BACKGROUND: Multiple endocrine neoplasia type 2B is a rare syndrome caused mainly by Met918Thr germline RET mutation, and characterised by medullary thyroid carcinoma, phaeochromocytoma, and extra-endocrine features. Data are scarce on the natural history of multiple endocrine neoplasia type 2B. We aimed to advance understanding of the phenotype and natural history of multiple endocrine neoplasia type 2B, to increase awareness and improve detection. METHODS: This study was a retrospective, multicentre, international study in patients carrying the Met918Thr RET variant with no age restrictions. The study was done with registry data from 48 centres globally. Data from patients followed-up from 1970 to 2016 were retrieved from May 1, 2016, to May 31, 2018. Our primary objectives were to determine overall survival, and medullary thyroid carcinoma-specific survival based on whether the patient had undergone early thyroidectomy before the age of 1 year. We also assessed remission of medullary thyroid carcinoma, incidence and treatment of phaeochromocytoma, and the penetrance of extra-endocrine features. FINDINGS: 345 patients were included, of whom 338 (98%) had a thyroidectomy. 71 patients (21%) of the total cohort died at a median age of 25 years (range <1-59). Thyroidectomy was done before the age of 1 year in 20 patients, which led to long-term remission (ie, undetectable calcitonin level) in 15 (83%) of 18 individuals (2 patients died of causes unrelated to medullary thyroid carcinoma). Medullary thyroid carcinoma-specific survival curves did not show any significant difference between patients who had thyroidectomy before or after 1 year (comparison of survival curves by log-rank test: p=0·2; hazard ratio 0·35; 95% CI 0.07-1.74). However, there was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). There was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). In the other 318 patients who underwent thyroidectomy after 1 year of age, biochemical and structural remission was obtained in 47 (15%) of 318 individuals. Bilateral phaeochromocytoma was diagnosed in 156 (50%) of 313 patients by 28 years of age. Adrenal-sparing surgery was done in 31 patients: three (10%) of 31 patients had long-term recurrence, while normal adrenal function was obtained in 16 (62%) patients. All patients with available data (n=287) had at least one extra-endocrine feature, including 106 (56%) of 190 patients showing marfanoid body habitus, mucosal neuromas, and gastrointestinal signs. INTERPRETATION: Thyroidectomy done at no later than 1 year of age is associated with a high probability of cure. The reality is that the majority of children with the syndrome will be diagnosed after this recommended age. Adrenal-sparing surgery is feasible in multiple endocrine neoplasia type 2B and affords a good chance for normal adrenal function. To improve the prognosis of such patients, it is imperative that every health-care provider be aware of the extra-endocrine signs and the natural history of this rare syndrome. The implications of this research include increasing awareness of the extra-endocrine symptoms and also recommendations for thyroidectomy before the age of 1 year. FUNDING: None.

Aix Marseille Université Institut National de la Santé et de la Recherche Médicale Marseille Medical Genetics Marseille France; Assistance Publique Hôpitaux de Marseille Department of Endocrinology Hôpital de la Conception Centre de Référence des Maladies Rares de l'hypophyse Marseille France

Centre Hospitalier Régional Universitaire de Lille Hopital Huriez Service d'Endocrinologie Lille France

Centre Hospitalier Universitaire de Bordeaux Hôpital du Haut Lévêque Service d'Endocrinologie Diabétologie et Maladies Métaboliques Pessac France

Centre Hospitalier Universitaire de Grenoble Hôpital Albert Michallon Service d'Endocrinologie Diabétologie Nutrition Grenoble France

Centre Hospitalier Universitaire de Toulouse Hôpital Larrey Service d'Endocrinologie Maladies métaboliques Nutrition Toulouse France

Centro de Investigaciones Endocrinológicas Dr César Bergadá Hospital de Niños Ricardo Gutiérrez Buenos Aires Argentina

Département de Biochimie et Génétique Centre Hospitalier Universitaire d'Angers Angers France

Department of Breast and Endocrine Surgery National Hospital Organization Higashinagoya National Hospital Nagoya Japan

Department of Endocrine Neoplasia and Hormonal Disorders University of Texas MD Anderson Cancer Center Houston TX USA

Department of Endocrine Surgery La Conception Hospital Marseille France

Department of Endocrinology and Nutrition Hospital Universitario Central de Asturias Oviedo Spain; Unit of Endocrinology Nutrition Diabetes and Obesity Institute of Sanitary Research of Asturias Oviedo Spain

Department of Endocrinology Diabetes and Nutrition Reference Centre of Rare Thyroid Disease Hospital of Angers Angers France

