Pseudohypoparathyroidism pathophysiology: Difference between revisions

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{{Pseudohypoparathyroidism}}
{{Pseudohypoparathyroidism}}
{{CMG}}; {{AE}}
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==Overview==
==Overview==
Pseudohypoparathyroidism is characterized by end organ resistance to [[parathyroid hormone]].Gene mutation results in failure of signal transduction.Blomstrand's Chondrodystrophy is lethal prenatally characterized by abnormal [[Endochondral ossification|endochondral]] bone formation with prematurely occurring [[mineralization]] of the [[cartilaginous]] bone templates.Acrodysostosis patients have resistance to [[parathormone]] with normal [[calcium]] and [[phosphorus]], in addition to resistance [[thyroid-stimulating hormone]] and [[growth hormone releasing hormone]].


==Pathophysiology==
==Pathophysiology==
The parathyroid glands help control calcium use and removal by the body. They do this by producing parathyroid hormone, or PTH. PTH helps control calcium, phosphorus, and vitamin D levels within the blood and bone.
*Pseudohypoparathyroidism is characterized by end organ resistance to [[parathyroid hormone]].
 
*[[Parathyroid hormone]] effect is mediated by the [[parathyroid hormone receptor type 1]], which acts on a stimulatory [[guanine-nucleotide–binding (Gs) protein]], which is composed of three subunits (α, β, and γ). The [[GNAS1]] gene encodes Gsα subunit that mediates [[cyclic AMP]] stimulation by [[parathyroid hormone]] and by several other peptide hormones, including [[thyrotropin]].<ref name="pmid17986833">{{cite journal |vauthors=Spiegel AM |title=Inherited endocrine diseases involving G proteins and G protein-coupled receptors |journal=Endocr Dev |volume=11 |issue= |pages=133–44 |year=2007 |pmid=17986833 |doi=10.1159/0000111069 |url=}}</ref>
Persons with pseudohypoparathyroidism produce the right amount of PTH, but the body is "resistant" to its effect. This causes low blood calcium levels and high blood phosphate levels.
*Gene mutation results in failure of signal transduction through  Gsα inability to activate [[Adenylate cyclase|adenyl cyclase]] that results in resistance of target tissues to [[parathyroid hormone]] evidenced by [[hypocalcemia]] and [[hyperphosphatemia]], in the presence of high plasma [[Parathyroid hormone|PTH]] level.<ref name="pmid4309802">{{cite journal |vauthors=Chase LR, Melson GL, Aurbach GD |title=Pseudohypoparathyroidism: defective excretion of 3',5'-AMP in response to parathyroid hormone |journal=J. Clin. Invest. |volume=48 |issue=10 |pages=1832–44 |year=1969 |pmid=4309802 |pmc=322419 |doi=10.1172/JCI106149 |url=}}</ref>
 
*Blomstrand's Chondrodystrophy is lethal prenatally characterized by abnormal [[Endochondral ossification|endochondral]] bone formation with prematurely occurring [[mineralization]] of the [[cartilaginous]] bone templates.
Pseudohypoparathyroidism is caused by abnormal genes. All forms of pseudohypoparathyroidism are very rare.
*Acrodysostosis patients have resistance to [[parathormone]] with normal [[calcium]] and [[phosphorus]], in addition to resistance [[thyroid-stimulating hormone]] and [[growth hormone releasing hormone]].
 
