Pseudohypoparathyroidism

Types of pseudohypoparathyroidism (PHP) based on clinical features, parathyroid hormone (PTH) responsiveness, and genotype[2]Mantovani G, Bastepe M, Monk D, et al. Recommendations for diagnosis and treatment of pseudohypoparathyroidism and related disorders: an updated practical tool for physicians and patients. Horm Res Paediatr. 2020;93(3):182-96. https://www.doi.org/10.1159/000508985 http://www.ncbi.nlm.nih.gov/pubmed/32756064?tool=bestpractice.com [3]Spiegel AM, Weinstein LS. Pseudohypoparathyroidism. In: Scriver CR, Beaudet AL, Sly WS, et al, eds. The metabolic and molecular bases of inherited disease. 7th ed. New York, NY: McGraw-Hill; 1995:3073-89.[4]American Society for Bone and Mineral Research. Primer on the metabolic bone diseases and disorders of mineral metabolism. 9th ed. 2018 [internet publication]. http://www.asbmr.org/publications/primer/default.aspx

Type 1a:

• Caused by mutations in GNAS, the gene that codes for the guanine nucleotide-binding protein (G-protein) Gs-alpha

• Associated Albright's hereditary osteodystrophy

• Decreased response to exogenous PTH as measured by urine cyclic adenosine monophosphate (cAMP) and urine phosphorus

• Serum calcium is low

• Hormone resistance is generalised (affecting any hormone that relies on Gs-alpha signalling)

• Autosomal dominant inheritance; linked to maternal allele.

Type 1b:

• Caused by mutations in GNAS

• No associated skeletal phenotype

• Decreased response to exogenous PTH as measured by urine cAMP and urine phosphorus

• Serum calcium is low

• Hormone resistance is limited to PTH target tissue; however, there are an increasing number of cases associated with thyroid-stimulating hormone resistance

• Inheritance is sporadic.

Type 1c:

• Normal Gs-alpha activity together with the absence of GNAS mutations are the hallmarks of type 1c.[6]Mantovani G. Pseudohypoparathyroidism: diagnosis and treatment. J Clin Endocrinol Metab. 2011 Oct;96(10):3020-30. http://www.ncbi.nlm.nih.gov/pubmed/21816789?tool=bestpractice.com However, two nonsense and two missense mutations in the GNAS carboxy terminus have been detected in a few type 1c patients[6]Mantovani G. Pseudohypoparathyroidism: diagnosis and treatment. J Clin Endocrinol Metab. 2011 Oct;96(10):3020-30. http://www.ncbi.nlm.nih.gov/pubmed/21816789?tool=bestpractice.com [7]Thiele S, de Sanctis L, Werner R, et al. Functional characterization of GNAS mutations found in patients with pseudohypoparathyroidism type Ic defines a new subgroup of pseudohypoparathyroidism affecting selectively Gsα-receptor interaction. Hum Mutat. 2011 Jun;32(6):653-60. http://www.ncbi.nlm.nih.gov/pubmed/21488135?tool=bestpractice.com [8]Al-Salameh A, Despert F, Kottler ML, et al. Resistance to epinephrine and hypersensitivity (hyperresponsiveness) to CB1 antagonists in a patient with pseudohypoparathyroidism type Ic. Eur J Endocrinol. 2010 Apr;162(4):819-24. http://www.ncbi.nlm.nih.gov/pubmed/20075145?tool=bestpractice.com

• Associated Albright's hereditary osteodystrophy

• Decreased response to exogenous PTH as measured by urine cAMP and urine phosphorus

• Serum calcium is low

• Hormone resistance is generalised (affecting any hormone that relies on Gs-alpha signalling)

• Inheritance similar to type 1a (i.e., autosomal dominant, linked to maternal allele).

Type 2:

• Underlying genetic mutation is unknown

• No associated skeletal phenotype

• Complex response to exogenous PTH; urine phosphorus response is decreased but urine cAMP response is normal

• Serum calcium is low

• Hormone resistance is limited to PTH target tissue

• Inheritance is unknown.

Pseudo-pseudohypoparathyroidism:

• Caused by mutations in GNAS

• Associated Albright's hereditary osteodystrophy

• Normal response to exogenous PTH as measured by urine cAMP and urine phosphorus

• Serum calcium is normal

• There is no hormone resistance

• Autosomal dominant inheritance, linked to paternal allele.