Familial Hypocalciuric Hypercalcemia Types 1 and 3 and Primary Hyperparathyroidism: Similarities and Differences

Vargas‐Poussou, Rosa; Mansour‐Hendili, Lamisse; Baron, Stéphanie; Bertocchio, Jean‐Philippe; Travers, C.; Simian, Christophe; Tréard, Cyrielle; Baudouin, Véronique; Beltran, Sonia; Broux, Françoise; Camard, Odile; Cloarec, Sylvie; Cormier, Catherine; Debussche, Xavier; Dubosclard, Emmanuelle; Eid, Celine; Haymann, Jean‐Philippe; Kiando, Soto Romuald; Kuhn, Jean-Marc; Lefort, G.; Linglart, Agnès; Lucas-Pouliquen, Bernadette; Macher, Marie‐Alice; Maruani, Gérard; Ouzounian, Sophie; Polak, Michel; Requeda, E.; Robier, Dominique; Silve, Caroline; Souberbielle, Jean‐Claude; Tack, Ivan; Vezzosi, Delphine; Jeunemaı̂tre, Xavier; Houillier, Pascal

doi:10.1210/jc.2015-3442

Cited by 102 publications

(116 citation statements)

References 35 publications

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“…AP2σ2 is involved in the clathrinmediated endocytosis of plasma membrane proteins such as CASR and Gα 11 couples CASR to intracellular signalling (86,87). Estimated glomerular filtration rate and urinary calcium concentrations were similar in HHC1 and HHC3 patients (75), though patients with HHC3 have higher plasma calcium concentration than patients with HHC1, indicating that the rate of renal tubular absorption of filtered calcium was higher in HHC3 than in HHC1 patients.…”

Section: Ap2s1 and Gna11mentioning

confidence: 98%

MECHANISMS IN ENDOCRINOLOGY: Kidney involvement in patients with primary hyperparathyroidism: an update on clinical and molecular aspects

Verdelli

Corbetta

2017

European Journal of Endocrinology

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Primary hyperparathyroidism (PHPT) is the third most common endocrine disease. Kidney is a target of both chronic elevated PTH and calcium in PHPT. The classic PHPT complications of symptomatic kidney stones and nephrocalcinosis have become rare and the PHPT current presentation is asymptomatic with uncertain and long-lasting progression. Nonetheless, the routine use of imaging and of biochemical determinations have revealed the frequent occurrence of asymptomatic kidney stones, hypercalciuria and reduced kidney function in asymptomatic PHPT patients. Though the pathogenesis is far from being elucidated, PHPT is associated with reduced renal function, in terms of estimated glomerular filtration rate, and related increased morbidity and mortality. In the last decade, the effort of the Kidney Disease: Improving Global Outcomes (KDIGO) panel of experts highlighted that even mild reduction of kidney function is associated with increased risk of cardiovascular disease. These considerations provided the basis for the Fourth Workshop recommendations of a more extensive diagnostic workout about kidney features and of wider criteria for parathyroid surgery including asymptomatic kidney disease. Moreover, kidney involvement in PHPT is likely to be affected by variants of genes coding the key molecules regulating the calcium and ions renal handling; these features might have clinical relevance and should be considered both during diagnostic workout and follow-up. Finally, the effects of parathyroid surgery and of medical treatment on kidney involvement of PHPT are reviewed.

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Section: Ap2s1 and Gna11mentioning

confidence: 98%

MECHANISMS IN ENDOCRINOLOGY: Kidney involvement in patients with primary hyperparathyroidism: an update on clinical and molecular aspects

Verdelli

Corbetta

2017

European Journal of Endocrinology

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“…These vesicles intervene in the internalisation of the receptors coupled with the G-proteins (GPCRs). Mutations of the σ sub-unit of AP2 decrease the sensitivity of the cells to the extracellular calcium and reduce CaSR endocytosis [24, 25]. …”

