2. Academic Validation
  3. Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals

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

  • Birth Defects Res C Embryo Today. 2016 Dec;108(4):309-320. doi: 10.1002/bdrc.21145.
Sorahia Domenice 1,  Aline Zamboni Machado 1,  Frederico Moraes Ferreira 2,  Bruno Ferraz-de-Souza 1,  Antonio Marcondes Lerario 1,  Lin Lin 3,  Mirian Yumie Nishi 1,  Nathalia Lisboa Gomes 1,  Thatiana Evelin da Silva 1,  Rosana Barbosa Silva 1,  Rafaela Vieira Correa 4,  Luciana Ribeiro Montenegro 1,  Amanda Narciso 1,  Elaine Maria Frade Costa 1,  John C Achermann 3,  Berenice Bilharinho Mendonca 1
Affiliations

Affiliations

  • 1 Sorahia Domenice, Aline Zamboni Machado, Bruno Ferraz-de-Souza, Antonio Marcondes Lerario, Mirian Yumie Nishi, Nathalia Lisboa Gomes, Thatiana Evelin da Silva, Rosana Barbosa Silva, Luciana R. Montenegro, Amanda Narciso, Elaine Maria Frade Costa, and Berenice Bilharinho Mendonca are from the Laboratório de Hormônios e Genética Molecular (LIM/42), Unidade de Endocrinologia do Desenvolvimento, Disciplina de Endocrinologia e Metabologia do Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brasil.
  • 2 Frederico Moraes Ferreira is from the Ciências da Saúde, Universidade Santo Amaro, São Paulo, Brasil and Laboratorio de Imunologia, Instituto do Coração, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brasil.
  • 3 Lin Lin and John C. Achermann are form the Genetics & Genomic Medicine, University College London (UCL) Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
  • 4 Rafaela V. Correa is from the Núcleo de Atenção Médica Integrada (NAMI), Universidade de Fortaleza, Ceará, Brasil.
PMID: 28033660 DOI: 10.1002/bdrc.21145
Abstract

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.

Keywords

NR5A1 gene; adrenal insufficiency; disorders of sex development; gonadal dysgenesis; ovotestis; primary ovarian failure.

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