New M I
Division of Pediatric Endocrinology, New York Hospital-Cornell University Medical College, NY 10021.
J Steroid Biochem. 1987;27(1-3):1-7. doi: 10.1016/0022-4731(87)90287-1.
Defective steroid 21-hydroxylation is the most common of the biochemical defects causing hyperplasia of the adrenal cortex. The genetic mode of transmission of all enzyme abnormalities seen in cortisol biosynthesis is autosomal recessive. Steroid 21-hydroxylase deficiency has three currently accepted forms: the simple virilizing and salt-wasting variants of the classical deficiency, and the nonclassical (attenuated) form, which shows a wide clinical range of effects and whose characterization emerged from co-ordinated hormonal testing and family studies. More recent molecular genetic studies have started to identify specific mutations altering 21-hydroxylase activity. Defects in the other enzymes occur more rarely and are less well known, although initial work with abnormal 11 beta-hydroxylase and 3 beta-hydroxylase indicates that allelic gene defects may be correlated with different clinical phenotypes seen for these disorders also. The gene for the enzyme steroid 21-hydroxylase, a cytochrome P-450, is situated within the major histocompatibility complex on the p arm of human chromosome 6, proximal to the HLA-B antigen locus. Linkage disequilibria between certain B and DR alleles and classical and nonclassical 21-hydroxylase deficiency permit the use of HLA genotyping in conjunction with hormonal evaluation for diagnosis of this disorder and for identification of carrier haplotypes in population studies. Test programs have shown the feasibility of neonatal screening for 21-hydroxylase deficiency by blood-spot hormonal assay for elevated 17-hydroxyprogesterone. Prenatal detection of disease currently depends on HLA serotyping of cultured aminocytes jointly with measurement of amniotic 17-hydroxyprogesterone (13-18 week gestation); molecular genetic techniques with more specific nuclear probes will improve the specificity of this test and will in addition permit even earlier definitive fetal genotyping by chorionic villus biopsy (6-10 week gestation).
类固醇21-羟化缺陷是导致肾上腺皮质增生的最常见生化缺陷。皮质醇生物合成中出现的所有酶异常的遗传传递模式均为常染色体隐性遗传。类固醇21-羟化酶缺乏症目前有三种公认的形式：经典缺乏症的单纯男性化和失盐型变体，以及非经典（轻型）形式，其临床表现范围广泛，其特征是通过协调的激素检测和家族研究得出的。最近的分子遗传学研究已开始鉴定改变21-羟化酶活性的特定突变。其他酶的缺陷较少见且了解较少，尽管对异常11β-羟化酶和3β-羟化酶的初步研究表明，等位基因缺陷也可能与这些疾病所见的不同临床表型相关。类固醇21-羟化酶（一种细胞色素P-450）的基因位于人类6号染色体p臂上的主要组织相容性复合体内，靠近HLA-B抗原位点。某些B和DR等位基因与经典和非经典21-羟化酶缺乏症之间的连锁不平衡使得在诊断该疾病以及在人群研究中鉴定携带者单倍型时，可以将HLA基因分型与激素评估结合使用。测试项目已表明，通过血斑激素测定法检测17-羟孕酮升高来对新生儿进行21-羟化酶缺乏症筛查是可行的。目前，疾病的产前检测依赖于培养羊膜细胞的HLA血清分型以及羊水中17-羟孕酮的测定（妊娠13-18周）；使用更特异的核探针的分子遗传学技术将提高该检测的特异性，此外还可通过绒毛膜绒毛取样（妊娠6-10周）更早地进行明确的胎儿基因分型。
