ESPE Abstracts (2021) 94 P1-150

1Department of Pediatrics, Division of Pediatric Endocrinology and Diabetes, Christian-Albrechts-University & UKSH, Kiel, Germany; 2Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany; 3Institute of Human Genetics, Christian-Albrechts-University & UKSH, Kiel, Germany; 4Department of Internal Medicine, Division III, University Hospital Bonn, Bonn, Germany; 5Department of Internal Medicine, Division IIPediatric Endocrinology Research Unit, Hospital Universitari Vall d’Hebron, Barcelona, Spain; 6Department of Pediatric Endocrinology, Ghent University Hospital & Ghent University, Ghent, Belgium; 7Department of Pediatric Endocrinology, UMC Amsterdam, Amsterdam, Netherlands; 8Division of Pediatric Endocrinology, Wilhelmina Kinderziekenhuis Utrecht, Utrecht, Netherlands; 9Department of Pediatrics, Division of Pediatric Endocrinology & University Luebeck, Luebeck, Germany

Introduction: Androgen insensitivity syndrome (AIS) is a 46,XY difference of sex development (DSD) classically caused by mutations in the X-chromosomal androgen receptor (AR) gene. Nevertheless, in over 50% of individuals with clinical AIS no AR coding gene mutation can be found. We previously established an assay (apolipoprotein D (APOD) assay) that measures androgen dependent AR-activity in genital skin fibroblasts (GFs). Using this assay we identified a group of GFs with reduced AR function in the absence of an AR coding gene mutation, called AIS type II.

Objective: Investigation of the prevalence of AIS type II based on GFs derived from a large cohort of patients with DSD and clinically presumed AIS and further characterization of this group of AR mutation-negative AIS.

Methods: Assessment of AR function in GFs from individuals with clinical AIS but no AR coding gene mutation (n = 95). AR mRNA and protein expression measurement in GFs with reduced AR function and male control GFs. DNA-methylation analysis on the AR promotor in GFs with reduced AR mRNA expression and male control GFs. Exome-sequencing of AIS type II GFs.

Results: 31 out of 95 GFs (33%) from individuals with clinical AIS but no mutation in the AR gene fell in the group AIS type II. Three of them (9.6%) showed normal AR mRNA but reduced AR protein expression levels, nine (29%) showed reduced AR mRNA and protein expression levels and 19 (61%) showed normal AR mRNA and protein expression. Out of the nine GFs with reduced AR mRNA expression, four showed significantly higher AR promotor methylation levels explaining the reduced AR expression. Exome-sequencing of 26 AIS type II GF revealed in 12 cases likely pathogenic variants in known DSD-genes other than the AR and in 10 cases likely pathogenic variants in genes so far unrelated to DSD. In four cases no candidate genes were identified.

Conclusion: One third of individuals clinically diagnosed with AIS but without a mutation in the AR coding gene show a reduced expression and/or function of the AR (AIS type II). Exome sequencing of AIS type II GFs revealed both known and unknown candidate DSD-genes as potential cofactors of AR-activity. Two thirds of examined cases show a normal APOD induction. In these cases either transcriptional targets downstream of the AR could be affected or the underlying DSD diagnosis is not AIS due to insufficient specificity of the clinical and hormonal findings.

Volume 94

59th Annual ESPE (ESPE 2021 Online)

22 Sep 2021 - 26 Sep 2021

European Society for Paediatric Endocrinology 

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