Department of Endocrinology Seth G S Medical College King Edward Memorial Hospital Parel Mumbai India

Department of Endocrinology St Bartholomew's Hospital London UK; London School of Medicine and Dentistry Queen Mary University of London London UK

Department of Endocrinology University Hospital Nancy France

Department of Endocrinology University Hospital Pisa Italy

Department of Endocrinology University Medical Center Groningen University of Groningen Groningen Netherlands

Department of Experimental and Clinical Biomedical Sciences Endocrinology Unit University of Florence Florence Italy

Department of General Visceral and Vascular Surgery Martin Luther University Halle Wittenberg Halle Germany

Department of Hypertension Institute of Cardiology Warsaw Poland

Department of Internal Medicine and Medical Specialties Sapienza University of Rome Rome Italy

Department of Medical Genetics and Genomics Sapporo Medical University School of Medicine Chuo ku Sapporo Hokkaido Japan

Department of Molecular Endocrinology Institute of Endocrinology Prague Czech Republic

Department of Nuclear Medicine and Endocrine Oncology Maria Sklodowska Curie Institute Oncology Center Gliwice Branch Gliwice Poland

Department of Nuclear Medicine and Endocrinology 2nd Faculty of Medicine Charles University Prague Czech Republic; Motol University Hospital Prague Czech Republic

Department of Otorhinolaryngology Head and Neck Surgery and Audiology Odense University Hospital Odense Denmark; Department of Clinical Research University of Southern Denmark Odense Denmark

Department of Pediatrics New York University Langone Medical Center New York NY USA

Department of Pediatrics University Hospital Centre Zagreb Zagreb Croatia

Department of Surgical Oncology University of Texas MD Anderson Cancer Center Houston TX USA

Departments of Oncologic and Urologic Surgery The 117th People's Liberation Army Hospital People's Liberation Army Hangzhou Clinical College Anhui Medical University Hangzhou China

Division of Endocrine and Metabolic Diseases Istituto di Ricovero e Cura a Carattere Scientifico Istituto Auxologico Italiano University of Milan Milan Italy; Department of Pathophysiology and Transplantation University of Milan Milan Italy

Division of Endocrine Surgery University College Hospital and Great Ormond Street Hospital London United Kingdom

Division of Metabolism Endocrinology and Diabetes Department of Internal Medicine University of Michigan Health System Ann Arbor MI USA

Endocrine and Nuclear Medicine Unit Hospital Italiano de Buenos Aires Buenos Aires Argentina

Endocrine Division Department of Medicine Centre Hospitalier de l'Universite í de Montréal Montreal QC Canada

Endocrine Genetics Unit Endocrinology Division Hospital das Clínicas University of São Paulo School of Medicine São Paulo Brazil; Endocrine Oncology Division Institute of Cancer of the State of São Paulo Faculty of Medicine of the University of São Paulo São Paulo Brazil

Endocrine Oncology Institut Gustave Roussy Ecole Doctorale de Cancerologie Villejuif France

Endocrine Section Universidad de Chile Hospital del Salvador Santiago de Chile Santiago Chile

Endocrinologie et Métabolismes Centre Hospitalier de Saint Denis Saint Denis France

Genomic Medicine Institute Lerner Research Institute and Taussig Cancer Institute Cleveland Clinic Cleveland OH USA

Hospices Civils de Lyon Fédération d'Endocrinologie Université Claude Bernard Lyon 1 Lyon France

Hungarian Academy of Sciences and Semmelweis University HSA SE Lendület Hereditary Endocrine Tumour Research Group Budapest Hungary

L'Institut du thorax Department of Endocrinology Centre Hospitalier Universitaire Nantes Nantes France

Noguchi Thyroid Clinic and Hospital Foundation Beppu Japan

Operative Unit of the Endocrinology Department of Medicine University of Padua Padua Italy

Pediatric Oncology Branch National Cancer Institute National Institutes of Health Bethesda MD USA

Section for Preventive Medicine Department of Nephrology and General Medicine Freiburg Germany

Section of Endocrine Surgery Department of General Visceral and Transplantation Surgery University Hospital Essen Essen Germany

Service d'Endocrinologie et Nutrition Cliniques Universitaires Saint Luc Universite Catholique de Louvain Brussels Belgium

Serviço de Endocrinologia Diabetes e Metabolismo Centro Hospitalar Universitário Lisboa Norte Hospital Santa Maria Lisboa Portugal; Centro Académico de Medicina de Lisboa Universidade Lisboa Lisboa Portugal

Thyroid Section Endocrinology Division Hospital de Cliínicas de Porto Alegre Universidade Federal do Rio Grande do Sul Porto Alegre Brazil

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