Familial hypocalciuric hypercalcemia pathophysiology: Difference between revisions
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==Gross Pathology== | ==Gross Pathology== | ||
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==Microscopic Pathology== | ==Microscopic Pathology== | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ajay Gade MD[2]]
Overview
The pathophysiology of [Familial hypocalciuric hypercalcemia] is due to 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 FBHH 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 concentrated and send this information through the signaling pathway to the Parathyroid gland that modifies the PTH secretion.
Pathophysiology
Pathogenesis
- The pathophysiology of familial hypocalciuric hypercalcemia is due to an inactivating mutation in the calcium sensing receptor (CaSR)[1][2][3] located on the short arm of the chromosome 3 (FBHH3q).[4]
- 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[5].
- CasR has the ability to sense the any changes in the circulating calcium concentrated and send this information through the signalling pathway to the Parathyroid gland that modifies the PTH secretion.
Genetics
- The development of FHH is the result of genetic mutations of CASR. CASR gene located on chromosome 3p13.3-21 can cause either hypercalcemia or hypocalcemia depending upon whether they are inactivating or activating, respectively. If the mutation is heterozygous, then FHH occurs with lifelong asymptomatic hypercalcemia. Neonatal severe hyperparathyroidism (NSHPT), a rare disorder characterized by extreme hypercalcemia and the bony changes of hyperparathyroidism in infancy occurs due to homozygous mutation. The gain-of-function mutations in the CASR gene lead to autosomal dominant hypocalcemia[6][7].
Associated Conditions
FHH, sometimes is associated with pancreatitis as mutation in CaSR can make the pancreas susceptible for inflammation[8].
Gross Pathology
- No gross pathology is seen in FHH.
Microscopic Pathology
- No microscopic histopathological changes seen in FHH.
References
- ↑ Bai M, Janicic N, Trivedi S, Quinn SJ, Cole DE, Brown EM, Hendy GN (1997). "Markedly reduced activity of mutant calcium-sensing receptor with an inserted Alu element from a kindred with familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism". J. Clin. Invest. 99 (8): 1917–25. doi:10.1172/JCI119359. PMC 508016. PMID 9109436.
- ↑ Pollak MR, Brown EM, Chou YH, Hebert SC, Marx SJ, Steinmann B, Levi T, Seidman CE, Seidman JG (1993). "Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism". Cell. 75 (7): 1297–303. PMID 7916660.
- ↑ "Recent advances in understanding the extracellular calcium-sensing receptor".
- ↑ Hendy GN, D'Souza-Li L, Yang B, Canaff L, Cole DE (2000). "Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia". Hum Mutat. 16 (4): 281–96. doi:10.1002/1098-1004(200010)16:4<281::AID-HUMU1>3.0.CO;2-A. PMID 11013439.
- ↑ "Mutations in the calcium-sensing receptor and their clinical implications. - PubMed - NCBI".
- ↑ "Redirecting".
- ↑ "Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia - Hendy - 2000 - Human Mutation - Wiley Online Library".
- ↑ Whitcomb DC (2010). "Genetic aspects of pancreatitis". Annu. Rev. Med. 61: 413–24. doi:10.1146/annurev.med.041608.121416. PMID 20059346.