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.
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.


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.
Developmental Endocrinology Research Group, UCL Institute of Child Health, University College London, London, UK. birgit.koehler@charite.de
Birgit
B
Köhler
Lin
L
Lin
Inas
I
Mazen
Cigdem
C
Cetindag
Heike
H
Biebermann
Ilker
I
Akkurt
Rainer
R
Rossi
Olaf
O
Hiort
Annette
A
Grüters
John C
JC
Achermann
D000309:Adrenal Insufficiency / Q000097:blood / Q000235:genetics; D054304:Anti-Mullerian Hormone / Q000097:blood; D015331:Cohort Studies; D004247:DNA / Q000737:chemistry / Q000235:genetics; D019314:Dehydroepiandrosterone Sulfate / Q000097:blood; D005640:Follicle Stimulating Hormone / Q000097:blood; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D006908:Hydroxyprogesterones / Q000097:blood; D007021:Hypospadias / Q000097:blood / Q000235:genetics*; D007231:Infant, Newborn; D007265:Inhibins / Q000097:blood; D008297:Male; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D017422:Sequence Analysis, DNA; D054339:Steroidogenic Factor 1 / Q000235:genetics*; D013739:Testosterone / Q000097:blood
D006908:Hydroxyprogesterones; C515057:NR5A1 protein, human; D054339:Steroidogenic Factor 1; C422364:inhibin B; D013739:Testosterone; D007265:Inhibins; D019314:Dehydroepiandrosterone Sulfate; D054304:Anti-Mullerian Hormone; D005640:Follicle Stimulating Hormone; D004247:DNA; D006854:Hydrocortisone