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Rachel S van Leeuwaarde, Joanne M de Laat, Carolina R C Pieterman, Koen Dreijerink, Menno R Vriens, and Gerlof D Valk

Multiple endocrine neoplasia type 1 is a rare autosomal inherited disorder associated with a high risk for patients to simultaneously develop tumors of the parathyroid glands, duodenopancreatic neuroendocrine tumors and tumors of the anterior pituitary gland. Early identification of MEN1 in patients enables presymptomatic screening of manifestations, which makes timely interventions possible with the intention to prevent morbidity and mortality. Causes of death nowadays have shifted toward local or metastatic progression of malignant neuroendocrine tumors. In early cohorts, complications like peptic ulcers in gastrinoma, renal failure in hyperparathyroidism, hypoglycemia and acute hypercalcemia were the primary causes of early mortality. Improved medical treatments of these complications led to a significantly improved life expectancy. The MEN1 landscape is still evolving, considering the finding of breast cancer as a new MEN1-related manifestation and ongoing publications on follow-up and medical care for patients with MEN1. This review aims at summarizing the most recent insights into the follow-up and medical care for patients with MEN1 and identifying the gaps for future research.

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G R Mundy and T A Guise

Tumors cause multiple effects on the skeleton and on calcium homeostasis, but they do so in specific patterns which are becoming better defined as the mediators responsible become more fully characterized. Metastatic bone disease occurs in the majority of patients with advanced cancer, and is particularly frequent in breast, lung and prostate cancers, which are the most common of all human tumors. Approximately 1,000 000 people die each year in Western Europe and the United States from these three malignancies, and the majority of these people have bone metastases. Bone is the third most common site of metastatic disease in tumors of all types and the second most common in breast and prostate cancer. In this review, the role of the tumor peptide parathyroid hormone-related peptide (PTH-rP) in the effects of cancer on the skeleton will be discussed.

Free access

Elham Barazeghi, Anthony J Gill, Stan Sidhu, Olov Norlén, Roberto Dina, F Fausto Palazzo, Per Hellman, Peter Stålberg, and Gunnar Westin

Primary hyperparathyroidism (pHPT) is rarely caused by parathyroid carcinoma (PC, <1–5% of pHPT cases). The TET proteins oxidize the epigenetic mark 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) and inactivation by mutation or epigenetic deregulation of TET1 and TET2 play important roles in various cancers. Recently, we found that 5hmC was severely reduced in all of the analyzed PCs and with deranged expression of TET1 for the majority of PCs. Here, we have examined the expression of the TET2 protein in 15 5hmC-negative PCs from patients who had local invasion or metastases. Cell growth and cell migratory roles for TET2 as well as epigenetic deregulated expression were addressed. Immunohistochemistry revealed very low/undetectable expression of TET2 in all PCs and verified for two PCs that were available for western blotting analysis. Knockdown of TET2 in the parathyroid cell line sHPT-1 resulted in increased cell growth and increased cell migration. DNA sequencing of TET2 in PCs revealed two common variants and no obvious inactivating mutations. Quantitative bisulfite pyrosequencing analysis of the TET2 promoter CpG island revealed higher CpG methylation level in the PCs compared to that in normal tissues and treatment of a PC primary cell culture with the DNA methylation inhibitor 5-aza-2′-deoxycytidine caused increased expression of the methylated TET2 gene. Hence, the data suggest that deregulated expression of TET2 by DNA hypermethylation may contribute to the aberrantly low level of 5hmC in PCs and further that TET2 plays a cell growth and cell migratory regulatory role and may constitute a parathyroid tumor suppressor gene.

Free access

F Cetani, E Pardi, E Ambrogini, P Viacava, S Borsari, M Lemmi, L Cianferotti, P Miccoli, A Pinchera, A Arnold, and C Marcocci

Early onset of primary hyperparathyroidism (PHPT) and multiglandular involvement suggest a familial form in which germline mutation of a PHPT-related gene(s) and a somatic event at the same locus can be often demonstrated. We investigated the involvement of multiple endocrine neoplasia type 1 (MEN1) and HRPT2 genes in a 39-year-old man with recurrent PHPT. PHPT was firstly diagnosed at the age of 21 and the patient had two recurrences separated by extended periods of normocalcemia. This unusual history prompted us to investigate other family members and study the MEN1 and HRPT2 genes. An HRPT2 germline missense mutation in exon 3 (R91P) was found in the index case, which was associated with different HRPT2 somatic alterations in each of the three examined parathyroid tumors. These findings are consistent with Knudson’s ‘two hit’ concept of biallelic inactivation of classical tumor suppressor genes. Screening of 15 asymptomatic relatives was negative for the R91P germline mutation. All the three abnormal parathyroid specimens showed cystic features at histology and were negative for parafibromin immunostaining. In one specimen, diffuse parafibromin staining was evident in a rim of normal parathyroid tissue surrounding the adenomatous lesion. Our study shows that different somatic genetic events at the HRPT2 locus are responsible for the asynchronous occurrence of multiple adenomas in a patient carrying an HRPT2 germline mutation. The finding of diffuse parafibromin staining in a rim of normal parathyroid tissue, but not in the contiguous adenomatous lesion, reinforces the concept that loss of parafibromin expression is responsible for the development of parathyroid tumors in this setting.

