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

• Published in: Birth defects research. Part C. Embryo today Vol. 108; no. 4; pp. 309 - 320
• Main Authors: Domenice, Sorahia, Zamboni Machado, Aline, Moraes Ferreira, Frederico, Ferraz-de-Souza, Bruno, Marcondes Lerario, Antonio, Lin, Lin, Yumie Nishi, Mirian, Lisboa Gomes, Nathalia, Evelin da Silva, Thatiana, Barbosa Silva, Rosana, Vieira Correa, Rafaela, Ribeiro Montenegro, Luciana, Narciso, Amanda, Maria Frade Costa, Elaine, Achermann, John C, Bilharinho Mendonca, Berenice
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.12.2016; Wiley Subscription Services, Inc; John Wiley and Sons Inc
• Subjects: Adolescent; Adrenal Insufficiency; Adult; Brazil; Child; Child, Preschool; disorders of sex development; Disorders of Sex Development - genetics; Disorders of Sex Development - metabolism; Female; Gonadal Disorders - genetics; Gonadal Disorders - metabolism; gonadal dysgenesis; Humans; Infant; Male; Mutation; NR5A1 gene; ovotestis; Phenotype; primary ovarian failure; Primary Ovarian Insufficiency - genetics; Primary Ovarian Insufficiency - metabolism; Review; Reviews; Steroidogenic Factor 1 - genetics; Steroidogenic Factor 1 - metabolism; Steroidogenic Factor 1 - physiology; primary ovarian failure; adrenal insufficiency; disorders of sex development; NR5A1 gene; gonadal dysgenesis; ovotestis
• ISSN: 1542-975X; 1542-9768; 1542-9768
• DOI: 10.1002/bdrc.21145

Steroidogenic factor 1 (NR5A1, SF‐1, Ad4BP) is a transcriptional regulator of genes involved in adrenal and gonadal development and function. Mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum. In 46,XY individuals, NR5A1‐related phenotypes may range from disorders of sex development (DSD) to oligo/azoospermia, and in 46,XX individuals, from 46,XX ovotesticular and testicular DSD to primary ovarian insufficiency (POI). The most common 46,XY phenotype is atypical or female external genitalia with clitoromegaly, palpable gonads, and absence of Müllerian derivatives. Notably, an undervirilized external genitalia is frequently seen at birth, while spontaneous virilization may occur later, at puberty. In 46,XX individuals, NR5A1 mutations are a rare genetic cause of POI, manifesting as primary or secondary amenorrhea, infertility, hypoestrogenism, and elevated gonadotropin levels. Mothers and sisters of 46,XY DSD patients carrying heterozygous NR5A1 mutations may develop POI, and therefore require appropriate counseling. Moreover, the recurrent heterozygous p.Arg92Trp NR5A1 mutation is associated with variable degrees of testis development in 46,XX patients. A clear genotype‐phenotype correlation is not seen in patients bearing NR5A1 mutations, suggesting that genetic modifiers, such as pathogenic variants in other testis/ovarian‐determining genes, may contribute to the phenotypic expression. Here, we review the published literature on NR5A1‐related disease, and discuss our findings at a single tertiary center in Brazil, including ten novel NR5A1 mutations identified in 46,XY DSD patients. The ever‐expanding phenotypic range associated with NR5A1 variants in XY and XX individuals confirms its pivotal role in reproductive biology, and should alert clinicians to the possibility of NR5A1 defects in a variety of phenotypes presenting with gonadal dysfunction. Birth Defects Research (Part C) 108:309–320, 2016. © 2016 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc.