{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T05:25:09Z","timestamp":1783488309035,"version":"3.55.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T00:00:00Z","timestamp":1724976000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017594","name":"Medical Science and Technology Project of Zhejiang Province","doi-asserted-by":"publisher","award":["2023KY1343, 2024KY1830"],"award-info":[{"award-number":["2023KY1343, 2024KY1830"]}],"id":[{"id":"10.13039\/501100017594","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>The aim of this study was to investigate the genotypic and clinical phenotypic characteristics of <jats:italic>MAX<\/jats:italic> germline mutation\u2013associated pheochromocytoma (PCC) and paraganglioma (PGL).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We retrospectively analyzed the family investigation data and clinical genetic characteristics of six individuals from three independent families with PCC carrying <jats:italic>MAX<\/jats:italic> germline mutations from December 2005 to March 2024. A literature review was then conducted of the six carriers and another 103 carriers from the other 84 families with <jats:italic>MAX<\/jats:italic> germline mutations reported previously.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>There were 109 patients in 87 families with all five exons and 53 types of <jats:italic>MAX<\/jats:italic> germline mutations. p.R33* (c.97C&amp;gt;T; 21.1%), p.R75* (c.223C&amp;gt;T; 13.8%), and p.A67D (c.200C&amp;gt;A; 7.3%), which accounted for 42.2% of mutations detected, were the most common mutations. Moreover, 101 (92.7%) patients developed PCCs, including 59 bilateral PCCs and 42 unilateral PCCs, and 19 (18.8%) patients showed metastasis. The mean age at diagnosis was 32.8 \u00b1 12.6 (13-80) years. The male-to-female ratio was 1.3:1. In 11 (10.9%) patients, the PCC was accompanied by chest or abdominal PGL, and one other patient had sole head and neck PGL. Nine (8.3%) patients also had functional pituitary adenomas, 11 (10.9%) developed other neuroendocrine tumors (NETs), and 7 (6.4%) presented with concomitant non-NET. Meanwhile, <jats:italic>MAX<\/jats:italic>-p.Q82Tfs*89 and p.E158A mutations are reported for the first time in this study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:italic>MAX<\/jats:italic> germline mutations may cause new types of multiple endocrine neoplasia. A comprehensive baseline assessment of neural crest cell\u2013derived diseases is recommended for all individuals with <jats:italic>MAX<\/jats:italic> germline mutations. The risk of bilateral and metastatic PCCs should also be considered.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2024.1442691","type":"journal-article","created":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T04:38:12Z","timestamp":1724992692000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Genotype and clinical phenotype characteristics of MAX germline mutation\u2013associated pheochromocytoma\/paraganglioma syndrome"],"prefix":"10.3389","volume":"15","author":[{"given":"Bijun","family":"Lian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xudong","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyuan","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feiping","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junwei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiying","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoping","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,8,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1995","DOI":"10.1007\/s12094-021-02622-9","article-title":"Multidisciplinary practice guidelines for the diagnosis, genetic counseling and treatment of pheochromocytomas and paragangliomas","volume":"23","author":"Garcia-Carbonero","year":"2021","journal-title":"Clin Transl Oncol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1210\/endrev\/bnab019","article-title":"Personalized management of pheochromocytoma and paraganglioma","volume":"43","author":"N\u00f6lting","year":"2022","journal-title":"Endocr Rev"},{"key":"B3","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1016\/j.critrevonc.2016.01.022","article-title":"Updates on the genetics and the clinical impacts on phaeochromocytoma and paraganglioma in the new era","volume":"100","author":"Pillai","year":"2016","journal-title":"Crit Rev Oncol Hematol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1097\/hjh.0000000000002438","article-title":"Genetics, diagnosis, management and future directions of research of phaeochromocytoma and paraganglioma: a position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension","volume":"38","author":"Lenders","year":"2020","journal-title":"J Hypertension"},{"key":"B5","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.trecan.2017.11.001","article-title":"Genomic landscape of pheochromocytoma and paraganglioma","volume":"4","author":"Jochmanova","year":"2018","journal-title":"Trends Cancer"},{"key":"B6","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1186\/s12885-021-08116-9","article-title":"Spectrum of Germline RET variants identified by targeted sequencing and associated Multiple Endocrine Neoplasia type 2 susceptibility in China","volume":"21","author":"Qi","year":"2021","journal-title":"BMC Cancer"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fsurg.2022.1057821","article-title":"Simultaneous bilateral laparoscopic cortical-sparing adrenalectomy for bilateral