Preserved fertility in a patient with a 46,XY disorder of sex development due to a new heterozygous mutation in the NR5A1/SF-1 gene: evidence of 46,XY and 46,XX gonadal dysgenesis phenotype variability in multiple members of an affected kindred.
In humans, steroidogenic factor 1 (NR5A1/SF-1) mutations have been reported to cause gonadal dysgenesis, with or without adrenal failure, in both 46,XY and 46,XX individuals. We have previously reported extreme within-family variability in affected 46,XY patients. Even though low ovarian reserve with preserved fertility has been reported in females harboring NR5A1 gene mutations, fertility has only been observed in one reported case in affected 46,XY individuals. A kindred with multiple affected members presenting gonadal dysgenesis was studied. Four 46,XY individuals presented severe hypospadias at birth, one of them associated with micropenis and cryptorchidism. The other 3 developed spontaneous male puberty, and 1 has fathered 5 children. Four 46,XX patients presented premature ovarian failure (one of them was not available for the study) or high follicle-stimulating hormone levels. Mutational analysis of the NR5A1 gene revealed a novel heterozygous mutation, c.938G→A, predicted to cause a p.Arg313Hys amino acid change. A highly conserved amino acid of the ligand-binding domain of the mature protein is affected, predicting abnormal protein function. We confirm that preserved fertility can be observed in patients with a 46,XY disorder of sex development due to heterozygous mutations in the NR5A1 gene.
Endocrinology Service, Hospital de Pediatría Garrahan, Buenos Aires, Argentina.
Marta
M
Ciaccio
Mariana
M
Costanzo
Gabriela
G
Guercio
Valeria
V
De Dona
Roxana
R
Marino
Pablo C
PC
Ramirez
Jessica
J
Galeano
Diana Monica
DM
Warman
Esperanza
E
Berensztein
Nora
N
Saraco
Maria Sonia
MS
Baquedano
Eduardo
E
Chaler
Mercedes
M
Maceiras
Juan Manuel
JM
Lazzatti
Marco A
MA
Rivarola
Alicia
A
Belgorosky
D000328:Adult; D002675:Child, Preschool; D058490:Disorder of Sex Development, 46,XY / Q000235:genetics*; D005260:Female; D005298:Fertility; D023961:Gonadal Dysgenesis, 46,XX / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D054339:Steroidogenic Factor 1 / Q000235:genetics*
C515057:NR5A1 protein, human; D054339:Steroidogenic Factor 1