Von Hippel Lindau（VHL）综合征由VHL基因的常染色体显性遗传或散发性生殖细胞系突变引起，已识别出500多种致病突变。约10-50%的VHL综合征患者会发生嗜铬细胞瘤，且在通常30岁左右，但极少数患者会在10岁之前发生。我们诊断了一名9岁女孩，外表正常，但存在严重难治性高血压，其嗜铬细胞瘤分泌去甲肾上腺素，与已知的家族生殖细胞系VHL基因（c.414A>G）杂合突变有关，其家庭中还有另外三名成员也存在该突变。13岁时，发现患者存在骨盆肿瘤和左侧肾上腺嗜铬细胞瘤，经检查发现两者都已转移到双肺，导致患者接受左肾上腺切除术和骨盆肿瘤切除术。除了生殖细胞系VHL基因突变外，通过下一代测序方法对血液样本进行分析还发现KIF1B基因存在一种新的杂合生殖细胞系突变（c.3331_3332del; p.Asn1111Glnfs*21），该突变仅存在于该女孩身上而不在其他家庭成员身上。目前，该患者正在接受类固醇替代治疗，并且过着正常的生活。这个家族以多发性神经嵴瘤早发生年龄和高恶性度及转移性扩散的特点而引人注目。与文献中大部分报告的VHL突变晚发生于成年人且具有良性进程的情况相反，我们的发现对该突变在该家族中的表型表达的作用提出了质疑。此外，两种易感神经嵴瘤的易感基因的共同突变存在问题，即它们在该家族肿瘤发展中的相应作用。我们的家族病例描述展示了在神经嵴瘤患者中系统使用靶向下一代测序和多基因检测面板的潜力，以确认已知易感基因的作用，同时发现新的基因变异，并为该特定医学领域的基因变异和表型相应建立全面的数据库做出贡献。版权所有©2023 Landen, De Leener, Le Roux, Brichard, Aydin, Maiter和Lysy。

Von Hippel Lindau (VHL) syndrome is caused by an autosomal dominant hereditary or sporadic germline mutation of the VHL gene with more than five hundred pathogenic mutations identified. Pheochromocytomas and rarely paragangliomas occur in 10-50% of patients with VHL syndrome usually around 30 years of age and exceptionally before the age of 10.We diagnosed a 9-year-old girl of normal appearance and severe refractory hypertension, with a norepinephrine-secreting pheochromocytoma related to VHL syndrome due to a known familial germline heterozygous mutation of VHL gene (c.414A>G), also present in three members of her family. At age 13, a pelvic tumor and a left adrenal pheochromocytoma that showed to be multi-metastatic to both lungs were discovered in the patient leading to left adrenalectomy and pelvic tumor resection. In addition to the germline VHL gene mutation, blood analysis using Next Generation Sequencing identified a novel heterozygous germline mutation of the KIF1B gene (c.3331_3332del; p.Asn1111Glnfs*21), which is only present in the girl and not the other family members. The patient is currently under steroid substitution therapy and leads a normal life.This family is notable by the early age of onset of multiple neural crest tumors associated with a high propensity for malignancy and metastatic spread. Most reports in the literature associated the VHL mutation with a later onset in adulthood and a benign course, which contrast with our findings and question the role of this mutation in the phenotype expressed in this kindred. Also, the presence of concomitant mutations in two susceptibility genes for neural crest tumors poses the question of their respective roles in the development of tumors in this family. Our familial case description illustrates the potential for systematic use of targeted Next Generation Sequencing with multi-gene panels in patients with neural crest tumors to confirm the role of known susceptibility genes as well as identifying new ones, but also to contribute to comprehensive databases on gene variants and their phenotypic counterparts in this specific area of medicine.Copyright © 2023 Landen, De Leener, Le Roux, Brichard, Aydin, Maiter and Lysy.