Hypoparathyroidism pathophysiology: Difference between revisions
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==Genetics== | ==Genetics== | ||
*[ | *'''Isolated hypoparathyroidism''' | ||
* | **'''Autosomal dominant inheritence''' | ||
* | ***[[Autosomal dominant]] familial isolated hypoparathyroidism caused by PTH [[gene mutation]]<ref name="pmid2212001">{{cite journal |vauthors=Arnold A, Horst SA, Gardella TJ, Baba H, Levine MA, Kronenberg HM |title=Mutation of the signal peptide-encoding region of the preproparathyroid hormone gene in familial isolated hypoparathyroidism |journal=J. Clin. Invest. |volume=86 |issue=4 |pages=1084–7 |year=1990 |pmid=2212001 |pmc=296835 |doi=10.1172/JCI114811 |url=}}</ref> | ||
***[[Autosomal dominant inheritance|Autosomal dominant]] familial isolated hypoparathyroidism caused by glial cells missing 2 ([[GCM2]]) [[gene mutation]]<ref name="pmid18712808">{{cite journal |vauthors=Canaff L, Zhou X, Mosesova I, Cole DE, Hendy GN |title=Glial cells missing-2 (GCM2) transactivates the calcium-sensing receptor gene: effect of a dominant-negative GCM2 mutant associated with autosomal dominant hypoparathyroidism |journal=Hum. Mutat. |volume=30 |issue=1 |pages=85–92 |year=2009 |pmid=18712808 |doi=10.1002/humu.20827 |url=}}</ref> | |||
****[[Dominant negative mutation]] | |||
***[[Autosomal dominant hypocalcemia]]<ref name="pmid27803672">{{cite journal |vauthors=Roszko KL, Bi RD, Mannstadt M |title=Autosomal Dominant Hypocalcemia (Hypoparathyroidism) Types 1 and 2 |journal=Front Physiol |volume=7 |issue= |pages=458 |year=2016 |pmid=27803672 |pmc=5067375 |doi=10.3389/fphys.2016.00458 |url=}}</ref> | |||
****[[Autosomal dominant hypocalcemia]] type 1 | |||
*****[[Calcium-sensing receptor|Calcium-sensing]] receptor gene activating mutation. | |||
*****'''Most common genetic form''' of hypoparathyroidism. | |||
*****Also known as familial hypercalciuric hypocalcemia. | |||
*****The activating mutation results in gain in function. | |||
*****Calcium-sensing receptor gene activating mutation can also cause Bartter syndrome type 5.This mutation cause the inhibition of apical potassium channel in the thick ascending limb of the loop of Henle in the kidney.<ref name="pmid17048213">{{cite journal |vauthors=Vezzoli G, Arcidiacono T, Paloschi V, Terranegra A, Biasion R, Weber G, Mora S, Syren ML, Coviello D, Cusi D, Bianchi G, Soldati L |title=Autosomal dominant hypocalcemia with mild type 5 Bartter syndrome |journal=J. Nephrol. |volume=19 |issue=4 |pages=525–8 |year=2006 |pmid=17048213 |doi= |url=}}</ref><ref name="pmid25932037">{{cite journal |vauthors=Choi KH, Shin CH, Yang SW, Cheong HI |title=Autosomal dominant hypocalcemia with Bartter syndrome due to a novel activating mutation of calcium sensing receptor, Y829C |journal=Korean J Pediatr |volume=58 |issue=4 |pages=148–53 |year=2015 |pmid=25932037 |pmc=4414630 |doi=10.3345/kjp.2015.58.4.148 |url=}}</ref> | |||
****[[Autosomal dominant hypocalcemia]] type 2 | |||
*****G protein G11 (GNA11) mutation. | |||
**'''Autosomal recessive inheritence''' | |||
***[[Autosomal recessive]] familial isolated hypoparathyroidism caused by PTH [[gene mutation]]<ref