Section: Genetic Causesmentioning

confidence: 99%

Diseases associated with calcium-sensing receptor

Vahé

Benomar

Espiard

et al. 2017

Orphanet J Rare Dis

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The calcium-sensing receptor (CaSR) plays a pivotal role in systemic calcium metabolism by regulating parathyroid hormone secretion and urinary calcium excretion. The diseases caused by an abnormality of the CaSR are genetically determined or are more rarely acquired. The genetic diseases consist of hyper- or hypocalcemia disorders. Hypercalcaemia disorders are related to inactivating mutations of the CASR gene either heterozygous (autosomal dominant familial benign hypercalcaemia, still named hypocalciuric hypercalcaemia syndrome type 1) or homozygous (severe neonatal hyperparathyroidism). The A986S, R990G and Q1011E variants of the CASR gene are associated with higher serum calcium levels than in the general population, hypercalciuria being also associated with the R990G variant. The differential diagnosis consists in the hypocalciuric hypercalcaemia syndrome, types 2 (involving GNA11 gene) and 3 (involving AP2S1 gene); hyperparathyroidism; abnormalities of vitamin D metabolism, involving CYP24A1 and SLC34A1 genes; and reduced GFR. Hypocalcemia disorders, which are more rare, are related to heterozygous activating mutations of the CASR gene (type 1), consisting of autosomal dominant hypocalcemia disorders, sometimes with a presentation of pseudo-Bartter’s syndrome. The differential diagnosis consists of the hypercalciuric hypocalcaemia syndrome type 2, involving GNA11 gene and other hypoparathyroidism aetiologies. The acquired diseases are related to the presence of anti-CaSR antibodies, which can cause hyper- or especially hypocalcemia disorders (for instance in APECED syndromes), determined by their functionality. Finally, the role of CaSR in digestive, respiratory, cardiovascular and neoplastic diseases is gradually coming to light, providing new therapeutic possibilities. Two types of CaSR modulators are known: CaSR agonists (or activators, still named calcimimetics) and calcilytic antagonists (or inhibitors of the CasR). CaSR agonists, such as cinacalcet, are indicated in secondary and primary hyperparathyroidism. Calcilytics have no efficacy in osteoporosis, but could be useful in the treatment of hypercalciuric hypocalcaemia syndromes.

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“…Type 2 FHH (FHH2) due to germline loss-of-function mutation of GNA11 , encoding the G protein α11 subunit 61,62 , and type 3 FHH (FHH3) due to germline loss-of-function mutation in AP2S1 , encoding the adaptor protein-2 sigma subunit involved in clathrin-mediated endocytosis, 63–66 have been recently described. Somatic mutation of neither GNA11 nor AP2S1 has been reported in sporadic parathyroid tumors.…”

Section: Clinical Features and Genetics Of Familial Hypocalciuric Hypmentioning

confidence: 99%

Genetics of Hyperparathyroidism, Including Parathyroid Cancer

Simonds

2017

Endocrinology and Metabolism Clinics of North America

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SYNOPSIS Primary hyperparathyroidism (HPT) is a metabolic disease caused by the excessive secretion of parathyroid hormone from one or more neoplastic parathyroid glands. HPT is largely sporadic, however it can be associated with a familial syndrome. The study of such families led to the discovery of tumor suppressor genes whose loss–of-function is now recognized to underlie the development of many sporadic parathyroid tumors. Heritable and acquired oncogenes causing parathyroid neoplasia are also known. Studies of somatic changes in parathyroid tumor DNA and investigation of kindreds with unexplained familial HPT promise to unmask more genes relevant to parathyroid neoplasia.

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Familial Hypocalciuric Hypercalcemia Types 1 and 3 and Primary Hyperparathyroidism: Similarities and Differences

Abstract: In our population, AP2S1 mutations affect calcium homeostasis more severely than CASR mutations. Due to overlap, the risk of confusion between FHH and PHPT is high.

Cited by 102 publications

References 35 publications

MECHANISMS IN ENDOCRINOLOGY: Kidney involvement in patients with primary hyperparathyroidism: an update on clinical and molecular aspects

MECHANISMS IN ENDOCRINOLOGY: Kidney involvement in patients with primary hyperparathyroidism: an update on clinical and molecular aspects

Diseases associated with calcium-sensing receptor

Genetics of Hyperparathyroidism, Including Parathyroid Cancer

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