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We thank Drs. Lilia D'Souza-Li and Svetlana Pidasheva, and Ruth Milkereit and Yaroslava Chtompei for their previous help with the database. We thank Drs. Lucie Canaff, Vito Guarnieri and Yves Sabbagh for revising and maintaining the present database.

Calcium Sensing Receptor Database

Disease Clinical Pages

Heterozygous loss-of-function mutations in CASR give rise to familial (benign) hypocalciuric hypercalcemia (FHH) in which the lifelong hypercalcemia is generally asymptomatic. The characteristic symptoms and complications afflicting patients with other forms of hypercalcemia appear not to be a part of FHH. Affected individuals from some FHH kindreds may experience pancreatitis, gall stones or chondrocalcinosis.

With respect to degree of hypercalcemia, the majority of FHH patients are similar to patients with mild primary hyperparathyroidism. In contrast to primary hyperparathyroid patients, those with FHH have serum magnesium levels at the upper end of the normal range or slightly above. FHH patients demonstrate inappropriately normal serum concentrations of parathyroid hormone (PTH) despite hypercalcemia, indicative of the derangement in the blood calcium sensing mechanism of the parathyroid. While the majority of primary hyperparathyroid patients have clearly elevated circulating intact PTH, diagnostic difficulties can arise in differentiating the ten percent of primary hyperparathyroid patients with PTH levels at the upper limit of normal.

Another important characteristic of FHH is the unusually high renal tubular reabsorption of calcium and magnesium in the face of hypercalcemia. In the majority of FHH patients, the renal calcium/creatinine clearance ratio is less than 0.01, while it is usually much higher in patients with primary hyperparathyroidism and other hypercalcemic disorders. However, occasionally affected members of some FHH families have hypercalciuria and/or nephrocalcinosis.

In FHH, in contrast to primary hyperparathyroidism, urine concentrating ability is normal. The renal CASR may mediate the polyuria and diminished urinary concentrating ability characteristic of hypercalcemia as seen in primary hyperparathyroidism.

Before identification of FHH as a clinical entity distinct from primary hyperparathyroidism, FHH patients often underwent parathyroidectomy. In the vast majority of cases the patient remained hypercalcemic, and the present consensus is that surgery is to be avoided if the patient is asymptomatic. Moreover, the enhanced renal tubular reabsorption of calcium persists following induction of hypoparathyroidism by total parathyroidectomy, illustrating the fact that the abnormal renal handling of calcium in FHH is independent of PTH.

Homozygous loss-of-function CASR mutations manifest as neonatal severe hyperparathyroidism (NSHPT), a rare disorder characterized by extreme hypercalcemia and the bony changes of hyperparathyroidism which occur in infancy. The cases of NSHPT almost invariably have involved multiglandular parathyroid hyperplasia rather than a single adenoma. If not treated by parathyroidectomy, NSHPT can be a devastating neurodevelopmental disorder and is often fatal. However, some forms of neonatal hyperparathyroidism, particularly those due to de novo mutations of the CASR gene, present with milder, less symptomatic disease that can be transient.

Activating mutations in the CASR gene have been identified in several families previously diagnosed with autosomal dominant hypocalcemia (ADH), autosomal dominant hypoparathyroidism, or hypocalcemic hypercalciura. In the parathyroid gland, the activated CASR suppresses PTH secretion and in the kidney it induces hypercalciuria which contributes to the hypocalcemia. In most cases of ADH, a family history is clear, but de novo mutations are known. ADH affected individuals may have mild hypocalcemia, and relatively few symptoms. Seizures can occur, especially in younger patients, and these often happen during febrile episodes due to intercurrent infection. Parathesias, tetany and laryngospasm - other symptoms of hypocalcemia - are uncommon. There is a tendency towards hyperphosphatemia, although serum phosphate may be normal. Serum magnesium concentrations can be at the lower end of the normal range or even subnormal in untreated patients.

Serum intact PTH levels are usually within the normal range. Urinary calcium excretion is higher than in typical hypoparathyroid patients, despite serum PTH levels being lower in hypoparathyroid patients than in ADH-affected individuals. Because of the marked hypercalciuria, there is a risk of other renal complications such as nephrocalcinosis, renal stones, and impaired renal function. Renal tubular cells, excessively inhibited from absorbing calcium by the overactive CASR, sustain the hypercalciuria. Thus caution should be exercised to avoid overtreatment of ADH with Vitamin D (and its metabolites) or calcium supplements.

Important Support
CIHR - Canadian Institutes of Health Research
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Kidney Foundation of Canada
MRC of Canada (Group in Medical Genetics) (Historical)

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