Legius Eric, Brems Hilde
Department of Human Genetics, University of Leuven, Herestraat 49, 3000, Leuven, Belgium.
Childs Nerv Syst. 2020 Oct;36(10):2285-2295. doi: 10.1007/s00381-020-04771-8. Epub 2020 Jun 29.
Neurofibromatosis type 1 (NF1) is a frequent autosomal dominant disorder characterised by café-au-lait maculae (CALM), skinfold freckling, iris Lisch nodules and benign peripheral nerve sheath tumours (neurofibromas).
The NF1 gene is a tumour suppressor gene and NF1 individuals have an increased risk for a long list of tumours, all resulting from a second hit in the normal copy of the NF1 gene. Remarkably, some non-tumour phenotypes such as CALM and pseudarthrosis are also caused by a "second hit". Germline mutations inactivating the NF1 gene show a large variability in genetic mechanisms ranging from single-nucleotide substitutions and somatic mosaicism to large deletions affecting neighbouring genes. Molecular confirmation of the clinical diagnosis is becoming increasingly more important to differentiate NF1 from other syndromes such as Legius syndrome, to investigate genotype-phenotype correlations relevant in 10% of cases and to detect somatic mosaicism.
Some degree of learning difficulties, attention deficit and social problems are observed in most children and affect quality of life. There is a large individual variability in complications and the evolution of the disease is difficult to predict. Specialised outpatient clinics for children have been widely established and are important for surveillance and guidance. Regular surveillance is also important for adolescents and adults because many tumour complications can be detected by whole-body MRI and treated even before symptoms develop and irreversible damage occurs. Recent data on nodular plexiform neurofibromas with continued growth in adolescents and young adults show that many of these tumours are premalignant lesions called atypical neurofibromatous neoplasm of uncertain biological potential (ANNUBP). Specific surveillance and timely local resection of these benign peripheral nerve sheath tumours might be important to prevent malignant degeneration. In the last years, targeted therapy with MEK inhibitors has shown promise to treat unresectable and symptomatic plexiform neurofibromas. Many more challenges remain to find the best way to monitor children and adults for potential complications and to find a satisfying cure for many complications in this disorder.
1型神经纤维瘤病（NF1）是一种常见的常染色体显性疾病，其特征为咖啡斑（CALM）、皮肤褶皱雀斑、虹膜Lisch结节和良性周围神经鞘瘤（神经纤维瘤）。
NF1基因是一种肿瘤抑制基因，NF1患者患一系列肿瘤的风险增加，所有这些肿瘤均由NF1基因正常拷贝中的第二次打击所致。值得注意的是，一些非肿瘤表型，如CALM和假关节，也由“第二次打击”引起。使NF1基因失活的种系突变在遗传机制上表现出很大的变异性，范围从单核苷酸替换和体细胞镶嵌到影响相邻基因的大片段缺失。临床诊断的分子确认对于区分NF1与其他综合征（如Legius综合征）、研究10%病例中相关的基因型-表型相关性以及检测体细胞镶嵌越来越重要。
大多数儿童存在一定程度的学习困难、注意力缺陷和社交问题，这些会影响生活质量。并发症存在很大的个体差异，疾病的发展难以预测。已广泛设立儿童专科门诊，这对监测和指导很重要。定期监测对青少年和成年人也很重要，因为通过全身MRI可以检测到许多肿瘤并发症，甚至在症状出现和发生不可逆损害之前就可以进行治疗。关于青少年和年轻成年人中持续生长的结节性丛状神经纤维瘤的最新数据表明，其中许多肿瘤是具有不确定生物学潜能的非典型神经纤维瘤性肿瘤（ANNUBP）这种癌前病变。对这些良性周围神经鞘瘤进行特定监测并及时局部切除可能对预防恶性变很重要。近年来，用MEK抑制剂进行靶向治疗已显示出治疗不可切除和有症状的丛状神经纤维瘤的前景。要找到监测儿童和成年人潜在并发症的最佳方法以及找到令人满意的治疗该疾病许多并发症的方法，仍有更多挑战。
