Phenotypic Refinement of ESAM-Related Tight-Junctionopathy: Novel Genetic and Ocular Findings and Literature Review

Endothelial cell-selective adhesion molecule (ESAM) is a tight junction protein essential for blood-brain barrier integrity and angiogenesis. Bi-allelic loss-of-function variants in ESAM cause NEDIHSS ("Neurodevelopmental disorder with intracranial hemorrhage, seizures, and spasticity"), a neurodevelopmental/neurovascular disorder with antenatal/neonatal onset, characterized by global developmental delay/intellectual disability (GDD/ID), epilepsy, spasticity, ventriculomegaly, and intracranial hemorrhages. Ocular involvement, particularly retinal vascular anomalies, has been variably reported.

A multidisciplinary team of pediatric neurologists, ophthalmologists, and clinical geneticists evaluated the proband through clinical assessment, neuro/ocular imaging, and whole-exome sequencing.

We describe a 3-year-old male from consanguineous Albanian parents carrying a novel homozygous splice-site ESAM variant (c.70+1G>T). He presented with GDD, seizures, and brain imaging abnormalities consistent with NEDIHSS. Remarkably, bilateral optic nerve hypoplasia, esotropia, retinal detachment, absent electroretinogram response, and structural eye anomalies, including left eyeball hypoplasia and iris displacement, were observed. Review of our and previous cases indicates that 45% (10/22) of NEDIHSS individuals present ocular manifestations, mainly retinal vascular defects, reinforcing the emerging role of ESAM in retinal endothelial integrity.

This case broadens the mutational and clinical spectrum of ESAM-related disease, underscores the need for detailed ocular evaluations in NEDIHSS, and supports inclusion of retinal anomalies within its core phenotype.