{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T14:59:29Z","timestamp":1753887569428,"version":"3.41.2"},"reference-count":47,"publisher":"American Academy of Pediatrics (AAP)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,9,1]]},"abstract":"<jats:p>Early onset medullary thyroid carcinoma, later pheochromocytomas, and nonspecific extra-endocrine features (hypermobility and persistent constipation) are part of the clinical phenotype of Multiple Endocrine Neoplasia type 2B (MEN2B). A de novo pathogenic M918T variant in the rearranged during transfection proto-oncogene is usually identified. Affected children are often seen by multiple clinicians over a long period before consideration of a diagnosis of MEN2B, with metastatic medullary thyroid carcinoma often the precipitator. We describe the clinical presentation and course of 5 children ultimately diagnosed with MEN2B in New South Wales and the Australian Capital Territory, Australia between 1989 and 2021. All cases had intestinal ganglioneuromatosis that could have prompted an earlier diagnosis. Population wide newborn genomic screening for rare diseases is on the horizon. We propose that MEN2B genomic screening should be included in newborn screening programs and that careful exclusion of intestinal ganglioneuromatosis would allow earlier identification leading to improved clinical outcomes.<\/jats:p>","DOI":"10.1542\/peds.2022-059517","type":"journal-article","created":{"date-parts":[[2024,8,16]],"date-time":"2024-08-16T08:06:29Z","timestamp":1723795589000},"source":"Crossref","is-referenced-by-count":1,"title":["Clues for Early Diagnosis of MEN2B Syndrome Before Medullary Thyroid Carcinoma"],"prefix":"10.1542","volume":"154","author":[{"given":"Tashunka","family":"Taylor-Miller","sequence":"first","affiliation":[{"name":"aCentre for Clinical Genetics, Sydney Children\u2019s Hospital Randwick, New Sout Wales, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine","family":"Tucker","sequence":"additional","affiliation":[{"name":"bHereditary Cancer Centre, Prince of Wales Hospital Randwick, New Sout Wales, Australia"},{"name":"cDiscipline of Paediatrics, School of Clinical Medicine, University of New South Wales, Medicine and Health, Sydney, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ella","family":"Sugo","sequence":"additional","affiliation":[{"name":"dDepartment of Anatomical Histopathology, John Hunter Hospital, Newcastle, New South Wales, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antoinette","family":"Anazodo","sequence":"additional","affiliation":[{"name":"cDiscipline of Paediatrics, School of Clinical Medicine, University of New South Wales, Medicine and Health, Sydney, Australia"},{"name":"eKids Cancer Centre, Sydney Children\u2019s Hospital, Randwick, New South Wales, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Mowat","sequence":"additional","affiliation":[{"name":"aCentre for Clinical Genetics, Sydney Children\u2019s Hospital Randwick, New Sout Wales, Australia"},{"name":"cDiscipline of Paediatrics, School of Clinical Medicine, University of New South Wales, Medicine and Health, Sydney, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"417","published-online":{"date-parts":[[2024,8,16]]},"reference":[{"issue":"8","key":"2024090102521686600_B1","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1111\/imj.14394","article-title":"Multiple endocrine neoplasia: an update","volume":"49","author":"McDonnell","year":"2019","journal-title":"Intern Med J"},{"issue":"1-2","key":"2024090102521686600_B2","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.mce.2013.08.002","article-title":"Multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4)","volume":"386","author":"Thakker","year":"2014","journal-title":"Mol Cell Endocrinol"},{"issue":"7","key":"2024090102521686600_B3","doi-asserted-by":"crossref","first-page":"L39","DOI":"10.1530\/ERC-17-0122","article-title":"Incidence and prevalence of multiple endocrine neoplasia 2B in Denmark: a nationwide study","volume":"24","author":"Mathiesen","year":"2017","journal-title":"Endocr Relat Cancer"},{"issue":"12","key":"2024090102521686600_B4","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1634\/theoncologist.2014-0277","article-title":"Epidemiology, clinical features, and genetics of multiple endocrine neoplasia type 2B in a complete population","volume":"19","author":"Znaczko","year":"2014","journal-title":"Oncologist"},{"issue":"3","key":"2024090102521686600_B5","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S2213-8587(18)30336-X","article-title":"Natural history, treatment, and long-term follow up of patients with multiple endocrine neoplasia type 2B: an international, multicentre, retrospective