Androgen insensitivity syndrome

Mongan, Nigel P.; Tadokoro-Cuccaro, Rieko; Bunch, Trevor; Hughes, Ieuan A.

doi:10.1016/j.beem.2015.04.005

Cited by 166 publications

(82 citation statements)

References 101 publications

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“…While the vast majority of CAIS cases (90-95%) are attributable to AR mutations, less than a third of cases with a phenotype consistent with PAIS are associated with AR mutations (15), To date, more than 800 mutations have been identified in the AR gene (7,16,17). In the current patient, detailed family history revealed male relatives from the maternal side with similar clinical phenotype suggesting an X-linked trait, which was an important clue for the diagnosis of PAIS.…”

Section: Discussionmentioning

confidence: 99%

A Novel Mutation in Human Androgen Receptor Gene Causing Partial Androgen Insensitivity Syndrome in a Patient Presenting with Gynecomastia at Puberty

Koçyiğit¹,

Sarıtaş²,

Çatlı³

et al. 2016

Jcrpe

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Partial androgen insensitivity syndrome (PAIS) typically presents with micropenis, perineoscrotal hypospadias, and a bifid scrotum with descending or undescending testes and gynecomastia at puberty. It is an X-linked recessive disorder resulting from mutations in the androgen receptor (AR) gene. However, AR gene mutations are found in less than a third of PAIS cases. A 16-year-old boy was admitted with complaints of gynecomastia and sparse facial hair. Family history revealed male relatives from maternal side with similar clinical phenotype. His external genitalia were phenotypically male with pubic hair Tanner stage IV, penoscrotal hypospadias, and a bifid scrotum with bilateral atrophic testes. He had elevated gonadotropins with a normal testosterone level. Chromosome analysis revealed a 46,XY karyotype. Due to the family history suggesting a disorder of X-linked trait, PAIS was considered and molecular analysis of AR gene was performed. DNA sequence analysis revealed a novel hemizygous mutation p.T576I (c.1727C>T) in the AR gene. The diagnosis of PAIS is based upon clinical phenotype and laboratory findings and can be confirmed by detection of a defect in the AR gene. An accurate approach including a detailed family history suggesting an X-linked trait is an important clue for a quick diagnosis.

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Section: Discussionmentioning

confidence: 99%

A Novel Mutation in Human Androgen Receptor Gene Causing Partial Androgen Insensitivity Syndrome in a Patient Presenting with Gynecomastia at Puberty

Koçyiğit¹,

Sarıtaş²,

Çatlı³

et al. 2016

Jcrpe

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“…8,9 Elucidating the underlying causes of DSD can facilitate sex assignment and lead to improved management, a better prognosis and a more accurate evaluation of gonadal function and gonadal germ cell cancer risk. 10 So far, mutations in genes encoding nuclear receptors, such as NR5A1 (also known as the steroidogenic factor 1 gene, or SF1) 11 and the androgen receptor NR3C4 gene 12 have been implicated in DSD pathogenesis as well as the duplication of the nuclear receptor subfamily 0 group B member 1 gene (NR0B1, DAX1). 13 Here, we identified biallelic and monoallelic estrogen receptor 2 (ESR2) variants in one syndromic and two nonsyndromic 46,XY DSD cases, respectively, putting forward ESR2 as a novel disease gene for 46,XY DSD and expanding the spectrum of nuclear receptors implicated in 46,XY DSD etiology.…”

Section: Introductionmentioning

confidence: 99%

Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development

Baetens

Güran

Mendonça

et al. 2018

Genetics in Medicine

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Purpose: Disorders or differences of sex development (DSDs) are rare congenital conditions characterized by atypical sex development. Despite advances in genomic technologies, the molecular cause remains unknown in 50% of cases.Methods: Homozygosity mapping and whole-exome sequencing revealed an ESR2 variant in an individual with syndromic 46,XY DSD. Additional cases with 46,XY DSD underwent whole-exome sequencing and targeted next-generation sequencing of ESR2. Functional characterization of the identified variants included luciferase assays and protein structure analysis. Gonadal ESR2 expression was assessed in human embryonic data sets and immunostaining of estrogen receptor-β (ER-β) was performed in an 8-week-old human male embryo.

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“…Androgen insensitivity syndrome (AIS) (online inheritance in man number 300068) is a DSD that is classically characterized as a disorder of hormone action due to a reduced or absent functionality of the androgen receptor (AR) protein encoded by the AR gene. AIS is often suspected to be a common cause of DSD in a 46,XY individual and may be associated with complete feminization of the external genitalia due to a complete lack of AR transcriptional activity (complete AIS [CAIS]) (4), a variable level of feminization/masculinization due to a partial lack of transcriptional activity (partial AIS [PAIS]), or isolated male infertility (mild AIS [MAIS]).…”

mentioning

confidence: 99%

Identification of an AR Mutation-Negative Class of Androgen Insensitivity by Determining Endogenous AR Activity

Hornig

Ukat

Schweikert

et al. 2016

The Journal of Clinical Endocrinology & Metabolism

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Context:Only approximately 85% of patients with a clinical diagnosis complete androgen insensitivity syndrome and less than 30% with partial androgen insensitivity syndrome can be explained by inactivating mutations in the androgen receptor (AR) gene.Objective:The objective of the study was to clarify this discrepancy by in vitro determination of AR transcriptional activity in individuals with disorders of sex development (DSD) and male controls.Design:Quantification of DHT-dependent transcriptional induction of the AR target gene apolipoprotein D (APOD) in cultured genital fibroblasts (GFs) (APOD assay) and next-generation sequencing of the complete coding and noncoding AR locus.Setting:The study was conducted at a university hospital endocrine research laboratory.Patients:GFs from 169 individuals were studied encompassing control males (n = 68), molecular defined DSD other than androgen insensitivity syndrome (AIS; n = 18), AR mutation-positive AIS (n = 37), and previously undiagnosed DSD including patients with a clinical suspicion of AIS (n = 46).Intervention(s):There were no interventions.Main Outcome Measure(s):DHT-dependent APOD expression in cultured GF and AR mutation status in 169 individuals was measured.Results:The APOD assay clearly separated control individuals (healthy males and molecular defined DSD patients other than AIS) from genetically proven AIS (cutoff < 2.3-fold APOD-induction; 100% sensitivity, 93.3% specificity, P < .0001). Of 46 DSD individuals with no AR mutation, 17 (37%) fell below the cutoff, indicating disrupted androgen signaling.Conclusions:AR mutation-positive AIS can be reliably identified by the APOD assay. Its combination with next-generation sequencing of the AR locus uncovered an AR mutation-negative, new class of androgen resistance, which we propose to name AIS type II. Our data support the existence of cellular components outside the AR affecting androgen signaling during sexual differentiation with high clinical relevance.

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Androgen insensitivity syndrome

Cited by 166 publications

References 101 publications

A Novel Mutation in Human Androgen Receptor Gene Causing Partial Androgen Insensitivity Syndrome in a Patient Presenting with Gynecomastia at Puberty

A Novel Mutation in Human Androgen Receptor Gene Causing Partial Androgen Insensitivity Syndrome in a Patient Presenting with Gynecomastia at Puberty

Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development

Identification of an AR Mutation-Negative Class of Androgen Insensitivity by Determining Endogenous AR Activity

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