Gly183Ser homozygous mutation of the steroid 5-a reductase type 2 (SRD5A2) gene in a Brazilian patient: case report.

OBJECTIVES: Steroid 5α-reductase type 2 deficiency (5α-RD2) is an autosomal recessive disorder caused by mutations in the SRD5A2 gene. This condition is characterized by reduced enzymatic activity of the 5α-reductase type 2 enzyme. Individuals with mutations in the SRD5A2 gene may exhibit various symptoms of under-masculinization in 46, XY individuals. We conducted a comprehensive analysis of the SRD5A2 gene in a patient with disorder of sex development (DSD). CASE PRESENTATION: We describe a patient with a homozygous Gly183Ser variant in the SRD5A2 gene. Their sibling also carries this variant in homozygosity, while both parents have it in a heterozygous state. The patient presents with predominantly female traits and was raised as a girl. Although the siblings exhibit distinct phenotypic characteristics, both have assumed a male gender identity. CONCLUSIONS: This study reveals different phenotypes for the two siblings, highlighting the complexity of establishing a genotype-phenotype correlation in the SRD5A2 gene. It is noteworthy that the Gly183Ser variant seems to be more prevalent among individuals of African descent, aligning with our patient's ethnic background.

5-α-Reductase type 2 deficiency: is there a genotype-phenotype correlation? A review.

5-α-Reductase type 2 enzyme catalyzes the conversion of testosterone into dihydrotestosterone, a potent androgen responsible for male sexual development during the fetal period and later during puberty. Its deficiency causes an autosomal recessive disorder of sex development characterized by a wide range of under-virilization of external genitalia in patients with a 46,XY karyotype. Mutations in the SRD5A2 gene cause 5-α-Reductase deficiency; although it is an infrequent disorder, it has been reported worldwide, with mutational heterogeneity. Furthermore, it has been proposed that there is no genotype-phenotype correlation, even in patients carrying the same mutation. The aim of this review was to perform an extensive search in various databases and to select those articles with a comprehensive genotype and phenotype description of the patients, classifying their phenotypes using the external masculinization score (EMS). Thus, it was possible to objectively compare the eventual genotype-phenotype correlation between them. The analysis showed that for most of the studied mutations no correlation can be established, although the specific location of the mutation in the protein has an effect on the severity of the phenotype. Nevertheless, even in patients carrying the same homozygous mutation, a variable phenotype was observed, suggesting that additional genetic factors might be influencing it. Due to the clinical variability of the disorder, an accurate diagnosis and adequate medical management might be difficult to carry out, as is highlighted in the review.

Molecular diagnosis of 5α-reductase type II deficiency in Brazilian siblings with 46,XY disorder of sex development.

The steroid 5α-reductase type II enzyme catalyzes the conversion of testosterone (T) to dihydrotestosterone (DHT), and its deficiency leads to undervirilization in 46,XY individuals, due to an impairment of this conversion in genital tissues. Molecular analysis in the steroid 5α-reductase type II gene (SRD5A2) was performed in two 46,XY female siblings. SRD5A2 gene sequencing revealed that the patients were homozygous for p.Gln126Arg missense mutation, which results from the CGA > CAA nucleotide substitution. The molecular result confirmed clinical diagnosis of 46,XY disorder of sex development (DSD) for the older sister and directed the investigation to other family members. Studies on SRD5A2 protein structure showed severe changes at NADPH binding region indicating that structural modeling analysis can be useful to evaluate the deleterious role of a mutation as causing 5α-reductase type II enzyme deficiency.