Partial androgen insensitivity syndrome due to somatic mosaicism of the androgen receptor

Batista, Rafael Loch; Rodrigues, Andresa De Santi; Machado, Aline Zamboni; Nishi, Mirian Yumie; Cunha, Flávia Siqueira; Silva, Rosana Barbosa; Costa, Elaine Maria Frade; Mendonca, Berenice B.; Domenice, Sorahia

doi:10.1515/jpem-2017-0095

Cited by 14 publications

(14 citation statements)

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“…Current in vitro methods are likely to be sensitive enough only to detect the most extreme of functional defects. There are also examples of mosaic expression of AR mutations in PAIS which can explain variable phenotypes [ [23] , [24] , [25] ]. The question of mosaicism was not systematically examined in this study.…”

Section: Discussionmentioning

confidence: 99%

Predicting puberty in partial androgen insensitivity syndrome: Use of clinical and functional androgen receptor indices

et al. 2018

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BackgroundPAIS exhibits a complex spectrum of phenotypes and pubertal outcomes. The paucity of reliable prognostic indicators can confound management decisions including sex-of-rearing. We assessed whether external masculinisation score (EMS) at birth or functional assays correlates with pubertal outcome in PAIS patients and whether the EMS is helpful in sex assignment.MethodsWe collected pubertal outcome data for 27 male-assigned PAIS patients, all with confirmed androgen receptor (AR) mutations, including two previously uncharacterized variants (I899F; Y916C). Patients were grouped as follows; EMS at birth <5 and ≥ 5 (EMS in normal males is 12; median EMS in PAIS is 4·7) and pubertal outcomes compared.FindingsOnly 6/9 patients (67%) with EMS <5 underwent spontaneous onset of puberty, versus all 18 patients with EMS ≥5 (p = .03). Only 1/6 patients (17%) with EMS <5 developed adult genitalia reaching Tanner stage 4 or 5, versus 11/13 (85%) with EMS ≥5 (p = 0·01). There was no significant difference between the two groups of patients in being prescribed androgen replacement, who reached adult testicular volume ≥ 15 ml, pubic hair Tanner stage 4 or 5, above average adult height, had gynaecomastia, and mastectomy. No correlation was observed between EMS and in vitro AR function.InterpretationIn PAIS with AR mutation, birth EMS is a simple predictor of spontaneous pubertal onset and satisfactory adult genitalia. This provides useful information when discussing the likely options for management at puberty.FundEuropean Commission Framework 7 Programme, NIHR Cambridge Biomedical Research Centre, BBSRC DTP.

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Section: Discussionmentioning

confidence: 99%

Predicting puberty in partial androgen insensitivity syndrome: Use of clinical and functional androgen receptor indices

et al. 2018

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“…As examples, synonymous variants of the Androgen Receptor (AR) gene proved to be causative of both partial and complete phenotype of AIS as well as post-zygotic mosaicism. 76,77 Epigenetic alterations compromising AR expression were reported in patients which were negative for AR mutations but presented clinical evidence of AIS. 78 Single nucleotide change in the 5ʹUTR region of the AR was able to cause a new open frame region leading to CAIS.…”

Section: Functional Studies On Allelic Variants Of the Srd5a2 Genementioning

confidence: 99%

<p>Integrative and Analytical Review of the 5-Alpha-Reductase Type 2 Deficiency Worldwide</p>

