Three new SF-1 (NR5A1) gene mutations in two unrelated families with multiple affected members: within-family variability in 46,XY subjects and low ovarian reserve in fertile 46,XX subjects.
BACKGROUND
Three novel heterozygous SF-1 gene mutations affecting multiple members of two unrelated families with a history of 46,XY disorders of sex development (DSD) and 46,XX ovarian insufficiency are described.


METHODS
clinical and mutational analysis of the SF-1 gene in 9 subjects of two families.


RESULTS
family 1 had 2 affected 46,XY DSD subjects. One, born with severe perineal hypospadias, was raised as a male, and presented normal adolescence. The other, born with ambiguous genitalia, uterus, and mild testicular dysgenesis, was raised as a female. A W279X heterozygous mutation and an intronic deletion (g3314-3317delTCTC (IVS 4 + 8) was found in the SF-1 gene. In family 2, 4/6 affected siblings had 46,XY DSD or hypospadias. An affected 46,XX sister had normal sexual development but increased FSH levels. The 37-year-old affected mother had entered menopause. An Y183X heterozygous mutation was detected.


CONCLUSIONS
an extreme within-family phenotypic variability, ranging from severe prenatal undervirilization to normal pubertal development, was observed in 46,XY-affected siblings, indicating that other unknown factors might be involved in the phenotype. Low ovarian reserve and preserved fertility in 46,XX subjects can be observed in heterozygous SF-1 gene mutations.
Warman
Diana Monica
DM
Endocrinology Service, Hospital de Pediatria Garrahan, Buenos Aires, Argentina.
Costanzo
Mariana
M
Marino
Roxana
R
Berensztein
Esperanza
E
Galeano
Jesica
J
Ramirez
Pablo C
PC
Saraco
Nora
N
Baquedano
Maria Sonia
MS
Ciaccio
Marta
M
Guercio
Gabriela
G
Chaler
Eduardo
E
Maceiras
Mercedes
M
Lazzatti
Juan Manuel
JM
Bailez
Marcela
M
Rivarola
Marco A
MA
Belgorosky
Alicia
A
D058489:46, XX Disorders of Sex Development / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D058490:Disorder of Sex Development, 46,XY / Q000235:genetics* / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation; D006059:Gonadal Dysgenesis / Q000235:genetics; D006801:Humans; D006965:Hyperplasia; D007021:Hypospadias / Q000235:genetics; D007223:Infant; D008297:Male; D009154:Mutation; D010375:Pedigree; D016649:Primary Ovarian Insufficiency / Q000235:genetics*; D054339:Steroidogenic Factor 1 / Q000235:genetics*; D013737:Testis / Q000473:pathology; D055815:Young Adult
C515057:NR5A1 protein, human; D054339:Steroidogenic Factor 1