name="pmid10523031">{{cite journal |vauthors=Sunthornthepvarakul T, Churesigaew S, Ngowngarmratana S |title=A novel mutation of the signal peptide of the preproparathyroid hormone gene associated with autosomal recessive familial isolated hypoparathyroidism |journal=J. Clin. Endocrinol. Metab. |volume=84 |issue=10 |pages=3792–6 |year=1999 |pmid=10523031 |doi=10.1210/jcem.84.10.6070 |url=}}</ref> | |||
***[[Autosomal recessive]] familial isolated hypoparathyroidism caused by glial cells missing 2 ([[GCM2]]) [[gene mutation]]<ref name="pmid11602629">{{cite journal |vauthors=Ding C, Buckingham B, Levine MA |title=Familial isolated hypoparathyroidism caused by a mutation in the gene for the transcription factor GCMB |journal=J. Clin. Invest. |volume=108 |issue=8 |pages=1215–20 |year=2001 |pmid=11602629 |pmc=209530 |doi=10.1172/JCI13180 |url=}}</ref><ref name="pmid18712808">{{cite journal |vauthors=Canaff L, Zhou X, Mosesova I, Cole DE, Hendy GN |title=Glial cells missing-2 (GCM2) transactivates the calcium-sensing receptor gene: effect of a dominant-negative GCM2 mutant associated with autosomal dominant hypoparathyroidism |journal=Hum. Mutat. |volume=30 |issue=1 |pages=85–92 |year=2009 |pmid=18712808 |doi=10.1002/humu.20827 |url=}}</ref> | |||
**'''X-linked inheritence''' | |||
***X-linked recessive familial isolated hypoparathyroidism | |||
****Caused by mutation in [[gene]] variant [[FHL1 (gene)|FHL1]] (exon 4, c.C283T, p.R95W) on chromosome locus Xq26-q27.<ref name="pmid28444561">{{cite journal |vauthors=Pillar N, Pleniceanu O, Fang M, Ziv L, Lahav E, Botchan S, Cheng L, Dekel B, Shomron N |title=A rare variant in the FHL1 gene associated with X-linked recessive hypoparathyroidism |journal=Hum. Genet. |volume=136 |issue=7 |pages=835–845 |year=2017 |pmid=28444561 |pmc=5487855 |doi=10.1007/s00439-017-1804-9 |url=}}</ref> | |||
*'''Congenital multisystem syndromes''' | |||
**'''[[DiGeorge syndrome]]'''<ref name="pmid21049214">{{cite journal |vauthors=Fomin AB, Pastorino AC, Kim CA, Pereira CA, Carneiro-Sampaio M, Abe-Jacob CM |title=DiGeorge Syndrome: a not so rare disease |journal=Clinics (Sao Paulo) |volume=65 |issue=9 |pages=865–9 |year=2010 |pmid=21049214 |pmc=2954737 |doi= |url=}}</ref> | |||
***[[Autosomal dominant inheritance]] pattern in present. | |||
***Presents with [[thymus]] [[dysfunction]], [[cardiac]] defects, [[immunodeficiency]], [[hypocalcemia]], and other clinical problems. | |||
***Caused by [[22q11.2 deletion syndrome|22q11.2 deletion]]. | |||
***Also known as [[22q11.2DS]], [[CATCH 22 syndrome]], [[Cayler cardiofacial syndrome]], [[conotruncal anomaly face syndrome]] ([[CTAF]]), [[deletion 22q11.2 syndrome]], [[Sedlackova syndrome]], [[Shprintzen syndrome]], VCFS, [[velocardiofacial syndrome]], and velo-cardio-facial syndrome. | |||
***[[CATCH 22 syndrome|CATCH 22]] stands for [[cardiac]] defects, abnormal facies, [[thymic]] [[aplasia]], [[cleft palate]], and [[hypocalcemia]] with [[22q11.2 deletion syndrome|22q11.2 deletion]]. | |||
**'''[[CHARGE syndrome]]'''<ref name="pmid21995344">{{cite journal |vauthors=Jain S, Kim HG, Lacbawan F, Meliciani I, Wenzel W, Kurth I, Sharma J, Schoeneman M, Ten S, Layman LC, Jacobson-Dickman