{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T16:53:17Z","timestamp":1782924797157,"version":"3.54.5"},"reference-count":26,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>\n                    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\u2019s diagnosis in adolescence to the proband\u2019s 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\n                    <jats:italic>AR<\/jats:italic>\n                    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&amp;gt;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\n                    <jats:italic>in situ<\/jats:italic>\n                    . 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\n                    <jats:italic>AR<\/jats:italic>\n                    variants; second, the 14-year delay between the eldest sister\u2019s 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.\n                  <\/jats:p>","DOI":"10.3389\/fendo.2026.1876397","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T16:17:09Z","timestamp":1782922629000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: Familial complete androgen insensitivity syndrome across four sisters from childhood to adulthood \u2014 a hemizygous AR p.Trp742Leu variant and a 14-year failure to initiate familial cascade evaluation"],"prefix":"10.3389","volume":"17","author":[{"given":"Burak","family":"\u00c7akmak","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Mus State Hospital","place":["Mus, 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