The H Syndrome: Molecular Diagnosis Using Next-Generation Sequencing

ABSTRACT Objective: H syndrome is a monogenic systemic inherited form of histiocytosis, with characteristic cutaneous findings accompanying systemic manifestations. The major common endocrine manifestations include hypogonadism, short stature, and diabetes mellitus with characteristic genodermatosis and lead to the diagnosis. Here, we report a rare case of H-syndrome, an autosomal recessive non-autoimmune disorder in a 19-year-old woman who presented with short stature, diabetes mellitus, and hypogonadism associated with characteristic hyperpigmentation and hypertrichosis. The molecular diagnosis was established utilizing next-generation sequencing (NGS) technology. Methods: We describe the clinical spectrum of H syndrome with endocrine and non endocrine multisystem involvement. The solute carrier family 29 (nucleoside transporters), member 3 (SLC29A3) gene was screened for molecular diagnosis utilizing NGS based mutational analysis. Results: H syndrome is caused by a mutation in the SLC29A3 gene, which encodes human equilibrative nucleoside transporter 3. A 19-year-old woman was diagnosed to have diabetes mellitus at the age of 6 years. Her clinical phenotype included short stature, hypogonadotropic hypogonadism, hearing loss, hypothyroidism, heart involvement, and hyperpigmentation with hypertrichosis. Her erythrocyte sedimentation rate and C-reactive protein levels were elevated. A clinical diagnosis of H syndrome was considered, and utilizing an NGS-based approach, we identified a reported homozygous missense mutation (c.400C>T, p.Arg134Cys) in the SLC29A3 gene, which was confirmed by Sanger sequencing. Conclusion: The characteristic pigmentary hypertrichosis and elevated inflammatory markers differentiate H syndrome from mitochondrial disorders and Turners syndrome with similar endocrine manifestations. With its multiplexing option, NGS offers a rapid and robust platform for molecular diagnosis at an affordable cost. Abbreviations: hENT3 = human equilibrative nucleoside transporter 3 NGS = next-generation sequencing SLC29A3 = solute carrier family 29 (nucleoside transporter), member 3