• PMID: 19439508
• Gene Name: NR5A1
• Condition: Penoscrotal hypospadias, 46,XY males without adrenal insufficiency
• Association: SF-1 (NR5A1) mutations should be considered in 46,XY individuals with severe (penoscrotal) hypospadias, especially if undescended testes, low testosterone, or low inhibin B/AMH levels are present. SF-1 mutations in milder forms of idiopathic hypospadias a
• Mutation: p.Q107X/WT, p.E11X/WT, intron 2 (c.103-3A/WT)
• Population size: 60
• Population details: 60 individuals with hypospadias, 46,XY males without adrenal insufficiency
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Penoscrotal hypospadias, 46,XY males without adrenal insufficiency

The spectrum of phenotypes associated with mutations in steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) includes severe penoscrotal hypospadias in 46,XY males without adrenal insufficiency

Köhler B, Lin L, Mazen I, Cetindag C, Biebermann H, Akkurt I, Rossi R, Hiort O, Grüters A, Achermann JC.

OBJECTIVE: Hypospadias is a frequent congenital anomaly but in most cases an underlying cause is not found. Steroidogenic factor 1 (SF-1, NR5A1, Ad4BP) is a key regulator of human sex development and an increasing number of SF-1 (NR5A1) mutations are reported in 46,XY disorders of sex development (DSD). We hypothesized that NR5A1 mutations could be identified in boys with hypospadias. DESIGN AND METHODS: Mutational analysis of NR5A1 in 60 individuals with varying degrees of hypospadias from the German DSD network. RESULTS: Heterozygous NR5A1 mutations were found in three out of 60 cases. These three individuals represented the most severe end of the spectrum studied as they presented with penoscrotal hypospadias, variable androgenization of the phallus and undescended testes (three out of 20 cases (15%) with this phenotype). Testosterone was low in all three patients and inhibin B/anti-Müllerian hormone (AMH) were low in two patients. Two patients had a clear male gender assignment. Gender re-assignment to male occurred in the third case. Two patients harbored heterozygous nonsense mutations (p.Q107X/WT, p.E11X/WT). One patient had a heterozygous splice site mutation in intron 2 (c.103-3A/WT) predicted to disrupt the main DNA-binding motif. Functional studies of the nonsense mutants showed impaired transcriptional activation of an SF-1-responsive promoter (Cyp11a). To date, adrenal insufficiency has not occurred in any of the patients. CONCLUSIONS: SF-1 (NR5A1) mutations should be considered in 46,XY individuals with severe (penoscrotal) hypospadias, especially if undescended testes, low testosterone, or low inhibin B/AMH levels are present. SF-1 mutations in milder forms of idiopathic hypospadias are unlikely to be common. FAU - Köhler, Birgit AU - Köhler B AD - Developmental Endocrinology Research Group, UCL Institute of Child Health, University College London, London, UK. birgit.koehler@charite.de FAU - Lin, Lin AU - Lin L FAU - Mazen, Inas AU - Mazen I FAU - Cetindag, Cigdem AU - Cetindag C FAU - Biebermann, Heike AU - Biebermann H FAU - Akkurt, Ilker AU - Akkurt I FAU - Rossi, Rainer AU - Rossi R FAU - Hiort, Olaf AU - Hiort O FAU - Grüters, Annette AU - Grüters A