Genotype versus phenotype in families with androgen insensitivity syndrome

Androgen insensitivity syndrome encompasses a wide range of phenotypes, whi ch are caused by numerous different mutations in the AR gene. Detailed info rmation on the genotype/ phenotype relationship in androgen insensitivity s yndrome is important for sex assignment, treatment of androgen insensitivit y syndrome patients, genetic counseling of their families, and insight into the functional domains of the AR. The commonly accepted concept of depende nce on fetal androgens of the development of Wolffian ducts was studied in complete androgen insensitivity syndrome (CAIS) patients. In a nationwide s urvey in The Netherlands, all cases (n = 49) with the presumptive diagnosis androgen insensitivity syndrome known to pediatric endocrinologists and cl inical geneticists were studied. After studying the clinical phenotype, mut ation analysis and functional analysis of mutant receptors were performed u sing genital skin fibroblasts and in vitro expression studies. Here we repo rt the findings in families with multiple affected cases. Fifty-nine percen t of androgen insensitivity syndrome patients had other affected relatives. A total of 17 families were studied, seven families with CAIS (IS patients ), nine families with partial androgen insensitivity (24 patients), and one family with female prepubertal phenotypes (two patients). No phenotypic va riation was observed in families with CAIS. However, phenotypic variation w as observed in one-third of families with partial androgen insensitivity re sulting in different sex of rearing and differences in requirement of recon structive surgery. Intrafamilial phenotypic variation was observed for muta tions R846H, M771I, and deletion of amino acid N682. Four newly identified mutations were found. Follow-up in families with different AR gene mutation s provided information on residual androgen action in vivo and the developm ent of the prepubertal and adult phenotype. Patients with a functional comp lete defective AR had some pubic hair, Tanner stage P2, and vestigial Wolff ian duct derivatives despite absence of AR expression. Vaginal length was f unctional in most but not all CAIS patients. The minimal incidence of andro gen insensitivity syndrome in The Netherlands, based on patients with molec ular proof of the diagnosis is 1:99,000. Phenotypic variation was absent in families with CAIS, but distinct phenotypic variation was observed relativ ely frequent in families with partial androgen insensitivity. Molecular obs ervations suggest that phenotypic variation had different etiologies among these families. Sex assignment of patients with partial androgen insensitiv ity cannot be based on a specific identified AR gene mutation because disti nct phenotypic variation in partial androgen insensitivity families is rela tively frequent. In genetic counseling of partial androgen insensitivity fa milies, this frequent occurrence of variable expression resulting in differ ences in sex of rearing and/or requirement of reconstructive surgery is imp ortant information. During puberty or normal dose androgen therapy, no or o nly minimal virilization may occur even in patients with significant (but s till deficient) prenatal virilization. Wolffian duct remnants remain detect able but differentiation does not occur in the absence of a functional AR. In many CAIS patients, surgical elongation of the vagina is not indicated.