Familial hypocalciuric hypercalcemia pathophysiology: Difference between revisions
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==Overview== | ==Overview== | ||
The [[pathophysiology]] of familial hypocalciuric hypercalcemia (FHH) | 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]]. | ||
==Pathophysiology== | ==Pathophysiology== | ||
*The [[pathogenesis]] of familial hypocalciuric hypercalcemia (FHH) includes the following mechanisms:<ref name="pmid9109436">{{cite journal |vauthors=Bai M, Janicic N, Trivedi S, Quinn SJ, Cole DE, Brown EM, Hendy GN |title=Markedly reduced activity of mutant calcium-sensing receptor with an inserted Alu element from a kindred with familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism |journal=J. Clin. Invest. |volume=99 |issue=8 |pages=1917–25 |year=1997 |pmid=9109436 |pmc=508016 |doi=10.1172/JCI119359 |url=}}</ref><ref name="pmid7916660">{{cite journal |vauthors=Pollak MR, Brown EM, Chou YH, Hebert SC, Marx SJ, Steinmann B, Levi T, Seidman CE, Seidman JG |title=Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism |journal=Cell |volume=75 |issue=7 |pages=1297–303 |year=1993 |pmid=7916660 |doi= |url=}}</ref><ref name="urlRecent advances in understanding the extracellular calcium-sensing receptor">{{cite web |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5074356/ |title=Recent advances in understanding the extracellular calcium-sensing receptor |format= |work= |accessdate=}}</ref><ref name="pmid11013439">{{cite journal| author=Hendy GN, D'Souza-Li L, Yang B, Canaff L, Cole DE| title=Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. | journal=Hum Mutat | year= 2000 | volume= 16 | issue= 4 | pages= 281-96 | pmid=11013439 | doi=10.1002/1098-1004(200010)16:4<281::AID-HUMU1>3.0.CO;2-A | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11013439 }} </ref><ref name="urlMutations in the calcium-sensing receptor and their clinical implications. - PubMed - NCBI">{{cite web |url=https://www.ncbi.nlm.nih.gov/pubmed/9362389 |title=Mutations in the calcium-sensing receptor and their clinical implications. - PubMed - NCBI |format= |work= |accessdate=}}</ref> | |||
*FHH | *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). | ||
*The [[pathophysiology]] of familial hypocalciuric hypercalcemia | *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|renal tubules.]] | ||
*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|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]]. | ||
*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. | |||
==Genetics== | ==Genetics== | ||
* The | * The [[genes]] involved in the [[pathogenesis]] of [[Familial hypocalciuric hypercalcemia|FHH]] include mainly CASR, rarely GNA11 and AP2S1.<ref name="urlRedirecting">{{cite web |url=https://doi.org/10.1016/0092-8674(93)90617-Y |title=Redirecting |format= |work= |accessdate=}}</ref><ref name="urlMutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia - Hendy - 2000 - Human Mutation - Wiley Online Library">{{cite web |url=http://onlinelibrary.wiley.com/doi/10.1002/1098-1004(200010)16:4%3C281::AID-HUMU1%3E3.0.CO;2-A/abstract |title=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 |format= |work= |accessdate=}}</ref> | ||
* The development of FHH is the result of genetic mutations of [[calcium]]-sensing receptor (CASR). | |||
* CASR [[gene]] located on [[chromosome 3]]<nowiki/>p13.3-21, 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 [[bone|bony]] changes of [[hyperparathyroidism]] in [[infancy]] occurs due to [[homozygous]] [[mutation]]. | |||
* 100 different types of | * The [[gain-of-function mutations|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. | |||
==Associated Conditions== | ==Associated Conditions== | ||
FHH sometimes is associated with [[pancreatitis]] | FHH sometimes is associated with [[pancreatitis]] because the [[mutation]] in CaSR can make the [[pancreas]] susceptible for [[inflammation]].<ref name="pmid20059346">{{cite journal |vauthors=Whitcomb DC |title=Genetic aspects of pancreatitis |journal=Annu. Rev. Med. |volume=61 |issue= |pages=413–24 |year=2010 |pmid=20059346 |doi=10.1146/annurev.med.041608.121416 |url=}}</ref> | ||
==Gross Pathology== | ==Gross Pathology== | ||
No gross pathology is seen in FHH. | No [[gross pathology]] is seen in FHH. | ||
==Microscopic Pathology== | ==Microscopic Pathology== | ||
On light microscopy | On [[light microscope|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]].<ref name="pmid6731460">{{cite journal |vauthors=Law WM, Carney JA, Heath H |title=Parathyroid glands in familial benign hypercalcemia (familial hypocalciuric hypercalcemia) |journal=Am. J. Med. |volume=76 |issue=6 |pages=1021–6 |year=1984 |pmid=6731460 |doi= |url=}}</ref><ref name="pmid7228018">{{cite journal |vauthors=Thorgeirsson U, Costa J, Marx SJ |title=The parathyroid glands in familial hypocalciuric hypercalcemia |journal=Hum. Pathol. |volume=12 |issue=3 |pages=229–37 |year=1981 |pmid=7228018 |doi= |url=}}</ref> | ||
==References== | ==References== | ||
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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 (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.
Pathophysiology
- 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.
Genetics
- 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.
Associated Conditions
FHH sometimes is associated with pancreatitis because the mutation in CaSR can make the pancreas susceptible for inflammation.[8]
Gross Pathology
No gross pathology is seen in FHH.
Microscopic Pathology
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]
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.
- ↑ Law WM, Carney JA, Heath H (1984). "Parathyroid glands in familial benign hypercalcemia (familial hypocalciuric hypercalcemia)". Am. J. Med. 76 (6): 1021–6. PMID 6731460.
- ↑ Thorgeirsson U, Costa J, Marx SJ (1981). "The parathyroid glands in familial hypocalciuric hypercalcemia". Hum. Pathol. 12 (3): 229–37. PMID 7228018.