Pseudohypoparathyroidism pathophysiology: Difference between revisions

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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 during the prenatal period and is 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]].
Pseudohypoparathyroidism is characterized by end-organ resistance to [[parathyroid hormone]]. [[Gene mutation]] results in failure of signal transduction. [[Chondrodystrophy|Blomstrand's chondrodystrophy]] results in [[intrauterine death]] and is 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==
==Pathogenesis==
*Pseudohypoparathyroidism is characterized by end organ resistance to [[parathyroid hormone]].  
*Pseudohypoparathyroidism is characterized by end-organ resistance to [[parathyroid hormone]].<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><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> 
*[[Parathyroid hormone|Parathyroid hormone(PTH)]]<nowiki/>effect is mediated by the [[PTH receptor 1|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>
*[[Parathyroid hormone|Parathyroid hormone (PTH)]] <nowiki/>effect is mediated by the [[PTH receptor 1|parathyroid hormone receptor type 1]], which acts on a stimulatory [[Gs alpha subunit|guanine-nucleotide–binding (Gs) protein]], which is composed of three subunits (α, β, and γ). The [[GNAS1]] gene encodes Gs-α subunit that mediates [[cyclic AMP]] stimulation by [[parathyroid hormone]] and by several other [[peptide hormones]], including [[thyrotropin]].
*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>
*[[Gene mutation]] results in failure of signal transduction through [[Gs alpha subunit|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.
*Blomstrand's Chondrodystrophy is lethal in the prenatal period characterized by abnormal [[Endochondral ossification|endochondral]] bone formation with prematurely occurring [[mineralization]] of the [[cartilaginous]] bone templates.
*Blomstrand's chondrodystrophy is lethal in the [[prenatal]] period characterized by abnormal [[Endochondral ossification|endochondral]] bone formation with prematurely occurring [[mineralization]] of the [[cartilaginous]] bone templates.
*Patients with acrodysostosis have:
*Patients with [[acrodysostosis]] have:
*Resistance to [[parathyroid hormone]]  
**Resistance to [[parathyroid hormone]]  
*Resistance to [[thyroid-stimulating hormone]]  
**Resistance to [[thyroid-stimulating hormone]]  
*Resistance to [[Growth hormone releasing hormone]].
**Resistance to [[growth hormone releasing hormone]]
 
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>
== Genetics ==
{| class="wikitable"
[[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>
! colspan="2" |Type of pseudohyoparathyroidism
 
