Peter M, Viemann M, Partsch C J, Sippell W G
Department of Pediatrics, Christian Albrechts University, Kiel, Germany.
J Clin Endocrinol Metab. 1998 Aug;83(8):2666-74. doi: 10.1210/jcem.83.8.5027.
X-linked congenital adrenal hypoplasia (AHC) is a rare developmental disorder of the human adrenal cortex and is caused by deletion or mutation of the DAX-1 gene, a recently discovered member of the nuclear hormone receptor superfamily. Hypogonadotropic hypogonadism is frequently associated with AHC. AHC occurs as part of a contiguous gene syndrome together with glycerol kinase deficiency (GKD) and Duchenne's muscular dystrophy. The present series, collected over the past 2 decades, includes 18 AHC boys from 16 families: 4 with AHC, GKD, and Duchenne's muscular dystrophy; 2 with AHC and GKD; and 12 with AHC (5 young adults with hypogonadotropic hypogonadism). Most of the boys presented with salt wasting and hyperpigmentation during the neonatal period. Plasma steroid determinations performed in the first weeks of life often showed confusing results, probably caused by steroids produced in the neonates' persisting fetocortex. Aldosterone deficiency usually preceded cortisol deficiency, which explains why the patients more often presented with salt-wasting rather than with hypoglycemic symptoms. An ACTH test was often necessary to detect cortisol deficiency in the very young infants. In some patients, serial testing was necessary to establish the correct diagnosis. In 4 boys studied during the first 3 months after birth, we found pubertal LH, FSH, and testosterone plasma levels indicating postnatal transient activation of the hypothalamic-pituitary-gonadal axis as in normal boys. Previous studies have shown that the DAX-1 gene is deleted in the AHC patients with a contiguous gene syndrome and is mutated in nondeletion patients. Most of the point mutations identified in AHC patients were frameshift mutations and stop mutations. In the 15 patients available for molecular analysis of the DAX-1 gene, there were large deletions in 6 patients and point mutations in another 7 patients. All of the point mutations identified in the present study resulted in a nonfunctional truncated DAX-1 protein. Two brothers with primary adrenal insufficiency and a medical history that strongly suggested AHC had no mutation in the DAX-1 gene. Thus, additional, as yet unknown genes must play a part in normal adrenal cortical development.
X连锁先天性肾上腺发育不全（AHC）是一种罕见的人类肾上腺皮质发育障碍疾病，由DAX-1基因的缺失或突变引起，DAX-1基因是核激素受体超家族中最近发现的成员。促性腺激素分泌不足性性腺功能减退常与AHC相关。AHC作为一种连续性基因综合征的一部分，与甘油激酶缺乏症（GKD）和杜兴氏肌营养不良症同时出现。本系列病例收集于过去20年，包括来自16个家庭的18名患有AHC的男孩：4名患有AHC、GKD和杜兴氏肌营养不良症；2名患有AHC和GKD；12名患有AHC（5名患有促性腺激素分泌不足性性腺功能减退的年轻成年人）。大多数男孩在新生儿期出现失盐和色素沉着。出生后第一周进行的血浆类固醇测定结果常常令人困惑，可能是由于新生儿持续存在的胎儿皮质产生的类固醇所致。醛固酮缺乏通常先于皮质醇缺乏，这解释了为什么患者更多地表现为失盐而非低血糖症状。对于非常小的婴儿，通常需要进行促肾上腺皮质激素（ACTH）试验来检测皮质醇缺乏。在一些患者中，需要进行系列检测以确立正确诊断。在出生后前3个月研究的4名男孩中，我们发现青春期促黄体生成素（LH）、促卵泡生成素（FSH）和睾酮的血浆水平表明下丘脑-垂体-性腺轴在出生后有短暂激活，如同正常男孩一样。先前的研究表明，在患有连续性基因综合征的AHC患者中DAX-1基因缺失，在非缺失患者中该基因发生突变。在AHC患者中鉴定出的大多数点突变是移码突变和终止突变。在可进行DAX-1基因分子分析的15名患者中，6名患者存在大片段缺失，另外7名患者存在点突变。本研究中鉴定出的所有点突变均导致无功能的截短型DAX-1蛋白。两名患有原发性肾上腺功能不全且病史强烈提示AHC的兄弟，其DAX-1基因未发生突变。因此，其他尚未知晓的基因必定在正常肾上腺皮质发育中发挥作用。