E |title=Unique phenotype in a patient with CHARGE syndrome |journal=Int J Pediatr Endocrinol |volume=2011 |issue= |pages=11 |year=2011 |pmid=21995344 |pmc=3216247 |doi=10.1186/1687-9856-2011-11 |url=}}</ref> | |||
***[[Autosomal dominant inheritance]] pattern in present. | |||
***Presents with [[coloboma]], [[heart]] defects, [[Choanal atresia|atresia choanae]], retarded growth and development, [[Genitourinary pathology|genitourinary abnormalities]], and [[ear]] anomalies and/or [[deafness]]. | |||
***Caused by CHD7 G744S [[missense mutation]]. | |||
**'''Kenny-Caffey syndrome'''<ref name="pmid23087875">{{cite journal |vauthors=Metwalley KA, Farghaly HS |title=Kenny-Caffey syndrome type 1 in an Egyptian girl |journal=Indian J Endocrinol Metab |volume=16 |issue=5 |pages=827–9 |year=2012 |pmid=23087875 |pmc=3475915 |doi=10.4103/2230-8210.100645 |url=}}</ref> | |||
***[[Autosomal recessive|Autosomal recessive inheritance]] pattern in present. | |||
***Deletion of the [[TBCE]] gene responsible for encoding a protein that participates in beta-tubulin folding. | |||
***Presents with [[hypoparathyroidism]] due to absent parathyroid tissue, growth retardation, medullary stenosis of tubular bones. | |||
**'''Sanjad-Sakati syndrome'''<ref name="pmid22043344">{{cite journal |vauthors=Rafique B, Al-Yaarubi S |title=Sanjad-Sakati Syndrome in Omani children |journal=Oman Med J |volume=25 |issue=3 |pages=227–9 |year=2010 |pmid=22043344 |pmc=3191633 |doi=10.5001/omj.2010.63 |url=}}</ref> | |||
***Sanjad-Sakati syndrome in exclusively found in arabian descent population. | |||
***[[Autosomal recessive|Autosomal recessive inheritance]] pattern in present. | |||
***Mutation in [[TBCE]] gene. | |||
***Presents with hypoparathyroidism, [[intellectual disability]], [[Dysmorphic feature|dysmorphism]]. | |||
**'''[[Barakat syndrome]]'''<ref name="pmid11389161">{{cite journal |vauthors=Muroya K, Hasegawa T, Ito Y, Nagai T, Isotani H, Iwata Y, Yamamoto K, Fujimoto S, Seishu S, Fukushima Y, Hasegawa Y, Ogata T |title=GATA3 abnormalities and the phenotypic spectrum of HDR syndrome |journal=J. Med. Genet. |volume=38 |issue=6 |pages=374–80 |year=2001 |pmid=11389161 |pmc=1734904 |doi= |url=}}</ref><ref name="pmid10935639">{{cite journal |vauthors=Van Esch H, Groenen P, Nesbit MA, Schuffenhauer S, Lichtner P, Vanderlinden G, Harding B, Beetz R, Bilous RW, Holdaway I, Shaw NJ, Fryns JP, Van de Ven W, Thakker RV, Devriendt K |title=GATA3 haplo-insufficiency causes human HDR syndrome |journal=Nature |volume=406 |issue=6794 |pages=419–22 |year=2000 |pmid=10935639 |doi=10.1038/35019088 |url=}}</ref> | |||
***[[Autosomal recessive|Autosomal recessive inheritance]] pattern in present. | |||
***[[Mutation|Mutations]] in the [[GATA3]] gene | |||
***Also known as hypoparathyroidism, [[deafness]], and renal dysplasia (HDR) syndrome | |||
***Presents with primary hypoparathyroidism, nerve [[deafness]], steroid-resistant [[nephrosis]]. | |||
==Associated Conditions== | ==Associated Conditions== | ||
Revision as of 14:19, 26 September 2017
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Overview
The exact pathogenesis of [disease name] is not fully understood.
