Phenotypic features, androgen receptor binding, and mutational analysis in278 clinical cases reported as androgen insensitivity syndrome

Androgen insensitivity syndrome (AIS) is the most common single entity that results in male under-masculinization, but large cohort studies of AIS hav e rarely been performed. Over the last decade, nationwide cooperation betwe en pediatric endocrinologists in the United Kingdom has allowed the creatio n of a database of cases of intersex and ambiguous genitalia where detailed clinical information on every notified case has been collected via a quest ionnaire. Among the 816 entries recorded by January 1999, there were 105 cl inically diagnosed cases of complete AIS (CAIS) and 173 cases of partial AI S (PAIS). A masculinization score was devised by scoring the external pheno type, and a score of 12 represented normal masculinization. Androgen recept or (AR) binding was determined by studying binding capacity (B-max) and rec eptor affinity (K-d), and cases were classified as either zero, abnormal, o r normal binding. Mutation screening of all eight exons of the AR gene was performed by single-strand conformational polymorphism analysis, followed b y direct DNA sequencing. All cases of PAIS presented within the first month of birth. The median age at presentation of children with CAIS was 14 yr (P10,P90: 0.1,10.4). The t estes were palpable in the labioscrotal folds or the inguinal region in 77% and 41% of cases of CAIS and PAIS, respectively. There was marked overlap between the masculinization score of those children with PAIS reared as gir ls [2.5(P10,P90:1, 6)] and those reared as boys [3(P10,P90:2, 7.5)]. Gonade ctomy was performed prepubertally in 66% and postpubertally in 29% of the c ases of CAIS. The median age of the latter group was older at 14 yr (P10,P9 0:0.1, 18). No cases of malignancy or carcinoma in situ were reported in th e 121 cases of AIS where histology results were available. Biochemical endo crine investigations were reported to have been performed in a greater numb er of cases of PAIS than CAIS (98% vs. 48%). AR binding was abnormal in 44 of 51 (86%) and 40 of 113 (35%) cases of CAIS and PAIS, respectively, Zero binding was encountered in 29 of 43 (67%) and 1 of 55 (2%) cases of CAIS an d PAIS, respectively. Mutational analysis of the AR gene, performed in 102 index cases was positive in 57 of 69 (83%) cases of CAIS and 12 of 43 (28%) cases of PAIS. In 24 of these cases, the mutation identified was novel. Th e mutations in PAIS cases were all missense, whereas in CAIS the mutations were more diverse. AR binding was only normal in 3 of 69 mutation-positive cases. In the PAIS group, mutation-positive cases had a significantly highe r K-d and B-max compared to the mutation negative cases. The clinical diagnosis of AIS can be confirmed in a significant number of c ases by a combination of androgen-binding studies and mutational analysis. There is some correlation between the phenotypic features and the abnormali ties discovered on mutational analysis of the AR gene, but there is a need to improve this further by developing optimal bioassays of AR function. The phenotypic heterogeneity among clinically diagnosed cases of AIS emphasize s the need for appropriate comprehensive evaluation of male under-masculini zation.