SCIENTIFIC BACKGROUND

AP2S1CASRGNA11
Category:

Hypocalciuric hypercalcemia (FHH) is a disorder of calcium balance that is characterized by elevated blood calcium levels and decreased urinary calcium excretion. The familial form is inherited in an autosomal dominant manner and is usually caused by inactivating variants in the CASR gene (familial hypocalciuric hypercalcemia type 1, FHH1). The calcium-sensitive receptor CaSR plays an important role in regulating extracellular calcium homeostasis. The signal transduction pathway of CaSR involves the α-11 G protein (Gα11) subunit and the adapter-related protein complex 2σ (AP2σ) subunit. These are encoded by the GNA11 and AP2S1 genes, respectively. CaSR can detect small changes in extracellular Ca2+ and maintains calcium homeostasis in the body by regulating the synthesis and secretion of PTH and urinary calcium reabsorption.

 

Approximately 65% of all cases are accounted for by FHH type 1. In a smaller number of cases, alterations are detected in the GNA11 gene (FHH2) and the AP2S1 gene (FHH3). FHH is usually asymptomatic, but rarely symptoms such as fatigue, weakness, excessive thirst and concentration problems occur. Recurrent pancreatitis, chondrocalcinosis, and premature vascular calcification have been described in isolated cases.

 

Typically, this form of calcium balance disorder does not require distinct treatment. However, it's important to distinguish FHH from other forms of hypercalcemia that require treatment, such as primary hyperparathyroidism, which is seen in syndromes like MEN1 and MEN2, and can be addressed surgically.

 

References

Marini et al. 2017, Clin Cases Miner Bone Metab 14:60 / Wasserman et al. 2017, Clin Cancer Res 23:e123 / Thakker et al. 2016, J Intern Med 280:574

GENES

AP2S1CASRGNA11

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