pheochromocytomas in multiple endocrine neoplasia type 2","volume":"9","author":"Qi","year":"2022","journal-title":"Front Surg"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1530\/eje-19-0159","article-title":"Pheochromocytoma and paraganglioma: clinical feature-based disease probability in relation to catecholamine biochemistry and reason for disease suspicion","volume":"181","author":"Geroula","year":"2019","journal-title":"Eur J Endocrinol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1806651","article-title":"Pheochromocytoma and paraganglioma","volume":"381","author":"Neumann","year":"2019","journal-title":"N Engl J Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/ng.861","article-title":"Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma","volume":"43","author":"Comino-M\u00e9ndez","year":"2011","journal-title":"Nat Genet"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.Ccr-12-0160","article-title":"MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma","volume":"18","author":"Burnichon","year":"2012","journal-title":"Clin Cancer Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2017.0223","article-title":"Clinical characterization of the pheochromocytoma and paraganglioma susceptibility genes SDHA, TMEM127, MAX, and SDHAF2 for gene-informed prevention","volume":"3","author":"Bausch","year":"2017","journal-title":"JAMA Oncol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.574662","article-title":"Genetic and clinical profiles of pheochromocytoma and paraganglioma: A single center study","volume":"11","author":"Ma","year":"2020","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa957","article-title":"Multiple endocrine tumors associated with germline MAX mutations: Multiple endocrine neoplasia type 5","volume":"106","author":"Seabrook","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1530\/erc-18-0065","article-title":"A Novel Phenotype of Germline in three patients with MAX exon deletions","volume":"25","author":"Daly","year":"2018","journal-title":"Endocr Relat Cancer"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1530\/erc-12-0339","article-title":"Genetics of pheochromocytoma and paraganglioma in Spanish pediatric patients","volume":"20","author":"Casc\u00f3n","year":"2013","journal-title":"Endocr Relat Cancer"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/6582014","article-title":"Whole exome sequencing uncovers germline variants of cancer-related genes in sporadic pheochromocytoma","volume":"2018","author":"Urbini","year":"2018","journal-title":"Int J Genomics"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/s12022-016-9460-5","article-title":"Pathological and genetic characterization of bilateral adrenomedullary hyperplasia in a patient with germline MAX mutation","volume":"28","author":"Romanet","year":"2017","journal-title":"Endocr Pathol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1111\/cen.12218","article-title":"Testing new susceptibility genes in the cohort of apparently sporadic phaeochromocytoma\/paraganglioma patients with clinical characteristics of hereditary syndromes","volume":"79","author":"P\u0119czkowska","year":"2013","journal-title":"Clin Endocrinol (Oxf)"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-2592","article-title":"Complex MAX rearrangement in a family with Malignant pheochromocytoma, renal oncocytoma, and erythrocytosis","volume":"101","author":"Korpershoek","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1210\/js.2017-00135","article-title":"Case report of a prolactinoma in a patient with a novel MAX mutation and bilateral pheochromocytomas","volume":"1","author":"Roszko","year":"2017","journal-title":"J Endocr Soc"},{"key":"B22","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1186\/s40792-017-0408-x","article-title":"Synchronous bilateral pheochromocytomas and paraganglioma with novel germline mutation in MAX: a case report","volume":"3","author":"Shibata","year":"2017","journal-title":"Surg Case Rep"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1097\/cad.0000000000000570","article-title":"Temozolomide treatment of a Malignant pheochromocytoma and an unresectable MAX-related paraganglioma","volume":"29","author":"Ferrara","year":"2018","journal-title":"Anti-cancer Drugs"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.27194","article-title":"Mutational profile and genotype\/ phenotype correlation of non-familial pheochromocytoma and paraganglioma","volume":"10","author":"Albattal","year":"2019","journal-title":"Oncotarget"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1055\/a-1186-0790","article-title":"Pancreatic neuroendocrine neoplasm associated with a familial MAX deletion","volume":"52","author":"Petignot","year":"2020","journal-title":"Horm Metab Res"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3803\/EnM.2020.683","article-title":"Genetic analysis and clinical characteristics of hereditary pheochromocytoma and paraganglioma syndrome in korean population","volume":"35","author":"Choi","year":"2020","journal-title":"Endocrinol Metab (Seoul)"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.00234","article-title":"A novel MAX gene mutation variant in a patient with multiple and \"Composite\" Neuroendocrine-neuroblastic tumors","volume":"11","author":"Pozza","year":"2020","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.00558","article-title":"A novel phenotype of germline pathogenic variants in MAX: concurrence of