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

WARMAN M,; CONSTANZO M,; MARINO R, .; BERENSZTEIN E, .; GALENO, J; RAMIREZ P, .; BAQUEDANO M,; SARACO N, .; CIACCIO, M; GUERCIO G;; CHALER E; MACEIRAS M,; LAZZATI J M,; BAILEZ M; .RIVAROLA MA.,; BELGOROSKY A

HORMONE RESEARCH

KARGER

Lugar: Basel; Año: 2011 vol. 75 p. 70 - 77

0301-0163

AbstractBackground: Three novel heterozygous SF-1 gene mutationsaffecting multiple members of two unrelated familieswith 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 subjectsof two families. Results: Family 1 had 2 affected 46,XY DSDsubjects. One, born with severe perineal hypospadias, wasraised as a male, and presented normal adolescence. Theother, born with ambiguous genitalia, uterus, and mildtesticular dysgenesis, was raised as a female. A W279Xheterozygous mutation and an intronic deletion (g3314-3317delTCTC (IVS 4 + 8) was found in the SF-1 gene. In family2, 4/6 affected siblings had 46,XY DSD or hypospadias. Anaffected 46,XX sister had normal sexual development butincreased FSH levels. The 37-year-old affected mother hadentered menopause. An Y183X heterozygous mutation wasdetected. Conclusion: An extreme within-family phenotypicvariability, ranging from severe prenatal undervirilizationto normal pubertal development, was observed in 46,XY-affectedsiblings, indicating that other unknown factors mightbe involved in the phenotype. Low ovarian reserve and preservedfertility in 46,XX subjects can be observed in heterozygousSF-1 gene mutations.