Cancer Genetics Laboratory, Kolling Institute, Royal North Shore Hospital, Sydney, Australia.
Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
J Clin Endocrinol Metab. 2021 Mar 25;106(4):1163-1182. doi: 10.1210/clinem/dgaa957.
Pathogenic germline MAX variants are associated with pheochromocytoma and paraganglioma (PPGL), pituitary neuroendocrine tumors and, possibly, other endocrine and nonendocrine tumors.
To report 2 families with germline MAX variants, pheochromocytomas (PCs) and multiple other tumors.
Clinical, genetic, immunohistochemical, and functional studies at University hospitals in Australia on 2 families with germline MAX variants undergoing usual clinical care. The main outcome measures were phenotyping; germline and tumor sequencing; immunohistochemistry of PC and other tumors; functional studies of MAX variants.
Family A has multiple individuals with PC (including bilateral and metastatic disease) and 2 children (to date, without PC) with neuroendocrine tumors (paravertebral ganglioneuroma and abdominal neuroblastoma, respectively). One individual has acromegaly; immunohistochemistry of PC tissue showed positive growth hormone-releasing hormone staining. Another individual with previously resected PCs has pituitary enlargement and elevated insulin-like growth factor (IGF-1). A germline MAX variant (c.200C>A, p.Ala67Asp) was identified in all individuals with PC and both children, with loss of heterozygosity in PC tissue. Immunohistochemistry showed loss of MAX staining in PCs and other neural crest tumors. In vitro studies confirmed the variant as loss of function. In Family B, the proband has bilateral and metastatic PC, prolactin-producing pituitary tumor, multigland parathyroid adenomas, chondrosarcoma, and multifocal pulmonary adenocarcinomas. A truncating germline MAX variant (c.22G>T, p.Glu8*) was identified.
Germline MAX mutations are associated with PCs, ganglioneuromas, neuroblastomas, pituitary neuroendocrine tumors, and, possibly, parathyroid adenomas, as well as nonendocrine tumors of chondrosarcoma and lung adenocarcinoma, suggesting MAX is a novel multiple endocrine neoplasia gene.
致病性种系 MAX 变体与嗜铬细胞瘤和副神经节瘤（PPGL）、垂体神经内分泌肿瘤以及可能的其他内分泌和非内分泌肿瘤有关。
报告 2 个携带种系 MAX 变体、嗜铬细胞瘤（PC）和多种其他肿瘤的家族。
在澳大利亚的大学医院对 2 个携带种系 MAX 变体的家族进行了临床、遗传、免疫组织化学和功能研究，这些家族正在接受常规临床护理。主要观察指标为表型；种系和肿瘤测序；PC 和其他肿瘤的免疫组织化学；MAX 变体的功能研究。
家族 A 有多个个体患有 PC（包括双侧和转移性疾病）和 2 名儿童（迄今为止，没有 PC）患有神经内分泌肿瘤（椎旁节神经节细胞瘤和腹部神经母细胞瘤）。1 名个体患有肢端肥大症；PC 组织的免疫组织化学显示生长激素释放激素染色阳性。另一名先前接受过 PC 切除术的个体有垂体增大和胰岛素样生长因子（IGF-1）升高。所有患有 PC 和 2 名儿童的个体以及这 2 名儿童均发现种系 MAX 变体（c.200C>A，p.Ala67Asp），PC 组织存在杂合性丢失。免疫组织化学显示 PC 和其他神经嵴肿瘤中 MAX 染色丢失。体外研究证实该变体具有功能丧失。在家族 B 中，先证者患有双侧和转移性 PC、催乳素分泌性垂体肿瘤、多腺体甲状旁腺腺瘤、软骨肉瘤和多灶性肺腺癌。发现截短的种系 MAX 变体（c.22G>T，p.Glu8*）。
种系 MAX 突变与 PC、神经节细胞瘤、神经母细胞瘤、垂体神经内分泌肿瘤以及可能的甲状旁腺腺瘤有关，也与软骨肉瘤和肺腺癌等非内分泌肿瘤有关，提示 MAX 是一种新的多发性内分泌肿瘤基因。
