The Glu331del mutation in the CYP17A1 gene causes atypical congenital adrenal hyperplasia in a 46,XX female

Abstract

17α-Hydroxylase deficiency is an uncommon type of congenital adrenal hyperplasia (CAH) caused by mutations in the CYP17A1 gene encoding both 17α-hydroxylase and 17,20-lyase, essential for sex steroids production. Main clinical features include lack of pubertal development, hypertension, and hypokalemia. We report the first case of a 46,XX female homozygote for the p.Glu331del mutation in the CYP17A1 gene showing an atypical clinical presentation. She was evaluated the first time for primary amenorrhea and delayed puberty in the presence of low levels of androgens, 17β-estradiol, serum cortisol, and high levels of progesterone and gonadotropins. After puberty, the patient did not show hypocortisolism and/or hypertension. She started estrogen therapy for pubertal induction, followed by ethinylestradiol/gestodene with clinical and biochemical stability during the follow-up period. At the age of 40 years, she developed hypokalemia and clinical signs of hypocortisolism. Oral corticosteroid treatment was started showing a prompt clinical improvement. Modeling analysis predicted the main outcome of the E331 deletion to impair cytochrome b5 binding, according to a major effect on the enzyme’s lyase activity. These data broaden the molecular and clinical spectrum of CAH caused by 17α-hydroxylase deficiency and adds to current genotype–phenotype correlations.

Chinese abstract

17α-羟化酶缺乏症是一种不常见的先天性肾上腺增生症（CAH）类型, 由编码17α-羟化酶和17,20-裂解酶的CYP17A1基因突变引起的, 17α羟化酶是性类固醇产生所必需的。

主要临床特征包括青春期发育不良、高血压和低钾血症。我们报告了CYP17A1基因中短臂第331位点编码谷氨酸片段缺失（p.Glu331del）的46, XX女性纯合子的第一例, 显示非典型临床表现。在低水平的雄激素, 17β-雌二醇, 血清皮质醇和高水平的孕酮和促性腺激素的存在下, 她首次被评估为原发性闭经和青春期延迟。青春期后, 患者没有显示肾上腺皮质功能减退和/或高血压。她开始进行青春期诱导的雌激素治疗, 随后是随访期间具有临床和生物化学稳定性的炔雌醇/孕二烯酮。 40岁时她出现低钾血症和肾上腺皮质功能减退的临床症状。开始口服皮质类固醇治疗, 出现即刻的临床改善。根据对酶的裂解酶活性的主要影响, 建模分析预测了E331缺失的主要结果是损害细胞色素b5结合。这些数据扩大了由17α-羟化酶缺乏引起的CAH的分子和临床范围, 并增加了目前的基因型和表型的相关性。

Keywords:

• 17α-Hydroxylase
• congenital adrenal hyperplasia
• CYP17A1 gene

Acknowledgements

The study was approved by local Ethics Committee.

Disclosure statement

No potential conflict of interest was reported by the authors.