Kim Ja Hye, Kim Gu-Hwan, Yoo Han-Wook, Choi Jin-Ho
Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Ann Pediatr Endocrinol Metab. 2023 Jun;28(2):77-86. doi: 10.6065/apem.2346108.054. Epub 2023 Jun 30.
Congenital adrenal hyperplasia (CAH) is a group of autosomally recessive disorders that result from impaired synthesis of glucocorticoid and mineralocorticoid. Most cases (~95%) are caused by mutations in the CYP21A2 gene, which encodes steroid 21-hydroxylase. CAH patients manifest a wide phenotypic spectrum according to their degree of residual enzyme activity. CYP21A2 and its pseudogene (CYP21A1P) are located 30 kb apart in the 6q21.3 region and share approximately 98% of their sequences in the coding region. Both genes are aligned in tandem with the C4, SKT19, and TNX genes, forming 2 segments of the RCCX modules that are arranged as STK19-C4A-CYP21A1P-TNXA-STK19B-C4B-CYP21A2-TNXB. The high sequence homology between the active gene and pseudogene leads to frequent microconversions and large rearrangements through intergenic recombination. The TNXB gene encodes an extracellular matrix glycoprotein, tenascin-X (TNX), and defects in TNXB cause Ehlers-Danlos syndrome. Deletions affecting both CYP21A2 and TNXB result in a contiguous gene deletion syndrome known as CAH-X syndrome. Because of the high homology between CYP21A2 and CYP21A1P, genetic testing for CAH should include an evaluation of copy number variations, as well as Sanger sequencing. Although it poses challenges for genetic testing, a large number of mutations and their associated phenotypes have been identified, which has helped to establish genotype-phenotype correlations. The genotype is helpful for guiding early treatment, predicting the clinical phenotype and prognosis, and providing genetic counseling. In particular, it can help ensure proper management of the potential complications of CAH-X syndrome, such as musculoskeletal and cardiac defects. This review focuses on the molecular pathophysiology and genetic diagnosis of 21-hydroxylase deficiency and highlights genetic testing strategies for CAH-X syndrome.
先天性肾上腺皮质增生症（CAH）是一组常染色体隐性疾病，由糖皮质激素和盐皮质激素合成受损所致。大多数病例（约95%）由CYP21A2基因突变引起，该基因编码类固醇21-羟化酶。根据残余酶活性程度，CAH患者表现出广泛的表型谱。CYP21A2及其假基因（CYP21A1P）位于6q21.3区域，相距30 kb，在编码区域共享约98%的序列。这两个基因与C4、SKT19和TNX基因串联排列，形成RCCX模块的2个片段，排列方式为STK19-C4A-CYP21A1P-TNXA-STK19B-C4B-CYP21A2-TNXB。活性基因与假基因之间的高序列同源性导致通过基因间重组频繁发生微转换和大的重排。TNXB基因编码一种细胞外基质糖蛋白，腱生蛋白-X（TNX），TNXB缺陷会导致埃勒斯-当洛综合征。影响CYP21A2和TNXB的缺失会导致一种称为CAH-X综合征的连续性基因缺失综合征。由于CYP21A2和CYP21A1P之间的高度同源性，CAH的基因检测应包括对拷贝数变异的评估以及桑格测序。尽管这给基因检测带来了挑战，但已鉴定出大量突变及其相关表型，这有助于建立基因型-表型相关性。基因型有助于指导早期治疗、预测临床表型和预后，并提供遗传咨询。特别是，它有助于确保对CAH-X综合征的潜在并发症，如肌肉骨骼和心脏缺陷进行适当管理。本综述重点关注21-羟化酶缺乏症的分子病理生理学和基因诊断，并强调CAH-X综合征的基因检测策略。
