Primary hyperparathyroidism as first manifestation in multiple endocrine neoplasia type 2A: an international multicenter study

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Abstract

Objective

Multiple endocrine neoplasia type 2A (MEN 2A) is a rare syndrome caused by RET germline mutations and has been associated with primary hyperparathyroidism (PHPT) in up to 30% of cases. Recommendations on RET screening in patients with apparently sporadic PHPT are unclear. We aimed to estimate the prevalence of cases presenting with PHPT as first manifestation among MEN 2A index cases and to characterize the former cases.

Design and methods

An international retrospective multicenter study of 1085 MEN 2A index cases. Experts from MEN 2 centers all over the world were invited to participate. A total of 19 centers in 17 different countries provided registry data of index cases followed from 1974 to 2017.

Results

Ten cases presented with PHPT as their first manifestation of MEN 2A, yielding a prevalence of 0.9% (95% CI: 0.4–1.6). 9/10 cases were diagnosed with medullary thyroid carcinoma (MTC) in relation to parathyroid surgery and 1/10 was diagnosed 15 years after parathyroid surgery. 7/9 cases with full TNM data were node-positive at MTC diagnosis.

Conclusions

Our data suggest that the prevalence of MEN 2A index cases that present with PHPT as their first manifestation is very low. The majority of index cases presenting with PHPT as first manifestation have synchronous MTC and are often node-positive. Thus, our observations suggest that not performing RET mutation analysis in patients with apparently sporadic PHPT would result in an extremely low false-negative rate, if no other MEN 2A component, specifically MTC, are found during work-up or resection of PHPT.

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Most cited references 58

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Guidelines for diagnosis and therapy of MEN type 1 and type 2.

M. Brandi, R F Gagel, A. Angeli … (2001)

This is a consensus statement from an international group, mostly of clinical endocrinologists. MEN1 and MEN2 are hereditary cancer syndromes. The commonest tumors secrete PTH or gastrin in MEN1, and calcitonin or catecholamines in MEN2. Management strategies improved after the discoveries of their genes. MEN1 has no clear syndromic variants. Tumor monitoring in MEN1 carriers includes biochemical tests yearly and imaging tests less often. Neck surgery includes subtotal or total parathyroidectomy, parathyroid cryopreservation, and thymectomy. Proton pump inhibitors or somatostatin analogs are the main management for oversecretion of entero-pancreatic hormones, except insulin. The roles for surgery of most entero-pancreatic tumors present several controversies: exclusion of most operations on gastrinomas and indications for surgery on other tumors. Each MEN1 family probably has an inactivating MEN1 germline mutation. Testing for a germline MEN1 mutation gives useful information, but rarely mandates an intervention. The most distinctive MEN2 variants are MEN2A, MEN2B, and familial medullary thyroid cancer (MTC). They vary in aggressiveness of MTC and spectrum of disturbed organs. Mortality in MEN2 is greater from MTC than from pheochromocytoma. Thyroidectomy, during childhood if possible, is the goal in all MEN2 carriers to prevent or cure MTC. Each MEN2 index case probably has an activating germline RET mutation. RET testing has replaced calcitonin testing to diagnose the MEN2 carrier state. The specific RET codon mutation correlates with the MEN2 syndromic variant, the age of onset of MTC, and the aggressiveness of MTC; consequently, that mutation should guide major management decisions, such as whether and when to perform thyroidectomy.

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Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A.

L M Mulligan, J B Kwok, C S Healey … (1993)

Multiple endocrine neoplasia type 2A (MEN 2A) is a dominantly inherited cancer syndrome that affects tissues derived from neural ectoderm. It is characterized by medullary thyroid carcinoma (MTC) and phaeochromocytoma. The MEN2A gene has recently been localized by a combination of genetic and physical mapping techniques to a 480-kilobase region in chromosome 10q11.2 (refs 2,3). The DNA segment encompasses the RET proto-oncogene, a receptor tyrosine kinase gene expressed in MTC and phaeochromocytoma and at lower levels in normal human thyroid. This suggested RET as a candidate for the MEN2A gene. We have identified missense mutations of the RET proto-oncogene in 20 of 23 apparently distinct MEN 2A families, but not in 23 normal controls. Further, 19 of these 20 mutations affect the same conserved cysteine residue at the boundary of the RET extracellular and transmembrane domains.

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Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC.

P. S. Wells, P N Goodfellow, S Dou … (1993)

Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are dominantly inherited conditions which predispose to the development of endocrine neoplasia. Evidence is presented that sequence changes within the coding region of the RET proto-oncogene, a putative transmembrane tyrosine kinase, may be responsible for the development of neoplasia in these inherited disorders. Single strand conformational variants (SSCVs) in exons 7 and 8 of the RET proto-oncogene were identified in eight MEN 2A and four FMTC families. The variants were observed only in the DNA of individuals who were either affected or who had inherited the MEN2A or FMTC allele as determined by haplotyping experiments. The seven variants identified were sequenced directly. All involved point mutations within codons specifying cysteine residues, resulting in nonconservative amino acid changes. Six of the seven mutations are located in exon 7. A single mutation was found in exon 8. Variants were not detected in four MEN 2B families studied for all exon assays available, nor were they detectable in 16 cases of well documented sporadic medullary thyroid carcinoma or pheochromocytoma that were tested for exon 7 variants. Coinheritance of the mutations with disease and the physical and genetic proximity of the RET proto-oncogene provide evidence that RET is responsible for at least two of the three inherited forms of MEN 2. Neither the normal function, nor the ligand of RET are yet known. However, its apparent involvement in the development of these inherited forms of neoplasia as well as in papillary thyroid carcinoma suggest an important developmental or cell regulatory role for the protein.

