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Last updated:
8/1/2023
Years published: 1988, 1989, 1990, 1998, 1999, 2007, 2023
NORD gratefully acknowledges Julia Zappa and Evan Baker, NORD Editorial Interns from the University of Notre Dame and Chad Haldeman-Englert, MD, FACMG, Mission Fullerton Genetics Center, Asheville, NC, for assistance in the preparation of this report.
Pseudohypoparathyroidism (PHP) is a hereditary disorder characterized by an inadequate response to the parathyroid hormone, although the hormone is present in normal amounts. Parathyroid hormone controls the amounts of calcium, phosphorus and vitamin D in bones and blood. This impacts bone growth and may cause facial and skeletal deformities. Affected individuals may have short stature, a round face and unusually short fourth fingers. They may also experience headaches, unusual sensations, weakness, fatigue, lack of energy, blurred vision, abnormal sensitivity (hypersensitivity) to light, body pains and weakness, muscle twitches and spasms, and intellectual disabilities. There are multiple subtypes of PHP, which are caused by harmful changes (variants) in certain genes, one of which is GNAS1. These subtypes show some variation in symptoms, and other hormones may also be affected (growth hormone, thyroid hormone, etc.). The symptoms of pseudohypoparathyroidism are usually first noticed in childhood. Possible treatments include calcium supplements, vitamin D supplements, low phosphate diets and growth hormone therapy. People with pseudohypoparathyroidism can lead a normal life.
There are two types of PHP, type 1 and type 2. Type 1 is broken into subtypes 1a, 1b, and 1c. Pseudopseudohypoparathyroidism (PPHP) is a limited form of PHP-1a, where an individual has the physical symptoms but not the hormone problems. Type 1a, type 1b, and PPHP are the most common subtypes. Both type 1 and type 2 PHP are characterized by resistance to parathyroid hormone, resulting in elevated phosphate levels and low calcium levels in the blood. The low calcium levels in the blood seen in all types of PHP may lead to childhood seizures in some individuals. Involuntary sudden movements, such as seen with paroxysmal kinesigenic dyskinesia (PKD), have also been reported in affected individuals. Beyond these shared characteristics, type 1 and type 2 differ greatly. Additional symptoms of type 1 are well-characterized while little is known about type 2.
PHP type 1 results in resistance to additional endocrine hormones, including thyroid-stimulating hormone (TSH), gonadotropins (LH and FSH) and growth hormone-releasing hormone (GHRH). Resistance to these hormones results in obesity as well as delayed or incomplete development during puberty. In females, this can lead to reduced fertility, menstrual disorders or irregularities and altered levels of LH and FSH. In males, this can lead to failure of the testes to descend (cryptorchidism) and elevated LH and FSH levels.
Type 1 is additionally characterized by skeletal abnormalities such as short stature, a round face, short neck and shortened bones in the hands and feet. These abnormalities are collectively referred to as Albright hereditary osteodystrophy (AHO) and vary in severity depending on the type of PHP. People with type 2 lack these physical abnormalities altogether while type 1b has only mild physical abnormalities. In some individuals with type 1, bone formation occurs in soft and connective tissue where bone does not normally exist (heterotopic ossification). This ossification can present as small, raised lesions.
In both type 1 and type 2, affected individuals show variable degrees of intellectual disability and developmental delay. Headaches, weakness, tiring easily, lethargy, spinal cord compression, cataracts and blurred vision or hypersensitivity to light may also be present. Teeth tend to erupt later than normal, and enamel is underdeveloped. Affected individuals may also have crooked teeth and a poor bite.
Pseudohypoparathyroidism is inherited as an autosomal dominant condition and caused by changes (variants) in the GNAS gene. GNAS variants have been found in about 76% percent of affected individuals, with 38% of those individuals having an affected parent. In the remaining individuals, the cause is unknown.
Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
PHP is a sex-influenced trait, meaning the symptoms seen in an individual vary depending on whether the affected gene is maternal or paternal. Maternal inheritance often results in PHP while paternal inheritance would lead to the physical symptoms but not the hormonal issues (PPHP).