pheochromocytoma and ganglioneuroma in a chinese family and literature review","volume":"11","author":"Chang","year":"2020","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1210\/jendso\/bvab085","article-title":"A novel, likely pathogenic MAX germline variant in a patient with unilateral pheochromocytoma","volume":"5","author":"Lam-Chung","year":"2021","journal-title":"J Endocr Soc"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.683492","article-title":"Familial acromegaly and bilateral asynchronous pheochromocytomas in a female patient with a MAX mutation: A case report","volume":"12","author":"Mamedova","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B31","doi-asserted-by":"publisher","first-page":"299","DOI":"10.3390\/clinpract12030035","article-title":"Bilateral pheochromocytoma with germline MAX\u2002Variant without family history","volume":"12","author":"Hata","year":"2022","journal-title":"Clin Pract"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1111\/cen.14618","article-title":"Genetic spectrum in a Canadian cohort of apparently sporadic pheochromocytomas and paragangliomas: New data on multigene panel retesting over time","volume":"96","author":"Parisien-La Salle","year":"2022","journal-title":"Clin Endocrinol (Oxf)"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2017-02324","article-title":"18F-FDOPA PET\/CT imaging of MAX-related pheochromocytoma","volume":"103","author":"Ta\u00efeb","year":"2018","journal-title":"J Clin Endocrinol Metab"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.609263","article-title":"Case report: pheochromocytoma and synchronous neuroblastoma in a family with hereditary pheochromocytoma associated with a MAX deleterious variant","volume":"12","author":"Duarte","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.cancergen.2021.01.004","article-title":"Clinical description & molecular modeling of novel MAX pathogenic variant causing pheochromocytoma in family, supports paternal parent-of-origin effect","author":"Richter","year":"2021","journal-title":"Cancer Genet"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1210\/jcemcr\/luad006","article-title":"Primary hyperparathyroidism in a patient with bilateral pheochromocytoma and a mutation in the tumor suppressor MAX","volume":"1","author":"Charoenngam","year":"2023","journal-title":"JCEM Case Rep"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1202750","article-title":"The basic region\/helix-loop-helix\/leucine zipper domain of Myc proto-oncoproteins: function and regulation","volume":"18","author":"L\u00fcscher","year":"1999","journal-title":"Oncogene"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cellbio.16.1.653","article-title":"The Myc\/Max\/Mad network and the transcriptional control of Cell behavior","volume":"16","author":"Grandori","year":"2000","journal-title":"Annu Rev Cell Dev Biol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-015-1306-y","article-title":"Functional and in silico assessment of MAX variants of unknown significance","volume":"93","author":"Comino-M\u00e9ndez","year":"2015","journal-title":"J Mol Med (Berl)"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1022192","article-title":"HIF and MYC signaling in adrenal neoplasms of the neural crest: implications for pediatrics","volume":"14","author":"Bechmann","year":"2023","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11081070","article-title":"Pheochromocytomas and paragangliomas: new developments with regard to classification, genetics, and cell of origin","volume":"11","author":"Koopman","year":"2019","journal-title":"Cancers (Basel)"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3760\/cma.j.cn112139-20220714-00312","article-title":"The trends in early precision diagnosis and treatment strategies of multiple endocrine neoplasia type 2","volume":"60","author":"Qi","year":"2022","journal-title":"Zhonghua Wai Ke Za Zhi"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1055\/a-0661-0341","article-title":"The\u20023PAs: an\u2002Update\u2002on the association of pheochromocytomas, paragangliomas, and\u2002Pituitary\u2002Tumors","volume":"51","author":"Xekouki","year":"2019","journal-title":"Horm Metab Res"},{"key":"B44","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1002\/(ISSN)1096-911X","article-title":"Loss of heterozygosity for chromosome 14q in neuroblastoma","volume":"36","author":"Thompson","year":"2001","journal-title":"Med Pediatr Oncol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"e220411","DOI":"10.1530\/EC-22-0411","article-title":"Multiple endocrine neoplasia type 4: a new member of the MEN family","volume":"12","author":"Singeisen","year":"2023","journal-title":"Endocr Connect"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-023-03497-2","article-title":"Multiple endocrine neoplasia type 4 (MEN4): a thorough update on the latest and least known men syndrome","volume":"82","author":"Ruggeri","year":"2023","journal-title":"Endocrine"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2024.1442691\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T04:38:16Z","timestamp":1724992696000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2024.1442691\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,30]]},"references-count":46,"alternative-id":["10.3389\/fendo.2024.1442691"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2024.1442691","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,30]]},"article-number":"1442691"}}