Resolution of the Diagnostic Odyssey in a Familial Form of Hackmann-Di Donato Syndrome With Structural Brain...

Hackmann-Di Donato syndrome is an X-linked neurodevelopmental disorder characterized by intellectual disability, developmental delay, dysmorphic features, marfanoid habitus, and hypotonia. Only 12 individuals harboring pathogenic NKAP variants have been reported in the literature. Among these cases, evidence of familial transmission has been documented in five individuals from three unrelated families. Here, we present a further familial case of Hackmann-Di Donato syndrome involving an inherited pathogenic NKAP variant, identified through trio exome sequencing. We also review and compare our patient with the reported cases in the literature and describe the oldest known patient with a pathogenic NKAP variant. Unlike previously reported cases, our male index patient showed no cardiac malformation. Brain MRI revealed stable white matter lesions. Neuroradiological abnormalities may be part of the clinical spectrum, but they have not been systematically assessed in reported cases.