Familial hypocalciuric hypercalcemia pathophysiology: Difference between revisions
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==Overview== | ==Overview== | ||
The [[pathophysiology]] of familial hypocalciuric hypercalcemia (FHH) 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 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 [[ | The [[pathophysiology]] of familial hypocalciuric hypercalcemia (FHH) 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 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]] concentrated and send this information through the signaling pathway to the [[parathyroid gland]] that modifies the PTH secretion. | ||
==Pathophysiology== | ==Pathophysiology== | ||
===Pathogenesis=== | ===Pathogenesis=== | ||
*The [[pathophysiology]] of familial hypocalciuric hypercalcemia is due to an inactivating mutation in the calcium-sensing receptor (CaSR)<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> located on the short arm of the chromosome 3 (FBHH3q).<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> | *The [[pathophysiology]] of familial hypocalciuric hypercalcemia is due to an inactivating mutation in the [[calcium-sensing receptor]] (CaSR)<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> located on the short arm of the chromosome 3 (FBHH3q).<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> | ||
*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<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>. | *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.]]<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>. | ||
*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. | *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 [[parathyroid hormone]] (PTH) secretion. | ||
==Genetics== | ==Genetics== | ||
* The development of FHH is the result of genetic mutations of CASR. | * The development of FHH is the result of genetic mutations of CASR. | ||
* CASR gene located on [[chromosome 3]]<nowiki/>p13.3-21 can cause either hypercalcemia or hypocalcemia depending upon whether they are inactivating or activating, respectively. | * CASR gene located on [[chromosome 3]]<nowiki/>p13.3-21 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. | * 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]]. | * 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.<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 gain-of-function mutations in the CASR gene lead to [[autosomal dominant]] hypocalcemia.<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> | ||
* 100 different CASR gene alterations have been described in the literature so far. | * 100 different CASR gene alterations have been described in the literature so far. | ||
==Associated Conditions== | ==Associated Conditions== | ||
FHH sometimes is associated with pancreatitis as 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>. | FHH sometimes is associated with [[pancreatitis]] as 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== | ||
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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) 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 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 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 any changes in the circulating calcium concentrated and send this information through the signaling pathway to the parathyroid gland that modifies the parathyroid hormone (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]
- 100 different CASR gene alterations have been described in the literature so far.
Associated Conditions
FHH sometimes is associated with pancreatitis as 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 percent parenchyma is reduced in parathyroid glands in patients with familial hypocalciuric hypercalcemia, whereas the percent fat 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.