study","volume":"7","author":"Castinetti","year":"2019","journal-title":"Lancet Diabetes Endocrinol"},{"issue":"3","key":"2024090102521686600_B6","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1016\/j.surg.2021.03.001","article-title":"Lymph node metastases in pediatric medullary thyroid carcinoma","volume":"170","author":"Oliver","year":"2021","journal-title":"Surgery"},{"issue":"13","key":"2024090102521686600_B7","doi-asserted-by":"crossref","first-page":"4423","DOI":"10.1245\/s10434-019-07869-9","article-title":"Long-term oncologic outcomes after curative resection of familial medullary thyroid carcinoma","volume":"26","author":"Spanheimer","year":"2019","journal-title":"Ann Surg Oncol"},{"issue":"4","key":"2024090102521686600_B8","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1097\/SLA.0b013e3182a6f43a","article-title":"Surgical curability of medullary thyroid cancer in multiple endocrine neoplasia 2B: a changing perspective","volume":"259","author":"Brauckhoff","year":"2014","journal-title":"Ann Surg"},{"issue":"2","key":"2024090102521686600_B9","doi-asserted-by":"crossref","first-page":"e28056","DOI":"10.1002\/pbc.28056","article-title":"Multiple endocrine neoplasia type 2B: frequency of physical stigmata-results of the GPOH-MET registry","volume":"67","author":"Redlich","year":"2020","journal-title":"Pediatr Blood Cancer"},{"issue":"7","key":"2024090102521686600_B10","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1038\/s41436-021-01124-x","article-title":"Universal newborn genetic screening for pediatric cancer predisposition syndromes: model-based insights","volume":"23","author":"Yeh","year":"2021","journal-title":"Genet Med"},{"issue":"11","key":"2024090102521686600_B11","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1038\/s41576-023-00621-w","article-title":"Genomic newborn screening for rare diseases","volume":"24","author":"Stark","year":"2023","journal-title":"Nat Rev Genet"},{"issue":"6","key":"2024090102521686600_B12","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1089\/thy.2014.0335","article-title":"Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma","volume":"25","author":"Wells","year":"2015","journal-title":"Thyroid"},{"key":"2024090102521686600_B13","doi-asserted-by":"crossref","first-page":"54324","DOI":"10.3389\/fendo.2020.543246","article-title":"5P strategies for management of multiple endocrine neoplasia type 2: a paradigm of precision medicine","volume":"11","author":"Li","year":"2020","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"5","key":"2024090102521686600_B14","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1530\/ERC-11-0117","article-title":"In silico and in\u00a0vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer","volume":"18","author":"Cosci","year":"2011","journal-title":"Endocr Relat Cancer"},{"issue":"4","key":"2024090102521686600_B15","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/sj.onc.1201199","article-title":"Oncogenic activation of RET by two distinct FMTC mutations affecting the tyrosine kinase domain","volume":"15","author":"Pasini","year":"1997","journal-title":"Oncogene"},{"key":"2024090102521686600_B16","doi-asserted-by":"crossref","first-page":"77","DOI":"10.6061\/clinics\/2012(Sup01)14","article-title":"Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2","volume":"67","author":"Wagner","year":"2012","journal-title":"Clinics (S\u00e3o Paulo)"},{"issue":"9","key":"2024090102521686600_B17","doi-asserted-by":"crossref","first-page":"698","DOI":"10.3390\/genes10090698","article-title":"Twenty-five years experience on RET genetic screening on hereditary MTC: an update on the prevalence of germline RET mutations","volume":"10","author":"Elisei","year":"2019","journal-title":"Genes (Basel)"},{"issue":"2","key":"2024090102521686600_B18","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1038\/s41431-019-0508-0","article-title":"Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database","volume":"28","author":"Nguengang Wakap","year":"2020","journal-title":"Eur J Hum Genet"},{"issue":"3","key":"2024090102521686600_B19","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1530\/EJE-12-0919","article-title":"Molecular epidemiology of multiple endocrine neoplasia 2: implications for RET screening in the new millenium","volume":"168","author":"Machens","year":"2013","journal-title":"Eur J Endocrinol"},{"issue":"6","key":"2024090102521686600_B20","doi-asserted-by":"crossref","first-page":"2069","DOI":"10.1210\/jc.2016-3640","article-title":"Risk profile of the RET A883F germline mutation: an international collaborative