The Long-Term Outcome of Boys With Partial Androgen Insensitivity Syndrome and a Mutation in the Androgen Receptor Gene

Abstract

Background:In boys with suspected partial androgen insensitivity syndrome (PAIS), systematic evidence that supports the long-term prognostic value of identifying a mutation in the androgen receptor gene (AR) is lacking.Objective:To assess the clinical characteristics and long-term outcomes in young men with suspected PAIS in relation to the results of AR analysis.Methods:Through the International Disorders of Sex Development Registry, clinical information was gathered on young men suspected of having PAIS (n = 52) who presented before the age of 16 years and had genetic analysis of AR.Results:The median ages at presentation and at the time of the study were 1 month (range, 1 day to 16 years) and 22 years (range, 16 to 52 years), respectively. Of the cohort, 29 men (56%) had 20 different AR mutations reported. At diagnosis, the median external masculinization scores were 7 and 6 in cases with and without AR mutation, respectively (P = .9), and median current external masculinization scores were 9 and 10, respectively (P = .28). Thirty-five men (67%) required at least one surgical procedure, and those with a mutation were more likely to require multiple surgeries for hypospadias (P = .004). All cases with an AR mutation had gynecomastia, compared to 9% of those without an AR mutation. Of the six men who had a mastectomy, five (83%) had an AR mutation.Conclusions:Boys with genetically confirmed PAIS are likely to have a poorer clinical outcome than those with XY DSD, with normal T synthesis, and without an identifiable AR mutation. Routine genetic analysis of AR to confirm PAIS informs long-term prognosis and management.

Large divergence in testosterone concentrations between men and women: Frame of reference for elite athletes in sex‐specific competition in sports, a narrative review

“…The testosterone levels in the genetic males with 5ARD2 and AIS are shown in Table 2. 7,[24][25][26][27][28][29][30][31][32][33][34] These values are from individuals with a range of phenotypes and varying degrees of virilization.…”

“…Males with AIS had mean/ medians ranging from 11.9 to 55.7 nmol/L (343-1605 ng/dL), and the overall absolute range was 4.8-68.3 nmol/L (138-1968 ng/dL)(Table 3) 7,28,[30][31][32][33][34]. 7,24-34 These values are from individuals with a range of phenotypes and varying degrees of virilization.…”

Association Between Extra-Genital Congenital Anomalies and Hypospadias Outcome

“…Proximal hypospadias is more likely to be associated with a reduced anogenital distance, a marker of prenatal androgen exposure [Cox et al, 2017]. Given that conditions associated with a defect in the androgen receptor (AR) are more likely to be associated with multiple hypospadias surgery [Lucas-Herald et al, 2016], it is plausible that the increased rate of complications in cases of proximal hypospadias may be partly related to the effect that reduced androgen exposure may exert during critical periods of prenatal development. In cases of hypospadias, extra-genital anomalies may also be part of a constellation that points towards a specific genetic aetiology [van der Zanden et al, 2012;Bouty et al, 2015].…”

Methodological Issues for Psychological Evaluation across the Lifespan of Individuals with a Difference/Disorder of Sex Development

“…Further potential methodological complications relate specifically to the evaluation of physical, psychological, and emotional sequelae of surgical intervention for genital malformations [Lucas-Herald et al, 2016;Mouriquand et al, 2016]. Although such studies often employ standardized measures for current functioning, conclusions may not apply to clinical practice going forward.…”