NF1基因突变致1型神经纤维瘤病8例临床分析

摘要

目的：了解1型神经纤维瘤病（NF）的临床表型特征及异质性。方法回顾分析8例NF患儿的临床及基因检测资料。结果8例患儿中男5例、女3例，均因生后多发牛奶咖啡斑就诊，2例伴丛状神经纤维瘤，1例伴多处皮肤神经纤维瘤。8例患儿有7种突变形式，NF1基因全部缺失2例；4种缺失突变，分别为c.4974_4977delCTAT, p.Y1659TfsX17、c.3987_3988delAG, p.S1329fsX4、c.1511delC, p.P504QfsX22和c.6388delC, p.L2130fsX3；1种c.3975-2delA剪切突变；1种c.3721C＞ T, p.R1241X无义突变。除全基因大片段缺失和无义突变之外，其余均为未报道的新突变。患儿父母外周血均未检测出相应的突变。结论NF1基因突变可致1型NF，此研究发现5种新的突变，且均为de novo突变。多发牛奶咖啡斑是1型NF最早的临床表现，对疑似患者应尽早行基因分析确诊。%Objective Neuroifbromatosis type(NF) 1 is an autosomal dominant inherited disorder caused byNF1 gene mutation. The characteristics of NF 1 include multiple Café-au-lait spots, neurofibroma, freckling in the axillary or inguinal regions, Optic glioma, Lisch nodules and skeletal abnormalities. We analyzedNF1 gene in 8 cases with multiple Café-au-lait spots in order to diagnose and understand clinical heterogeneity of NF1 in children.Methods Eight patients, 5 males and 3 females aged 1- 12 years, were selected from hospital during June 2013 to October 2015. All of them complained of multiple Café-au-lait macules since birth, and two were accompanied by plexiform neuroifbromas, one with multiple cutaneous neurofibromas. All parents were non-consanguineous and asymptomatic. Variable Café-au-lait macules were found in 3 parents, one with multiple Café-au-lait spots, and the other two with 1-2 skin lesions.NF1 gene was studied by direct PCR sequencing and followed by MLPA analysis if the sequencing was negative. All patients had no echocardiography and ophthalmic examinations.Results Seven mutations were found in 8 patients, including completeNF1 deletion in 2 cases, 4 deletion mutations (c.4974_4977delCTAT, p.Y1659TfsX17, c.3987_3988delAG, p.S1329fsX4, c.1511delC, p.P504QfsX22 and c.6388delC, p.L2130fsX3), 1 splicing mutation (c.3975-2delA) and 1 nonsense mutation (c.3721C> T,p.R1241X). The mutations were not found in the peripheral blood of all the parents. All mutations except large deletion and nonsense mutation were not reported.Conclusions Mutations inNF1 gene can cause NF 1. Multiple Café-au-lait macules may be the earliest clinical manifestation of NF1.NF1 gene analysis can be performed to confirm the diagnosis and provide necessary genetic counseling, even though there is no family history and other clinical abnormalities. In this study, there were 7 mutations found in 8 patients,5 of which were not reported, all mutations were de novo.