Long-Term Follow-Up of Patients with 46,XY Partial Gonadal Dysgenesis Reared as Males

Andrade, Juliana Gabriel Ribeiro de; Marques-de-Faria, Antônia Paula; Fabbri, Helena Campos; Mello, Maricilda Palandi de; Guerra‐Júnior, Gil; Maciel‐Guerra, Andréa Trevas

doi:10.1155/2014/480724

Cited by 25 publications

(20 citation statements)

References 23 publications

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“…Progressive androgen production and virilization in adolescence has been observed in several XY patients with NR5A1 mutations, in contrast to the severe undervirilized external genitalia found in most patients (Cools et al, 2012; Gabriel Ribeiro de Andrade et al, 2014; Tantawy et al, 2014; Fabbri et al, 2016). The almost normal testosterone levels after hCG stimulation or at pubertal age suggest that NR5A1 action may be less implicated in pubertal steroidogenesis than during fetal life.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Domenice¹,

Machado²,

Ferreira

et al. 2016

Birth Defects Research Pt C

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Domenice¹,

Machado²,

Ferreira

et al. 2016

Birth Defects Research Pt C

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“…In one retrospective study on pubertal development of 46,XY PGD patients, 9 of 10 patients had gone through spontaneous puberty with high FSH levels and progressive elevation of LH . These patients had a mild‐gonadal‐dysgenesis phenotype as 60% had a penile urethra opening and all of them were assigned male at birth …”

Section: Discussionmentioning

confidence: 99%

“…There are scarce data on long‐term follow‐up of 46,XY partial gonadal dysgenesis (PGD) patients, regarding spontaneous puberty, risk of a gonadal tumour development and gender adjustment, making it difficult to provide comprehensive information to parents.…”

Section: Introductionmentioning

confidence: 99%

Long‐term outcomes and molecular analysis of a large cohort of patients with 46,XY disorder of sex development due to partial gonadal dysgenesis

Gomes

Lerário

Machado

et al. 2018

Clinical Endocrinology

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“…Male sex assignment was maintained, both gonads were preserved, and correction of hypospadias was performed at the age of 6 years. He has been followed‐up for the last 29 years and showed normal growth, spontaneous puberty with gynecomastia, and elevated gonadotropins with normal testosterone (Gabriel Ribeiro de Andrade et al., ). NR5A1 analysis revealed the mutation c.95G > A (p.Ser32Asn) within exon 2.…”

Section: Methodsmentioning

confidence: 99%

Functional characterization of fiveNR5A1gene mutations found in patients with 46,XY disorders of sex development

et al. 2017

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Steroidogenic factor-1 (SF1), encoded by the NR5A1 gene, is a key regulator of steroidogenesis and reproductive development. NR5A1 mutations described in 46,XY patients with disorders of sex development (DSD) can be associated with a range of conditions of phenotypes; however, the genotype-phenotype correlation remains elusive in many cases. In the present study, we describe the impact of five NR5A1 variants (three novel: p.Arg39Cys, p.Ser32Asn, and p.Lys396Argfs*34; and two previously described: p.Cys65Tyr and p.Cys247*) on protein function, identified in seven patients with 46,XY DSD. In vitro functional analyses demonstrate that NR5A1 mutations impair protein functions and result in the DSD phenotype observed in our patients. Missense mutations in the DNA binding domain and the frameshift mutation p.Lys396Argfs*34 lead to both, markedly affected transactivation assays, and loss of DNA binding, whereas the mutation p.Cys247* retained partial transactivation capacity and the ability to bind a consensus SF1 responsive element. SF1 acts in a dose-dependent manner and regulates a cascade of genes involved in the sex determination and steroidogenesis, but in most cases reported so far, still lead to a sufficient adrenal steroidogenesis and function, just like in our cases, in which heterozygous mutations are associated to 46,XY DSD with intact adrenal steroid biosynthesis.

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Long-Term Follow-Up of Patients with 46,XY Partial Gonadal Dysgenesis Reared as Males

Cited by 25 publications

References 23 publications

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

Long‐term outcomes and molecular analysis of a large cohort of patients with 46,XY disorder of sex development due to partial gonadal dysgenesis

Functional characterization of fiveNR5A1gene mutations found in patients with 46,XY disorders of sex development

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