Free access

F Lumachi, M Ermani, S Basso, P Zucchetta, N Borsato, and G Favia

A series of 253 consecutive patients with proved primary hyperparathyroidism due to parathyroid tumours was reviewed. There were 68 (26.9%) men and 185 (73.1%) women, with a median age of 57 years (range 13-82 years). All patients, prior to successful parathyroidectomy, underwent one or more preoperative localization procedures such as: neck ultrasonography (US) in 191 (75.5%), (201)Tl/(99m)Tc-pertechnetate subtraction scintigraphy (TPS) in 144 (56.9%), CT scan in 92 (36.4%), (99m)Tc-sestamibi/(99m)Tc-pertechnetate subtraction scintigraphy (MPS) in 90 (35.6%), selective venous sampling (SVS) with parathyroid hormone (PTH) assay in 30 (11.9%), and magnetic resonance imaging (MRI) in 6 (2.4%) patients. The results were compared with operative and histological findings that showed 235 (92.9%) solitary parathyroid adenomas, 13 (5.1%) carcinomas and 5 (2.0%) double adenomas. Sensitivity and positive predictive value were 82.9% and 93.8% for US, 83.6% and 91.8% for TPS, 81.3% and 98.7% for CT scan, 85.1% and 96.1% for MPS, 65.4% and 80.9% for SVS, and 80.0% and 80.0% for MRI respectively. No different results (P=NS) were found using US, TPS, MPS or CT scan, whereas SVS and MRI sensitivity was lower (P<0.05). The combination of MPS and US was 94.0% sensitive (P<0.05) but when TPS, CT scan or MRI were also used overall sensitivity did not improve significantly (P=NS). In conclusion, MPS should be used as the starting preoperative localization procedure, while US and MPS together represent the most reliable noninvasive localization tool. If MPS and US are negative or not in agreement, further studies are not cost-effective and the patient should undergo bilateral neck exploration.

Restricted access

Yulong Li, Jianhua Zhang, Poorni R Adikaram, James Welch, Bin Guan, Lee S Weinstein, Haobin Chen, and William F Simonds

Mutation of the CDC73 gene, which encodes parafibromin, has been linked with parathyroid cancer. However, no correlation between genotypes of germline CDC73 mutations and the risk of parathyroid cancer has been known. In this study, subjects with germline CDC73 mutations were identified from the participants of two clinical protocols at National Institutes of Health (Discovery Cohort) and from the literature (Validation Cohort). The relative risk of developing parathyroid cancer was analyzed as a function of CDC73 genotype, and the impact of representative mutations on structure of parafibromin was compared between genotype groups. A total of 419 subjects, 68 in Discovery Cohort and 351 in Validation Cohort, were included. In both cohorts, percentages of CDC73 germline mutations that predicted significant conformational disruption or loss of expression of parafibromin (referred as ‘high-impact mutations’) were significantly higher among the subjects with parathyroid cancers compared to all other subjects. The Kaplan–Meier analysis showed that high-impact mutations were associated with a 6.6-fold higher risk of parathyroid carcinoma compared to low-impact mutations, despite a similar risk of developing primary hyperparathyroidism between two groups. Disruption of the C-terminal domain (CTD) of parafibromin is directly involved in predisposition to parathyroid carcinoma, since only the mutations impacting this domain were associated with an increased risk of parathyroid carcinoma. Structural analysis revealed that a conserved surface structure in the CTD is universally disrupted by the mutations affecting this domain. In conclusion, high-impact germline CDC73 mutations were found to increase risk of parathyroid carcinoma by disrupting the CTD of parafibromin.

Free access

Inga-Lena Nilsson, Jan Zedenius, Li Yin, and Anders Ekbom

In order to evaluate the link between primary hyperparathyroidism (pHPT) and malignancies, cases subjected to parathyroid adenomectomy (PTX) during 1958–1997 in Sweden were identified by analyzing the National Swedish Cancer Registry. To minimize the influence of confounding by detection, cases with malignant disease diagnosed before or at the same time as pHPT or during the first year after PTX were excluded. Altogether 9782 cases (7642♀) were included and followed for up to 40 years. Thus, the study comprises 89 571 person-years of observation. The incidence of malignancies was compared with that in the Swedish population standardized for age, sex, and calendar year. An increased overall incidence of cancer was demonstrated in both genders (standardized incidence ratio (SIR) 1.43, 95% confidence interval (CI) 1.35–1.52). This remain unchanged beyond 15 years after PTX. Breast cancer contributed a quarter of the cancer incidence in women (SIR 1.44, 95% CI 1.25–1.62). An increased risk of kidney (SIR 2.40, 95% CI 1.72–3.25), colonic (SIR 1.46, 95% CI 1.19–1.77), and squamous cell skin cancer (SIR 2.79, 95% CI 2.25–3.43) was found in both genders. The risk of endocrine and pancreas cancer was increased in the minority of patients who had their PTX before the age of 40. We conclude that pHPT is associated with an increased risk of developing malignancies that persists even after PTX. This suggests a causal disassociation with the biochemical derangements caused by parathyroid adenoma, while potentially common etiological mechanisms may include genetic predisposition or acquired disability to withstand environmental influence.

