Familial hypocalciuric hypercalcemia and related disorders

Abstract

Familial hypocalciuric hypercalcemia (FHH) causes hypercalcemia by three genetic mechanisms: inactivating mutations in the calcium-sensing receptor, the G-protein subunit α₁₁, or adaptor-related protein complex 2, sigma 1 subunit. While hypercalcemia in other conditions causes significant morbidity and mortality, FHH generally follows a benign course. Failure to diagnose FHH can result in unwarranted treatment or surgery for the mistaken diagnosis of primary hyperparathyroidism (PHPT), given the significant overlap of biochemical features. Determinations of urinary calcium excretion greatly aid in distinguishing PHPT from FHH, but overlap still exists in certain cases. It is important that 24-h urine calcium and creatinine be included in the initial workup of hypercalcemia. FHH should be considered if low or even low normal urinary calcium levels are found in what is typically an asymptomatic hypercalcemic patient. The calcimimetic cinacalcet has been used to treat hypercalcemia in certain symptomatic causes of FHH.

Keywords: Ca-sensing receptor; familial hypocalciuric hypercalcemia; hyperparathyroidism.

Fig. 1.

Schematic model of calcium-sensing receptor and selected downstream pathways. AP2: Adaptor Protein 2, β-arrestin, Ca²⁺: Calcium ion, CaSR: Calcium-Sensing Receptor, DAG: Diacylglycerol, GDPαβγ: G-protein, PLC-β: Phospholipase C β, PKC: Protein kinase C, P: Phosphothreonine, IP3: Inositol triphosphate. FHH: Familial Hypocalciuric Hypercalcemia, CASR: Calcium-sensing receptor gene, GNA11: G Protein Subunit Alpha 11 gene, AP2S1: Adaptor Related Protein Complex 2 Sigma 1 Subunit gene.

Fig. 2.

Relationship between plasma PTH (expressed asa%of maximal secretion) and plasma ionized calcium (mmol/L) showing the extremely steep relationship between PTH levels in vivo and plasma calcium concentrations (blue curve). The set-point is defined as the plasma or extracellular calcium concentration at which PTH secretion is 50% suppressed versus maximal secretion. Patients with FHH typically have a modest shift to the right in the set-point for secretion as shown (red curve).