Phenotypic Divergence in Siblings with the Same Genotype: Diffuse Dermal Melanocytosis in Infantile-Onset...

Galactosialidosis (GS) is an ultra-rare autosomal recessive lysosomal storage disorder caused by pathogenic variants in the CTSA gene. The resulting deficiency of protective protein/cathepsin A leads to reduced β-galactosidase and α-neuraminidase activity, causing multisystem involvement. While typical features include dysmorphic facies, organomegaly, skeletal dysplasia, and neurological impairment, dermatologic manifestations remain poorly characterized.

We report a 9-month-old girl presenting with hepatosplenomegaly and diffuse dermal melanocytosis. Her history included nonimmune hydrops fetalis, congenital cataract, developmental delay, and recurrent respiratory infections. Clinical and radiological evaluation revealed coarse facial features, dysostosis multiplex, and periventricular white matter changes. Enzyme assay demonstrated markedly reduced β-galactosidase activity. Genetic testing identified a homozygous CTSA c.359T>C (p.Ile120Thr) variant, classified as likely pathogenic. Family screening revealed her 10-year-old brother carried the same variant in homozygosity. He exhibited milder features, including developmental delay, hearing loss, and skeletal abnormalities without cutaneous involvement or organomegaly. Enzymatic deficiency was confirmed in both siblings.

This report highlights diffuse dermal melanocytosis as a possible novel cutaneous marker of GS, potentially aiding early recognition. It also illustrates intrafamilial phenotypic variability despite identical genotypes. Our findings underscore the importance of dermatologic clues in the diagnostic workup of lysosomal storage disorders and advocate for family-based genetic screening to identify asymptomatic or mildly affected individuals.