Thompson Talia, Gurfinkel Dennis, Silveira Lori, Klamut Natalia, Ferdinandsen Kate, Fu Cary, Ananth Amitha L, Lane Jane B, Marsh Eric D, Neul Jeffrey L, Percy Alan K, Benke Timothy A
Pediatrics, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, Colorado, USA.
Accords, University of Colorado School of Medicine, Aurora, Colorado, USA.
Am J Med Genet A. 2025 Jun 14:e64147. doi: 10.1002/ajmg.a.64147.
Rett syndrome (RTT) is a rare neurodevelopmental disorder typically caused by loss-of-function variants in the transcriptional regulator methyl-CpG binding protein-2 (MECP2) gene. These variants were historically believed to be incompatible with life in males; however, recent advances in genetic testing have revealed significant clinical heterogeneity. The current study aimed to improve our understanding of diagnostic experiences in males with confirmed pathogenic alteration of MECP2. An international sample of caregivers completed a survey of diagnostic experiences (N = 47) and phenomenological interviews (n = 32). Median [interquartile range; IQR] age of genetic diagnosis was 3 years [1.08, 6.75]. Multivariate analysis showed that for every year increase in year of birth, age of diagnosis (in years) decreased by 0.31. Qualitative findings demonstrate that medical biases and widespread misconceptions contribute to delays in accurate clinical diagnosis, which negatively impacts child health and family functioning. As genetic testing becomes more widely available, age of genetic diagnosis is decreasing, resulting in more providers and families with unexpected results and a notable lack of male-specific anticipatory guidance and clinical recommendations. Diagnostic providers must increase their awareness of males with confirmed pathogenic alterations of MECP2 and be prepared to deliver the diagnosis with empathy and accurate, up-to-date information on prognosis and treatment options.
瑞特综合征（RTT）是一种罕见的神经发育障碍，通常由转录调节因子甲基-CpG结合蛋白2（MECP2）基因的功能丧失变异引起。历史上认为这些变异在男性中与生命不相容；然而，基因检测的最新进展揭示了显著的临床异质性。本研究旨在增进我们对确诊为MECP2致病性改变的男性诊断经历的理解。一个国际样本的照料者完成了一项诊断经历调查（N = 47）和现象学访谈（n = 32）。基因诊断的中位年龄[四分位间距；IQR]为3岁[1.08，6.75]。多变量分析表明，出生年份每增加1年，诊断年龄（以年计）下降0.31。定性研究结果表明，医学偏见和普遍存在的误解导致准确临床诊断的延迟，这对儿童健康和家庭功能产生负面影响。随着基因检测越来越普及，基因诊断年龄正在降低，导致更多的医疗服务提供者和家庭得到意外结果，并且明显缺乏针对男性的预期指导和临床建议。诊断医疗服务提供者必须提高对确诊为MECP2致病性改变男性的认识，并准备好以同理心提供诊断，并提供有关预后和治疗选择的准确、最新信息。
