Pseudopseudohypoparathyroidism (pseudoPHP) is an inherited disorder, named for its similarity to pseudohypoparathyroidism in presentation. The term pseudopseudohypoparathyroidism is used to describe a condition where the individual has the phenotypic appearance of pseudohypoparathyroidism type 1a, but is biochemically normal.
Hormone resistance is not present in pseudopseudohypoparathyroidism.Short stature may be present.Obesity is less common in pseudopseudohypoparathyroidism than in pseudohypoparathyroidism.Osteoma cutis may be present.
The GNAS1 gene involved in both pseudohypoparathyroidism type 1a and pseudopseudohypoparathyroidism is greatly affected by imprinting. When a father who has pseudohypoparathyroidism undergoes spermatogenesis, imprinting of the GNAS1 gene inactivates both copies of his genes, including the defective one. The seemingly contradictory presentation of symptoms can be explained by the fact that most tissues in the body (e.g., bone) reactivate the GNAS1 copy, whereas the kidneys do not. Thus, the result is haploinsufficiency of the GNAS1 product in most tissues, giving the phenotype of pseudohypoparathyroidism type 1a. In the kidneys, however, the paternally-derived gene remains imprinted and inactive, leaving only the non-imprinted maternally-derived gene. As a result, as long as the maternally-derived GNAS1 gene is functional, renal handling of calcium and phosphate is normal, and homeostasis is maintained.
A male with pseudohypoparathyroidism has a 50% chance of passing on the defective GNAS gene to his children, although in an imprinted, inactive form. Any of his children receiving this gene will have pseudopseudohypoparathyroidism. Any of his daughters that have pseudopseudohypoparathyroidism may in turn pass along pseudohypoparathyroidism 1A to her children as the imprinting pattern on the inherited paternal gene will be changed to the maternal pattern in the mother's ovum during meiosis. The gene will be reactivated in any children who inherit it.
Pseudopseudohypoparathyroidism and pseudohypoparathyroidism both involve the same GNAS gene, but pseudopseudohypoparathyroidism has normal calcium homeostasis because of the normal maternal allele in the kidney.