Genotype versus phenotype in families with androgen insensitivity syndrome
Genotype versus phenotype in families with androgen insensitivity syndrome
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DOI：
10.1210/jc.86.9.4151
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发表时间：
2001-09-01
影响因子：
5.8
通讯作者：
Drop, SLS
中科院分区：
文献类型：
--
作者：
Boehmer, ALM;Brüggenwirth, H;Drop, SLS
雄激素不敏感综合征包括广泛的表型，其由AR基因中的许多不同突变引起。雄激素不敏感综合征中基因型/表型关系的详细信息对于性别分配、雄激素不敏感综合征患者的治疗、其家庭的遗传咨询以及深入了解AR的功能域非常重要。在完全性雄激素不敏感综合征（CAIS）患者中研究了沃尔夫管发育依赖于胎儿雄激素的普遍接受的概念。在荷兰进行的一项全国性调查中，研究了儿科内分泌学家和临床遗传学家已知的推定诊断为雄激素不敏感综合征的所有病例（n = 49）。在研究临床表型后，使用生殖器皮肤成纤维细胞和体外表达研究进行突变受体的突变分析和功能分析。在这里，我们报告了多个受影响病例的家庭中的发现。59%的雄激素不敏感综合征患者有其他受影响的亲属。共研究了17个家族，7个CAIS家族（IS患者），9个雄激素部分不敏感家族（24例患者），1个女性青春期前表型家族（2例患者）。在CAIS家系中未观察到表型变异。然而，在三分之一的雄激素部分不敏感的家庭中观察到表型变异，导致不同的性别养育和重建手术的要求差异。观察到家族内表型变异的突变R846 H，M771 I，和氨基酸N682的缺失。四个新发现的突变被found. Follow在不同的AR基因突变的家庭提供了信息残留雄激素的作用在体内和青春期前和成人表型的发展。功能完全缺陷型AR患者有一些阴毛，坦纳P2期，尽管缺乏AR表达，但仍有残留的沃尔夫管衍生物。阴道长度在大多数但不是所有CAIS患者中是功能性的。根据具有分子诊断证据的患者，荷兰雄激素不敏感综合征的最低发病率为1：99，000。CAIS家族中不存在表型变异，但在部分雄激素不敏感的家族中观察到相对频繁的明显表型变异。分子生物学观察表明，表型变异有不同的病因在这些家庭。部分雄激素不敏感患者的性别分配不能基于特定的AR基因突变，因为部分雄激素不敏感家族中不同的表型变异相对频繁。在部分雄激素不敏感家族的遗传咨询中，这种频繁发生的可变表达导致养育性别和/或重建手术要求的差异是重要的信息。在青春期或正常剂量雄激素治疗期间，即使在产前男性化明显（但仍然缺乏）的患者中，也可能不会发生或仅发生极轻微的男性化。沃尔夫管残余物仍然可检测，但分化不发生在没有功能性AR。在许多CAIS患者中，阴道延长术并不适用。
Androgen insensitivity syndrome encompasses a wide range of phenotypes, which are caused by numerous different mutations in the AR gene. Detailed information on the genotype/ phenotype relationship in androgen insensitivity syndrome is important for sex assignment, treatment of androgen insensitivity syndrome patients, genetic counseling of their families, and insight into the functional domains of the AR. The commonly accepted concept of dependence on fetal androgens of the development of Wolffian ducts was studied in complete androgen insensitivity syndrome (CAIS) patients. In a nationwide survey in The Netherlands, all cases (n = 49) with the presumptive diagnosis androgen insensitivity syndrome known to pediatric endocrinologists and clinical geneticists were studied. After studying the clinical phenotype, mutation analysis and functional analysis of mutant receptors were performed using genital skin fibroblasts and in vitro expression studies. Here we report the findings in families with multiple affected cases. Fifty-nine percent 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 variation was observed in families with CAIS. However, phenotypic variation was observed in one-third of families with partial androgen insensitivity resulting in different sex of rearing and differences in requirement of reconstructive surgery. Intrafamilial phenotypic variation was observed for mutations R846H, M771I, and deletion of amino acid N682. Four newly identified mutations were found. Follow-up in families with different AR gene mutations provided information on residual androgen action in vivo and the development of the prepubertal and adult phenotype. Patients with a functional complete defective AR had some pubic hair, Tanner stage P2, and vestigial Wolffian duct derivatives despite absence of AR expression. Vaginal length was functional in most but not all CAIS patients. The minimal incidence of androgen insensitivity syndrome in The Netherlands, based on patients with molecular proof of the diagnosis is 1:99,000. Phenotypic variation was absent in families with CAIS, but distinct phenotypic variation was observed relatively frequent in families with partial androgen insensitivity. Molecular observations suggest that phenotypic variation had different etiologies among these families. Sex assignment of patients with partial androgen insensitivity cannot be based on a specific identified AR gene mutation because distinct phenotypic variation in partial androgen insensitivity families is relatively frequent. In genetic counseling of partial androgen insensitivity families, this frequent occurrence of variable expression resulting in differences in sex of rearing and/or requirement of reconstructive surgery is important information. During puberty or normal dose androgen therapy, no or only minimal virilization may occur even in patients with significant (but still deficient) prenatal virilization. Wolffian duct remnants remain detectable but differentiation does not occur in the absence of a functional AR. In many CAIS patients, surgical elongation of the vagina is not indicated.