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

This schematic illustrates the genetic, molecular, and clinical consequences of ESAM loss-of-function variants identified in two unrelated Turkish families. Family 1 harbors a splice-site variant (c.451 + 5G>C) predicted to cause aberrant splicing between exons 3 and 4, leading to defective mRNA processing and loss of functional ESAM protein. Family 2 carries a nonsense variant (c.605 T>G; p.Leu202Ter) that introduces a premature stop codon within the second immunoglobulin-like domain, resulting in a truncated protein and expected nonsense-mediated mRNA decay (NMD). Both variants abolish ESAM's membrane anchoring and disrupt endothelial junctional cohesion. Clinically, affected individuals present with a distinct neurovascular phenotype characterized by intrauterine or perinatal intracranial hemorrhage, ventriculomegaly, microcephaly, spastic quadriparesis, and congenital cataracts. The lower panel summarizes the pathophysiological cascade: (1) hemorrhagic stroke resulting from vascular fragility, (2) blood-brain barrier (BBB) disruption due to tight junction dysfunction and increased transcytosis, and (3) impaired vascular network formation caused by defective endothelial tubulogenesis. Collectively, these findings establish ESAM deficiency as a congenital tight-junctionopathy linking molecular endothelial defects to severe neurodevelopmental impairment.