School of Clinical and Experimental Medicine, Institute of Biomedical Research, Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Wolfson Drive, Birmingham B15 2TT, UK.
Eur J Endocrinol. 2012 Dec;167(6):881-5. doi: 10.1530/EJE-12-0450. Epub 2012 Sep 11.
Cytochrome P450 side-chain cleavage enzyme (CYP11A1) catalyses the first and rate-limiting step of steroidogenesis, the conversion of cholesterol to pregnenolone. CYP11A1 deficiency is commonly associated with adrenal insufficiency, and in 46,XY individuals, with variable degrees of disorder of sex development (DSD).
The patient was born with hyperpigmentation, micropenis, penoscrotal hypospadias, and mild cryptorchidism. Biochemical and hormonal findings were normal except for low testosterone and low-borderline cortisol. However, no short synacthen test was undertaken. Development was unremarkable apart from an episode labeled as sepsis with documented hyperkalemia and elevated C-reactive protein at age 15 days. Diagnosis of 46,XY DSD was made at age 2.5 months. Progression of hyperpigmentation prompted further investigations and the diagnosis of adrenal insufficiency was established at 2 years with raised ACTH, normal renin activity, and failure of cortisol to respond to short synacthen test. Genetic analyses were performed. The novel CYP11A1 mutations were characterized in vitro and in silico.
The patient was compound heterozygous for two novel CYP11A1 mutations, p.R360W and p.R405X. p.R360W retained 30-40% of wild-type activity. In silico analyses confirmed these findings and indicated that p.R405X is severe.
This study demonstrates the pathogenicity of two novel CYP11A1 mutations found in a patient with delayed diagnosis of CYP11A1 deficiency. Patients with partial deficiencies of steroidogenic enzymes are at risk to be misdiagnosed if adrenal function is not assessed. The adrenocortical function should be routinely assessed in all patients with DSD including severe hypospadias of unknown origin to prevent life-threatening adrenal crises.
细胞色素 P450 侧链裂解酶（CYP11A1）催化类固醇生成的第一步和限速步骤，即将胆固醇转化为孕烯醇酮。CYP11A1 缺乏通常与肾上腺功能不全有关，而在 46,XY 个体中，与不同程度的性别发育障碍（DSD）有关。
患者出生时即出现皮肤色素沉着过度、小阴茎、阴茎阴囊型尿道下裂和轻度隐睾。除了睾酮和边缘低值的皮质醇外，生化和激素检查均正常。然而，并未进行短 Synacthen 试验。除了在 15 天大时因被诊断为伴有高钾血症和 C 反应蛋白升高的败血症而出现的一次发病外，其发育无明显异常。2.5 月龄时诊断为 46,XY DSD。随着皮肤色素沉着的加重，进一步检查发现其患有肾上腺功能不全，2 岁时 ACTH 升高，肾素活性正常，皮质醇对短 Synacthen 试验无反应，从而确诊。进行了基因分析。对 CYP11A1 的新突变进行了体外和计算机分析。
患者为 CYP11A1 两种新突变 p.R360W 和 p.R405X 的复合杂合子。p.R360W 保留了野生型活性的 30-40%。计算机分析证实了这一发现，并表明 p.R405X 是严重的突变。
本研究表明了在延迟诊断 CYP11A1 缺乏症的患者中发现的两种 CYP11A1 新突变的致病性。如果不评估肾上腺功能，部分类固醇生成酶缺乏的患者有被误诊的风险。所有患有 DSD 的患者，包括病因不明的严重尿道下裂患者，都应常规评估肾上腺皮质功能，以防止危及生命的肾上腺危象。
