ESPE Abstracts (2018) 89 P-P1-217

aDepartment of Pediatrics, Division of Pediatric Endocrinology and Diabetes, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Kiel, Germany; bInstitute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Kiel, Germany; cInstitute of Biochemistry and Molecular Biology, University of Bonn, Bonn, Germany; dDepartment of Internal Medicine, Division III, Universitätsklinikum Bonn, Bonn, Germany; ePediatric Endocrinology Research Unit, VHIR (Vall d’Hebron Institut de Recerca), Hospital Universitari Vall d’Hebron, CIBERER (Center for Biomedical Research on Rare Diseases), Instituto de Salud Carlos III, Barcelona, Spain; fDepartment of Pediatrics, Division of Pediatric Endocrinology, University Luebeck, Luebeck, Germany

Background: Individuals born with a 45,X/46,XY karyotype can present with diverging phenotypes from normal male, Turner-like to ambiguous genitalia, the latter classically being called mixed gonadal dysgenesis. No correlation between phenotype and degree of mosaicisms in the karyotype could be ascertained so far, making clinical management of these patients difficult.

Objective: To understand, if androgen action through the androgen receptor (AR) is compromised in 45,X/46,XY genital skin fibroblasts (GF).

Method: GF from 12 individuals with the clinical diagnosis mixed gonadal dysgenesis and a 45,X/46,XY karyotype were tested for AR-mRNA expression as well as AR-activity by measuring DHT-dependent induction of the AR target gene Apolipoprotein D (APOD- assay). Clinical data on external virilization as well as gonadal structures were collected when available.

Results: Six patients presented with hypospadias and a predominantly male phenotype, five patients showed ambiguous genitalia and one patient was phenotypically female. In four GF AR-activity lay below the threshold calculated for male control GF (<2,3 fold induction; (1)). These four GF also showed a lower AR mRNA expression as compared to male control GF. However, there was no correlation between AR-expression or activity and 1) the percentage of Y-chromosome aneuploidy, 2) structural aberrations of the Y-chromosome, 3) presence or absence of Muellerian remnants or 4) gonadal development (two cases revealed one dysgenetic gonad on one side and no or one streak gonad on the other side, the other two cases showed at least one scrotal testis). In three out of the four individuals with low AR expression in their GF a HCG-test had been performed showing a low normal to normal rise in T.

Conclusion: Four out of 12 (30%) GF from individuals with 45,X/46,XY mosaicism revealed an AR-activity under the calculated cut-off using the APOD-assay. The normal T levels and the apparent undervirilization in these individuals indicate some form of androgen resistance. Our results suggest that in some cases of 45,X/46,XY mosaicism AR signaling and AR expression might be disrupted. This may modify the androgen dependent phenotype. Long-term studies are needed to analyze if this reduced AR expression is constant or changes e.g. in puberty.

Reference: (1) Hornig NC et al. JCEM 2016, 101(11):4468–4477.

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