Institute of Mother and Child, Cystic Fibrosis Department, ul. Kasprzaka 17A, 01-211, Warsaw, Poland.
Children's Memorial Health Institute, Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland.
BMC Pediatr. 2020 Feb 27;20(1):90. doi: 10.1186/s12887-020-1980-y.
Cystic fibrosis (CF) is the most common, life-threatening, autosomal-recessive disorder among Caucasians. To date, approximately 2000 mutations in the CFTR gene have been reported. Some of these mutations are very rare, and some represent individual sequence changes in the gene. The introduction of newborn screening (NBS) in high prevalence countries for CF has considerably changed the diagnosing of this metabolic disease. Currently, in most cases, a diagnosis is made based on NBS, including or expanded with DNA analysis and confirmed with sweat chloride tests, rather than waiting until the child has already developed signs and symptoms. However, in rare cases, NBS does not provide enough information to confirm or reject a CF diagnosis. Not only are there small groups of patients who have false-negative or false-positive NBS results, but there is also a growing number of patients with positive NBS results in whom results of sweat tests and genetic examinations do not provide definite conclusions. Despite all knowledge and modern diagnostic tools at our disposal, sometimes the clinical presentation is so inconclusive, that making a final diagnosis remains a challenge.
In this case report, we present a male infant of Polish origin, whose symptoms and laboratory findings (including metabolic acidosis) were strongly suggestive of metabolic disease other than cystic fibrosis. Newborn screening for CF was positive, but the first sweat test results were equivocal, and initial and extended molecular tests were negative. Finally, after considering broad differential diagnosis, introducing treatment specific for CF and excluding other metabolic diseases, a third expanded genetic test revealed the presence of a rare pathogenic mutation in both alleles of the CFTR gene: c.4035_4038dupCCTA (p.Ser1347ProfsX13).
Although CF is considered a monogenic disorder, the relationship between genotype and phenotype is very complex. The reported case shows the unusual presentation of the disease. The patient's clinical symptoms and laboratory findings, in combination with molecular test results, provide useful information for further observing the genotype-phenotype correlations in cystic fibrosis.
囊性纤维化（CF）是白种人中最常见、最致命的常染色体隐性遗传病。迄今为止，已经报道了大约 2000 种 CFTR 基因突变。其中一些突变非常罕见，而另一些则代表基因中的个体序列变化。高 CF 流行国家引入新生儿筛查（NBS）极大地改变了这种代谢疾病的诊断方式。目前，在大多数情况下，诊断是基于 NBS 进行的，包括或扩展了 DNA 分析，并通过汗液氯测试确认，而不是等到孩子已经出现症状和体征后再进行诊断。然而，在少数情况下，NBS 提供的信息不足以确认或排除 CF 诊断。不仅存在一小部分患者的 NBS 结果为假阴性或假阳性，而且还有越来越多的 NBS 结果阳性的患者，其汗液测试和基因检查结果无法提供明确的结论。尽管我们拥有所有的知识和现代诊断工具，但有时临床表现如此不确定，使得最终诊断仍然具有挑战性。
本病例报告介绍了一名波兰裔男性婴儿，其症状和实验室发现（包括代谢性酸中毒）强烈提示为 CF 以外的代谢性疾病。CF 的新生儿筛查结果阳性，但第一次汗液测试结果不确定，最初和扩展的分子测试结果均为阴性。最后，在考虑了广泛的鉴别诊断、引入 CF 特异性治疗并排除其他代谢性疾病后，第三次扩展基因测试显示 CFTR 基因的两个等位基因均存在罕见的致病性突变：c.4035_4038dupCCTA(p.Ser1347ProfsX13)。
尽管 CF 被认为是一种单基因疾病，但基因型和表型之间的关系非常复杂。本报告病例显示了该病不寻常的表现。患者的临床症状和实验室发现，结合分子测试结果，为进一步观察 CF 中的基因型-表型相关性提供了有用的信息。
