X-linked congenital adrenal hypoplasia: new mutations and long-term follow-up in three patients
X-linked congenital adrenal hypoplasia: new mutations and long-term follow-up in three patients
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DOI：
10.1046/j.1365-2265.2000.01038.x
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发表时间：
2000-08-01
影响因子：
3.2
通讯作者：
Ranke, MB
中科院分区：
文献类型：
--
作者：
Binder, G;Wollmann, TF;Ranke, MB
DAX-1基因编码新发现的核激素受体家族成员，据报道其突变可导致x连锁先天性肾上腺发育不全和促性腺功能减退症。虽然有关DAX-1的遗传数据正在积累，但有关该疾病临床病程的信息却很少。在这里，我们提出了有关三个病例的纵向数据的详细文件。我们回顾性地收集了3名男孩（6岁、14岁和14.5岁）的临床资料，我们对他们进行了5至14年的检查。DAX-1基因的突变分析是通过PCR产物的直接测序进行的。患者在4 - 6周时出现盐消耗，但没有低血糖的证据。所有三个病例最初都被误诊为孤立性醛固酮缺乏症。在4个月、3岁和13岁时通过促肾上腺皮质激素刺激试验确定糖皮质激素缺乏。一名男孩在4个月大时停止治疗，直到13岁时发生肾上腺危机，他的发育正常。在所有三个病例中，先天性性腺功能减退症在婴儿期被排除，因为阴茎勃起正常，睾丸下降，血清样本含有正常的睾丸激素水平。一个男孩在9岁时表现出短暂的促性腺功能亢进，但没有青春期的临床症状或血清睾酮升高。在他的病例中，青春期的开始和LHRH测试证明是正常的，在另一个被研究的患者中也是如此。在两名患者中，遗传分析显示DAX-1的c端发生了新的突变，分别是遗传自母亲的1个碱基缺失（656delG）和DAX-1基因的2个碱基重新插入（728insCA），两者都导致帧移位和密码子263和398处过早停止。一名男孩从母亲那里遗传了密码子39 （W39X）的无义突变。矿化皮质激素缺乏先于糖皮质激素缺乏，可在新生儿期后通过促肾上腺皮质激素刺激诊断。先天性肾上腺发育不全（AHC）可发生短暂性肾上腺功能恢复。短暂性促性腺功能亢进症可能是性腺轴缺陷的第一个指标之一，尽管正常的青春期开始并不罕见。通过DAX-1基因的分子分析确定了明确的诊断。突变类型与表型之间没有相关性。在没有其他明确病因的情况下，以肾上腺危机为表现的男性儿童和青少年的诊断程序应包括ACTH刺激试验和DAX-1突变分析。
Mutations of the DAX-1 gene, which encodes a newly discovered member of the nuclear hormone receptor family, were reported to cause X-linked congenital adrenal hypoplasia and hypogonadotrophic hypogonadism. While genetic data on DAX-1 are accumulating, information on the clinical course of the disorder are scarce. Here we present a detailed documentation of longitudinal data relating to three cases.We retrospectively collected clinical data on three boys (6, 14 and 14.5 years old) who we examined over a period ranging between 5 and 14 years. Mutational analysis of the DAX-1 gene was performed by means of direct sequencing of PCR products.The patients presented at ages between 4 and 6 weeks with salt-wasting, but there was no evidence of hypoglycaemia. All three cases were initially erroneously diagnosed with isolated aldosterone deficiency. Glucocorticoid deficiency was established by means of ACTH stimulation tests at 4 months, 3 and 13 years of age. One boy, whose therapy was discontinued at the age of 4 months, developed normally until adrenal crisis occurred at the age of 13 years. In all three cases, congenital hypogonadism was ruled out during infancy, as penis sire was normal, the testes were descended, and serum samples contained normal testosterone levels. One boy exhibited transient hypergonadotrophism at age 9 but showed no clinical signs of puberty or an increase in serum testosterone. Onset of puberty and LHRH tests proved to be normal in his case as well as in another patient studied. In two patients, genetic analysis revealed new mutations at the C-terminus of DAX-1, these being a 1-base deletion (656delG) inherited from the mother and a de-novo 2-base insertion (728insCA) of the DAX-1 gene, respectively, both causing frame shift and premature stops at codons 263 and 398. One boy was affected by a new nonsense mutation of codon 39 (W39X) inherited from his mother.Mineralocorticoid deficiency preceded glucocorticoid deficiency which could be diagnosed through ACTH stimulation after the neonatal period. Transitory functional recovery of the adrenal glands can occur in adrenal hypoplasia congenita (AHC). Transient hypergonadotrophism may be one of the first indicators of defects in the gonadal axis, although normal initiation of puberty is not rare. The definitive diagnosis was established by means of molecular analysis of the DAX-1 gene. There was no correlation between types of mutations and phenotypes. The diagnostic procedure in male children and adolescents presenting with adrenal crisis should include ACTH stimulation tests and mutational analysis of DAX-1 in the absence of another proven aetiology.