Dörr Helmuth-Günther, Schulze Nadja, Bettendorf Markus, Binder Gerhard, Bonfig Walter, Denzer Christian, Dunstheimer Desiree, Salzgeber Kirsten, Schmidt Heinrich, Schwab Karl Otfried, Voss Egbert, Wabitsch Martin, Wölfle Joachim
Paediatric Endocrinology, University Children's Hospital, Erlangen, Germany.
Paediatric Endocrinology, University Children's Hospital, Heidelberg, Germany.
Mol Cell Pediatr. 2020 Jul 9;7(1):8. doi: 10.1186/s40348-020-00100-w.
Nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency is caused by mutations in the active 21-hydroxylase gene (CYP21A2). The clinical symptoms can vary greatly. To date, no systematic studies have been undertaken in Germany.
Description of the phenotype, evaluation of the diagnostics and genotype-phenotype correlation PATIENTS AND METHODOLOGY: Retrospective analysis of the data of 134 patients (age range 0.1-18.6 years) in a multicentre study covering 10 paediatric endocrinology centres in Bavaria and Baden-Württemberg. The data was gathered on site from the medical records. Two hundred and thirty-three alleles with a mutation of the CYP21A2 gene were identified in 126 patients. A genotype-phenotype correlation of the mutation findings was undertaken (C1, severe/mild; C2, mild/mild). Individuals with a heterozygous mutation of the CYP21A2 were also included (C3). The data was collected with the approval of the ethics committee of the University Hospital of Erlangen during the period of 2014 and 2015. RESULTS (MW ± SD): One hundred and seventeen out of 134 patients (115 f, 29 m) were symptomatic. The chronological age (CA) at diagnosis was 7.1 ± 4.4 years. The most frequent symptom (73.5%) was premature pubarche. The height-SDS on diagnosis was 0.8 ± 1.3 and the BMI-SDS was 0.8 ± 1.2. Bone age (BA) was ascertained in 82.9% of the symptomatic patients. The difference between BA and CA was 1.9 ± 1.4 years. Basal 17OHP concentrations were 14.5 ± 19.1 ng/ml (18 patients < 2 ng/ml). In total, 58.1% mild and 34.7% severe mutations were found. The most common mutation was p.Val281Leu (39.1%); 65.8% of the patients could be allocated to group C1. No phenotypical differences were found between the 3 mutation groups. The 17OHP levels (basal and after ACTH) in the standard ACTH stimulation test were highest in group C1 and also significantly higher in group C2 as in C3, the ACTH-stimulated cortisol levels (ng/ml) were significantly lower in groups C1 (192.1 ± 62.5) and C2 (218 ± 50) than in C3 (297.3 ± 98.7).
Most of the patients have symptoms of mild androgenisation. Male patients are underdiagnosed. Diagnostics are not standardised. Differences between the types of mutations are found in the hormone concentrations but not in phenotype. We speculate that further, as yet not clearly defined, factors are responsible for the development of the respective phenotypes.
21-羟化酶缺乏所致的非经典型先天性肾上腺皮质增生是由活性21-羟化酶基因（CYP21A2）突变引起的。临床症状差异很大。迄今为止，德国尚未进行系统研究。
描述表型，评估诊断方法及基因型与表型的相关性
对巴伐利亚州和巴登-符腾堡州10个儿科内分泌中心的134例患者（年龄范围0.1 - 18.6岁）的数据进行回顾性分析。数据从病历中现场收集。在126例患者中鉴定出233个具有CYP21A2基因突变的等位基因。对突变结果进行基因型与表型的相关性分析（C1，重度/轻度；C2，轻度/轻度）。携带CYP21A2杂合突变的个体也被纳入（C3）。数据在2014年至2015年期间经埃尔朗根大学医院伦理委员会批准后收集。
结果（均值±标准差）：134例患者中有117例（115例女性，2例男性）有症状。诊断时的实际年龄为7.1±4.4岁。最常见的症状（73.5%）是阴毛早现。诊断时的身高标准差分数为0.8±1.3，体重指数标准差分数为0.8±1.2。82.9%有症状的患者测定了骨龄。骨龄与实际年龄的差值为1.9±1.4岁。基础17-OHP浓度为14.5±19.1 ng/ml（18例患者<2 ng/ml）。共发现58.1%的轻度突变和34.7%的重度突变。最常见的突变是p.Val281Leu（39.1%）；65.8%的患者可归入C1组。3个突变组之间未发现表型差异。标准ACTH刺激试验中，C1组的17-OHP水平（基础和ACTH刺激后）最高，C2组也显著高于C3组；ACTH刺激后的皮质醇水平（ng/ml），C1组（192.1±62.5）和C2组（218±50）显著低于C3组（297.3±98.7）。
大多数患者有轻度雄激素化症状。男性患者诊断不足。诊断方法未标准化。激素浓度存在突变类型差异，但表型无差异。我们推测还有其他尚未明确的因素导致了各自表型的形成。
