Late diagnosis of 3β-Hydroxysteroid dehydrogenase deficiency: the pivotal role of gas chromatography-mass spectrometry urinary steroid metabolome analysis and a novel homozygous nonsense mutation in the gene.

Objectives: 3β-Hydroxysteroid dehydrogenase (3β-HSD) deficiency is a rare type of congenital adrenal hyperplasia caused by recessive loss-of-function mutations in gene.

Case Presentation: We report an 8.5-year-old, 46XY, Roma boy with advanced adrenarche signs born to consanguineous parents. He was born at term with ambiguous genitalia. At 15 days of age, he underwent replacement therapy with hydrocortisone and fludrocortisone due to a salt wasting (SW) crisis and adrenal insufficiency. At 3.5 years, he was admitted again with SW crisis attributed to the low - unadjusted to body surface area - hydrocortisone dose and presented with bilateral gynecomastia and adrenarche. At 8.5 years, his bone age was four years more advanced than his chronological age and he was prepubertal, with very high testosterone levels. Gas chromatography-mass spectrometry (GC-MS) urinary steroid metabolome analysis revealed the typical steroid metabolic fingerprint of 3β-HSD deficiency. Sequencing of the gene identified in homozygosity the novel p.Lys36Ter nonsense mutation. Furthermore, this patient was found to be heterozygous for p.Val281Leu in the gene. Both parents were identified as carriers of the p.Lys36Ter in .

Conclusions: A novel nonsense p.Lys36Ter mutation in was identified in a male patient with hypospadias. 3β-HSD deficiency due to mutations in the gene is extremely rare and the finding of a patient with this rare type of disorders of sex development (DSD) is one of the very few reported to date. The complexity of such diseases requires a multidisciplinary team approach regarding the diagnosis and follow-up.