New Territory for an Old Disease: 5-Alpha-Reductase Type 2 Deficiency in Bulgaria

Abstract

Disorders/differences of sexual development (DSD) are a group of conditions, some of which can be clinically indistinguishable mainly due to their phenotypic variability. Defining the molecular basis of their wide spectrum is still in progress. The diagnosis of 5-alpha-reductase type 2 (5α-reductase-2) deficiency is difficult especially in newborns and pre-pubertal individuals, and as a result its frequency might be underestimated. In the present study, we describe the clinical characteristics and molecular defects in 3 nonrelated 5α-reductase-2 deficiency patients of Bulgarian descent. Sequencing analysis revealed the mutations p.Y188CfsX9 and p.G196S, and MLPA analysis showed a deletion of exon 1 in the SRD5A2 gene. The observed genetic substitutions were not detected in 76 additionally screened unrelated controls, but a heterozygous healthy carrier of the p.R171S mutation was found. This is the first study on the molecular basis of 5α-reductase-2 deficiency in Bulgaria. It suggests that the carrier frequency of mutations in the SRD5A2 gene might be noteworthy worldwide. There is no correlation between cultural aspects, location, and/or population size and the number of different mutations in SRD5A2 detected, and more efforts should be made to determine the prevalence of this condition in different geographic areas. Our study supports the importance of genetic testing in 46,XY DSD patients, especially in countries or regions where 5α-reductase-2 deficiency has not been reported so far.

<p>Integrative and Analytical Review of the 5-Alpha-Reductase Type 2 Deficiency Worldwide</p>

“…The main one is the SRD5A2 gene in which several allelic variants have been reported in individuals with 5α-reductase type 2 deficiency, a rare difference of sex differentiation among 46,XY individuals resulting from defective conversion from T to DHT. 5,6,8,21,26 The role of the others 5α-reductases in human diseases are still not fully understood. 5α-reductases isoenzymes irreversibly catalyze A-ring reduction of pregnene-based steroids, which includes glucocorticoids and androgens.…”

“…It is noteworthy that many cases have recently been reported in China and Turkey, [32][33][34] besides reports in countries without no previous cases, as Bulgaria. 8 Neonatal diagnosis was carried out in 29.7%. Most cases had the 5α-reductase type 2 deficiency diagnosis later in life (mean 12.56 ± 8.41, from 1 to 47 years of age).…”

“…Intriguingly, 5α-reductase type 2 deficiency is reported with an extensive phenotype variability, even in affected individuals carrying the same SRD5A2 mutation. 7,8 It suggests that factors others than residual 5α-reductase type 2 activity may play a role on 5α-reductase type 2 deficiency phenotype.…”

Novel genotype in two siblings with 5-α-reductase 2 deficiency: Different clinical course due to the time of diagnosis

“…Delayed diagnosis of 5-ARD is still common [12][13][14]. The XY karyotype in an individual with female or undermasculinized external genitalia should raise suspicion of 5-ARD.…”

“…About 100 different changes in the SRD5A2 gene have been described, most of which are missense/nonsense loss of function mutations, including 65.0% homozygous and 35.0% compound heterozygous ones [3,7,17]. So far, only a few deletions have been described, without details about the borders of the deletions [3,4,14]. Our patients carry two changes in exon 1 of the SRD5A2 gene, one novel mis-sense mutation inherited from the mother, and a large deletion encompassing the entire exon 1 including part of the adjacent intron, inherited from the father.…”