!Molecular Defect
{|
!Origin Of Mutation
! colspan="2" style="background: #4479BA; text-align: center;" |{{fontcolor|#FFF|Type of Pseudohyoparathyroidism}}
!Inheritence
! style="background: #4479BA; text-align: center;" |{{fontcolor|#FFF|Molecular Defect}}
! style="background: #4479BA; text-align: center;" |{{fontcolor|#FFF|Origin Of Mutation}}
! style="background: #4479BA; text-align: center;" |{{fontcolor|#FFF|Inheritance}}
|-
|-
| rowspan="4" |Pseudohypoparathyroidism type I
| rowspan="5" style="padding: 5px 5px; background: #DCDCDC;" align="center" |'''[[Pseudohypoparathyroidism]] type I'''
|Type 1a
| style="padding: 5px 5px; background: #DCDCDC;" align="center" |'''[[Pseudohypoparathyroidism]] Type 1a'''
|[[Heterozygous]] ''[[GNAS1|GNAS]]'' inactivating mutations that reduce expression or function of Gα<sub>s</sub>
| style="padding: 5px 5px; background: #F5F5F5;" |[[Heterozygous]] ''[[GNAS1|GNAS]]'' inactivating [[mutations]] that reduce expression or function of Gα<sub>s</sub>
|Maternal   
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |Maternal   
|[[Autosomal dominant]]  
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[Autosomal dominant]]  
|-
|-
| rowspan="2" |Type 1b
| rowspan="2" style="padding: 5px 5px; background: #DCDCDC;" align="center" |'''[[Pseudohypoparathyroidism]] Type 1b'''
|[[Familial]]- [[heterozygous]] deletions in ''[[STX16|STX]]16'', NESP55, and/or AS exons or loss of [[methylation]] at ''[[GNAS1|GNAS]]''
| style="padding: 5px 5px; background: #F5F5F5;" |[[Familial]]- [[heterozygous]] deletions in ''[[STX16|STX]]16'', NESP55, and/or AS [[exons]] or loss of [[methylation]] at ''[[GNAS1|GNAS]]''
|Maternal
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |Maternal
|[[Autosomal dominant]]  
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[Autosomal dominant]]  
|-
|-
|Sporadic- paternal [[Uniparental disomy]] of chromosome 20q in some or [[methylation]] defect affecting all four ''[[GNAS1|GNAS]]'' DMRs
| style="padding: 5px 5px; background: #F5F5F5;" |Sporadic- paternal [[Uniparental disomy]] of [[chromosome]] 20q in some or [[methylation]] defect affecting all four ''[[GNAS1|GNAS]]'' DMRs
|Maternal
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |Maternal
|[[Genomic imprinting]]
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[Genomic imprinting]]
|-
|-
|Type 1c
| style="padding: 5px 5px; background: #DCDCDC;" align="center" |'''[[Pseudohypoparathyroidism]] Type 1c'''
|[[Heterozygous]] ''[[GNAS1|GNAS]]'' inactivating mutations that reduce expression or function of Gα<sub>s</sub>
| style="padding: 5px 5px; background: #F5F5F5;" |[[Heterozygous]] ''[[GNAS1|GNAS]]'' inactivating [[mutations]]
|Maternal
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |Maternal
|[[Autosomal dominant]]  
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[Autosomal dominant]]  
|-
|-
| colspan="2" |Pseudopseudohypoparathyroidism
| style="padding: 5px 5px; background: #DCDCDC;" align="center" |'''[[Pseudopseudohypoparathyroidism]]'''
|Combination of inactivating mutations of ''[[GNAS1]]'' and [[Albright's hereditary osteodystrophy|Albright's osteodystrophy]]
| style="padding: 5px 5px; background: #F5F5F5;" |Combination of inactivating [[mutations]] of ''[[GNAS1]]'' and [[Albright's hereditary osteodystrophy|Albright's osteodystrophy]]
|Paternal 
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |Paternal
|[[Genomic imprinting]]
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[Genomic imprinting]]
|-
|-
| colspan="2" |Pseudohypoparathyroidism type II
| colspan="2" style="padding: 5px 5px; background: #DCDCDC;" align="center" |'''[[Pseudohypoparathyroidism]] type II'''
|Insufficient data to suggest genetic or familial source
| style="padding: 5px 5px; background: #F5F5F5;" |Insufficient data to suggest [[genetic]] or familial source
|N/A
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |N/A
|N/A
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |N/A
|-
|-
| colspan="2" |Blomstrand chondrodysplasia
| colspan="2" style="padding: 5px 5px; background: #DCDCDC;" align="center" |'''Blomstrand chondrodysplasia'''
|Homozygous or heterozygous mutations in both alleles encoding the type 1 parathyroid hormone receptor
| style="padding: 5px 5px; background: #F5F5F5;" |[[Homozygous]] or [[Heterozygous|heterozygous mutations]] in both [[alleles]] encoding the type 1 [[parathyroid hormone]] receptor
|N/A
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |N/A
|[[Autosomal recessive]]
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[Autosomal recessive]]
|-
|-
| colspan="2" |Acrodysostosis type 1
| rowspan="2" style="padding: 5px 5px; background: #DCDCDC;" align="center" |[[Acrodysostosis|'''Acrodysostosis''']]
|''PRKAR1A'' germ-line mutation in the encoding gene
| style="padding: 5px 5px; background: #DCDCDC;" align="center" |[[Acrodysostosis|'''Acrodysostosis''']] '''type 1'''
|N/A
| style="padding: 5px 5px; background: #F5F5F5;" |''PRKAR1A'' [[germ-line]] [[mutation]] in the encoding [[gene]]
|[[Autosomal dominant]]
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |N/A
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[Autosomal dominant]]
|-
|-
| colspan="2" |Acrodysostosis type 2 
| style="padding: 5px 5px; background: #DCDCDC;" align="center" |[[Acrodysostosis|'''Acrodysostosis''']] '''type 2''' 
|''Phosphodiesterase 4D (PDE4D) gene'' 
| style="padding: 5px 5px; background: #F5F5F5;" |[[Phosphodiesterase]] 4D (PDE4D) [[gene]] 
|N/A
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |N/A
|[[Autosomal dominant]]
| style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[Autosomal dominant]]
|}
|}
==Gross Pathology==
On gross pathology, enlarged [[Parathyroid gland|parathyroid glands]] occur as a result of associated [[hypocalcemia]].
==Microscopic Pathology==
On microscopic histopathological analysis, secondary [[hyperplasia]] of the [[Parathyroid gland|parathyroid glands]] occurs as a result of associated [[hypocalcemia]].


==References==
==References==

Latest revision as of 18:39, 20 October 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 results in intrauterine death and is 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.

Pathogenesis

Genetics

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

Type of Pseudohyoparathyroidism Molecular Defect Origin Of Mutation Inheritance
Pseudohypoparathyroidism type I Pseudohypoparathyroidism Type 1a Heterozygous GNAS inactivating mutations that reduce expression or function of Gαs Maternal Autosomal dominant
Pseudohypoparathyroidism 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
Pseudohypoparathyroidism Type 1c Heterozygous GNAS inactivating mutations 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 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

Gross Pathology

On gross pathology, enlarged parathyroid glands occur as a result of associated hypocalcemia.

Microscopic Pathology

On microscopic histopathological analysis, secondary hyperplasia of the parathyroid glands occurs as a result of associated hypocalcemia.


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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