study","volume":"102","author":"Mathiesen","year":"2017","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2024090102521686600_B21","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1210\/jc.2017-01884","article-title":"Long-term survivorship in multiple endocrine neoplasia type 2B diagnosed before and in the new millennium","volume":"103","author":"Raue","year":"2018","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"2024090102521686600_B22","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1016\/j.surg.2008.08.028","article-title":"Premonitory symptoms preceding metastatic medullary thyroid cancer in MEN 2B: an exploratory analysis","volume":"144","author":"Brauckhoff","year":"2008","journal-title":"Surgery"},{"key":"2024090102521686600_B23","first-page":"61","volume-title":"Recent Results in Cancer Research","author":"Friedhelm","year":"2015"},{"issue":"1","key":"2024090102521686600_B24","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1245\/s10434-007-9665-4","article-title":"Failure to recognize multiple endocrine neoplasia 2B: more common than we think?","volume":"15","author":"Wray","year":"2008","journal-title":"Ann Surg Oncol"},{"issue":"10","key":"2024090102521686600_B25","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1038\/nrendo.2011.139","article-title":"Management of medullary thyroid carcinoma and MEN2 syndromes in childhood","volume":"7","author":"Waguespack","year":"2011","journal-title":"Nat Rev Endocrinol"},{"issue":"2","key":"2024090102521686600_B26","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1159\/000508850","article-title":"Diarrhea as an initial presentation in patients with medullary thyroid cancer: delaying the diagnosis","volume":"14","author":"Shakir","year":"2020","journal-title":"Case Rep Gastroenterol"},{"issue":"2","key":"2024090102521686600_B27","doi-asserted-by":"crossref","first-page":"E336","DOI":"10.1210\/jc.2012-3192","article-title":"Peak incidence of pheochromocytoma and primary hyperparathyroidism in multiple endocrine neoplasia 2: need for age-adjusted biochemical screening","volume":"98","author":"Machens","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"issue":"11","key":"2024090102521686600_B28","doi-asserted-by":"crossref","first-page":"E1813","DOI":"10.1210\/jc.2013-1653","article-title":"The characterization of pheochromocytoma and its impact on overall survival in multiple endocrine neoplasia type 2","volume":"98","author":"Thosani","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"2024090102521686600_B29","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1056\/NEJMra1806651","article-title":"Pheochromocytoma and paraganglioma","volume":"381","author":"Neumann","year":"2019","journal-title":"N Engl J Med"},{"issue":"3","key":"2024090102521686600_B30","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1272\/jnms.JNMS.2018_85-26","article-title":"The reality of multiple endocrine neoplasia type 2B diagnosis: awareness of unique physical appearance is important","volume":"85","author":"Nagaoka","year":"2018","journal-title":"J Nippon Med Sch"},{"issue":"1","key":"2024090102521686600_B31","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1111\/cge.13173","article-title":"Diagnosis and genetics of alacrima","volume":"94","author":"Adams","year":"2018","journal-title":"Clin Genet"},{"issue":"3","key":"2024090102521686600_B32","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1007\/s12020-021-02607-2","article-title":"Timely diagnosis of multiple endocrine neoplasia 2B by identification of intestinal ganglioneuromatosis: a case series","volume":"72","author":"van den Broek","year":"2021","journal-title":"Endocrine"},{"issue":"7","key":"2024090102521686600_B33","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1016\/j.jpedsurg.2016.10.054","article-title":"Identification of intestinal ganglioneuromatosis leads to early diagnosis of MEN2B: role of rectal biopsy","volume":"52","author":"Gfroerer","year":"2017","journal-title":"J Pediatr Surg"},{"issue":"23","key":"2024090102521686600_B34","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1056\/NEJM197612022952304","article-title":"Alimentary-tract ganglioneuromatosis. A major component of the syndrome of multiple endocrine neoplasia, type 2b","volume":"295","author":"Carney","year":"1976","journal-title":"N Engl J Med"},{"issue":"5","key":"2024090102521686600_B35","first-page":"783","article-title":"Multiple endocrine neoplasia 2B presenting with pseudo-Hirschsprung\u2019s disease","volume":"98","author":"Erdogan","year":"2006","journal-title":"J Natl Med Assoc"},{"issue":"1","key":"2024090102521686600_B36","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/1687-9856-2012-25","article-title":"Medullary thyroid cancer in a 9-week-old infant with familial MEN 2B: implications for