TMX2-Related Neurodevelopmental Disorder With Bilateral Polymicrogyria and Syndactyly: A Case Report From Morocco

Thioredoxin-related transmembrane protein 2 (TMX2)-related neurodevelopmental disorder (OMIM #618730) is an exceedingly rare autosomal recessive condition caused by biallelic pathogenic variants in TMX2, a gene encoding an endoplasmic reticulum (ER)-resident oxidoreductase involved in neuronal survival and cortical development. The condition is characterized by severe intellectual disability, microcephaly, spasticity, epilepsy, and cortical malformations, primarily polymicrogyria. We report a 13-month-old Moroccan male infant born to second-cousin consanguineous parents, presenting with severe global developmental delay, profound axial hypotonia, absent head control, and progressive microcephaly (head circumference 41 cm, < -3 standard deviation (SD)). Epilepsy was diagnosed at seven months of age and managed with valproic acid. Clinical examination revealed characteristic dysmorphic features, including microcephaly, a sloping forehead, bilateral strabismus, retrognathism, low-set ears and hairline, and bilateral second-third toe syndactyly - a feature not previously described in association with TMX2-related disorder. Brain MRI demonstrated bilateral frontoparietal polymicrogyria. Electroencephalography showed right hemispheric dysfunction with focal epileptic activity. Whole-exome sequencing identified a homozygous pathogenic missense variant in TMX2 (NM_015959.4:c.614G>A; p.Arg205Gln), classified as pathogenic in ClinVar (VCV000804370), confirming the diagnosis. This case expands the phenotypic spectrum of TMX2-related disorder by documenting bilateral second-third toe syndactyly and highlights the diagnostic value of whole-exome sequencing in consanguineous families presenting with cortical malformations and severe neurodevelopmental delay. Early molecular diagnosis is essential for appropriate genetic counseling and multidisciplinary management.