Parathyroid Adenoma in a Subject with Familial Hypocalciuric Hypercalcemia: Coincidence or Causality?

Burski, K; Torjussen, B.; Paulsen, Aksel; Boman, Helge; Bollerslev, Jens

doi:10.1210/jcem.87.3.8304

Cited by 52 publications

(17 citation statements)

References 10 publications

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“…Whether this represents a coexistence of two disorders or whether the CaSR mutation has contributed to the initiation or progression of HPT is a matter of debate. Burski et al 26 estimated that coexistence should be observed by chance in one in 10 million middle‐aged women, making the combination a rare but not improbable event. The 2·9% prevalence in our hypercalcaemic outpatient cohort argues against just a co‐occurrence.…”

Section: Discussionmentioning

confidence: 99%

Inactivating calcium‐sensing receptor mutations in patients with primary hyperparathyroidism

Frank‐Raue¹,

Leidig-Bruckner²,

Haag³

et al. 2011

Clinical Endocrinology

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Section: Discussionmentioning

confidence: 99%

Inactivating calcium‐sensing receptor mutations in patients with primary hyperparathyroidism

Frank‐Raue¹,

Leidig-Bruckner²,

Haag³

et al. 2011

Clinical Endocrinology

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“…At the molecular level, this phenomenon is mainly attributed to mutant CaSR in the kidney, preventing the normal physiological hypercalciuric response to hypercalcaemia 4 7 13 30 32 42 75–77 141. Although concurrent primary HPT due to a parathyroid adenoma can occur, the majority of patients with FHH-1 do not have detectable parathyroid disease, and therefore rarely benefit from parathyroidectomy 7 13 29 30 34 42 141 180 181. Pathologically, parathyroid enlargement (hyperplasia) has been reported in 15–20% of cases 3 32 42 44 83 182 183…”

Section: Pathogenesis and Molecular Genetics Of Hptmentioning

confidence: 99%

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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“…Presumably, rare parathyroid cells in such patients stochastically acquire inactivating mutations in their remaining normal CASR allele, and if these cells had a proliferative advantage, then large clonal outgrowths causing dramatic hypercalcemia ought to evolve reasonably frequently. Although cases of FHH consistent with this pathogenic scenario have been reported, as has homozygosity for a mildly inactivating CASR mutation presenting in adulthood with marked hyperparathyroidism and multiple “adenomas” of undetermined clonality, they appear to be exceedingly rare. Notwithstanding, they have contributed to the uncertainty surrounding the clonal status of hypercellular parathyroids in NSHPT, leading some to expect these glands would prove to be monoclonal, whereas others expected a polyclonal outcome…”

Section: Discussionmentioning

confidence: 99%

Polyclonality of Parathyroid Tumors in Neonatal Severe Hyperparathyroidism

Corrado

Andrade

Bellizzi

et al. 2015

Journal of Bone and Mineral Research

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Neonatal severe hyperparathyroidism (NSHPT) is a rare disorder characterized by major hypercalcemia, elevated parathyroid hormone levels, and marked enlargement of multiple parathyroid glands, usually associated with germline mutations in the calcium receptor gene CASR. However, little is known about the outgrowth of parathyroid tumors in NSHPT, including whether they represent monoclonal or polyclonal expansions. We sought to examine the clonality of parathyroid tissues resected from a patient with NSHPT and biallelic CASR mutations. DNA from two distinct parathyroid tumors resected from a girl with NSHPT, plus polyclonal/monoclonal control samples, were subjected to analyses of clonality by two independent methods, X-chromosome inactivation analysis at the androgen receptor locus (HUMARA) and BAC array comparative genomic hybridization (CGH). Both parathyroid tumor samples revealed polyclonal patterns by X-inactivation analysis, with polyclonal and monoclonal controls yielding the expected patterns. Similarly, by BAC array CGH, neither parathyroid sample contained monoclonal copy number changes and both appeared identical to the patient-matched polyclonal controls. Our observations provide direct experimental evidence that the markedly enlarged parathyroid tumors in the setting of NSHPT constitute polyclonal, generalized hyperplastic growths rather than monoclonal neoplasms.

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Parathyroid Adenoma in a Subject with Familial Hypocalciuric Hypercalcemia: Coincidence or Causality?

Cited by 52 publications

References 10 publications

Inactivating calcium‐sensing receptor mutations in patients with primary hyperparathyroidism

Inactivating calcium‐sensing receptor mutations in patients with primary hyperparathyroidism

Clinicopathological correlates of hyperparathyroidism

Polyclonality of Parathyroid Tumors in Neonatal Severe Hyperparathyroidism

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