Istanbul University, Istanbul Faculty of Medicine, Department of Pediatrics, Pediatric Endocrinology Unit, Istanbul, 34093, Turkey.
Istanbul University, Istanbul Faculty of Medicine, Department of Medical Genetics, Istanbul, 34093, Turkey.
J Steroid Biochem Mol Biol. 2018 Jul;181:88-97. doi: 10.1016/j.jsbmb.2018.04.001. Epub 2018 Apr 4.
Congenital adrenal hyperplasia (CAH) due to 11β-hydroxylase deficiency (11BOHD) is a rare autosomal recessive disorder and the second most common form of CAH.
To investigate genotype-phenotype correlation and to evaluate clinical characteristics and long-term outcomes of patients with 11BOHD.
A total of 28 patients (n = 14, 46,XX; n = 14, 46,XY) with classical 11BOHD from 25 unrelated families were included in this study. Screening of CYP11B1 is performed by Sanger sequencing. Pathogenic features of novel variants are investigated by the use of multiple in silico prediction tools and with family based co-segregation studies. Protein simulations were investigated for two novel coding region alterations.
The age at diagnosis ranged from 6 days to 12.5 years. Male patients received diagnose at older ages than female patients. The rate of consanguinity was high (71.4%). Five out of nine 46,XX patients were diagnosed late (age 2-8.7 years) and were assigned as male due to severe masculinization. Twenty one patients have reached adult height and sixteen were ultimately short due to delayed diagnosis. Two male patients had testicular microlithiasis and 5 (35.7%) patients had testicular adrenal rest tumor during follow up. Four patients (28.6%) had gynecomastia. Mutation analyses in 25 index patients revealed thirteen different mutations in CYP11B1 gene, 4 of which were novel (c.393 + 3A > G, c.428G > C, c.1398 + 2T > A, c.1449_1451delGGT). The most frequent mutations were c.896T > C with 32%, c.954G > A with 16% and c.1179_1180dupGA with 12% in frequency. There was not a good correlation between genotype and phenotype; phenotypic variability was observed among the patients with same mutation.
This study presents the high allelic heterogeneity of CYP11B1 mutations in CAH patients from Turkey. Three dimensional protein simulations may provide additional support for the pathogenicity of the genetic alterations. Our results provide reliable information for genetic counseling, preventive and therapeutic strategies for the families.
11β-羟化酶缺乏症（11BOHD）所致先天性肾上腺皮质增生症（CAH）是一种罕见的常染色体隐性遗传病，也是 CAH 的第二大常见形式。
研究基因型-表型相关性，评估 11BOHD 患者的临床特征和长期结局。
本研究共纳入 25 个无关家系的 28 例经典 11BOHD 患者（14 例 46,XX 患者，14 例 46,XY 患者）。通过 Sanger 测序对 CYP11B1 进行筛查。使用多种计算机预测工具和家系共分离研究对新变异的致病特征进行分析。对两种新的编码区改变进行蛋白模拟。
诊断年龄为 6 天至 12.5 岁。男性患者的诊断年龄大于女性患者。近亲婚配率高（71.4%）。9 例 46,XX 患者中有 5 例（2-8.7 岁）因严重男性化而被误诊为男性，且诊断较晚。21 例患者达到成年身高，16 例因诊断延迟最终身材矮小。2 例男性患者存在睾丸微石症，5 例（35.7%）患者在随访期间存在肾上腺残余肿瘤。4 例（28.6%）患者存在乳腺发育。25 例指数患者的突变分析显示 CYP11B1 基因有 13 种不同的突变，其中 4 种是新的（c.393+3A>G、c.428G>C、c.1398+2T>A、c.1449_1451delGGT）。最常见的突变为 c.896T>C，占 32%，c.954G>A 占 16%，c.1179_1180dupGA 占 12%。基因型与表型之间无良好相关性；同一突变的患者表型存在变异性。
本研究显示土耳其 CAH 患者 CYP11B1 基因突变的等位基因高度异质性。三维蛋白模拟可为遗传改变的致病性提供额外支持。我们的研究结果为家系的遗传咨询、预防和治疗策略提供了可靠的信息。
