Endocrine Abstracts

JOINT35295

Background: 5α-reductase type 2 deficiency (5αRD2) is a rare cause for 46, XY DSD. The enzyme catalyzes the conversion of testosterone (T) into dihydrotestosterone (DHT). In the fetus, T is responsible for the masculinization of the internal genitalia while DHT is needed for the masculinization of the external genitalia. During puberty, T facilitates changes in psychosocial behaviour, deepening of the voice, increase of muscular mass and the further masculinization of the external genitalia. Individuals with 5αRD2 present at birth with a wide clinical spectrum ranging from total female appearance to a nearly complete male phenotype with mild symptoms depending on the resting enzyme activity. During puberty, they often virilize both physically and psychologically. The first 5αRD2 studies describe a population in the Dominican Republic where affected individuals often changed gender identity after puberty from female to male, which resulted in a general recommendation for male gender identity. 5α-reductase 2 is encoded by the SRD5A2 gene on chromosome 2. More than 100 different pathogenic variants of SRD5A2 have been described, with no strong genotype-phenotype correlation. However, recent studies have suggested that the location of the mutation in the protein plays a role in the severity of the phenotype.

Methods: A cohort of 18 patients followed at pediatric endocrinology, endocrine gynecology and andrology departments is described according to their phenotype at diagnosis, genetics, hormonal profile and gender identity. The external genitalia score (EGS) was used to describe the genitalia phenotype.

Results: A wide range of phenotypes with 12 females and 6 males was observed. Treatment ranged from hypospadias operation and early treatment with DHT to treatment with estrogen or oral contraceptives. In some cases gonadectomy was performed in early puberty to prevent further masculinization. The genetic investigation showed different pathogenic variants, both homo- and heterozygous. The majority of the patients had a non-caucasian background. Late diagnosis, which could be caused by more female-looking genitalia (i.e. a more severe phenotype), seemed to more often lead to a female gender identity also after puberty.

Conclusions: The variation in gender outcome in the described cohort underlines the importance of patient-centered care, individual counseling for families with children born with 5αRD2 where the initial phenotype and genetics, including information about the expected enzyme activity, may provide guidance in clinical decisions.