OR
It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
OR
[Pathogen name] is usually transmitted via the [transmission route] route to the human host.
OR
Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
OR
[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
OR
The progression to [disease name] usually involves the [molecular pathway].
OR
The pathophysiology of [disease/malignancy] depends on the histological subtype.
Pathophysiology
Parathyroid, Vitamin D, and mineral homeostasis
The effect of parathyroid hormone on mineral metabolism is as follows:[1][2]
- Effect of parathyroid hormone on inorganic phosphate metabolism:
- Increases excretion of inorganic phosphate from kidney resulting in decreased serum concentration of phosphate.
- Effect on parathyroid hormone on calcium metabolism:
- Direct effect:
- Increased resorption of bones.
- Decreases excretion from kidney.
- Indirect effect:
- Increases conversion of inactive 25-hydroxy vitamin D to the active 1,25-dihydroxy vitamin D which increases absorption of calcium from gut. Decreased phosphate concentration also increases this conversion process. Vitamin D shows synergism with parathyroid hormone action on bone.
- Decreased serum inorganic phosphate concentration prevents precipitation of calcium phosphate in bones.
- Both these direct and indirect mechanism results in an increased serum calcium concentration.
- Direct effect:
- Effect of parathyroid hormone on magnesium concentration:
Effect of minerals and vitamin D on parathyroid hormone:
- Decrease in serum calcium concentration stimulates parathyroid hormone.
- Calcium provides negative feedback on parathyroid hormone.
- Magnesium provides negative feedback on parathyroid hormone.
- Vitamin D decreases the concentration of parathyroid hormone.
The sequence of events is shown in the algorithm below:
| Parathyroid hormone | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Kidney | Bone | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Decreased excretion of magnesium | Increasead conversion of inactive 25-hydroyxvitamin D to the active 1,25-dihydroyxvitamin D | Increase excretion of inorganic phosphate | Decrease excretion of calcium | Increased resorption of bone | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Increased serum concentration of magnesium | Increased absorption of calcium from gut | Decreased serum concentration of inorganic phosphate | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prevents precipitation of calcium phosphate in bones | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Increased serum concentration of calcium | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Calcium-sensing receptors
- Calcium-sensing receptors are present on parathyroid glands. They are a type of 7-transmembrane receptors in G-protein coupled receptors superfamily of receptors.[3]
- Calcium-sensing receptors sense change in extracellular concentration of ionized calcium.[4]
Pathogenesis
- There is deficiency of parathyroid hormone in hypoparathyroidism.
- Deficiency of parathyroid hormone causes body to decrease:
- Reabsorption of calcium from bone
- Excretion of phosphate
- Reabsorbtion of calcium from distal tubules
- Vitamin D mediated absorption of calcium from intestine.
- This leads to hypocalcemia.
Post-surgical Hypoparathyroidism
Genetics
- Isolated hypoparathyroidism
- Autosomal dominant inheritence
- Autosomal dominant familial isolated hypoparathyroidism caused by PTH gene mutation[5]
- Autosomal dominant familial isolated hypoparathyroidism caused by glial cells missing 2 (GCM2) gene mutation[6]
- Autosomal dominant hypocalcemia[7]
- Autosomal dominant hypocalcemia type 1
- Calcium-sensing receptor gene activating mutation.
- Most common genetic form of hypoparathyroidism.
- Also known as familial hypercalciuric hypocalcemia.
- The activating mutation results in gain in function.
- Calcium-sensing receptor gene activating mutation can also cause Bartter syndrome type 5.This mutation cause the inhibition of apical potassium channel in the thick ascending limb of the loop of Henle in the kidney.[8][9]
- Autosomal dominant hypocalcemia type 2
- G protein G11 (GNA11) mutation.
