Pseudopseudohypoparathyroidism is a very rare autosomal dominant genetic disorder that is considered to be a variant of Albright's hereditary osteodystrophy. Transmission of GNAS mutations from the father is the mechanism of the disease. Typical findings include short stature, obesity, round facies, and reduced length of metacarpal and metatarsal bones, but without resistance to parathyroid hormone (PTH), which is one of the main biochemical clues in the diagnosis of pseudopseudohypoparathyroidism. A positive family history and subsequent genetic studies are vital for confirming the diagnosis.
Pseudopseudohypoparathyroidism (PPHP), a very rare disorder initially described more than 50 years ago, stems from a genetic phenomenon known as "genomic imprinting", where the expression of mutated genes differs for maternal and paternal transmission   . Namely, PPHP is a subtype of Albright's hereditary osteodystrophy (AHO), an autosomal dominant disease that develops due to mutations of the genes encoding the α subunit of the Gs protein (GNAS1) located on chromosome 20  . If this mutation is transferred from the chromosome of the mother, pseudohypoparathyroidism (PHP) type 1a will develop, but if paternal transmission occurs, children suffer from pseudopseudohypoparathyroidism     . The clinical presentation is practically identical for both forms - a short stature with reduced growth of metacarpal and metatarsal bones (manifesting as shorter fingers and toes, or brachydactyly), as well as obesity and a round face  . However, the distinguishing feature of PPHP is normal circulating levels of parathyroid hormone (PTH) and its unchanged activity in the kidneys, which in the case of PHP leads to hypocalcemia and hyperphosphatemia . Rare reports have described the appearance of cardiac arrhythmias (atrioventricular blocks) and syncope in these patients .
The rare occurrence of pseudopseudohypoparathyroidism in clinical practice might present a challenge for the physicians when attempting to make the diagnosis, which is why the initial interview with the patient is crucial. In fact, the autosomal dominant pattern of inheritance mandates a positive family history, particularly from fathers who are responsible for PPHP transmission to their children, thus this piece of information may be essential for making a presumptive diagnosis . Furthermore, the father should be examined as well, given the fact that they will universally present with the same signs and symptoms . After a detailed physical examination that will ensure identification of skeletal-related findings, a full biochemical workup should be the next step, where serum electrolyte assessment reveals normal serum calcium and phosphate levels, whereas hormonal evaluation shows parathyroid hormone (PTH) levels within physiological limits. These findings will further point toward pseudopseudohypoparathyroidism but in order to establish a definite diagnosis, genetic testing to confirm GNAS gene mutations (both in the parents and in the affected patients) is necessary  .