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Author and article information

Journal

Journal ID (nlm-ta): Endocr Connect

Journal ID (iso-abbrev): Endocr Connect

Journal ID (hwp): EC

Title: Endocrine Connections

Publisher: Bioscientifica Ltd (Bristol )

ISSN (Electronic): 2049-3614

Publication date Collection: June 2020

Publication date (Electronic): 06 May 2020

Volume: 9

Issue: 6

Pages: 489-497

Affiliations

[1 ]Department of ORL Head & Neck Surgery and Audiology , Odense University Hospital, Odense, Denmark

[2 ]Laboratoire de Biochimie et Biologie Moléculaire , CHU Angers, Université d’Angers, UMR CNRS 6015, INSERM U1083, MITOVASC, Angers, France

[3 ]Department of Breast & Endocrine Surgery , National Hospital Organization, Higashinagoya National Hospital, Nagoya, Japan

[4 ]Endocrinology and Nutrition Department , University Hospital ‘La Paz’, Madrid, Spain

[5 ]Department of Nuclear Medicine and Endocrine Oncology , Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland

[6 ]Endocrinology Unit , Department of Medicine (DIMED), University of Padua, Padua, Italy

[7 ]Department of Endocrinology , Endocrine Oncology Unit, Instituto do Cancer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

[8 ]Department of Medical Genetics and Genomics , Sapporo Medical University School of Medicine, Sapporo, Japan

[9 ]Department of Surgery , Kuma Hospital, Kobe, Hyogo, Japan

[10 ]Department of Breast and Endocrine Surgery , Tokyo Women’s Medical University, Tokyo, Japan

[11 ]AP-HP , Sorbonne Université, Laboratoire Commun de Biologie et Génétique Moléculaires, Hôpital St Antoine & INSERM CRSA, Paris, France

[12 ]Réseau TenGen , Marseille, France

[13 ]Fédération d’Endocrinologie , Hospices Civils de Lyon, Université Lyon 1, France

[14 ]Service de Génétique , AP-HP, Hôpital européen Georges Pompidou, Paris, France

[15 ]Université de Paris , PARCC, INSERM, Paris, France

[16 ]Laboratoire de Biochimie et Oncologie Moléculaire , CHU Lille, Lille, France

[17 ]Laboratoire de Génétique Moléculaire , CHU Lyon, Lyon, France

[18 ]Endocrine Section , Hospital del Salvador, Santiago de Chile, Department of Medicine, University of Chile, Santiago, Chile

[19 ]Genomic Medicine Institute , Lerner Research Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA

[20 ]Department of Endocrinology And Metabolic Diseases , Ankara University School of Medicine, Ankara, Turkey

[21 ]Department of Research Studies & Additional Projects , Cancer Patients Aid Association, Dr. Vithaldas Parmar Research & Medical Centre, Worli, Mumbai, India

[22 ]Department of Molecular Endocrinology , Institute of Endocrinology, Prague, Czech Republic

[23 ]Aix-Marseille Université , Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Marseille, France

[24 ]Department of Endocrinology , Assistance Publique-Hôpitaux de Marseille (AP-HM), Hôpital de la Conception, Centre de Référence des Maladies Rares de l’hypophyse HYPO, Marseille, France

[25 ]HAS-SE Momentum Hereditary Endocrine Tumors Research Group , Semmelweis University, Budapest, Hungary

[26 ]Department of Surgical Oncology , Institute of Oncology, Ljubljana, Slovenia

[27 ]Department of Endocrinology , University of Groningen, University Medical Center Groningen, Groningen, Netherlands

[28 ]Department of Hypertension , Institute of Cardiology, Warsaw, Poland

[29 ]Cancer Genetics , Kolling Institute, Royal North Shore Hospital and University of Sydney, Sydney, New South Wales, Australia

[30 ]Department of Nuclear Medicine and Endocrine Oncology , Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland

[31 ]Section for Preventive Medicine , Medical Center-University of Freiburg, Faculty of Medicine, Albert Ludwigs-University of Freiburg, Freiburg, Germany

[32 ]Hereditary Endocrine Cancer Group , Spanish National Cancer Research Center (CNIO), Madrid, Spain

[33 ]Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) , Madrid, Spain

[34 ]Department of Endocrine Surgery , Noguchi Thyroid Clinic and Hospital Foundation, Beppu, Oita, Japan

[35 ]Aix Marseille Univ , APHM, INSERM, MMG, Laboratory of Molecular Biology, Hospital La Conception, Marseille, France

[36 ]Department of Clinical Research , University of Southern Denmark, Odense, Denmark

Author notes

Correspondence should be addressed to J S Mathiesen: jes_mathiesen@ 123456yahoo.dk

Author information

Jes Sloth Mathiesen http://orcid.org/0000-0002-9770-3188

Article

Publisher ID: EC-20-0163

DOI: 10.1530/EC-20-0163

PMC ID: 7354718

PubMed ID: 32375120

SO-VID: b6f0c507-57e1-4433-8735-096ebed25261

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This work is licensed under a Creative Commons Attribution 4.0 International License.

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Primary hyperparathyroidism as first manifestation in multiple endocrine neoplasia type 2A: an international multicenter study

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Abstract

Objective

Design and methods

Results

Conclusions

Related collections

Bioscientifica Open Endocrinology

Most cited references 58

Guidelines for diagnosis and therapy of MEN type 1 and type 2.

Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A.

Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC.

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Journal

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