Editing 5α-Reductase 2 deficiency (section)

==History==
An autosomal recessive disorder of sex development, described as pseudovaginal perineoscrotal hypospadias (PPSH), was discovered in males in 1961.<ref>{{cite journal |last1=NOWAKOWSKI |first1=H |last2=LENZ |first2=W |title=Genetic aspects in male hypogonadism. |journal=Recent Progress in Hormone Research |date=1961 |volume=17 |pages=53–95 |pmid=13729828}}</ref> The main feature of this syndrome was a vulva with the presence of bilateral testes and male urogenital tracts in which the ejaculatory ducts terminate in a blind-ending vagina.<ref name="Mendonca2016"/> This disorder was consistent with 5αR2D as the underlying cause as observed in animal models.<ref name="Recent Studies on the Mechanism of"/> 5αR2D was confirmed as the cause in humans in 1974, when studies were done of 24 participants in the Dominican Republic<ref name="Imperato-McGinley1974">{{cite journal |last1=Imperato-McGinley |first1=J |last2=Guerrero |first2=L |last3=Gautier |first3=T |last4=Peterson |first4=RE |title=Steroid 5alpha-reductase deficiency in man: an inherited form of male pseudohermaphroditism. |journal=Science |date=27 December 1974 |volume=186 |issue=4170 |pages=1213–5 |doi=10.1126/science.186.4170.1213 |pmid=4432067|bibcode=1974Sci...186.1213I |s2cid=36427689 }}</ref> and 2 in Dallas Texas, USA.<ref>{{cite journal |last1=Walsh |first1=PC |last2=Madden |first2=JD |last3=Harrod |first3=MJ |last4=Goldstein |first4=JL |last5=MacDonald |first5=PC |last6=Wilson |first6=JD |title=Familial incomplete male pseudohermaphroditism, type 2. Decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. |journal=The New England Journal of Medicine |date=31 October 1974 |volume=291 |issue=18 |pages=944–9 |doi=10.1056/NEJM197410312911806 |pmid=4413434}}</ref> One of the cases in Dallas began to virilize at puberty and underwent surgery to remove testes and "repair" the apparent [[clitoromegaly]]. During surgery, a normal male urogenital tract was observed as well as other features consistent with PPSH. DHT was almost undetectable in cultured fibroblasts from foreskin,<ref>{{cite journal|last1=Moore|first1=R J|last2=Griffin|first2=J E|last3=Wilson|first3=J D|date=September 1975|title=Diminished 5alpha-reductase activity in extracts of fibroblasts cultured from patients with familial incomplete male pseudohermaphroditism, type 2.|journal=Journal of Biological Chemistry|volume=250|issue=18|pages=7168–7172|doi=10.1016/S0021-9258(19)40924-1|pmid=240819 |doi-access=free}}</ref> epididymis and the presumed "labia majora" whereas in normal males DHT is detected, suggesting impaired DHT formation.<ref name="Wilson1993">{{cite journal |last1=Wilson |first1=Jean D. |last2=Griffin |first2=James E. |last3=Russell |first3=David W. |title=Steroid 5α-Reductase 2 Deficiency* |journal=Endocrine Reviews |date=October 1993 |volume=14 |issue=5 |pages=577–593 |doi=10.1210/edrv-14-5-577|pmid=8262007 }}</ref> Similar conclusions were obtained for participants in a family in the Dominican Republic study, in whom high serum concentration ratios of T to DHT and low concentrations of urinary 5a-reduced androgens were observed. This disorder is now known to be due to homozygous or compound heterozygous loss-of-function mutations of the SRD5A2 gene.<ref name="Thigpen1992">{{cite journal |last1=Thigpen |first1=A E |last2=Davis |first2=D L |last3=Milatovich |first3=A |last4=Mendonca |first4=B B |last5=Imperato-McGinley |first5=J |last6=Griffin |first6=J E |last7=Francke |first7=U |last8=Wilson |first8=J D |last9=Russell |first9=D W |title=Molecular genetics of steroid 5 alpha-reductase 2 deficiency. |journal=Journal of Clinical Investigation |date=1 September 1992 |volume=90 |issue=3 |pages=799–809 |doi=10.1172/JCI115954|pmid=1522235 |pmc=329933 }}</ref> The frequency of the deficiency was found to be unusually high in Las Salinas, with occurrence ratio of 1 ''güevedoce'' to every 90 unaffected males.<ref name="Imperato-McGinley1974" />