Preserved Fertility in a Patient with a 46,XY Disorder of Sex Development due to a New Heterozygous Mutation in the <b><i>NR5A1/SF-1 </i></b>Gene: Evidence of 46,XY and 46,XX Gonadal Dysgenesis Phenotype Variability in Multiple Members of an Affected Kindred

Abstract

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.

Fertility preservation in a family with a novel <i>NR5A1</i> mutation

“…To date preserved fertility in 46,XY male who carrying NR5A1 mutations have been reported in only three individuals [4][5][6]. Two of the three males were asymptomatic and one presented hypospadias.…”

“…In 46,XY individuals, phenotype of external genitalia ranges from complete female-type to normal male-type. However, an asymptomatic and fertile 46,XY male with heterozygous NR5A1 mutations is rare.To date preserved fertility in 46,XY male who carrying NR5A1 mutations have been reported in only three individuals [4][5][6]. Two of the three males were asymptomatic and one presented hypospadias.…”

Aetiological bases of 46,XY disorders of sex development in the Hong Kong Chinese population

“…Phenotypic variability in NR5A1 gene mutation within a kindred has been reported and this may explain why patient 21 had ambiguous external genitalia to such an extent that he required the attention of a paediatric specialist, even though his father was fertile, and denied any symptoms of DSD or need for medical Patients with AR mutation Patients without AR mutation attention. 22 For the AMH gene, the 3' end of exon 5 is one of the mutational hotspots in patients with PMDS. 23 Exon 5 encodes the bioactive C-terminal domain.…”

Wide spectrum of NR5A1‐related phenotypes in 46,XY and 46,XX individuals

“…In South America, familial and sporadic DSD patients bearing NR5A1 defects have been described in Brazil and Argentina (Lourenço et al, 2009; Ciaccio et al, 2012; Gabriel Ribeiro de Andrade et al, 2014; Fabbri et al, 2016). Here, we review the phenotype associated with ten novel and one previously described NR5A1 allelic variants identified in a Brazilian cohort of 46,XY and 46,XX DSD patients followed at a single tertiary center.…”