Free access

Andreas Machens and Henning Dralle

Genetic association studies hinge on definite clinical case definitions of the disease of interest. This is why more penetrant mutations were overrepresented in early multiple endocrine neoplasia type 2 (MEN2) studies, whereas less penetrant mutations went underrepresented. Enrichment of genetic association studies with advanced disease may produce a flawed understanding of disease evolution, precipitating far-reaching surgical strategies like bilateral total adrenalectomy and 4-gland parathyroidectomy in MEN2. The insight into the natural course of the disease gleaned over the past 25 years caused a paradigm shift in MEN2: from the removal of target organs at the expense of greater operative morbidity to close biochemical surveillance and targeted resection of adrenal tumors and hyperplastic parathyroid glands. The lead time provided by early identification of asymptomatic MEN2 carriers under biochemical surveillance delimits a ‘window of opportunity’, within which (i) pre-emptive total thyroidectomy alone is adequate, circumventing morbidity attendant to central node dissection; (ii) subtotal ‘tissue-sparing’ adrenalectomy is sufficient, trading the risk of steroid dependency for the risk of a second pheochromocytoma in the adrenal remnant and (iii) parathyroidectomy is limited to enlarged glands, trading the risk of postoperative hypoparathyroidism for the risk of leaving behind hyperactive parathyroid glands. Future research should delineate further the mutation-specific, age-dependent penetrance of pheochromocytoma and primary hyperparathyroidism to refine the risk-oriented approach to MEN2. The sweeping changes in the management of MEN2 since the new millenium hold the hope that death and major morbidity from this uncommon disease can be eliminated in our lifetime.

Free access

Michael A Hahn, Viive M Howell, Anthony J Gill, Adele Clarkson, Graham Weaire-Buchanan, Bruce G Robinson, Leigh Delbridge, Oliver Gimm, Wolfgang D Schmitt, Bin T Teh, and Deborah J Marsh

The tumor suppressor HRPT2/CDC73 is mutated in constitutive DNA from patients with the familial disorder hyperparathyroidism–jaw tumor syndrome and in ∼70% of all parathyroid carcinomas. In a number of HRPT2 mutant tumors however, expression of the encoded protein parafibromin is lost in the absence of a clear second event such as HRPT2 allelic loss or the presence of a second mutation in this tumor suppressor gene. We sought to determine whether hypermethylation of a 713 bp CpG island extending 648 nucleotides upstream of the HRPT2 translational start site and 65 nucleotides into exon 1 might be a mechanism contributing to the loss of expression of parafibromin in parathyroid tumors. Furthermore, we asked whether mutations might be present in the 5′-untranslated region (5′-UTR) of HRPT2. We investigated a pool of tissue from 3 normal parathyroid glands, as well as 15 individual parathyroid tumor samples including 6 tumors with known HRPT2 mutations, for hypermethylation of the HRPT2 CpG island. Methylation was not identified in any specimens despite complete loss of parafibromin expression in two parathyroid carcinomas with a single detectable HRPT2 mutation and retention of the wild-type HRPT2 allele. Furthermore, no mutations of a likely pathogenic nature were identified in the 5′-UTR of HRPT2. These data strongly suggest that alternative mechanisms such as mutation in HRPT2 intronic regions, additional epigenetic regulation such as histone modifications, or other regulatory inactivation mechanisms such as targeting by microRNAs may play a role in the loss of parafibromin expression.

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W P Bocchinfuso and K S Korach

Introduction Estrogen has been thought to be required for the development, differentiation and function of the female reproductive tract (George & Wilson 1988). It promotes the proliferation of the uterine and vaginal epithelium and ovarian follicular development (Canez et al. 1992); the development of the mammary gland, external genitalia, appropriate reproductive sexual behavior, and other secondary sexual characteristics (George & Wilson 1988). In more non-traditional target tissues, estrogen action has been shown to influence bone development, lipid metabolism and cardiovascular function (Auchus & Fuqua 1994, Ciocca & Vargas Roig 1995). The biological actions of estrogens, particularly 17β-estradiol(estradiol), are mediated through the estrogen receptor, which functions as a ligand-inducible transcription factor and is a member of the nuclear receptor superfamily that bind steroids, thyroid hormone, retinoids, prostanoids and vitamin D1 (Tsai & O'Malley 1994). Like other nuclear receptors, the estrogen receptor is composed of distinct functional domains (Fig. 1)