Type Ia is inherited in an autosomal dominant manner. That means only one parent needs to pass you the defective gene in order for you to develop the condition. The condition causes short stature, round face, and short hand bones, and is also called Albright's hereditary osteodystrophy.
Genetic mutations associated with parathyroid hormone resistance are discussed below <ref name="pmid23076042">{{cite journal |vauthors=Levine MA |title=An update on the clinical and molecular characteristics of pseudohypoparathyroidism |journal=Curr Opin Endocrinol Diabetes Obes |volume=19 |issue=6 |pages=443–51 |year=2012 |pmid=23076042 |pmc=3679535 |doi=10.1097/MED.0b013e32835a255c |url=}}</ref><ref name="pmid21816789">{{cite journal |vauthors=Mantovani G |title=Clinical review: Pseudohypoparathyroidism: diagnosis and treatment |journal=J. Clin. Endocrinol. Metab. |volume=96 |issue=10 |pages=3020–30 |year=2011 |pmid=21816789 |doi=10.1210/jc.2011-1048 |url=}}</ref><ref name="pmid25891861">{{cite journal |vauthors=Lee S, Mannstadt M, Guo J, Kim SM, Yi HS, Khatri A, Dean T, Okazaki M, Gardella TJ, Jüppner H |title=A Homozygous [Cys25]PTH(1-84) Mutation That Impairs PTH/PTHrP Receptor Activation Defines a Novel Form of Hypoparathyroidism |journal=J. Bone Miner. Res. |volume=30 |issue=10 |pages=1803–13 |year=2015 |pmid=25891861 |pmc=4580526 |doi=10.1002/jbmr.2532 |url=}}</ref><ref name="pmid9649554">{{cite journal |vauthors=Jobert AS, Zhang P, Couvineau A, Bonaventure J, Roume J, Le Merrer M, Silve C |title=Absence of functional receptors for parathyroid hormone and parathyroid hormone-related peptide in Blomstrand chondrodysplasia |journal=J. Clin. Invest. |volume=102 |issue=1 |pages=34–40 |year=1998 |pmid=9649554 |pmc=509062 |doi=10.1172/JCI2918 |url=}}</ref><ref name="pmid22464250">{{cite journal |vauthors=Michot C, Le Goff C, Goldenberg A, Abhyankar A, Klein C, Kinning E, Guerrot AM, Flahaut P, Duncombe A, Baujat G, Lyonnet S, Thalassinos C, Nitschke P, Casanova JL, Le Merrer M, Munnich A, Cormier-Daire V |title=Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis |journal=Am. J. Hum. Genet. |volume=90 |issue=4 |pages=740–5 |year=2012 |pmid=22464250 |pmc=3322219 |doi=10.1016/j.ajhg.2012.03.003 |url=}}</ref><ref name="pmid21651393">{{cite journal |vauthors=Linglart A, Menguy C, Couvineau A, Auzan C, Gunes Y, Cancel M, Motte E, Pinto G, Chanson P, Bougnères P, Clauser E, Silve C |title=Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance |journal=N. Engl. J. Med. |volume=364 |issue=23 |pages=2218–26 |year=2011 |pmid=21651393 |doi=10.1056/NEJMoa1012717 |url=}}</ref>
 
{| class="wikitable"
Type Ib involves resistance to PTH only in the kidneys. Type Ib is less understood than type Ia. Type II is very similar to type I in its clinical features, but the events that take place in the kidneys are different.
! colspan="2" |Type of pseudohyoparathyroidism
 
!Molecular Defect
Type II pseudohypoparathyroidism also involves low blood calcium and high blood phosphate levels, but persons with this form do not develop the physical characteristics seen in those with Type Ia.
!Origin Of Mutation
 
!Inheritence
All forms of pseudohypoparathyroidism are very rare.
|-
| rowspan="4" |Pseudohypoparathyroidism type I
|Type 1a
|[[Heterozygous]] ''[[GNAS1|GNAS]]'' inactivating mutations that reduce expression or function of Gα<sub>s</sub>
|Maternal 
|[[Autosomal dominant]]
|-
| rowspan="2" |Type 1b
|[[Familial]]- [[heterozygous]] deletions in ''[[STX16|STX]]16'', NESP55, and/or AS exons or loss of [[methylation]] at ''[[GNAS1|GNAS]]''
|Maternal
|[[Autosomal dominant]]
|-
|Sporadic- paternal [[Uniparental disomy]] of chromosome 20q in some or [[methylation]] defect affecting all four ''[[GNAS1|GNAS]]'' DMRs
|Maternal
|[[Genomic imprinting]]
|-
|Type 1c
|[[Heterozygous]] ''[[GNAS1|GNAS]]'' inactivating mutations that reduce expression or function of Gα<sub>s</sub>
|Maternal
|[[Autosomal dominant]]
|-
| colspan="2" |Pseudopseudohypoparathyroidism
|Combination of inactivating mutations of ''[[GNAS1]]'' and [[Albright's hereditary osteodystrophy|Albright's osteodystrophy]]
|Paternal 
|[[Genomic imprinting]]
|-
| colspan="2" |Pseudohypoparathyroidism type II
|Insufficient data to suggest genetic or familial source
|N/A
|N/A
|-
| colspan="2" |Blomstrand chondrodysplasia
|Homozygous or heterozygous mutations in both alleles encoding the type 1 parathyroid hormone receptor
|N/A
|[[Autosomal recessive]]
|-
| colspan="2" |Acrodysostosis type 1
|''PRKAR1A'' germ-line mutation in the encoding gene
|N/A
|[[Autosomal dominant]]
|-
| colspan="2" |Acrodysostosis type 2 
|''Phosphodiesterase 4D (PDE4D) gene'' 
|N/A
|[[Autosomal dominant]]
|}
==References==
==References==
{{Reflist|2}}
{{Reflist|2}}

Revision as of 19:27, 28 September 2017

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mazia Fatima, MBBS [2]

Overview

Pseudohypoparathyroidism is characterized by end organ resistance to parathyroid hormone.Gene mutation results in failure of signal transduction.Blomstrand's Chondrodystrophy is lethal prenatally characterized by abnormal endochondral bone formation with prematurely occurring mineralization of the cartilaginous bone templates.Acrodysostosis patients have resistance to parathormone with normal calcium and phosphorus, in addition to resistance thyroid-stimulating hormone and growth hormone releasing hormone.

