GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts

Mayr, B; Schnabel, Dirk; Dörr, Helmuth-Günther; Schöfl, Christof

doi:10.1530/eje-15-1028

Cited by 68 publications

(61 citation statements)

References 126 publications

(154 reference statements)

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“…Besides rehydratation with normal saline, treatment is based on cinacalcet (which is not always effective), biphosphonates, low-calcium milk and, as a last resort, on total parathyroidectomy [39]. …”

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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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 gene(s) presumed to cause a second hit and monoclonal or oligoclonal progression has not been characterized in these six cases. Seventh, biallelic CASR mutation often causes neonatal severe PHPT, the severest form of PHPT . Eighth, chronic hypercalcemia is similar in frequency and in amplitude in FHH and PHPT; the amplitude is somewhat higher in FHH3 than FHH1 .…”

Section: Resultsmentioning

confidence: 99%

“…Total parathyroidectomy has been deliberately done in some neonates with severe PHPT . Total parathyroidectomy has rarely been attempted in adults with FHH, but it has occasionally been done unintentionally during attempts at subtotal parathyroidectomy .…”

Section: Discussionmentioning

confidence: 99%

Familial Hypocalciuric Hypercalcemia as an Atypical Form of Primary Hyperparathyroidism

Marx

2017

Journal of Bone and Mineral Research

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Familial hypocalciuric hypercalcemia (FHH) causes lifelong hypercalcemia with features that overlap with typical primary hyperparathyroidism (PHPT). The incompleteness of this overlap has led to divergent nomenclatures for FHH. I compare two nomenclatures. One sets FHH as an entity distinct from PHPT. The other groups FHH with PHPT but conditions FHH as atypical PHPT. I analyzed selected articles about calcium-sensing receptors, FHH, PHPT, CASR, GNA11, and AP2S1. FHH usually results from a heterozygous germline inactivating mutation of the CASR, and less frequently from mutation of GNA11 or AP2S1. The CASR encodes the calcium-sensing receptors. These are highly expressed on parathyroid cells, where they sense serum calcium concentration and regulate suppression of PTH secretion by serum calcium. Their mutated expression in the kidney in FHH causes increased renal tubular reabsorption of calcium (hypocalciuria). Many FHH features are shared with PHPT and thus support FHH as a form of PHPT. These include a driver mutation expressed mainly in the parathyroid cells. The mutation causes a parathyroid cell insensitivity to extracellular calcium in vivo and in vitro, a right-shift of the set point for suppression of PTH secretion by calcium. Serum PTH is normal or mildly elevated; ie, it is not appropriately suppressed by hypercalcemia. Total parathyroidectomy causes hypoparathyroidism and durable remission of hypercalcemia. Some other features are not shared with PHPT and could support FHH as a distinct entity. These include onset of hypercalcemia in the first week of life, frequent persistence of hypercalcemia after subtotal parathyroidectomy, and hypocalciuria. The features supporting FHH as a form of PHPT are stronger than those favoring FHH as a distinct entity. Classifying FHH as an atypical form of PHPT represents compact nomenclature and supports current concepts of pathophysiology of FHH and PHPT. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

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“…Furthermore, normal or elevated 24‐hour urinary Ca (24‐h U Ca ) excretion is a diagnostic marker characteristically applied to diagnose PHPT. It is used to distinguish familial hypocalciuric hypercalcaemia (FHH), which is caused by an inactivating mutation in the CaSR gene, from PHPT by calculating the Ca/creatinine clearance ratio (CCCR) . By definition, CCCR<1% indicates FHH, 1%‐2% is a grey area and >2% designates PHPT …”

Section: Introductionmentioning

confidence: 99%

“…to distinguish familial hypocalciuric hypercalcaemia (FHH), which is caused by an inactivating mutation in the CaSR gene, from PHPT by calculating the Ca/creatinine clearance ratio (CCCR). [2][3][4] By definition, CCCR<1% indicates FHH, 1%-2% is a grey area and >2% designates PHPT. 3 The variance of urinary Ca excretion in patients with PHPT is considerable.…”

mentioning

confidence: 99%