Heterozygous Nonsense Mutation in the Androgen Receptor Gene Associated with Partial Androgen Insensitivity Syndrome in an Individual with 47,XXY Karyotype

Batista, Rafael Loch; Rodrigues, Andresa De Santi; Nishi, Mirian Yumie; Feitosa, Alina Coutinho Rodrigues; Gomes, Nathália Lisboa; F., José Antonia; Domenice, Sorahia; Costa, Elaine Maria Frade; Mendonça, Berenice Bilharinho

doi:10.1159/000468957

Cited by 8 publications

(4 citation statements)

References 14 publications

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“…It is hypothesized that AR co-regulators (activators and repressors) are implicated with this phenomenon. Other possibilities are variations in the level of 5α-reductase type 2 activity resulting in different DHT availability, and the presence of germ-line AR allelic variants at a post zygote stage conferring somatic mosaicism (31).…”

Section: Molecular Defects In the Androgen Receptor Genementioning

confidence: 99%

Androgen insensitivity syndrome: a review

Batista¹,

Costa²,

Rodrigues³

et al. 2018

Archives of Endocrinology and Metabolism

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129

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Androgenic insensitivity syndrome is the most common cause of disorders of sexual differentiation in 46,XY individuals. It results from alterations in the androgen receptor gene, leading to a frame of hormonal resistance, which may present clinically under 3 phenotypes: complete (CAIS), partial (PAIS) or mild (MAIS). The androgen receptor gene has 8 exons and 3 domains, and allelic variants in this gene occur in all domains and exons, regardless of phenotype, providing a poor genotype - phenotype correlation in this syndrome. Typically, laboratory diagnosis is made through elevated levels of LH and testosterone, with little or no virilization. Treatment depends on the phenotype and social sex of the individual. Open issues in the management of androgen insensitivity syndromes includes decisions on sex assignment, timing of gonadectomy, fertility, physcological outcomes and genetic counseling.

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Section: Molecular Defects In the Androgen Receptor Genementioning

confidence: 99%

Androgen insensitivity syndrome: a review

Batista¹,

Costa²,

Rodrigues³

et al. 2018

Archives of Endocrinology and Metabolism

Self Cite

129

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“…Patients carrying a digenic or combined DSD disease have been described even before the era of high throughput sequencing (HTS), when either the phenotype suggested the involvement of more than one gene defect or, incidentally, when an abnormal sex-chromosome karyotype is combined with an another gene defect [29][30][31][32][33][34][35].…”

Section: Introductionmentioning

confidence: 99%

“…Androgen receptor gene (AR) defects have occasionally been described in patients with a complete or partial androgen insensitivity syndrome (CAIS or PAIS) in whom sex chromosome analysis revealed a 47,XXY karyotype corresponding to a Klinefelter syndrome [29][30][31][32]. Similarly, a patient with a clinical and molecular diagnosis of familial male-limited precocious puberty due to an activating LHCGR mutation was demonstrated to have a 47,XXY karyotype upon detection of abnormally increased gonadotropin levels [33].…”

Section: Introductionmentioning

confidence: 99%

Oligogenic Origin of Differences of Sex Development in Humans

Camats

Flück

Audí

2020

IJMS

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Sex development is a very complex biological event that requires the concerted collaboration of a large network of genes in a spatial and temporal correct fashion. In the past, much has been learned about human sex development from monogenic disorders/differences of sex development (DSD), but the broad spectrum of phenotypes in numerous DSD individuals remains a conundrum. Currently, the genetic cause of less than 50% of DSD individuals has been solved and oligogenic disease has been proposed. In recent years, multiple genetic hits have been found in individuals with DSD thanks to high throughput sequencing. Our group has been searching for additional genetic hits explaining the phenotypic variability over the past years in two cohorts of patients: 46,XY DSD patients carriers of NR5A1 variants and 46,XY DSD and 46,XX DSD with MAMLD1 variants. In both cohorts, our results suggest that the broad phenotypes may be explained by oligogenic origin, in which multiple hits may contribute to a DSD phenotype, unique to each individual. A search for an underlying network of the identified genes also revealed that a considerable number of these genes showed interactions, suggesting that genetic variations in these genes may affect sex development in concert.

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“…The current study included three cases of ambiguous genitalia with KS. There are three cases of 47,XXY karyotype and AR gene mutation published in the literature ( 26 , 27 , 28 ). Two of them were reported to have complete androgen insensitivity syndrome whereas the other one had partial androgen insensitivity syndrome.…”

Section: Discussionmentioning

confidence: 99%

Klinefelter Syndrome in Childhood: Variability in Clinical and Molecular Findings

Akcan

Poyrazoğlu

Baş

et al. 2018

Jcrpe

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Objective:Klinefelter syndrome (KS) is the most common (1/500–1/1000) chromosomal disorder in males, but only 10% of cases are identified in childhood. This study aimed to review the data of children with KS to assess the age and presenting symptoms for diagnosis, clinical and laboratory findings, together with the presence of comorbidities.Methods:Twenty-three KS patients were analyzed retrospectively. Age at admission, presenting symptoms, comorbid problems, height, weight, pubertal status, biochemical findings, hormone profiles, bone mineral density and karyotype were evaluated. Molecular analysis was also conducted in patients with ambiguous genitalia.Results:The median age of patients at presentation was 3.0 (0.04-16.3) years. Most of the cases were diagnosed prenatally (n=15, 65.2%). Other reasons for admission were scrotal hypospadias (n=3, 14.3%), undescended testis (n=2, 9.5%), short stature (n=1, 4.8%), isolated micropenis (n=1, 4.8%) and a speech disorder (n=1, 4.8%). The most frequent clinical findings were neurocognitive disorders, speech impairment, social and behavioral problems and undescended testes. All except two patients were prepubertal at admission. Most of the patients (n=20, 86.9%) showed the classic 47,XXY karyotype. Steroid 5 alpha-reductase 2 gene and androgen receptor gene mutations were detected in two of the three cases with genital ambiguity.Conclusion:Given the large number of underdiagnosed KS patients before adolescence, pediatricians need to be aware of the phenotypic variability of KS in childhood. Genetic analysis in KS patients may reveal mutations associated with other forms of disorders of sex development besides KS.

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Heterozygous Nonsense Mutation in the Androgen Receptor Gene Associated with Partial Androgen Insensitivity Syndrome in an Individual with 47,XXY Karyotype

Cited by 8 publications

References 14 publications

Androgen insensitivity syndrome: a review

Androgen insensitivity syndrome: a review

Oligogenic Origin of Differences of Sex Development in Humans

Klinefelter Syndrome in Childhood: Variability in Clinical and Molecular Findings

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