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Clinical, Hormonal, Behavioral, and Genetic Characteristics of Androgen Insensitivity Syndrome in a Brazilian Cohort: Five Novel Mutations in the Androgen Receptor Gene

Unidade de Endocrinologia do Desenvolvimento e Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia (K.F.S.M., B.B.M., A.E.C.B., E.M.F.C., M.I., A.C.L., I.J.P.A.) and Disciplina de Urologia (F.A.Q.S.), Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900; and Disciplina de Endocrinologia (A.M.O.L.), Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo 14049-900, Brasil

Address all correspondence and requests for reprints to: Ivo J. P. Arnhold, M.D., Laboratório de Hormonios, Hospital das Clínicas, Avenida Eneas de Carvalho Aguiar 155, PAMB 2° andar Bloco 6, 05403-900 São Paulo, SP, Brasil. E-mail: iarnhold{at}usp.br.

Androgen insensitivity syndrome (AIS) is caused by mutations in the androgen receptor gene and is associated with a variety of phenotypes in 46,XY individuals, ranging from phenotypic women [complete form (CAIS)] to men with minor degrees of undervirilization or infertility [partial form (PAIS)]. We studied 32 subjects with male pseudohermaphroditism from 20 families (9 CAIS, 11 PAIS) with the following criteria for AIS: 46,XY karyotype, normal male basal and human chorionic gonadotropin-stimulated levels of serum testosterone and steroid precursors, gynecomastia at puberty, and, in prepubertal patients, a family history suggestive of X-linked inheritance.

The entire coding region of the androgen receptor gene was analyzed, and mutations were found in all families with CAIS and in eight of 11 families with PAIS. Fifteen different mutations were identified, including five (S119X, T602P, L768V, I898F, and P904V) that have not been described previously.

Detailed clinical and hormonal features were compared with genotype in 25 subjects with AIS and confirmed by mutational analysis. LH hormone levels and the LH x testosterone product were high in all postpubertal subjects with AIS. All subjects with PAIS maintained at postpubertal age the gender identity and social sex that was assigned to them in infancy, in contrast to other forms of pseudohermaphroditism.

This study was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo [98/00242-2 (to K.F.S.M.) and 97/01196-1] and Conselho Nacional de Desenvolvimento Científico e Tecnológico (301246/95-5 to B.B.M. and 300859/98-8 to I.J.P.A.).

Abbreviations: AIS, Androgen insensitivity syndrome; AR, androgen receptor; CAIS, complete AIS; DGGE, denaturing gradient gel electrophoresis; dGTP, deoxy-GTP; DHT, dihydrotestosterone; hCG, human chorionic gonadotropin; PAIS, partial AIS; T, testosterone.

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