Familial Primary Hyperparathyroidism (Including MEN, FHH, and HPT‐JT)

Arnold, Andrew; Marx, Stephen J.

doi:10.1002/9781118453926.ch69

Cited by 18 publications

(46 citation statements)

References 11 publications

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“…In cases where MEN-1 is suspected on the basis of multiglandular primary HPT with or without other concomitant MEN-1 associated tumours, testing for a MEN1 mutation is recommended 86. A definite diagnosis of FHH may ultimately require demonstration of a germline mutation in CASR, GNA11 and AP2S1 4 13 30 32 42 77 79 87–91. A severe neonatal phenotype (neonatal severe HPT) has also been described, presenting with severe HPT and life-threatening hypercalcaemia in the first six months of life 4 5 7 42 44…”

Section: Clinical and Biochemical Featuresmentioning

confidence: 99%

“…Common hereditary syndromes associated with HPT include familial cancer predisposition syndromes (MEN-1, MEN-2A, MEN-4 and HPT-JT syndromes) and hereditary ‘hypercalcemic’ syndromes related to aberrant CaSR signalling (FHH-1, FHH-2, FHH-3, neonatal severe HPT and familial hypercalciuric hypercalcaemia) 13 29 30 32 38 42 44 46 83 99 141 143. Rarely, inherited HPT can occur in a non-syndromic fashion, also known as ‘familial isolated hyperparathyroidism’, due to germline mutations of MEN1, CDC73/HRPT2, CaSR or cyclin-dependent kinase inhibitor ( CDKI )-encoding genes ( CDKN1B , CDKN1A , CDKN2B and CDKN2C ) 13 29 30 42 99 141 173…”

Section: Pathogenesis and Molecular Genetics Of Hptmentioning

confidence: 99%

“…MEN syndromes represent a group of autosomal-dominant cancer predisposition syndromes 4 7 32 42 141 143 174. Three distinct types (MEN-1, MEN-2A, MEN-4) are associated with HPT 32 42 141 143 .…”

Section: Pathogenesis and Molecular Genetics Of Hptmentioning

confidence: 99%

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Clinicopathological correlates of hyperparathyroidism

2015

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Hyperparathyroidism is a common endocrine disorder with potential complications on the skeletal, renal, neurocognitive and cardiovascular systems. While most cases (95%) occur sporadically, about 5% are associated with a hereditary syndrome: multiple endocrine neoplasia syndromes (MEN-1, MEN-2A, MEN-4), hyperparathyroidism-jaw tumour syndrome (HPT-JT), familial hypocalciuric hypercalcaemia (FHH-1, FHH-2, FHH-3), familial hypercalciuric hypercalcaemia, neonatal severe hyperparathyroidism and isolated familial hyperparathyroidism. Recently, molecular mechanisms underlying possible tumour suppressor genes (MEN1, CDC73/HRPT2, CDKIs, APC, SFRPs, GSK3β, RASSF1A, HIC1, RIZ1, WT1, CaSR, GNA11, AP2S1) and proto-oncogenes (CCND1/PRAD1, RET, ZFX, CTNNB1, EZH2) have been uncovered in the pathogenesis of hyperparathyroidism. While bi-allelic inactivation of CDC73/HRPT2 seems unique to parathyroid malignancy, aberrant activation of cyclin D1 and Wnt/β-catenin signalling has been reported in benign and malignant parathyroid tumours. Clinicopathological correlates of primary hyperparathyroidism include parathyroid adenoma (80–85%), hyperplasia (10–15%) and carcinoma (<1–5%). Secondary hyperparathyroidism generally presents with diffuse parathyroid hyperplasia, whereas tertiary hyperparathyroidism reflects the emergence of autonomous parathyroid hormone (PTH)-producing neoplasm(s) from secondary parathyroid hyperplasia. Surgical resection of abnormal parathyroid tissue remains the only curative treatment in primary hyperparathyroidism, and parathyroidectomy specimens are frequently encountered in this setting. Clinical and biochemical features, including intraoperative PTH levels, number, weight and size of the affected parathyroid gland(s), are crucial parameters to consider when rendering an accurate diagnosis of parathyroid proliferations. This review provides an update on the expanding knowledge of hyperparathyroidism and highlights the clinicopathological correlations of this prevalent disease.

