Familial hypocalciuric hypercalcemia pathophysiology

The pathophysiology of familial hypocalciuric hypercalcemia (FHH) consists of an inactivating missense mutation in the calcium-sensing receptor (CaSR) located on the short arm of the chromosome 3 (FBHH3q). The mutation of CaSR is associated with two inherited conditions FHH and neonatal hyperparathyroidism. CaSR is a plasma membrane G protein-coupled receptor which is expressed on the chief cells of the parathyroid glands and the cells lining the renal tubules. CasR has the ability to sense any changes in the circulating calcium concentration and send this information through the signaling pathway to the parathyroid gland that modifies PTH secretion.

• The pathogenesis of familial hypocalciuric hypercalcemia (FHH) includes the following mechanisms:^{[1][2][3][4][5]}
• The pathophysiology of familial hypocalciuric hypercalcemia (FHH) consists of an inactivating mutation in the calcium-sensing receptor (CaSR) located on the short arm of the chromosome 3 (FBHH3q).
• CaSR is a plasma membrane G protein-coupled receptor which is expressed on the chief cells of the parathyroid glands and the cells lining the renal tubules.
• CasR has the ability to sense any changes in the circulating calcium and send this information through the signaling pathway to the parathyroid gland that modifies the parathyroid hormone (PTH) secretion.

• The genes involved in the pathogenesis of FHH include mainly CASR, rarely GNA11 and AP2S1.^[6][7]
• The development of FHH is the result of genetic mutations of calcium-sensing receptor (CASR).
• CASR gene located on chromosome 3p13.3-21, inactivating mutation in this gene can cause hypercalcemia whereas the activating mutation causes hypocalcemia.
• If the mutation is heterozygous, then FHH occurs with lifelong asymptomatic hypercalcemia.
• Neonatal severe hyperparathyroidism (NSHPT), a rare disorder characterized by extreme hypercalcemia and bony changes of hyperparathyroidism in infancy occurs due to homozygous mutation.
• The gain of function mutation in the CaSR gene lead to autosomal dominant hypocalcemia.
• 100 different types of CaSR gene alterations have been described in the literature.

FHH sometimes is associated with pancreatitis because the mutation in CaSR can make the pancreas susceptible for inflammation.^[8]

No gross pathology is seen in FHH.

On light microscopy the percentage parenchyma is reduced in parathyroid glands in patients with familial hypocalciuric hypercalcemia, whereas the adipose tissue percentage is increased in the parathyroid glands.^[9][10]

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