Background: 5α-reductase type 2 deficiency (SRD5A2) is a rare cause of 46,XY DSD. Consensus guidelines on sex of rearing assignment at birth favours male gender. Typically undervirilised genitalia at birth virilise variably at puberty, posing gender identity challenges.
Aim: We describe relevant data on clinical phenotype, hormonal and molecular workup and gender preference in patients with SRD5A2 deficiency from a single regional centre.
Materials and methods: Retrospective patient data was collected from the medical records of SRD5A2 deficiency patients referred to the West Midlands-DSD-MDT clinic from 1993-2022. Clinical phenotype gender assignment, hormonal, molecular data including pathogenic variations in the SRD5A2 gene were analysed.
Results: 17 subjects were identified with genetic data available in 16. Age at presentation varied from birth in 9 (53%), mid-childhood in 5 (29%) and puberty in 3 (17%). Birth gender assignment was male in 8 (47%), with 9 (53%) assigned female gender, of which 2 were born outside the UK and underwent gonadectomies ages 2 and 11y. Female to male gender change at diagnosis occurred in 4 subjects; (2 < 1yrof age and 2 at puberty). One 3y old subject remains female gender assigned by parental choice, with the child to make a gender decision when older. Hypospadias (isolated or with microphallus, cryptorchidism or undervirilised genitalia with palpable gonads (100%)) was the most common birth presentation. The diagnostic sensitivity of stimulated T/DHT ratio was limited. Clinical presentation at puberty in 4 subjects(23%), varied with clitoromegaly, primary amenorrhoea, absent breast development, palpable gonad, Hernia 2(11%) and change in voice; two teenage children changed gender to male after diagnosis; one had a gonadectomy at 16 years and choose to retain female gender identity. Gonadectomy was opted as parental choice of a severely autistic child diagnosed at 8yr of age. Molecular analysis of (SRD5A2) gene identified homozygous recessive (n=12); compound heterozygous (n=3) and frame-shift (n=1) mutations. Most frequent pathogenic variants were p.Arg246Gln, p.Glu200Lys; p.Arg227ter and p.Ala192Thr homozygous mutations. Management included orchidopexy (n=4), hypospadias repair (n=6), DHT gel for microphallus (n=8) and gonadectomy (n=4). Psychological issues (n=6) were more obvious during the teenage years where counselling was offered, concerns were mostly around patient dissatisfaction due to microphallus or undervirilised genitalia, despite corrective surgeries.
Conclusion: Our data supports the clinical-genotype heterogeneity of SRD5A2 demonstrating a spectrum of phenotypes and age at clinical presentation. We highlight the importance of open choice of gender in long-term follow up patients with SRD5A2 deficiency.
15 Sep 2022 - 17 Sep 2022