Øzdemir Cagla Margit, Nielsen Mette Mølby, Liimatta Jani, Voegel Clarissa D, Elzenaty Rawda Naamneh, Wasehuus Victor S, Lind-Holst Marie, Ornstrup Marie Juul, Gram Stine Bjørn, Ousager Lilian Bomme, Flück Christa E, Gravholt Claus H
Department of Endocrinology, Aarhus University Hospital, Aarhus N, Denmark.
Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus N, Denmark.
Endocrinol Diabetes Metab Case Rep. 2024 Aug 1;2024(3). doi: 10.1530/EDM-23-0090. Print 2024 Jul 1.
Congenital adrenal hyperplasia (CAH) is one of the most common inherited rare endocrine disorders. This case report presents two female siblings with delayed diagnosis of non-classical CAH 3β-hydroxysteroid dehydrogenase type 2 (3βHSD2D/HSD3B2) despite early hospital admission and apparent CAH manifestations such as infections, hirsutism, menstrual disturbances, and PCOS phenotype. Initially, sister 1 was misdiagnosed with PCOS and then 11-hydroxylase deficiency (CYP11B1), based on ultrasound, biochemical findings, and negative genetic testing for 21-hydroxylase deficiency (CYP21A2). Additional diagnostic workup was performed when sister 2also presented with symptoms of androgen excess. Genetic testing for CAH/steroid disorders finally revealed that both siblings were compound heterozygous for two variants in the HSD3B2 gene: a frameshift variant, c.558dup, p.(Thr187Hisfs17) and a novel missense variant, c.65T>C, p.(Leu22Ser). A Synacthen test showed an insufficient cortisol increase. In vitro studies of the variants in a cell model revealed loss of function for the p.(Thr187Hisfs17) and partial activity for p.(Leu22Ser) confirming non-classic CAH. Overlapping symptomatology and lack of specialized knowledge on steroid biosynthesis and associated rarest forms of CAH may explain the delayed diagnosis. However, with newer diagnostic methods comprising a less biased approach, very rare forms of non-classical CAH may no longer be overlooked in the future.
Non-classic 3βHSD2 is likely underdiagnosed. Late diagnosis of mild non-classic 3βHSD2 does occur and one should be aware of this diagnosis. Early diagnosis of NCCAH may prevent many consequences such as severe hirsutism, prolonged menstrual irregularities, infertility, or even adrenal crisis with severe infections. Comprehensive steroid profiling and genetic testing should be used earlier, especially when in doubt about a diagnosis.
先天性肾上腺皮质增生症（CAH）是最常见的遗传性罕见内分泌疾病之一。本病例报告介绍了两名女性同胞，尽管她们早期入院且有明显的CAH表现，如感染、多毛症、月经紊乱和多囊卵巢综合征（PCOS）表型，但非经典CAH 3β-羟基类固醇脱氢酶2型（3βHSD2D/HSD3B2）的诊断仍被延迟。最初，姐姐1基于超声、生化检查结果以及21-羟化酶缺乏症（CYP21A2）基因检测呈阴性，被误诊为PCOS，随后又被误诊为11-β羟化酶缺乏症（CYP11B1）。当妹妹2也出现雄激素过多症状时，进行了进一步的诊断检查。CAH/类固醇疾病的基因检测最终显示，两名同胞在HSD3B2基因中有两个变异的复合杂合子：一个移码变异，c.558dup，p.（Thr187Hisfs17）和一个新的错义变异，c.65T>C，p.（Leu22Ser）。促肾上腺皮质激素（Synacthen）试验显示皮质醇升高不足。在细胞模型中对这些变异进行的体外研究表明，p.（Thr187Hisfs17）功能丧失，p.（Leu22Ser）有部分活性，证实为非经典CAH。症状重叠以及对类固醇生物合成和相关最罕见形式的CAH缺乏专业知识，可能解释了诊断延迟的原因。然而，随着采用较少偏差方法的更新诊断方法出现，未来可能不再会忽视非常罕见形式的非经典CAH。
非经典3βHSD2可能诊断不足。轻度非经典3βHSD2确实会出现诊断延迟，人们应该意识到这一诊断。NCCAH的早期诊断可能预防许多后果，如严重多毛症、长期月经不规律、不孕，甚至严重感染引发的肾上腺危象。应更早地使用全面的类固醇分析和基因检测，尤其是在对诊断有疑问时。
