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
Frontiers in Endocrinology, cilt.17, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 17
- Basım Tarihi: 2026
- Doi Numarası: 10.3389/fendo.2026.1876397
- Dergi Adı: Frontiers in Endocrinology
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, EMBASE, MEDLINE, Directory of Open Access Journals
- Anahtar Kelimeler: 46,XY DSD, AR gene, CAIS, cascade genetic testing, complete androgen insensitivity syndrome, familial case, ligand-binding domain, p.Trp742Leu
- Sağlık Bilimleri Üniversitesi Adresli: Evet
Özet
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.