- Autosomal dominant hypocalcemia type 1
- Autosomal recessive inheritence
- Autosomal recessive familial isolated hypoparathyroidism caused by PTH gene mutation[10]
- Autosomal recessive familial isolated hypoparathyroidism caused by glial cells missing 2 (GCM2) gene mutation[11][6]
- X-linked inheritence
- Autosomal dominant inheritence
- Congenital multisystem syndromes
- DiGeorge syndrome[13]
- Autosomal dominant inheritance pattern in present.
- Presents with thymus dysfunction, cardiac defects, immunodeficiency, hypocalcemia, and other clinical problems.
- Caused by 22q11.2 deletion.
- Also known as 22q11.2DS, CATCH 22 syndrome, Cayler cardiofacial syndrome, conotruncal anomaly face syndrome (CTAF), deletion 22q11.2 syndrome, Sedlackova syndrome, Shprintzen syndrome, VCFS, velocardiofacial syndrome, and velo-cardio-facial syndrome.
- CATCH 22 stands for cardiac defects, abnormal facies, thymic aplasia, cleft palate, and hypocalcemia with 22q11.2 deletion.
- CHARGE syndrome[14]
- Autosomal dominant inheritance pattern in present.
- Presents with coloboma, heart defects, atresia choanae, retarded growth and development, genitourinary abnormalities, and ear anomalies and/or deafness.
- Caused by CHD7 G744S missense mutation.
- Kenny-Caffey syndrome[15]
- Autosomal recessive inheritance pattern in present.
- Deletion of the TBCE gene responsible for encoding a protein that participates in beta-tubulin folding.
- Presents with hypoparathyroidism due to absent parathyroid tissue, growth retardation, medullary stenosis of tubular bones.
- Sanjad-Sakati syndrome[16]
- Sanjad-Sakati syndrome in exclusively found in arabian descent population.
- Autosomal recessive inheritance pattern in present.
- Mutation in TBCE gene.
- Presents with hypoparathyroidism, intellectual disability, dysmorphism.
- Barakat syndrome[17][18]
- DiGeorge syndrome[13]
Associated Conditions
Gross Pathology
- On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Microscopic Pathology
- On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
References
- ↑ HARRISON MT (1964). "INTERRELATIONSHIPS OF VITAMIN D AND PARATHYROID HORMONE IN CALCIUM HOMEOSTASIS". Postgrad Med J. 40: 497–505. PMC 2482768. PMID 14184232.
- ↑ Nussey, Stephen (2001). Endocrinology : an integrated approach. Oxford, UK Bethesda, Md: Bios NCBI. ISBN 1-85996-252-1.
- ↑ Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O; et al. (1993). "Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid". Nature. 366 (6455): 575–80. doi:10.1038/366575a0. PMID 8255296.
- ↑ Brown EM, Pollak M, Seidman CE, Seidman JG, Chou YH, Riccardi D; et al. (1995). "Calcium-ion-sensing cell-surface receptors". N Engl J Med. 333 (4): 234–40. doi:10.1056/NEJM199507273330407. PMID 7791841.
- ↑ Arnold A, Horst SA, Gardella TJ, Baba H, Levine MA, Kronenberg HM (1990). "Mutation of the signal peptide-encoding region of the preproparathyroid hormone gene in familial isolated hypoparathyroidism". J. Clin. Invest. 86 (4): 1084–7. doi:10.1172/JCI114811. PMC 296835. PMID 2212001.
- ↑ 6.0 6.1 Canaff L, Zhou X, Mosesova I, Cole DE, Hendy GN (2009). "Glial cells missing-2 (GCM2) transactivates the calcium-sensing receptor gene: effect of a dominant-negative GCM2 mutant associated with autosomal dominant hypoparathyroidism". Hum. Mutat. 30 (1): 85–92. doi:10.1002/humu.20827. PMID 18712808.
- ↑ Roszko KL, Bi RD, Mannstadt M (2016). "Autosomal Dominant Hypocalcemia (Hypoparathyroidism) Types 1 and 2". Front Physiol. 7: 458. doi:10.3389/fphys.2016.00458. PMC 5067375. PMID 27803672.
