Health Technology Assessment Area-AETSA, Andalusian Public Foundation for Progress and Health ("Fundación Progreso y Salud"-"FPS"), Seville, Spain.
Research Group HUM604: Lifestyle Development in the Life Cycle and Health Promotion, University of Huelva, Huelva, Spain.
PLoS One. 2024 Jul 11;19(7):e0303880. doi: 10.1371/journal.pone.0303880. eCollection 2024.
NKX2-1-related disorders (NKX2-1-RD) are rare conditions affecting lung, thyroid, and brain development, primarily caused by pathogenic variants or deletions in the NKX2-1 gene. Congenital hypothyroidism (CH) is a common endocrine manifestation, leading to irreversible intellectual disability if left untreated.
The aim was to evaluate the current evidence for the use of screening and diagnostic techniques for endocrine alterations in patients with NKX2-1-RD.
This systematic review was reported following the PRISMA guidelines. Two separate research questions in PICO format were addressed to cover initial screening and diagnosis procedures for endocrine diseases in patients with NKX2-1-RD. Eligibility criteria focused on patients with genetic confirmation of the disease and hypothyroidism. Various databases were searched, and data were extracted and assessed independently by two reviewers.
Out of 1012 potentially relevant studies, 46 were included, for a total of 113 patients. CH was the most frequent endocrine alteration (45% of patients). Neonatal screening was reported in only 21% of patients based on blood TSH measurements. TSH thresholds varied widely across studies, making hypothyroidism detection ranges difficult to establish. Diagnostic tests using serum TSH were used to diagnose hypothyroidism or confirm its presence. 35% of patients were diagnosed at neonatal age, and 42% at adult age. Other hormonal dysfunctions identified due to clinical signs, such as anterior pituitary deficiencies, were detected later in life. Thyroid scintigraphy and ultrasonography allowed for the description of the thyroid gland in 30% of cases of hypothyroidism. Phenotypic variability was observed in individuals with the same variants, making genotype-phenotype correlations challenging.
This review highlights the need for standardized protocols in endocrine screening for NKX2-1-RD, emphasizing the importance of consistent methodology and hormone threshold levels. Variability in NKX2-1 gene variants further complicates diagnostic efforts. Future research should concentrate on optimizing early screening protocols and diagnostic strategies.
NKX2-1 相关障碍（NKX2-1-RD）是一种罕见的疾病，主要影响肺、甲状腺和脑的发育，主要由 NKX2-1 基因的致病性变异或缺失引起。先天性甲状腺功能减退症（CH）是一种常见的内分泌表现，如果不治疗，会导致不可逆转的智力障碍。
评估 NKX2-1-RD 患者内分泌改变的筛查和诊断技术的现有证据。
本系统评价按照 PRISMA 指南进行报告。采用 PICO 格式提出了两个独立的研究问题，以涵盖 NKX2-1-RD 患者内分泌疾病的初始筛查和诊断程序。纳入标准主要集中在基因确诊为 NKX2-1-RD 且伴有甲状腺功能减退的患者。对各种数据库进行了搜索，并由两名评审员独立提取和评估数据。
在 1012 项潜在相关研究中，有 46 项研究被纳入，共纳入 113 例患者。CH 是最常见的内分泌改变（45%的患者）。仅有 21%的患者基于血液 TSH 测量进行了新生儿筛查。各研究间 TSH 阈值差异较大，难以确定甲状腺功能减退的检测范围。使用血清 TSH 的诊断试验用于诊断甲状腺功能减退或确认其存在。35%的患者在新生儿期被诊断，42%的患者在成年期被诊断。由于临床症状（如前垂体功能减退）发现的其他激素功能障碍，在以后的生活中被发现。甲状腺闪烁扫描和超声检查可在 30%的甲状腺功能减退症患者中描述甲状腺。在具有相同变异的个体中观察到表型变异性，使基因型-表型相关性变得复杂。
本综述强调了 NKX2-1-RD 内分泌筛查中标准化方案的必要性，强调了一致的方法和激素阈值水平的重要性。NKX2-1 基因变异的变异性进一步增加了诊断的难度。未来的研究应集中在优化早期筛查方案和诊断策略上。
