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 [1] [2] [3]. 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 [1] [4]. 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 [1] [5] [6] [7] [8]. 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 [1] [4]. 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 [9]. Rare reports have described the appearance of cardiac arrhythmias (atrioventricular blocks) and syncope in these patients [9].

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 [7]. Furthermore, the father should be examined as well, given the fact that they will universally present with the same signs and symptoms [8]. 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 [1] [9].

There is no specific treatment for PPHP, as it does not cause the biochemical imbalances seen in PHP. Management focuses on addressing any associated symptoms or complications:

• Orthopedic Interventions: For bone abnormalities.
• Educational Support: For developmental delays.
• Nutritional Counseling: To manage obesity.

The prognosis for individuals with PPHP is generally good, as they do not experience the metabolic complications associated with PHP. Life expectancy is typically normal, and quality of life can be maintained with appropriate management of symptoms.

PPHP is caused by mutations in the GNAS gene, which plays a role in the signaling pathways of various hormones. The condition is inherited in an autosomal dominant pattern, meaning a single copy of the altered gene can cause the disorder.

PPHP is an extremely rare condition, with its exact prevalence unknown. It affects both males and females equally and can occur in any ethnic group. Due to its rarity, many cases may go undiagnosed or misdiagnosed.

The GNAS gene mutation in PPHP affects the production of a protein involved in hormone signaling. However, unlike PHP, the mutation does not lead to hormone resistance, which is why patients do not exhibit the biochemical abnormalities of low calcium and high phosphate levels.

As a genetic disorder, there is no known prevention for PPHP. Genetic counseling may be beneficial for families with a history of the condition to understand the risks and implications for future generations.

Pseudopseudohypoparathyroidism is a rare genetic disorder characterized by physical features of Albright's hereditary osteodystrophy without the hormonal imbalances seen in pseudohypoparathyroidism. Diagnosis involves clinical evaluation and genetic testing, and management focuses on symptom relief. The condition is caused by mutations in the GNAS gene and is inherited in an autosomal dominant manner.

If you or a family member has been diagnosed with PPHP, it's important to understand that this condition primarily affects physical appearance and does not typically lead to serious health issues. Regular check-ups with your healthcare provider can help manage any symptoms and ensure a good quality of life. Genetic counseling can provide valuable information for family planning and understanding the inheritance pattern of the disorder.

1. Simpson C, Grove E, Houston BA. Pseudopseudohypoparathyroidism. Lancet. 2015;385(9973):1123.
2. Kottler ML, Linglart A, Carel JC. Albright hereditary osteodystrophy. Orphanet Encyclopedia 2004. https://www.orpha.net/data/patho/GB/uk-AHO.pdf
3. Wilson LC, Hall CM. Albright's hereditary osteodystrophy and pseudohypoparathyroidism. Semin musculoskelet Radiol 2002;2013:273–83.
4. Hamasaki H, Mukaino T, Kaneko H, et al. Journal of Endocrinology and Metabolism. 2013:3(6):150-152.
5. Turan S, Bastepe M. GNAS spectrum of disorders. Curr Osteoporos Rep. 2015;13(3):146-158.
6. Davies AJ, Hughes HE. Imprinting in Albright’s hereditary osteodystrophy. J Med Genet. 1993;30:101–103.
7. Wilson LC, Oude-Luttikhuis MEM, Clayton PT, et al. Parental origin of Gsα gene mutations in Albright’s hereditary osteodystrophy. J Med Genet. 1994;31:835–839.
8. Lemos MC, Thakker RV. GNAS Mutations in Pseudohypoparathyroidism Type 1a and Related Disorders. Hum Mutat. 2015;36(1):11-19.
9. Rahmat N, Venables P. Sinus pauses and high-grade atrioventricular block in Albright’s hereditary osteodystrophy with pseudopseudohypoparathyroidism. BMJ Case Rep. 2013;2013:bcr2013010116.