The changes in the GNAS gene seen that cause PHP vary, but overall, these changes have been associated with reduced or absent expression of the alpha subunit of G-proteins. These proteins are involved in cellular messaging in the body. In addition to GNAS, a nearby gene STX16 has been associated with some forms of the disorder. Other genes that may be associated with pseudohypoparathyroidism include PRKAR1A, PDE4D and PDE3A.
PHP is a rare disorder that affects both males and females. The prevalence of PHP and AHO has been estimated to be 0.79 per 100,000 individuals.
Blood and urine tests can be used to measure the calcium, phosphorus and parathyroid hormone levels in the body. High levels of parathyroid hormone and phosphorus with low calcium levels suggests that pseudohypoparathyroidism is a possible diagnosis. Subtypes of the disorder that do not involve hormone resistance, like PPHP, cannot be detected using these lab tests. Diagnosis can be confirmed by using genetic testing to look for mutations in the GNAS1 gene.
Treatment of pseudohypoparathyroidism should aim to bring calcium and phosphorus levels into the normal range. This can be achieved using calcium supplements and vitamin D supplements, which promote reabsorption of calcium in the kidneys. Low-phosphate diets or medications that bind phosphate may be used to reduce the effects of high phosphorus levels. Growth hormone therapy may also be used to improve height.
Bone ossifications can be removed surgically, if necessary. In the case of other skeletal abnormalities that cause spinal cord compression, surgical outcomes have been poor. Obesity can be treated with usual methods such as increased exercise and reduced caloric intake. Other symptoms should be treated on a more individualized basis.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
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For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
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JOURNAL ARTICLES
Jüppner H. Molecular definition of pseudohypoparathyroidism variants. J Clin Endocrinol Metab. 2021;106(6):1541-1552. doi:10.1210/clinem/dgab060
Tan X, Guo Y, Liu Y, Liu C, Pei L. Symptomatic spinal cord compression: an uncommon symptom in pseudohypoparathyroidism. Ann N Y Acad Sci. 2021;1503(1):38-47. doi:10.1111/nyas.14584
Hejlesen J, Underbjerg L, Gjørup H, Sikjaer T, Rejnmark L, Haubek D. Dental anomalies and orthodontic characteristics in patients with pseudohypoparathyroidism. BMC Oral Health. 2020;20(1). doi:10.1186/S12903-019-0978-Z
Zhang C, Zhou X, Feng M, Yue W. Paroxysmal dyskinesia and epilepsy in pseudohypoparathyroidism. Mol Genet Genomic Med. 2020;8(10):e1423. doi:10.1002/mgg3.1423
Germain-Lee EL. Management of pseudohypoparathyroidism. Curr Opin Pediatr. 2019;31(4):537-549. doi:10.1097/MOP.0000000000000783
Mantovani G, Elli FM. Inactivating PTH/PTHrP signaling disorders. Front Horm Res. 2019;51:147-159. doi:10.1159/000491045
Schneller-Pavelescu L, Vergara de Caso E, Pastor-Tomás N, Gutiérrez Agulló M, Ruiz Pérez L, Betlloch Mas I. Presentation of pseudohypoparathyroidism and pseudopseudohypoparathyroidism with skin lesions: Case reports and review. Pediatr Dermatol. 2019;36(3):355-359. doi:10.1111/pde.13769
Bastepe M. GNAS mutations and heterotopic ossification. Bone. 2018;109:80-85. doi:10.1016/j.bone.2017.09.002
Linglart A, Levine MA, Jüppner H. Pseudohypoparathyroidism. Endocrinol Metab Clin North Am. 2018;47(4):865-888. doi:10.1016/j.ecl.2018.07.011
Perez KM, Curley KL, Slaughter JC, Shoemaker AH. Glucose homeostasis and energy balance in children with pseudohypoparathyroidism. J Clin Endocrinol Metab. 2018;103(11):4265-4274. doi:10.1210/jc.2018-01067
INTERNET
Haldeman-Englert CR, Hurst ACE, Levine MA. Disorders of GNAS Inactivation. 2017 Oct 26. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459117/ Accessed Nov May 15, 2023.
Pseudohypoparathyroidism. Genetic and Rare Diseases Information Center (GARD).Nov 8, 2021. https://rarediseases.info.nih.gov/diseases/10758/pseudohypoparathyroidism Accessed May 15, 2023.
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