Batista¹,

Mendonca²

2020

TACG

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The conversion of testosterone into dihydrotestosterone is catalyzed by the 5αreductase type 2 enzyme which plays a crucial role in the external genitalia virilization. It is encoded by the SRD5A2 gene. Allelic variants in this gene cause a 46,XY DSD with no genotype-phenotype relationship. It was firstly reported in the early 70s from isolated clusters. Since then, several cases have been reported. Putting together, it will expand the knowledge on the molecular bases of androgen milieu. Methods: We searched for SRD5A2 allelic variants (AV) in the literature (PubMed, Embase, MEDLINE) and websites (ensembl, HGMD, ClinVar). Only cases with AV in both alleles, either in homozygous or compound heterozygous were included. The included cases were analyzed according to ethnicity, exon, domain, aminoacid (aa) conservation, age at diagnosis, sex assignment, gender reassignment, external genitalia virilization and functional studies. External genitalia virilization was scored using Sinnecker scale. Conservation analysis was carried out using the CONSURF platform. For categorical variables, we used X2 test and Cramer's V. Continuous variables were analyzed by t test or ANOVA. Concordance was estimated by Kappa. Results: We identified 434 cases of 5ARD2 deficiencies from 44 countries. Most came from Turkey (23%), China (17%), Italy (9%), and Brazil (7%). Sixty-nine percent were assigned as female. There were 70% of homozygous allelic variants and 30% compound heterozygous. Most were missense variants (76%). However, small indels (11%), splicing (5%) and large deletions (4%) were all reported. They were distributed along with all exons with exon 1 (33%) and exon 4 (25%) predominance. Allelic variants in the exon 4 (NADPH-binding domain) resulted in lower virilization (p<0.0001). The codons 55, 65, 196, 235 and 246 are hotspots making up 25% of all allelic variants. Most of them (76%) were located at conserved aa. However, allelic variants at non-conserved aa were more frequently indels (28% vs 6%; p<0.01). The overall rate of gender change from female to male ranged from 16% to 70%. The lowest rate of gender change from female to male occurred in Turkey and the highest in Brazil. External genitalia virilization was similar between those who changed and those who kept their assigned gender. The gender change rate was significantly different across the countries (V=0.44; p<0.001) even with similar virilization scores. Conclusion: 5ARD2 deficiency has a worldwide distribution. Allelic variants at the NADPHligand region cause lower virilization. Genitalia virilization influenced sex assignment but not gender change which was influenced by cultural aspects across the countries. Molecular diagnosis influenced on sex assignment, favoring male sex assignment in newborns with 5α-reductase type 2 deficiency.

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“…Current in vitro methods are likely to be sensitive enough only to detect the most extreme of functional defects. There are also examples of mosaic expression of AR mutations in PAIS which can explain variable phenotypes [23][24][25]. The question of mosaicism was not systematically examined in this study.…”

Section: Discussionmentioning

confidence: 98%

Predicting Puberty in Partial Androgen Insensitivity Syndrome: Use of Clinical and Functional Androgen Receptor Indices

et al. 2018

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Background: PAIS exhibits a complex spectrum of phenotypes and pubertal outcomes. The paucity of reliable prognostic indicators can confound management decisions including sex-of-rearing. We assessed whether external masculinisation score (EMS) at birth or functional assays correlates with pubertal outcome in PAIS patients and whether the EMS is helpful in sex assignment. Methods: We collected pubertal outcome data for 27 male-assigned PAIS patients, all with confirmed androgen receptor (AR) mutations, including two previously uncharacterized variants (I899F; Y916C). Patients were grouped as follows; EMS at birth b5 and ≥ 5 (EMS in normal males is 12; median EMS in PAIS is 4•7) and pubertal outcomes compared. Findings: Only 6/9 patients (67%) with EMS b5 underwent spontaneous onset of puberty, versus all 18 patients with EMS ≥5 (p = .03). Only 1/6 patients (17%) with EMS b5 developed adult genitalia reaching Tanner stage 4 or 5, versus 11/13 (85%) with EMS ≥5 (p = 0•01). There was no significant difference between the two groups of patients in being prescribed androgen replacement, who reached adult testicular volume ≥ 15 ml, pubic hair Tanner stage 4 or 5, above average adult height, had gynaecomastia, and mastectomy. No correlation was observed between EMS and in vitro AR function. Interpretation: In PAIS with AR mutation, birth EMS is a simple predictor of spontaneous pubertal onset and satisfactory adult genitalia. This provides useful information when discussing the likely options for management at puberty.

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Partial androgen insensitivity syndrome due to somatic mosaicism of the androgen receptor

Cited by 14 publications

References 20 publications

Predicting puberty in partial androgen insensitivity syndrome: Use of clinical and functional androgen receptor indices

Predicting puberty in partial androgen insensitivity syndrome: Use of clinical and functional androgen receptor indices

<p>Integrative and Analytical Review of the 5-Alpha-Reductase Type 2 Deficiency Worldwide</p>

Predicting Puberty in Partial Androgen Insensitivity Syndrome: Use of Clinical and Functional Androgen Receptor Indices

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