46,XY difference of sex development due to 5-alpha-reductase 2 deficiency (ORPHA:753)
A rare difference of sex development (DSD) due to a defect in metabolizing testosterone to dihydrotestosterone and characterized by incomplete intrauterine masculinization which ranges from a female genitalia with a blind vaginal pouch to a fully male phenotype with pseudovaginal posterior hypospadias and micropenis.
Epidemiology
The disease has been described in large pedigrees from the Dominican Republic, Southern Lebanon and the Eastern Highlands Province of Papua New Guinea. It is relatively rare among Caucasians, but is recognized as a significant cause of DSD and mutational analysis is part of initial investigations.
Clinical description
Patients present at birth with characteristics of dihydrotestosterone (DHT) deficiency, such as posterior hypospadias, micropenis/clitoris-like phallus, bifid scrotum, cryptorchid testes (with normal or reduced spermatogenesis), and rudimentary prostate. The clinical spectrum is heterogeneous, ranging from a female with a blind vaginal pouch to a fully male phenotype with hypospadias and micropenis. Two-thirds of patients are initially assigned female gender, and thus clinical presentation maybe later during childhood with abnormal genitalia or during puberty with scarce facial and body hair (with normal sebum production) and virilization without breast development. Wolffian duct differentiation (testosterone-dependent) and regression of Müllerian structures (AMH-dependent) are not involved.
Etiology
The disease is caused by mutations in the SRD5A2-gene (2p23.1) leading to a reduced or absent function of the steroid 5 alpha-reductase type 2 enzyme which converts testosterone into DHT in the external genitalia. As a result, male differentiation fails to occur during fetal development, despite high circulating testosterone levels. Manifestations at birth vary according to the levels of residual enzymatic function.
Diagnostic methods
Diagnostic criteria include genital ambiguity, a family history of DSD, and genital/karyotype discordance. Biochemical findings reveal increase in the testosterone/DHT ratio after human chorionic gonadotropin stimulation and normal testosterone and anti-Müllerian hormone concentration. Diagnosis also relies on 5-alpha-reductase activity assessment using the urinary steroid profiling (ratio of androsterone to etiocholanolone and 5-alpha-tetrahydrocortisol/tetrahydrocortisol and 5-alpha-tetrahydrocorticosterone to tetrahydrocorticosterone below the lower limit of normal). Nowadays, the diagnosis is most commonly determined directly by genetic screening.
Differential diagnosis
Differential diagnosis includes many other causes of severe hypospadias like partial androgen insensitivity syndrome, 17-beta-hydroxysteroid dehydrogenase 3 deficiency and Leydig cell hypoplasia.
Antenatal diagnosis
Prenatal diagnosis with ultrasound is uncommon but may occur in families with a previously diagnosed child.
Genetic counseling
Transmission is autosomal recessive and genetic counseling should be offered to at-risk couples. The parents are almost always carriers and without symptoms, but 25% of their boys will be affected. Girls with 46,XX karyotype and who are homozygous for mutations in the gene, will have no symptoms, but will transmit the mutation to their children.
Management and treatment
For patients raised as male, the main concern is to keep the testis for later hormone production. Topical DHT cream on the pubic area can be applied neonatally after diagnosis at least during the minipuberty. Surgical repair of hypospadias (chordee correction, urethral reconstruction and orchidopexia with or without scrotalplasty,) should be performed at 6-18 months of age. For patients raised as female, management may include surgical correction of the external genitalia (vaginal opening into the perineum with early separation of the vagina and urethra), early removal of gonadal tissue to prevent masculinization before puberty, clitoral reduction (if severe masculinization) and cyclic hormonal therapy at puberty for development of secondary sexual characteristics. Choosing a female sex is nowadays only an option in XY children with a total deficiency.
Prognosis
The risk of gonadal tumors in individuals with SRD5A2 mutations is quite low. Prostate diseases (prostate cancer, benign prostate hyperplasia) have not been reported in affected males. Most men are infertile due to the small prostate gland causing diminished semen volume and lack of spontaneous fertility; however, artificial reproductive techniques are a possibility.

                            Last update: 
                            July 2020


                            - Expert reviewer(s): 
                            Pr Agneta NORDENSKJÖLD