timing of prophylactic thyroidectomy","volume":"2012","author":"Shankar","year":"2012","journal-title":"Int J Pediatr Endocrinol"},{"issue":"10","key":"2024090102521686600_B37","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1016\/j.jpedsurg.2019.02.009","article-title":"Surgical management of pediatric thyroid disease: complication rates after thyroidectomy at the Children\u2019s Hospital of Philadelphia high-volume Pediatric Thyroid Center","volume":"54","author":"Baumgarten","year":"2019","journal-title":"J Pediatr Surg"},{"key":"2024090102521686600_B38","doi-asserted-by":"crossref","first-page":"717769","DOI":"10.3389\/fendo.2021.717769","article-title":"Complications after thyroidectomy in children: lymph node dissection is a risk factor for permanent hypocalcemia","volume":"12","author":"van Rooijen","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"2","key":"2024090102521686600_B39","first-page":"92","article-title":"Hypoparathyroidism after thyroidectomy: a 20-year experience at a children\u2019s hospital","volume":"69","author":"Garc\u00eda-Garc\u00eda","year":"2022","journal-title":"Endocrinol Diabetes Nutr (Engl Ed)"},{"key":"2024090102521686600_B40","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/j.jss.2022.11.035","article-title":"Short-term complications after total thyroidectomy in children","volume":"283","author":"Reiter","year":"2023","journal-title":"J Surg Res"},{"volume-title":"Principles and Practice of Screening for Disease. Public Health Paper No 34","year":"1968","author":"Wilson","key":"2024090102521686600_B41"},{"key":"2024090102521686600_B42","doi-asserted-by":"crossref","first-page":"S6","DOI":"10.1038\/ejhg.2010.249","article-title":"Genetic testing and common disorders in a public health framework: how to assess relevance and possibilities. Background document to the ESHG recommendations on genetic testing and common disorders","volume":"19 Suppl 1","author":"Becker","year":"2011","journal-title":"Eur J Hum Genet"},{"issue":"14","key":"2024090102521686600_B43","doi-asserted-by":"crossref","first-page":"E422","DOI":"10.1503\/cmaj.171154","article-title":"Consolidated principles for screening based on a systematic review and consensus process","volume":"190","author":"Dobrow","year":"2018","journal-title":"CMAJ"},{"issue":"1","key":"2024090102521686600_B44","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.ajhg.2018.11.016","article-title":"Interpretation of genomic sequencing results in healthy and ill newborns: results from the BabySeq project","volume":"104","author":"Ceyhan-Birsoy","year":"2019","journal-title":"Am J Hum Genet"},{"issue":"5","key":"2024090102521686600_B45","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1038\/s41436-019-0745-1","article-title":"Exome sequencing in newborns with congenital deafness as a model for genomic newborn screening: the Baby Beyond Hearing project","volume":"22","author":"Downie","year":"2020","journal-title":"Genet Med"},{"issue":"5","key":"2024090102521686600_B46","doi-asserted-by":"crossref","first-page":"101077","DOI":"10.1016\/j.gim.2024.101077","article-title":"Gene selection for genomic newborn screening: moving toward consensus?","volume":"26","author":"Downie","year":"2024","journal-title":"Genet Med"},{"issue":"7","key":"2024090102521686600_B47","doi-asserted-by":"crossref","first-page":"2520","DOI":"10.1210\/jc.2018-02102","article-title":"Fifty years after the first description, men 2b syndrome diagnosis is still late: descriptions of two recent cases","volume":"104","author":"Elisei","year":"2019","journal-title":"J Clin Endocrinol Metab"}],"container-title":["Pediatrics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/publications.aap.org\/pediatrics\/article-pdf\/doi\/10.1542\/peds.2022-059517\/1702017\/peds.2022-059517.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/publications.aap.org\/pediatrics\/article-pdf\/doi\/10.1542\/peds.2022-059517\/1702017\/peds.2022-059517.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,1]],"date-time":"2024-09-01T02:53:16Z","timestamp":1725159196000},"score":1,"resource":{"primary":{"URL":"https:\/\/publications.aap.org\/pediatrics\/article\/154\/3\/e2022059517\/198957\/Clues-for-Early-Diagnosis-of-MEN2B-Syndrome-Before"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,16]]},"references-count":47,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,8,16]]},"published-print":{"date-parts":[[2024,9,1]]}},"URL":"https:\/\/doi.org\/10.1542\/peds.2022-059517","relation":{},"ISSN":["0031-4005","1098-4275"],"issn-type":[{"type":"print","value":"0031-4005"},{"type":"electronic","value":"1098-4275"}],"subject":[],"published":{"date-parts":[[2024,8,16]]},"article-number":"e2022059517"}}