关键词: 神经纤维瘤病1型, 基因, 神经纤维瘤病1型, 突变, 表型, 皮肤表现, 多发牛奶咖啡斑

Abstract: 【Abstract】 Objective To investigate clinical characteristics of and genetic variants in the NF1 gene in children with neurofibromatosis type 1 （NF1）. Methods Clinical data were collected from 22 children with NF1, who were admitted to the Department of Dermatology, Children′s Hospital, Capital Institute of Pediatrics from January 2022 to September 2023, and were analyzed. Next-generation sequencing was performed to detect NF1 mutations in the probands, and the variants were verified in the family members by Sanger sequencing. A homology modeling software was used to predict the three-dimensional protein structure, and analyze the characteristics of gene mutations. Results Among the 22 children with NF1, there were 14 males and 8 females, and they were aged from 3 months to 12 years at the clinic visit. All the 22 children presented with multiple café-au-lait spots, and their age at onset ranged from birth to 2 years. Nine patients were accompanied by freckles in the axillary or inguinal regions, 2 by cutaneous neurofibromas, 2 by juvenile xanthogranuloma, 2 by learning disabilities, and Lisch nodules of the iris, central precocious puberty and scoliosis occurred in 1 case each; 5 cases showed characteristic manifestations of neurofibroma on brain magnetic resonance imaging. A total of 5 types of NF1 gene variants were identified in the 22 patients, including complete heterozygous deletion of the NF1 gene （1 patient）, missense variants （4 patients, one of whom carried 2 types of missense variants）, frameshift variants （8 patients）, nonsense variants （6 patients）, and classical splicing variants （3 patients）. Among the 22 variants, 7 were unreported variants, including c.758T>A（p.Val253Glu）, c.2360dupC（p.Thr788Asnfs*5）, c.5513T>G（p.Leu1838*）, c.2774dupT（p.Leu925Phefs*11）, c.6894dupT（p.Val2299Cysfs*7）, c.6882_6883delCT（p.Phe2295Leufs*10）, and c.6448A>T（p.Lys2150*）. Of the unreported variants, 6 were frameshift or nonsense variants leading to different degrees of truncated protein expression, and severely affecting protein function; based on the three-dimensional protein structure prediction analysis, it was uncertain if the missense variant c.758T>A （p.Val253Glu） affected protein conformation. In 2 children, the NF1 variants were inherited from their mothers; 1 child carried 2 NF1 missense variants, 1 of which was a spontaneous mutation potentially causing the disease, while the other one with unknown pathogenicity was inherited from the phenotypically normal father; the remaining 19 children all carried spontaneous mutations. Conclusions Children with NF1 mainly present with multiple café-au-lait spots at the early stage, and some characteristic manifestations such as cutaneous neurofibroma, juvenile xanthogranuloma, and Lisch nodules of the iris can also occur. NF1 gene pathogenic variants are complex and diverse, and 22 variants were identified in this study, enriching the spectrum of NF1 gene variants.

Key words: Neurofibromatosis 1, Genes, neurofibromatosis 1, Mutation, Phenotype, Skin manifestations, café-au-lait spots