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

Abstract

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 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. Findings: Only 6/9 patients (67%) with EMS <5 underwent spontaneous onset of puberty, versus all 18 patients with EMS ≥5 (p=0.03). 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 ≥15ml, pubic hair Tanner stage 4 or 5, above average adult height, had gynaecomastia, mastectomy, or evidence of spermatogenesis. 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 a pragmatic contribution to decision making for PAIS sex assignment. Funding: NL was funded by Singapore National Medical Research Council (NMRC) Transition Award (NMRC/TA/0037/2015). RTC was supported by the National Institute for Health Research Cambridge Biomedical Research Centre. JW and VM were supported by the University of Nottingham BBSRC Doctoral Training program (BB/M008770/1). BM was supported by a University of Nottingham Vice Chancellors scholarship. Declaration of Interest: We declare no competing interests. Ethical Approval: Ethical approval for this study was obtained from the local research ethics committee (09/H0308/158), and institutional approval was obtained from the Research and Development Committee at the Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.