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Section: Clinical and Biochemical Featuresmentioning

confidence: 99%

Section: Pathogenesis and Molecular Genetics Of Hptmentioning

confidence: 99%

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Clinicopathological correlates of hyperparathyroidism

2015

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“…Easy fatigue, weakness, thought disturbance, or polydipsia is generally less common and less severe than in typical PHPT (7). The clinical complications observed in FHH patients mainly consist of chondrocalcinosis (usually clinically silent), premature vascular calcification (8,9), and pancreatitis (10).…”

Section: Introductionmentioning

confidence: 99%

“…Parathyroid cells respond to the decrease in extracellular calcium concentration through activation of the CASR gene, a cell surface seven-membranespanning G protein-coupled receptor, modulating phosphatidylinositol turnover and intracellular calcium amount that ultimately leads to an increase in the secretion of PTH (7). CASR is able to sense small changes in circulating calcium concentration and when activated inhibits PTH secretion and renal tubule calcium reabsorption.…”

Section: Introductionmentioning

confidence: 99%

A novel germline inactivating mutation in the CASR gene in an Italian kindred affected by familial hypocalciuric hypercalcemia

Falchetti

Gozzini

Terranegra

et al. 2012

European Journal of Endocrinology

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Objective: Familial hypocalciuric hypercalcemia (FHH) syndrome is a rare benign condition, inherited as an autosomal dominant trait, in which inactivating mutations of the calcium-sensing receptor (CASR) gene affects the body's ability to regulate calcium homeostasis. Its outcome is featured by increased levels of serum calcium, moderate hypophosphatemia, and inadequately normal or elevated circulating parathyroid hormone levels. Affected patients are mostly asymptomatic and do not benefit from surgical resection of their mildly enlarged parathyroids. Design: We evaluated for hypercalcemia an Italian family that was identified via a young adult male proband referred to our center for parathyroidectomy. Methods: The patients and the family members were evaluated both biochemically and genetically as suspected FHH subjects. An in vitro functional study was performed by site-directed mutagenesis, and CASR activity was monitored by measuring intracellular calcium ([Ca 2C ] i ). Results: The patient had a novel germline heterozygous CASR mutation (c.361_364GATT; p.D121del/fsX122). The mutation caused a premature stop codon at codon 122, exiting a truncated protein. The biochemical phenotype of all family members carrying the heterozygous deletion was concordant with classic FHH syndrome. Conclusions: Our findings confirm the role of CASR gene mutational analysis to offer a valuable addition for the recognition of FHH in hypercalcemic patients not yet characterized for a positive familial history of hypercalcemia, the only condition that identifies CASR gene mutations in hypercalcemia.European Journal of Endocrinology 166 933-940

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Molecular profiling in primary hyperparathyroidism

et al. 2014

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Primary hyperparathyroidism (HPT) is one of the most common endocrine disorders, defined by hypersecretion of parathormone. Primary HPT can be caused by adenoma, hyperplasia, and carcinoma. A great amount of mechanisms contribute to the pathogenesis of this disease, such as genetic predispositions because of the germline-inactivating mutations in the multiple endocrine neoplasia type 1 (MEN1) and HRPT2 tumor suppressor genes. Somatic mutations in these genes were found also in sporadic parathyroid neoplasias. Cell cycle regulators, growth factors, apoptosis-inducing ligands, death receptors, and other transmitter substances have also been implicated in the etiology of primary HPT. Parathyroid carcinoma is often misdiagnosed as parathyroid adenoma and long-term survival is conditioned by the extent of the primary surgical resection, therefore, of great interest is the discovery of definitive diagnostic markers for carcinoma. This article presents current state of knowledge of the molecular pathogenesis of primary HPT.

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Familial Primary Hyperparathyroidism (Including MEN, FHH, and HPT‐JT)

Cited by 18 publications

References 11 publications

Clinicopathological correlates of hyperparathyroidism

Clinicopathological correlates of hyperparathyroidism

A novel germline inactivating mutation in the CASR gene in an Italian kindred affected by familial hypocalciuric hypercalcemia

Molecular profiling in primary hyperparathyroidism

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