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

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 sp...

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Autores principales: Domenice, Sorahia, Machado, Aline Zamboni, Ferreira, Frederico Moraes, Ferraz‐de‐Souza, Bruno, Lerario, Antonio Marcondes, Lin, Lin, Nishi, Mirian Yumie, Gomes, Nathalia Lisboa, da Silva, Thatiana Evelin, Silva, Rosana Barbosa, Correa, Rafaela Vieira, Montenegro, Luciana Ribeiro, Narciso, Amanda, Costa, Elaine Maria Frade, Achermann, John C, Mendonca, Berenice Bilharinho
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347970/
https://www.ncbi.nlm.nih.gov/pubmed/28033660
http://dx.doi.org/10.1002/bdrc.21145
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author Domenice, Sorahia
Machado, Aline Zamboni
Ferreira, Frederico Moraes
Ferraz‐de‐Souza, Bruno
Lerario, Antonio Marcondes
Lin, Lin
Nishi, Mirian Yumie
Gomes, Nathalia Lisboa
da Silva, Thatiana Evelin
Silva, Rosana Barbosa
Correa, Rafaela Vieira
Montenegro, Luciana Ribeiro
Narciso, Amanda
Costa, Elaine Maria Frade
Achermann, John C
Mendonca, Berenice Bilharinho
author_facet Domenice, Sorahia
Machado, Aline Zamboni
Ferreira, Frederico Moraes
Ferraz‐de‐Souza, Bruno
Lerario, Antonio Marcondes
Lin, Lin
Nishi, Mirian Yumie
Gomes, Nathalia Lisboa
da Silva, Thatiana Evelin
Silva, Rosana Barbosa
Correa, Rafaela Vieira
Montenegro, Luciana Ribeiro
Narciso, Amanda
Costa, Elaine Maria Frade
Achermann, John C
Mendonca, Berenice Bilharinho
author_sort Domenice, Sorahia
collection PubMed
description 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.
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spelling pubmed-53479702017-03-23 Wide spectrum of NR5A1‐related phenotypes in 46,XY and 46,XX individuals Domenice, Sorahia Machado, Aline Zamboni Ferreira, Frederico Moraes Ferraz‐de‐Souza, Bruno Lerario, Antonio Marcondes Lin, Lin Nishi, Mirian Yumie Gomes, Nathalia Lisboa da Silva, Thatiana Evelin Silva, Rosana Barbosa Correa, Rafaela Vieira Montenegro, Luciana Ribeiro Narciso, Amanda Costa, Elaine Maria Frade Achermann, John C Mendonca, Berenice Bilharinho Birth Defects Res C Embryo Today Reviews 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. John Wiley and Sons Inc. 2016-12-29 2016-12 /pmc/articles/PMC5347970/ /pubmed/28033660 http://dx.doi.org/10.1002/bdrc.21145 Text en © 2016 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Reviews
Domenice, Sorahia
Machado, Aline Zamboni
Ferreira, Frederico Moraes
Ferraz‐de‐Souza, Bruno
Lerario, Antonio Marcondes
Lin, Lin
Nishi, Mirian Yumie
Gomes, Nathalia Lisboa
da Silva, Thatiana Evelin
Silva, Rosana Barbosa
Correa, Rafaela Vieira
Montenegro, Luciana Ribeiro
Narciso, Amanda
Costa, Elaine Maria Frade
Achermann, John C
Mendonca, Berenice Bilharinho
Wide spectrum of NR5A1‐related phenotypes in 46,XY and 46,XX individuals
title Wide spectrum of NR5A1‐related phenotypes in 46,XY and 46,XX individuals
title_full Wide spectrum of NR5A1‐related phenotypes in 46,XY and 46,XX individuals
title_fullStr Wide spectrum of NR5A1‐related phenotypes in 46,XY and 46,XX individuals
title_full_unstemmed Wide spectrum of NR5A1‐related phenotypes in 46,XY and 46,XX individuals
title_short Wide spectrum of NR5A1‐related phenotypes in 46,XY and 46,XX individuals
title_sort wide spectrum of nr5a1‐related phenotypes in 46,xy and 46,xx individuals
topic Reviews
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347970/
https://www.ncbi.nlm.nih.gov/pubmed/28033660
http://dx.doi.org/10.1002/bdrc.21145
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