Endocrine Abstracts

The human CYP17A1 enzyme exerts two activities, 17a-hydroxylase and 17,20 lyase, catalysing key steps in human adrenal steroid biosynthesis. An in frame deletion of 3 bp in exon 1 of the CYP17A1 gene, resulting in the loss of phenylalanine in position 53 (F53del), is one of the first CYP17A1 mutations described (JBC 1989, 264:18076). Reported patients have invariably presented with severe hypokalaemic hypertension, reflecting 17α-hydoxylase deficiency, and severe sex steroid deficiency due to 17,20 lyase deficiency. Here we describe a family affected by F53del with an unusually mild clinical presentation. The index case was a 13 yr-old boy born of consanguineous parents originating from Afghanistan. He presented with learning difficulties, gynaecomastia, microphallus, glandular hypospadias and cryptorchidism, with a history of orchidopexy for a left undescended testis at age 5 yrs. His blood pressure and serum potassium levels were normal. Serum testosterone was inappropriately low (2.4 nmol/L) with a raised FSH (14.2 IU/L) and LH (24.4 U/L). 17-hydroxyprogesterone (17OHP) was moderately increased (17.4 nmol/L). Urinary steroid profiling by gas chromatography/mass spectrometry (GC/MS) revealed raised corticosterone metabolites with detectable androgen and cortisol metabolites, in keeping with a diagnosis of incomplete CYP17A1 deficiency. Unusually, the 17OHP metabolite pregnanetriol was raised. Direct sequencing analysis identified a homozygous F53del mutation in CYP17A1. Complete genetic work-up of the family revealed that both parents were heterozygous for F53del as were 5 of the siblings with one brother being unaffected. Of note, an elder sister was also found to be homozygous for F53del and like her brother she was normotensive and normokalaemic. Pubertal development had been normal apart from delayed menarche. Taken together, this family strikingly illustrates that there is considerable variability in phenotypic presentation of CYP17A1 deficiency and that very mild cases might be overlooked if not appropriately analysed, further illustrating the value of urinary GC/MS steroid profiling.