- ↑ Vezzoli G, Arcidiacono T, Paloschi V, Terranegra A, Biasion R, Weber G, Mora S, Syren ML, Coviello D, Cusi D, Bianchi G, Soldati L (2006). "Autosomal dominant hypocalcemia with mild type 5 Bartter syndrome". J. Nephrol. 19 (4): 525–8. PMID 17048213.
- ↑ Choi KH, Shin CH, Yang SW, Cheong HI (2015). "Autosomal dominant hypocalcemia with Bartter syndrome due to a novel activating mutation of calcium sensing receptor, Y829C". Korean J Pediatr. 58 (4): 148–53. doi:10.3345/kjp.2015.58.4.148. PMC 4414630. PMID 25932037.
- ↑ Sunthornthepvarakul T, Churesigaew S, Ngowngarmratana S (1999). "A novel mutation of the signal peptide of the preproparathyroid hormone gene associated with autosomal recessive familial isolated hypoparathyroidism". J. Clin. Endocrinol. Metab. 84 (10): 3792–6. doi:10.1210/jcem.84.10.6070. PMID 10523031.
- ↑ Ding C, Buckingham B, Levine MA (2001). "Familial isolated hypoparathyroidism caused by a mutation in the gene for the transcription factor GCMB". J. Clin. Invest. 108 (8): 1215–20. doi:10.1172/JCI13180. PMC 209530. PMID 11602629.
- ↑ Pillar N, Pleniceanu O, Fang M, Ziv L, Lahav E, Botchan S, Cheng L, Dekel B, Shomron N (2017). "A rare variant in the FHL1 gene associated with X-linked recessive hypoparathyroidism". Hum. Genet. 136 (7): 835–845. doi:10.1007/s00439-017-1804-9. PMC 5487855. PMID 28444561.
- ↑ Fomin AB, Pastorino AC, Kim CA, Pereira CA, Carneiro-Sampaio M, Abe-Jacob CM (2010). "DiGeorge Syndrome: a not so rare disease". Clinics (Sao Paulo). 65 (9): 865–9. PMC 2954737. PMID 21049214.
- ↑ Jain S, Kim HG, Lacbawan F, Meliciani I, Wenzel W, Kurth I, Sharma J, Schoeneman M, Ten S, Layman LC, Jacobson-Dickman E (2011). "Unique phenotype in a patient with CHARGE syndrome". Int J Pediatr Endocrinol. 2011: 11. doi:10.1186/1687-9856-2011-11. PMC 3216247. PMID 21995344.
- ↑ Metwalley KA, Farghaly HS (2012). "Kenny-Caffey syndrome type 1 in an Egyptian girl". Indian J Endocrinol Metab. 16 (5): 827–9. doi:10.4103/2230-8210.100645. PMC 3475915. PMID 23087875.
- ↑ Rafique B, Al-Yaarubi S (2010). "Sanjad-Sakati Syndrome in Omani children". Oman Med J. 25 (3): 227–9. doi:10.5001/omj.2010.63. PMC 3191633. PMID 22043344.
- ↑ Muroya K, Hasegawa T, Ito Y, Nagai T, Isotani H, Iwata Y, Yamamoto K, Fujimoto S, Seishu S, Fukushima Y, Hasegawa Y, Ogata T (2001). "GATA3 abnormalities and the phenotypic spectrum of HDR syndrome". J. Med. Genet. 38 (6): 374–80. PMC 1734904. PMID 11389161.
- ↑ Van Esch H, Groenen P, Nesbit MA, Schuffenhauer S, Lichtner P, Vanderlinden G, Harding B, Beetz R, Bilous RW, Holdaway I, Shaw NJ, Fryns JP, Van de Ven W, Thakker RV, Devriendt K (2000). "GATA3 haplo-insufficiency causes human HDR syndrome". Nature. 406 (6794): 419–22. doi:10.1038/35019088. PMID 10935639.