Rev Esp Endocrinol Pediatr

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Rev Esp Endocrinol Pediatr 2018;9 Suppl(1):5-5 | Doi. 10.3266/RevEspEndocrinolPediatr.pre2018.Apr.477
Update of calcium/phosphorous metabolism focusing on calcium receptor pathology and in other pediatric uncommon situations
Patología del sensor del calcio en la edad pediátrica

Enviado a Revisar: 27 Abr. 2018 | _ACCEPTED: 27 Abr. 2018  | En Publicación: 8 May. 2018
Agnès Linglart
CHU Paris-Sud, Hôpital de Bicêtre. Paris (France)
Correspondencia para Agnès Linglart, CHU Paris-Sud, Hôpital de Bicêtre, Paris, France

The calcium-sensing receptor (CASR) is a widely expressed guanine nucleotide-binding protein (G-protein) coupled receptor (GPCR) and its activation, correlated with an elevated extracellular calcium concentration, causes G-protein dependent stimulation of phospholipase C through Gq and G11, which results in an accumulation of inositol 1.4.5-triphosphate and a decrease of the extracellular calcium concentration. The CASR is expressed in numerous tissues, yet its roles have been most delineated in parathyroid cells and in the kidney. The CASR contributes to the renal handling of calcium; in the ascending branch of the Henlé loop, the CASR is expressed; through ligand binding, the CASR activation prevents the passive calcium reabsorption form the ultrafiltrate to the plasma.

Autosomal dominant hypocalcaemia hypercalciuria (ADHH) is a rare disorder characterized by the calcium-independent and autonomous activation of the calcium-sensing receptor (CASR). Activating point-mutations in CASR cause ADHH type 1; more than 300 different mutations have been described so far; recently, point-mutations affecting G11, a G-protein subunit interacting with the CASR have been described in ADHH type 2. Patients affected with ADHH present with variable degrees of hypocalcaemia ranging from asymptomatic moderately low level of serum calcium to profound hypocalcaemia with repeated seizures and developmental delay. The hypocalcaemia is the consequence of the decreased release of PTH by parathyroid cells, leading to hypoparathyroidism. The urinary excretion of calcium is classically described as elevated in ADHH. It is true that, in comparison with other causes of hypoparathyroidism, the urinary excretion of calcium is superior in ADHH. However, in conditions of vitamin D and/or dietary calcium deficiency, or after a prolonged period of profound hypocalcemia, the urinary excretion of calcium may be low, preventing the simplistic distinction between ADHH and hypoparathyroidism. Nephrocalcinosis leading to renal failure and kidney stones is the foremost complication of hypercalciuria in ADHH. In ADHH, the tendency to elevated urinary calcium excretion results from both the decreased PTH-dependent reabsorption of calcium in the distal renal tubule, and the decreased CASR-dependent paracellular reabsorption of calcium in the Henlé loop. In most situations, chronic hypoparathyroidism is treated with calcium supplements and vitamin D analogues. Therapy should restore low-normal calcium levels (2-2.2 mM total calcium). Normalization of calcium is to be avoided, because it can cause hypercalciuria in the absence of PTH-stimulated reabsorption of calcium in the distal renal tubule. In ADH, it may be particularly difficult to increase the serum calcium without causing hypercalciuria. Although not approved by regulatory agencies, recPTH may be an alternative to current therapy in patients with severe ADH who experience life-threatening complications of their disease.

Familial hypocalciuric hypercalcemia (FHH) is, in most cases, an asymptomatic genetic disorder characterized by lifelong moderate hypercalcemia along with normo- or hypocalciuria and elevated plasma PTH concentration. FHH type 1 accounts for 65% of cases and is due to inactivating mutations in the CASR gene. Loss of CASR function results in a reduction in the sensitivity of parathyroid and renal cells to calcium levels. FHH type 2 are caused by GNA11 mutations. GNA11 encodes the G-protein subunit α 11 involved in calcium-sensing receptor signaling. Finally, mutations in the adaptor-related protein complex 2, sigma 1 subunit (AP2S1) gene localized to 19q13.2-q13.3, have recently been identified in FHH type 3.  Symptoms of FHH (e.g., fatigue, weakness, or thought disturbances) may be frequent, but they are usually mild. Hypercalcemia is present at birth and remains stable throughout life. Most FHH are well tolerated and do not require specific treatment beside vitamin D supplements. Case reports of symptomatic FHH have been successfully treated with calcimimetics.

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