Morales-Tirado Ana, Blitz-Castro Enrique, Vicente-Santamaría Saioa, Luna-Paredes Carmen, Salcedo-Lobato Enrique, Tabares-González Ana, Gascón-Galindo Celia, Boutry Simon, Lamas-Ferreiro Adelaida
Cystic Fibrosis Unit, Department of Pediatric Medicine, Ramon y Cajal University Hospital, M-607, Km. 9, 100, Fuencarral-El Pardo, 28034 Madrid, Spain.
Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain.
Children (Basel). 2025 Jun 14;12(6):778. doi: 10.3390/children12060778.
One of the most common genetic variants among individuals with cystic fibrosis screen-positive inconclusive diagnosis (CFSPID) is 5T;12TG. Classified as having "varying clinical consequences" (VVCC), it may produce a wide spectrum of CF phenotypes when combined in trans with a pathogenic variant on the other CFTR allele, ranging from asymptomatic cases to CFTR-related disorders (CFTR-RD) or classical cystic fibrosis (CF). The 5T;12TG variant is currently eligible for modulator treatment in the United States. We conducted a retrospective analysis of CFSPID children born between July 2009 and June 2023 in the Community of Madrid (Spain) who carried at least one 5T;12TG variant in trans with another CFTR variant. Data collected included trends in sweat chloride (SC) values, respiratory and digestive symptoms, lung function by spirometry, microbiological findings in nasopharyngeal aspirates, anthropometric data, and fecal elastase levels. Twenty-one children (52.3% females; median age: 4.66 years [IQR 3.6-6.9]) were included. Eighteen had 5T;12TG in trans with a CF-causing variant (CFc), two had another VVCC variant, and one had a variant of unknown significance (VUS). After a median follow-up of 3.45 years [IQR 1.4-4.3], all the children remained asymptomatic. However, SC values rose to intermediate levels in nine (42.8%) of the children. No isolates of Pseudomonas aeruginosa were identified. Lung function and pancreatic markers remained normal. This is the first Spanish cohort of children with CFSPID and the 5T;12TG allele. Although clinical symptoms did not manifest during childhood, the SC value increased to intermediate values in 42.8% of the cohort, so these may require long-term follow-up to observe conversions to CFTR-RD or CF. The potential initiation of modulator therapy based solely on SC levels or emerging symptoms warrants careful consideration.
在囊性纤维化筛查呈阳性但诊断不确定（CFSPID）的个体中，最常见的基因变异之一是5T;12TG。该变异被归类为具有“不同临床后果”（VVCC），当与另一个CFTR等位基因上的致病变异反式组合时，可能产生广泛的囊性纤维化表型，从无症状病例到CFTR相关疾病（CFTR-RD）或经典囊性纤维化（CF）。目前，5T;12TG变异在美国符合调节剂治疗的条件。我们对2009年7月至2023年6月在西班牙马德里社区出生的携带至少一个与另一个CFTR变异反式组合的5T;12TG变异的CFSPID儿童进行了回顾性分析。收集的数据包括汗液氯化物（SC）值的变化趋势、呼吸和消化症状、通过肺活量测定法测得的肺功能、鼻咽抽吸物中的微生物学发现、人体测量数据以及粪便弹性蛋白酶水平。纳入了21名儿童（52.3%为女性；中位年龄：4.66岁[四分位间距3.6 - 6.9]）。18名儿童的5T;12TG与一个导致CF的变异（CFc）反式组合，2名儿童有另一个VVCC变异，1名儿童有一个意义不明的变异（VUS）。经过中位3.45年[四分位间距1.4 - 4.3]的随访，所有儿童均无症状表现。然而，9名（42.8%）儿童的SC值升至中间水平。未鉴定出铜绿假单胞菌分离株。肺功能和胰腺标志物保持正常。这是西班牙首个针对携带CFSPID和5T;12TG等位基因儿童的队列研究。尽管在儿童期未出现临床症状，但该队列中42.8%的儿童SC值升高至中间值，因此可能需要长期随访以观察是否转变为CFTR-RD或CF。仅基于SC水平或新出现的症状而潜在启动调节剂治疗值得谨慎考虑。
