Case Report: Familial complete androgen insensitivity syndrome across four sisters from childhood to adulthood - a hemizygous AR p.Trp742Leu variant and a 14-year failure to initiate familial cascade evaluation.

Authors

Burak Çakmak, Savaş Gündoğan, Dilek Tektaş

Published in

Frontiers in endocrinology. Volume 17. Pages 1876397. Epub Jul 01, 2026.

Abstract

We describe a family, with the same biological mother and father, in which complete androgen insensitivity syndrome (CAIS) was identified across 4 phenotypic female sisters spanning a 14-year diagnostic interval from the eldest sister's diagnosis in adolescence to the proband's self-presentation as an adult. The proband, a 27-year-old, presented with primary amenorrhea, Tanner 5 breast development, absent axillary and pubic hair, and bilateral inguinal gonads on imaging. Pre-operative hormonal evaluation revealed elevated luteinizing hormone (28.1 mIU/mL), total testosterone within the adult male reference range (8.2 ng/mL; 820 ng/dL; 28.5 nmol/L), and estradiol within the lower female range (42 pg/mL; 154 pmol/L). Sequencing of the AR gene in the proband, a 22-year-old affected dizygotic twin sister, and a 14-year-old youngest sister consistently identified the same hemizygous missense variant, NM_000044.6:c.2225G>T, p.(Trp742Leu), in exon 6 within the ligand-binding domain. The variant was absent from gnomAD and classified as pathogenic per American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria, with co-segregation across three affected siblings. Laparoscopic bilateral gonadectomy was performed in the proband; histopathology showed immature testicular tissue without germ cell neoplasia in situ. Two features of this family deserve attention: first, AR Trp742 is well known as a recurrent gain-of-function hot-spot residue in castration-resistant prostate cancer, and its identification as a hemizygous germline variant associated with a complete loss-of-function phenotype underlines the context-dependent interpretation of AR variants; second, the 14-year delay between the eldest sister's diagnosis at age 16 years and the recognition of the family cluster reflects a tractable failure to initiate cascade evaluation rather than a biological challenge. The case argues for embedding pediatric-initiated structured genetic counseling and protocol-driven sibling assessment into the standard care plan for any 46,XY difference of sex development (DSD) diagnosis.

PMID:
42460323
Bibliographic data and abstract were imported from PubMed on 16 Jul 2026.

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