Pseudohypoparathyroidism

• Imprinting disorders (PAP)
  • Pseudohypoparathyroidism
  • Angelman syndrome (AS)
  • Prader–Willi syndrome

• Pathology: 
  • tissue resistance to the effects of PTH 
  • The PTH receptor itself is normal but the downstream signaling pathways are defective due to GNAS1 mutations
  • PTH level elevated

• When the GNAS1 mutation is inherited on the maternal chromosome.

( pseudohypoparathyroidism type 1a / Albright’s hereditary osteodystrophy (AHO).

• hypocalcaemia, hyperphosphatemia, raised PTH levels

• short stature, short fourth metacarpals and metatarsals, 

• rounded face, obesity, delayed puberty 

• ectopic calcification: subcutaneous, basal ganglion 

• When the GNAS1 mutation is inherited on the paternal chromosome

               ( pseudopseudohypoparathyroidism) 

• patients have clinical features of AHO but normal serum calcium and PTH level 

• Facts: The difference in clinical features occurs as a result of the fact that renal cells exclusively express the maternal GNAS1 allele, whereas both maternal and paternal alleles are expressed in other cell types; this explains why maternal inheritance is associated with hypocalcemia and resistance to PTH (which regulates serum calcium and phosphate levels largely by an effect on the renal tubule), and why paternal inheritance is associated with skeletal and other abnormalities in the absence of hypocalcaemia and raised PTH values.

Investigation:

Management: 

• Oral calcium salts and vitamin D analogues: 
  • to maintain blood calcium levels within the normal range and PTH levels in the upper end of normal or slightly elevated.
  • careful monitoring: risks of iatrogenic hypercalcaemia, hypercalciuria and nephrocalcinosis. 
• Recombinant PTH SC injection:  no role (used i hypoparathyroidism)