Department of Neurology, West China Hospital, Sichuan University, Guo Xuexiang #37, Chengdu, 610041, Sichuan, China.
Neurol Sci. 2022 Feb;43(2):1295-1301. doi: 10.1007/s10072-021-05353-5. Epub 2021 Jun 5.
Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder characterized by café-au-lait macules (CALMs), skinfold freckling, Lisch nodules, and neurofibromas. It is associated with heterozygous mutations in the neurofibromatosis type 1 (NF1) gene. Whole NF1 deletion has been described in some cases, but most cases are sporadic, and familial forms are extremely rare. To date, only two-generation familial forms have been described.
To describe a whole NF1 gene deletion in a three-generation family with neurofibromatosis type 1.
Physical examinations, laboratory tests, structural neuroimaging studies, whole-exome sequencing, and multiplex ligation-dependent probe amplification analysis were carried out.
All the affected individuals within this three-generation family, including the 14-year-old female proband, her 40-year-old father, and 63-year-old grandmother, exhibited such typical manifestations of NF1 as CALMs and cutaneous neurofibromas, CALMs increased in size with age. The affected subjects had more localized hyperpigmentation and CALMs within the lesion areas, mainly in the chest, abdomen, waist, and back. In addition, learning disorder was observed in the proband, and brain MRI revealed abnormal high signal lesions in the brainstem. All the affected subjects had normal birth history and had no significant past medical history. Whole-exome sequencing and subsequent multiplex ligation-dependent probe amplification analysis identified deletion of the whole NF1 gene, co-segregating with the NF1 phenotype in an autosomal dominant pattern.
Our findings are the first to identify whole NF1 deletion in a three-generation family with autosomal dominant NF1 and broaden the understanding of the genetic spectrum of NF1-associated NF1.
神经纤维瘤病 1 型（NF1）是一种常染色体显性神经皮肤疾病，其特征为咖啡牛奶斑（CALMs）、皮肤褶皱雀斑、Lisch 结节和神经纤维瘤。它与神经纤维瘤病 1 型（NF1）基因的杂合突变有关。已经在一些病例中描述了整个 NF1 缺失，但大多数病例是散发性的，家族形式极为罕见。迄今为止，仅描述了两代家族形式。
描述一个三代 NF1 家族中整个 NF1 基因缺失。
进行了体格检查、实验室检查、结构神经影像学研究、全外显子组测序和多重连接依赖性探针扩增分析。
这个三代家族中的所有受影响个体，包括 14 岁的女性先证者、40 岁的父亲和 63 岁的祖母，都表现出 NF1 的典型表现，如 CALMs 和皮肤神经纤维瘤，CALMs 随年龄增长而增大。受影响的个体在病变区域内有更多的局部性色素沉着和 CALMs，主要在胸部、腹部、腰部和背部。此外，先证者存在学习障碍，脑部 MRI 显示脑干异常高信号病变。所有受影响的个体均有正常的出生史，且无明显的既往病史。全外显子组测序和随后的多重连接依赖性探针扩增分析确定了整个 NF1 基因缺失，与常染色体显性遗传模式中的 NF1 表型共分离。
我们的发现首次在一个三代 NF1 家族中发现了常染色体显性 NF1 相关的整个 NF1 缺失，并拓宽了对 NF1 相关 NF1 遗传谱的理解。