Pathophysiology

Genetic mutations associated with parathyroid hormone resistance are discussed below [3][4][5][6][7][8]

Type of pseudohyoparathyroidism Molecular Defect Origin Of Mutation Inheritence
Pseudohypoparathyroidism type I Type 1a Heterozygous GNAS inactivating mutations that reduce expression or function of Gαs Maternal Autosomal dominant
Type 1b Familial- heterozygous deletions in STX16, NESP55, and/or AS exons or loss of methylation at GNAS Maternal Autosomal dominant
Sporadic- paternal Uniparental disomy of chromosome 20q in some or methylation defect affecting all four GNAS DMRs Maternal Genomic imprinting
Type 1c Heterozygous GNAS inactivating mutations that reduce expression or function of Gαs Maternal Autosomal dominant
Pseudopseudohypoparathyroidism Combination of inactivating mutations of GNAS1 and Albright's osteodystrophy Paternal  Genomic imprinting
Pseudohypoparathyroidism type II Insufficient data to suggest genetic or familial source N/A N/A
Blomstrand chondrodysplasia Homozygous or heterozygous mutations in both alleles encoding the type 1 parathyroid hormone receptor N/A Autosomal recessive
Acrodysostosis type 1 PRKAR1A germ-line mutation in the encoding gene N/A Autosomal dominant
Acrodysostosis type 2  Phosphodiesterase 4D (PDE4D) gene  N/A Autosomal dominant

References

  1. ↑ Spiegel AM (2007). "Inherited endocrine diseases involving G proteins and G protein-coupled receptors". Endocr Dev. 11: 133–44. doi:10.1159/0000111069. PMID 17986833.
  2. ↑ Chase LR, Melson GL, Aurbach GD (1969). "Pseudohypoparathyroidism: defective excretion of 3',5'-AMP in response to parathyroid hormone". J. Clin. Invest. 48 (10): 1832–44. doi:10.1172/JCI106149. PMC 322419. PMID 4309802.
  3. ↑ Levine MA (2012). "An update on the clinical and molecular characteristics of pseudohypoparathyroidism". Curr Opin Endocrinol Diabetes Obes. 19 (6): 443–51. doi:10.1097/MED.0b013e32835a255c. PMC 3679535. PMID 23076042.
  4. ↑ Mantovani G (2011). "Clinical review: Pseudohypoparathyroidism: diagnosis and treatment". J. Clin. Endocrinol. Metab. 96 (10): 3020–30. doi:10.1210/jc.2011-1048. PMID 21816789.
  5. ↑ Lee S, Mannstadt M, Guo J, Kim SM, Yi HS, Khatri A, Dean T, Okazaki M, Gardella TJ, Jüppner H (2015). "A Homozygous [Cys25]PTH(1-84) Mutation That Impairs PTH/PTHrP Receptor Activation Defines a Novel Form of Hypoparathyroidism". J. Bone Miner. Res. 30 (10): 1803–13. doi:10.1002/jbmr.2532. PMC 4580526. PMID 25891861.
  6. ↑ Jobert AS, Zhang P, Couvineau A, Bonaventure J, Roume J, Le Merrer M, Silve C (1998). "Absence of functional receptors for parathyroid hormone and parathyroid hormone-related peptide in Blomstrand chondrodysplasia". J. Clin. Invest. 102 (1): 34–40. doi:10.1172/JCI2918. PMC 509062. PMID 9649554.
  7. ↑ Michot C, Le Goff C, Goldenberg A, Abhyankar A, Klein C, Kinning E, Guerrot AM, Flahaut P, Duncombe A, Baujat G, Lyonnet S, Thalassinos C, Nitschke P, Casanova JL, Le Merrer M, Munnich A, Cormier-Daire V (2012). "Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis". Am. J. Hum. Genet. 90 (4): 740–5. doi:10.1016/j.ajhg.2012.03.003. PMC 3322219. PMID 22464250.
  8. ↑ Linglart A, Menguy C, Couvineau A, Auzan C, Gunes Y, Cancel M, Motte E, Pinto G, Chanson P, Bougnères P, Clauser E, Silve C (2011). "Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance". N. Engl. J. Med. 364 (23): 2218–26. doi:10.1056/NEJMoa1012717. PMID 21651393.


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