Familial isolated 17,20-lyase deficiency in three siblings caused by a CYP17A1 mutation

Summary: 17α-hydroxylase/17,20-lyase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia, inherited in an autosomal recessive manner. The CYP17A1 gene on chromosome 10 encodes cytochrome P450c17, a single bifunctional enzyme with both 17α-hydroxylase activity (essential for cortisol synthesis) and 17,20-lyase activity (essential for sex steroid synthesis). Mutations in CYP17A1 can impair either or both activities, resulting in a clinical spectrum ranging from combined 17α-hydroxylase/17,20-lyase deficiency to isolated 17,20-lyase deficiency. We report a case of three siblings, all raised as females, who presented with bilateral inguinal swellings at variable ages in early childhood. The karyotype was 46,XY in all three siblings, and genetic testing confirmed a homozygous CYP17A1 mutation. Initially labeled as combined 17α-hydroxylase/17,20-lyase deficiency, the clinical course and preserved cortisol levels favored isolated 17,20-lyase deficiency, a rarer variant within the same enzyme spectrum. All three children subsequently underwent gonadectomy, were reared as females, and were planned for estrogen replacement therapy at puberty. This case was particularly challenging as all three siblings were affected, causing significant emotional and psychosocial distress for the parents. A multidisciplinary approach was adopted, and gender of rearing was assigned early with great sensitivity and ethical caution, in alignment with our cultural context, where parents are the primary decision-makers. Learning points: The clinical course may evolve over time, refining the initial diagnosis, as seen in our patients, where follow-up biochemical evaluation clarified the presence of isolated 17,20-lyase deficiency despite an initial genetic finding consistent with combined 17α-hydroxylase/17,20-lyase deficiency. Consanguinity significantly increases the recurrence risk of rare autosomal recessive disorders, as demonstrated in this family; this highlights the crucial role of early genetic testing, familial screening, and genetic counseling in high-risk populations. Management of disorders of sex development (DSD) within individual cultural settings requires sensitivity, ethical caution, and multidisciplinary coordination tailored to the cultural practices ensuring that decisions around sex of rearing prioritize both medical appropriateness and long-term psychosocial well-being.