Landen Lucie, De Leener Anne, Le Roux Manon, Brichard Bénédicte, Aydin Selda, Maiter Dominique, Lysy Philippe A
Division of Pediatric Endocrinology, Specialized Pediatrics Service, Cliniques Universitaires Saint-Luc, Université catholique de Louvain (UCLouvain), Brussels, Belgium.
Division of Clinical Genetics, Cliniques Universitaires Saint-Luc, Université catholique de Louvain (UCLouvain), Brussels, Belgium.
Front Endocrinol (Lausanne). 2023 Jul 25;14:1204793. doi: 10.3389/fendo.2023.1204793. eCollection 2023.
Von Hippel Lindau (VHL) syndrome is caused by an autosomal dominant hereditary or sporadic germline mutation of the 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 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 gene mutation, blood analysis using Next Generation Sequencing identified a novel heterozygous germline mutation of the 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 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.
冯·希佩尔-林道（VHL）综合征由该基因的常染色体显性遗传或散发性种系突变引起，已鉴定出五百多种致病突变。10%至50%的VHL综合征患者会发生嗜铬细胞瘤，很少发生副神经节瘤，通常在30岁左右，极少数在10岁之前。
我们诊断出一名外表正常但患有严重难治性高血压的9岁女孩，其患有与VHL综合征相关的分泌去甲肾上腺素的嗜铬细胞瘤，原因是已知该基因的家族性种系杂合突变（c.414A>G），她的三名家庭成员也存在该突变。13岁时，在该患者中发现盆腔肿瘤和左肾上腺嗜铬细胞瘤，显示已发生双肺多处转移，于是进行了左肾上腺切除术和盆腔肿瘤切除术。除了种系基因突外，使用下一代测序进行的血液分析还鉴定出该基因的一种新的杂合种系突变（c.3331_3332del；p.Asn1111Glnfs*21），该突变仅存在于该女孩而非其他家庭成员中。该患者目前正在接受类固醇替代治疗，生活正常。
这个家族的显著特点是多个神经嵴肿瘤发病年龄早，且具有高度恶性和转移扩散倾向。文献中的大多数报告将该突变与成年期较晚发病和良性病程相关联，这与我们的发现形成对比，并对该突变在这个家族所表达的表型中的作用提出了质疑。此外，在两个神经嵴肿瘤易感基因中同时存在突变，也引发了它们在这个家族肿瘤发生中各自作用的问题。我们对这个家族病例的描述表明，对于神经嵴肿瘤患者，系统使用靶向多基因面板的下一代测序技术有潜力确认已知易感基因的作用以及识别新的易感基因，同时也有助于建立关于该特定医学领域基因变异及其表型对应关系的综合数据库。
