Clinical, Psychological, and Molecular Aspects of a Large Androgen Insensitivity Syndrome Cohort

Batista Rafael Loch; Marlene Inacio; Afonso Ane Caroline; Filomena Carvalho; Raquel Ramos; Flora Craveiro; Renata Dallago; Ferrari Maria Tereza; Julio Batatinha; Miriam Nishi; Sorahia Domenice; Mendonca Berenice Bilharinho

Introduction: Androgen Insensitivity Syndrome (AIS) is the most common cause of the 46,XY Differences in Sexual Development (DSD). It is an X-linked genetic disease caused by allelic variants in the Androgen Receptor Gene (Xq11-12). Methods: Patients with clinical suspicion of AIS performed hormonal serum analysis (LH, FSH, estradiol, testosterone) and whole AR gene sequencing. Psychosexual variables (gender identity, gender role, and sexual orientation) were evaluated through psychological questionnaires. Histopathological and immunostaining of CD240 and OCT3/4 studies were carried out for all individuals submitted to gonadectomy. Results: This cohort comprises 97 individuals: CAIS (n=50) and PAIS (n=47). The inguinal hernia was the first clinical presentation in 35% of CAIS subjects. Among PAIS, 25 (52%) were assigned as females at birth, while 23 (48%) as males. Among PAIS, the degree of external genitalia virilization (Sinnecker score) influenced sex assignment (P<0.01). Standing final height and weight were similar between PAIS and CAIS. The bone mineral apparent density (BMAD) by DXA was similar between individuals who had or had no previous gonadectomy and between CAIS and PAIS. Furthermore, gender identity in adulthood, gender role in childhood, and sexual orientation agreed with sex assignment in all but one PAIS individual. Molecular diagnosis was obtained in 96% of CAIS and 87% of PAIS, including ten novel AR variants (4 in CAIS and 6 in PAIS). LH ranged from 9 to 48 IU/L (mean 19), and testosterone from 190 to 1500 ng/dL (mean 438 ng/dL), without phenotype differences. After puberty, gonadal tumors were identified in 2 out of 25 (8%) of CAIS (Seminoma and Sertoli cell tumor). We also identified a borderline serous tumor in another post-pubertal CAIS patient. Among PAIS, there were 2 cases of germ cell neoplasia in situ (at 3 and 19 years of age). Conclusion: Hormonal levels did not differ CAIS from PAIS. The psychosexual development in AIS is usually aligned with sex assignment, but the external genitalia appearance in PAIS influenced the sex assignment. BMAD was not impacted either by previous gonadectomy or phenotype. There is a risk of gonadal tumors in CAIS, especially after puberty, which is not low enough to be ignored.

IMPE Abstracts

P139