A novel mutation of the 5α-reductase type 2 gene in two unrelated Egyptian children with ambiguous genitalia

Objective: To establish an etiological diagnosis in two unrelated Egyptian children with ambiguous genitalia through biochemical and molecular analyses. Patients and Methods: Two XY patients were referred: one at the age of 14 years presenting with delayed puberty and menarche and the second at the age of 4 months with ambiguous genitalia. Basal and post-HCG stimulation plasma levels of testosterone (T) and dihydrotestosterone (DHT) were determined. Direct sequencing of the five exons of the 5αR type 2 gene and exons 2 to 8 of the androgen receptor gene was carried out. Results: The high T/DHT value indicated 5αR deficiency in the first patient while the absence of parental consanguinity along with normal T/DHT value in the second patient suggested androgen insensitivity. In both patients, we identified a homozygous A→G mutation in exon 3 that replaced the asparagine residue at position 160 by an aspartic acid. The parents of both patients were all heterozygotes for the N160D substitution. Conclusions: 1) We report a new mutation that enlarges the spectrum of genetic defects in 5αR deficiency. 2) Although the two patients were referred at very different ages, the clinical presentations raise the possibility of phenotypic variability for the same mutation. 3) These reports underline the difficulty of diagnosing 5αR deficiency based only on clinical and biochemical grounds. Molecular study remains the only definitive tool for diagnosis of ambiguous genitalia.