Mutational analysis of rare subtypes of congenital adrenal hyperplasia in a highly inbred population

Context Apart from 21 Hydroxylase deficiency, other subtypes of congenital adrenal hyperplasia (CAH) are rare. We studied the clinical features and molecular genetics of a relatively large series of patients with CYP17A1, HSD3β2 and StAR deficiencies. Patients and methods We studied 21 patients including 7 patients with CYP17A1, 10 patients with HSD3β2 and 4 patients with StAR deficiencies. For mutation detection, we isolated DNA from peripheral leucocytes, amplified genes of interest using polymerase chain reaction and directly sequenced the amplicons using Dideoxy Chain Termination method. Results Regardless of their karyotype, patients with CYP17A1 deficiency presented with normally looking external female genitalia and were raised as females. Hypertension and hypokalemia were prominent features in 4 of 7 patients. Two missense (p.R416H, p.R239Q) and 2 non-sense (p.Y329X, p.Y329X) mutations were found in these 7 cases. In 3 unrelated families with 10 affected siblings with HSD3β2 mutations, two non-sense mutations were found (p.Q334X, p.R335X). 46XY patients with HSD3β2 deficiency presented with ambiguous genitalia while 46XX patients presented with normal female external genitalia. Adrenal crisis was common in patients with both karyotypes. In the 4 patients with StAR deficiency, both genetic male and female patients presented with normally looking female external genitalia and adrenal crisis. One previously reported missense mutation (p.R182H) was found in 3 unrelated patients and a novel non-sense mutation (p.Q264X) in the fourth patient. Conclusions These cases of rare subtypes of CAH illustrate the heterogeneous phenotypic and genetic features of these subtypes and add unique novel mutations to the previously known ones.