Delayed puberty from partial 17-alpha hydroxylase enzyme deficiency

An 18-year-old daughter of unrelated Indian parents was referred for further endocrine assessment of primary amenorrhoea and pubertal delay. Early growth had been unremarkable with height on the 50th percentile, BMI 18 kg/m2. Breast development as well as axillary and pubic hair had begun 3 years earlier but progressed only to Tanner Stage II. She was found to have normal external genitalia and vaginal appearances.*Normal reference ranges for age, weight and Tanner Stage II.Cortisol and metabolites were reduced while intermediate mineralocorticoid precursors proximal to 17α hydroxylase action were increased, consistent with 17α hydroxylase enzyme deficiency. Whole gene sequencing of CYP17A1 demonstrated c.160_162delTTC (p.Phe54del) homozygous mutation.On confirmation of the diagnosis, her glucocorticoid supplements were modified to maintain diurnal ACTH suppression using dexamethasone 0.25 mg pre-bed and hydrocortisone 5 mg on waking. Her blood pressure fell further to 90/60 and both serum progesterone and ACTH also fell appropriately. Weekly percutaneous oestradiol was added to advance puberty. Additional radiology showed epiphyseal closure but osteopenia with a t score of -2.6 prior to beginning estradiol replacement.Figure 1. Illustration of the measured hormones decreased or increased in relation to the partial enzyme deficiencyCongenital adrenal hyperplasia due to 17α hydroxylase deficiency is a rare form of congenital adrenal hyperplasia with less than 200 cases reported and approximately 50 different mutations of the CYP17A gene identified.1 Partial CYP17A1 deficiency associated with the homozygous phenylalanine 53 or 54 deletion was first described by Yanese et al2 who showed <37% wild type 17α hydroxylase activity and < 8% 17,20 lyase activity in a cell expression system.Gonadotrophin levels were normal. One 46XY phenotypic male had hypospadias and cryptorchidism. Hypospadias or microphallus has been reported in a further two phenotypic 46XY males due to partial loss of function mutation at the same site (p.Phe54del) in CYP17.4Overt cortisol deficiency and adrenal crises are rare because the increased corticosterone production has glucocorticoid activity.