Why is urinary cyclic adenosine monophosphate (cAMP) defective in Pseudohypoparathyroidism type 1 (PHP1) and normal in Pseudohypoparathyroidism type 2 (PHP2)?

Differences in Urinary cAMP Response Between Pseudohypoparathyroidism Type 1 and Type 2

In pseudohypoparathyroidism type 1 (PHP1), urinary cyclic adenosine monophosphate (cAMP) excretion is defective in response to parathyroid hormone (PTH), while in pseudohypoparathyroidism type 2 (PHP2), urinary cAMP response is normal despite PTH resistance. This key difference reflects their distinct molecular pathophysiology.

Molecular Basis of the Difference

• PHP1 is characterized by a defect in the Gsα-adenylyl cyclase pathway, specifically involving mutations or epigenetic alterations in GNAS, which encodes the α subunit of the stimulatory G protein (Gsα) 1
• In PHP1, the defective Gsα protein fails to properly activate adenylyl cyclase, preventing the normal production of cAMP in response to PTH binding to its receptor 2
• This molecular defect results in the inability to increase urinary cAMP excretion following PTH administration, which serves as a diagnostic marker for PHP1 2
• PHP2, in contrast, has a normal Gsα-adenylyl cyclase system that produces appropriate cAMP in response to PTH, but has a defect in the post-cAMP signaling pathway 3

Diagnostic Implications

• Urinary cAMP excretion testing in response to PTH infusion is a sensitive and accurate diagnostic tool for differentiating between PHP1 and PHP2 2
• In PHP1 patients, PTH infusion fails to increase urinary cAMP excretion despite elevated circulating PTH levels 2
• In PHP2 patients, PTH infusion produces a normal increase in urinary cAMP excretion, but the phosphaturic response remains impaired 3
• The basal excretion of cAMP is typically lower than normal in hypocalcemic disorders including both types of PHP 2

Genetic and Inheritance Patterns

• PHP1 is associated with inherited mutations in the GNAS gene, with variable expression depending on parental origin of the affected allele 4, 5
• Patients with PHP1 show partial deficiency of the receptor-cyclase coupling protein (N protein) in blood cells, often associated with Albright's hereditary osteodystrophy 5
• Some family members of PHP1 patients may have deficient N protein activity but normal urinary cAMP responses to PTH, a condition sometimes called pseudo-pseudohypoparathyroidism 4, 5
• PHP2 has less clearly defined genetic underpinnings but appears to involve defects downstream of cAMP production 3

Clinical Relevance

• The distinction between PHP1 and PHP2 based on urinary cAMP response helps guide genetic testing and counseling for patients and families 1
• PHP1 often presents with additional hormone resistance patterns beyond PTH, including TSH resistance, due to the broader role of Gsα in multiple hormone signaling pathways 5
• PHP2 typically presents with isolated PTH resistance affecting phosphate excretion 3
• Understanding the specific defect helps predict potential involvement of other hormone systems and guides monitoring for additional endocrine abnormalities 1

Treatment Considerations

• In PHP2, calcium channel blockers may enhance the phosphaturic response to PTH, suggesting a role for intracellular calcium in the pathophysiology 3
• Treatment with vitamin D analogs (e.g., 1α(OH)D3) can improve phosphaturic response in PHP2 patients 3
• Management of both conditions focuses on normalizing calcium levels, but the underlying molecular differences may eventually lead to targeted therapeutic approaches 1