Diagnosis, management, histology and genetics of sporadic primary hyperparathyroidism: old knowledge with new tricks

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Abstract

Primary hyperparathyroidism (pHPT) is a common endocrinopathy resulting from inappropriately high PTH secretion. It usually results from the presence of a single gland adenoma, multiple gland hyperplasia or rarely parathyroid carcinoma. All these conditions require different management, and it is important to be able to differentiate the underlined pathology, in order for the clinicians to provide the best therapeutic approach. Elucidation of the genetic background of each of these clinical entities would be of great interest. However, the molecular factors that control parathyroid tumorigenesis are poorly understood. There are data implicating the existence of specific genetic pathways involved in the emergence of parathyroid tumorigenesis. The main focus of the present study is to present the current optimal diagnostic and management protocols for pHPT as well as to review the literature regarding all molecular and genetic pathways that are to be involved in the pathophysiology of sporadic pHPT.

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Life and death by death receptors.

Gregory J. Gores, Maria Guicciardi (2009)

Death receptors are members of the tumor necrosis factor receptor superfamily characterized by a cytoplasmic region known as the "death domain" that enables the receptors to initiate cytotoxic signals when engaged by cognate ligands. Binding to the ligand results in receptor aggregation and recruitment of adaptor proteins, which, in turn, initiates a proteolytic cascade by recruiting and activating initiator caspases 8 and 10. Death receptors were once thought to primarily induce cytotoxic signaling cascades. However, recent data indicate that they initiate multiple signaling pathways, unveiling a number of nonapoptosis-related functions, including regulation of cell proliferation and differentiation, chemokine production, inflammatory responses, and tumor-promoting activities. These noncytotoxic cascades are not simply a manifestation of inhibiting proapoptotic pathways but are intrinsically regulated by adaptor protein and receptor internalization processes. Insights into these various death receptor signaling pathways provide new therapeutic strategies targeting these receptors in pathophysiological processes.

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Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene.

Rajesh Thakker, Manuel C. Lemos (2007)

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the occurrence of tumors of the parathyroids, pancreas, and anterior pituitary. The MEN1 gene, which was identified in 1997, consists of 10 exons that encode a 610-amino acid protein referred to as menin. Menin is predominantly a nuclear protein that has roles in transcriptional regulation, genome stability, cell division, and proliferation. Germline mutations usually result in MEN1 or occasionally in an allelic variant referred to as familial isolated hyperparathyroidism (FIHP). MEN1 tumors frequently have loss of heterozygosity (LOH) of the MEN1 locus, which is consistent with a tumor suppressor role of MEN1. Furthermore, somatic abnormalities of MEN1 have been reported in MEN1 and non-MEN1 endocrine tumors. The clinical aspects and molecular genetics of MEN1 are reviewed together with the reported 1,336 mutations. The majority (>70%) of these mutations are predicted to lead to truncated forms of menin. The mutations are scattered throughout the>9-kb genomic sequence of the MEN1 gene. Four, which consist of c.249_252delGTCT (deletion at codons 83-84), c.1546_1547insC (insertion at codon 516), c.1378C>T (Arg460Ter), and c.628_631delACAG (deletion at codons 210-211) have been reported to occur frequently in 4.5%, 2.7%, 2.6%, and 2.5% of families, respectively. However, a comparison of the clinical features in patients and their families with the same mutations reveals an absence of phenotype-genotype correlations. The majority of MEN1 mutations are likely to disrupt the interactions of menin with other proteins and thereby alter critical events in cell cycle regulation and proliferation. (c) 2007 Wiley-Liss, Inc.

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Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors.

Thomas A Milne, Christina M Hughes, Ricardo Lloyd … (2005)

Mutations in the MEN1 gene are associated with the multiple endocrine neoplasia syndrome type 1 (MEN1), which is characterized by parathyroid hyperplasia and tumors of the pituitary and pancreatic islets. The mechanism by which MEN1 acts as a tumor suppressor is unclear. We have recently shown that menin, the MEN1 protein product, interacts with mixed lineage leukemia (MLL) family proteins in a histone methyltransferase complex including Ash2, Rbbp5, and WDR5. Here, we show that menin directly regulates expression of the cyclin-dependent kinase inhibitors p27Kip1 and p18Ink4c. Menin activates transcription by means of a mechanism involving recruitment of MLL to the p27Kip1 and p18Ink4c promoters and coding regions. Loss of function of either MLL or menin results in down-regulation of p27Kip1 and p18Ink4c expression and deregulated cell growth. These findings suggest that regulation of cyclin-dependent kinase inhibitor transcription by cooperative interaction between menin and MLL plays a central role in menin's activity as a tumor suppressor.

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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: February 2018

Publication date (Electronic): 12 January 2018

Volume: 7

Issue: 2

Pages: R56-R68

Affiliations

[1 ]Department of Endocrinology Diabetes and Metabolism, Hellenic Red Cross Hospital, Athens, Greece

[2 ]Second Department of Surgery Endocrine Surgery Unit, Aretaieion University Hospital, National and Kapodistrian University of Athens, Athens, Greece

[3 ]Unit of Endocrinology Diabetes and Metabolism, Aretaieion University Hospital, National and Kapodistrian University of Athens, Athens, Greece

[4 ]Department of Pathology Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK

[5 ]Department of Basic Medical Sciences Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

[6 ]Department of Thyroid and Endocrine Surgery Imperial College London, London, UK

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Correspondence should be addressed to M Mizamtsidi: maria.mizamtsidi@ 123456gmail.com

Article

Publisher ID: EC170283

DOI: 10.1530/EC-17-0283

PMC ID: 5801557

PubMed ID: 29330338

SO-VID: 3dcfb23d-3375-4260-83fb-521e04e95e19

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

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Diagnosis, management, histology and genetics of sporadic primary hyperparathyroidism: old knowledge with new tricks

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Bioscientifica Open Endocrinology

Most cited references 80

Life and death by death receptors.

Multiple endocrine neoplasia type 1 (MEN1): analysis of 1336 mutations reported in the first decade following identification of the gene.

Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors.

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