Fylaktou Irene, Mertzanian Anny, Farakla Ioanna, Gryparis Alexandros, Vasilakis Ioannis Anargyros, Binou Maria, Charmandari Evangelia, Kanaka-Gantenbein Christina, Sertedaki Amalia
Division of Endocrinology, Diabetes and Metabolism 'Aghia Sophia' Children's Hospital ENDO-ERN Center for Rare Paediatric Endocrine Diseases, First Department of Pediatrics, Medical School, National and Kapodistrian University of Athens, 'Aghia Sophia' Children's Hospital, 11527 Athens, Greece.
Department of Speech and Language Therapy, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece.
Curr Issues Mol Biol. 2024 Sep 24;46(10):10696-10713. doi: 10.3390/cimb46100635.
21-hydroxylase deficiency (21-OHD) represents the most common form of congenital adrenal hyperplasia (CAH) due to gene pathogenic variants. Τhe aim of this study was the identification of variants in 500 subjects of Greek origin with a suspicion of 21-OHD and, by using the existing hormonal assessment and genotypes of the 500 subjects tested, to identify a biomarker that could differentiate between the heterozygotes and the cases with no pathogenic variants identified. Five hundred subjects with clinical suspicion of 21-OHD underwent gene sequencing and Multiplex Ligation Dependent Probe Amplification (MLPA). Genetic diagnosis was achieved in 27.4% of the subjects tested, most of which presented with the non-classic form (NC) of 21-OHD. Heterozygotes accounted for 42.6% of cases, whereas no pathogenic variants were identified in 27% of cases. De novo aberrations, duplications, and five novel variants were also identified. Statistical analysis revealed that the difference between the basal and 60' post-ACTH stimulation 17-hydroxyprogesterone concentrations (Δ17-OHP) could be a potential biomarker ( < 0.05) distinguishing the heterozygotes from the cases with no pathogenic variants identified, although no clear cut-off value could be set. Further analysis revealed overlapping clinical manifestations among all the subjects tested. The presented phenotypic traits of the subjects tested and the inability to identify a discriminative biochemical marker highlight the importance of comprehensive genotyping to ascertain the correct genetic diagnosis and proper genetic counselling.
21-羟化酶缺乏症（21-OHD）是由基因致病变异导致的先天性肾上腺皮质增生症（CAH）最常见的形式。本研究的目的是在500名疑似21-OHD的希腊裔受试者中鉴定变异，并通过对这500名受试者进行现有的激素评估和基因分型，确定一种能够区分杂合子和未鉴定出致病变异的病例的生物标志物。500名临床疑似21-OHD的受试者接受了基因测序和多重连接依赖探针扩增（MLPA）。在27.4%的受试对象中实现了基因诊断，其中大多数表现为非经典型（NC）21-OHD。杂合子占病例的42.6%，而27%的病例未鉴定出致病变异。还鉴定出了新生畸变、重复和五个新变异。统计分析表明，促肾上腺皮质激素（ACTH）刺激后60分钟时的基础17-羟孕酮浓度与刺激后浓度的差值（Δ17-OHP）可能是区分杂合子和未鉴定出致病变异的病例的潜在生物标志物（P<0.05），尽管无法设定明确的临界值。进一步分析显示，所有受试对象的临床表现存在重叠。受试对象呈现出的表型特征以及无法鉴定出有鉴别意义的生化标志物，凸显了全面基因分型对于确定正确的基因诊断和进行适当遗传咨询的重要性。
