Pseudopseudohypoparathyroidism, also known as pseudoPHP or PPHP, is a rare inherited disorder caused by an abnormal response to the parathyroid hormone. A variety of mutations in a gene located on the twentieth chromosome can result in this disease. Patients with pseudoPHP typically develop Albright's hereditary osteodystrophy (AHO), which causes abnormalities in bone structure and physical appearance. Unlike patients with pseudohypoparathyroidism (PHP), those with pseudoPHP do not have abnormalities in their blood levels of the minerals calcium and phosphorus.
Mutations in a gene called guanine nucleotide-binding protein alpha-stimulating activity polypeptide 1 (GNAS-1) are responsible for causing pseudopseudohypoparathyroidism. Different families suffering from the disease have displayed different specific mutations within this gene. As a result of the altered deoxyribonucleic acid (DNA) sequence of GNAS-1, there is an abnormal cellular response to the parathyroid hormone.
Patients with pseudopseudohypoparathyroidism typically develop a condition called AHO. Often these patients have a characteristic appearance, including having a round face, a short stature, and obesity. They commonly have abnormal deposits of calcification throughout their body, a process also known as heterotopic calcification. Additionally, patients with AHO can have bone deformities, including short fourth and fifth toes, and curves in the bones of the arms. Occasionally patients with AHO have deficits in their senses of smell and taste.
PHP is the term used to describe diseases caused by other mutations in GNAS-1. Unlike patients with pseudoPHP, these patients do have abnormalities in their blood levels of calcium and phosphate. Some patients with PHP also display the characteristic physical findings of AHO.
Despite the fact that patients with pseudopseudohypoparathyroidism have an abnormal response to the parathyroid hormone, they typically have normal levels of calcium and phosphate in their blood. This was somewhat unexpected to the researchers who initially studied the disease, as the parathyroid hormone plays a critical role in monitoring the levels of these minerals within the body. For this reason they labeled the disease pseudoPHP because it shares some characteristics of PHP but does not affect the body’s blood mineral levels.
Whether a patient develops pseudoPHP or PHP can depend on which parent the individual inherited the mutated copy of GNAS-1 from. This genetic phenomenon is known as imprinting. Patients who receive a mutated gene from their mothers develop problems with their calcium and phosphate blood levels because the maternal gene is activated in the kidneys, the organs that respond to the parathyroid hormone and can alter blood mineral levels. In contrast, patients who receive a mutated gene from their fathers do not have problems with mineral levels in their blood because the unaltered maternal copy of GNAS-1 is activated in the kidneys.