Androgen receptor (AR) defects and 5α-reductase (5α-RD) deficiency in 46,XY disorders of sexual development (DSD) present with indistinguishable phenotype. Affected individuals can present with a wide spectrum, from a female genital tract to ambiguous genitalia and mild virilization. The hemizygous mutations in the AR (Xq11.2-q12) encoding AR are associated with X-linked androgen insensitivity, and bi-allelic mutations in SRD5A2 cause enzyme deficiency, converting testosterone (T) to dihydrotestosterone (DHT). Based on genetic diagnostic algorithm, SRD5A2 is screened when T/DHT is >10, and AR is screened when <10, and vice versa for cases with unidentified mutations, presenting with locus and allelic heterogeneity. Identifications of mutations responsible for phenotypes is effective in genetic counseling, managements, and follow-ups.
In this study, we aimed to investigate the genotype-phenotype relationship by evaluating clinical, hormonal, and genetic findings of four cases with ADS or 5α-RD deficiency in 46,XY DSD.
Clinical manifestations and hormone levels (basal luteinizing hormone, follicle-stimulating hormone, T, DHT, T/DHT ratio with short-term stimulation of hCG test) were evaluated and chromosomal abnormalities were excluded in cases with 46,XY. AR (NM_000044.3) and SRD5A2 (NM_000348.3) were evaluated by Sanger sequencing and variants were investigated by using molecular databases.
AR was screened in three cases whose T/DHT <10 (Case 1-2-3) revealed three novel variants in each: synonym (c.330G>C; p.Leu110=), frameshift (c.2585delAGCTCCTG; p.K862Rfs*16), and missense (c.2084C>T; p.Pro695Leu). SRD5A2 was screened in one case whose ratio was >10 and revealed two different variants (one known and one novel) in compound heterozygous status, confirmed by parental testing; c.[164T>A];[269A>C](p[Leu55Gln];[ His90Pro]. The all novel mutations were analyzed by in silico programs and family segregation for inheritance model.