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      Familial Hyperparathyroidism

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          Abstract

          Regulation of the serum calcium level in humans is achieved by the endocrine action of parathyroid glands working in concert with vitamin D and a set of critical target cells and tissues including osteoblasts, osteoclasts, the renal tubules, and the small intestine. The parathyroid glands, small highly vascularized endocrine organs located behind the thyroid gland, secrete parathyroid hormone (PTH) into the systemic circulation as is needed to keep the serum free calcium concentration within a tight physiologic range. Primary hyperparathyroidism (HPT), a disorder of mineral metabolism usually associated with abnormally elevated serum calcium, results from the uncontrolled release of PTH from one or several abnormal parathyroid glands. Although in the vast majority of cases HPT is a sporadic disease, it can also present as a manifestation of a familial syndrome. Many benign and malignant sporadic parathyroid neoplasms are caused by loss-of-function mutations in tumor suppressor genes that were initially identified by the study of genomic DNA from patients who developed HPT as a manifestation of an inherited syndrome. Somatic and inherited mutations in certain proto-oncogenes can also result in the development of parathyroid tumors. The clinical and genetic investigation of familial HPT in kindreds found to lack germline variants in the already known HPT-predisposition genes represents a promising future direction for the discovery of novel genes relevant to parathyroid tumor development.

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          Most cited references153

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          Mutation and Cancer: Statistical Study of Retinoblastoma

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

            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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              Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1).

              The aim was to provide guidelines for evaluation, treatment, and genetic testing for multiple endocrine neoplasia type 1 (MEN1). The group, which comprised 10 experts, including physicians, surgeons, and geneticists from international centers, received no corporate funding or remuneration. Guidelines were developed by reviews of peer-reviewed publications; a draft was prepared, reviewed, and rigorously revised at several stages; and agreed-upon revisions were incorporated. MEN1 is an autosomal dominant disorder that is due to mutations in the tumor suppressor gene MEN1, which encodes a 610-amino acid protein, menin. Thus, the finding of MEN1 in a patient has important implications for family members because first-degree relatives have a 50% risk of developing the disease and can often be identified by MEN1 mutational analysis. MEN1 is characterized by the occurrence of parathyroid, pancreatic islet, and anterior pituitary tumors. Some patients may also develop carcinoid tumors, adrenocortical tumors, meningiomas, facial angiofibromas, collagenomas, and lipomas. Patients with MEN1 have a decreased life expectancy, and the outcomes of current treatments, which are generally similar to those for the respective tumors occurring in non-MEN1 patients, are not as successful because of multiple tumors, which may be larger, more aggressive, and resistant to treatment, and the concurrence of metastases. The prognosis for MEN1 patients might be improved by presymptomatic tumor detection and undertaking treatment specific for MEN1 tumors. Thus, it is recommended that MEN1 patients and their families should be cared for by multidisciplinary teams comprising relevant specialists with experience in the diagnosis and treatment of patients with endocrine tumors.

                Author and article information

                Contributors
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                25 February 2021
                2021
                : 12
                : 623667
                Affiliations
                [1] 1 Early Clinical Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca , Gaithersburg, MD, United States
                [2] 2 Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, MD, United States
                Author notes

                Edited by: Naris Nilubol, National Institutes of Health (NIH), United States

                Reviewed by: Daniela Pasquali, University of Campania Luigi Vanvitelli, Italy; Sabrina Corbetta, University of Milan, Italy

                *Correspondence: William F. Simonds, bills@ 123456niddk.nih.gov

                This article was submitted to Cancer Endocrinology, a section of the journal Frontiers in Endocrinology

                Article
                10.3389/fendo.2021.623667
                7947864
                33716975
                05a2cc68-9d83-43d6-965e-f617819584af
                Copyright © 2021 Blau and Simonds

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 30 October 2020
                : 13 January 2021
                Page count
                Figures: 2, Tables: 1, Equations: 0, References: 153, Pages: 14, Words: 7265
                Funding
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases 10.13039/100000062
                Categories
                Endocrinology
                Review

                Endocrinology & Diabetes
                tumor suppressor,oncogene,multiple endocrine neoplasia,men1,jaw tumor syndrome,casr,cdc73,gcm2

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