5G>C and c.605T>G; p.Leu202Ter). Affected individuals present a characteristic congenital neurovascular phenotype including intrauterine/perinatal intracranial hemorrhage, ventriculomegaly, microcephaly, spastic quadriparesis, and congenital cataracts. The mechanism involves disruption of endothelial junctional cohesion and transcytotic transport, establishing ESAM deficiency as a congenital tight-junctionopathy.

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The convergence of two independent families with severe congenital neurovascular phenotype and distinct ESAM LOF variants constitutes convincing evidence of causality. In practice, this phenotype (congenital intracranial hemorrhage + cataracts + microcephaly) should prompt exome/genome analysis now including ESAM among candidate genes.

Clinical impact: 2/3 · Evidence quality: 1/3 · Novelty: 2/2 · Sample size: 0/1 · Journal quality: 0/1 → Total: 5/10