Supplementary Material for: Phenotypic Divergence in Siblings with the Same Genotype: Diffuse Dermal Melanocytosis in Infantile-Onset Galactosialidosis

Background: 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.
Case Presentation: We report a 9-month-old girl presenting with hepatosplenomegaly and diffuse dermal melanocytosis. Her history included non-immune hydrops fetalis, congenital cataract, developmental delay, and recurrent respiratory infections. Clinical and radiologic 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.
Conclusion: This report highlights diffuse dermal melanocytosis as a possible novel cutaneous marker of galactosialidosis, 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.

背景：半乳糖唾液酸贮积症（Galactosialidosis, GS）是一种超罕见常染色体隐性溶酶体贮积症，由CTSA基因致病性变异所致。该基因突变导致保护性蛋白/组织蛋白酶A（protective protein/cathepsin A）缺乏，进而引起β-半乳糖苷酶与α-神经氨酸酶活性降低，最终引发多系统受累。该病典型临床表现包括面容粗陋、器官肿大、骨骼发育不良及神经功能损害，但皮肤表现的相关研究仍较为匮乏。病例报告：本文报告1例9月龄女婴，以肝脾肿大及弥漫性皮肤黑素沉着症为首发表现。患儿既往史包括非免疫性胎儿水肿、先天性白内障、发育迟缓及反复呼吸道感染。临床及影像学评估显示其存在面容粗陋、多发性骨发育异常及脑室周围白质改变。酶学检测提示β-半乳糖苷酶活性显著降低。基因检测发现其携带纯合子CTSA c.359T>C（p.Ile120Thr）变异，该变异被归类为可能致病性变异。家系筛查显示，其10岁兄长亦为该变异的纯合携带者。该兄长临床表现较轻，仅存在发育迟缓、听力损失及骨骼异常，无皮肤受累及器官肿大表现。两兄妹均经酶学检测证实存在酶学缺陷。结论：本研究首次报道弥漫性皮肤黑素沉着症可作为半乳糖唾液酸贮积症的新型皮肤标志物，或有助于该病的早期识别。同时，本病例亦提示，即便基因型完全一致，家族内仍可存在表型异质性。本研究结果强调了皮肤线索在溶酶体贮积症诊断流程中的重要性，并主张开展家系式基因筛查以识别无症状或轻症患者。