Pseudohypoparathyroidism pathophysiology

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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

Pseudohypoparathyroidism is characterized by end-organ resistance to parathyroid hormone.^[1]^[2]
Parathyroid hormone (PTH) 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 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 adenyl cyclase that results in resistance of target tissues to parathyroid hormone evidenced by hypocalcemia and hyperphosphatemia, in the presence of high plasma PTH level.
Blomstrand's chondrodystrophy is lethal in the prenatal period characterized by abnormal endochondral bone formation with prematurely occurring mineralization of the cartilaginous bone templates.
Patients with acrodysostosis have:
- Resistance to parathyroid hormone
- Resistance to thyroid-stimulating hormone
- Resistance to growth hormone releasing hormone

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 Gα_s	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
	Pseudohypoparathyroidism Type 1b	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	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

↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.

Template:WikiDoc Sources

[pmid17986833-1] 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.

[pmid4309802-2] 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.

[pmid23076042-3] 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.

[pmid21816789-4] 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.

[pmid25891861-5] 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.

[pmid9649554-6] 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.

[pmid22464250-7] 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.

[pmid21651393-8] 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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