Progressive osseous heteroplasia

What causes progressive osseous heteroplasia?

The genetics of progressive osseous heteroplasia (POH) is complex and may not yet be fully understood. It is known to be associated with mutations in the GNAS gene and has been thought to occur only when a mutation affects the paternally inherited copy of the gene.

The GNAS gene give the body instructions for making parts of protein complexes called G proteins, which trigger signaling pathways that influence the functions of cells. G proteins are believed to play a key role in signaling pathways that regulate bone development (osteogenesis), preventing bone from being produced outside the skeleton. GNAS mutations that cause POH are thought to disrupt G protein function, impairing its ability to regulate osteogenesis. As a result, bone is permitted to grow outside the skeleton, causing the features of POH.

Last updated on 05-01-20

How is progressive osseous heteroplasia diagnosed?

Progressive osseous heteroplasia (POH) must first be differentiated from nonhereditary causes of heterotopic ossification (HO) as well as other hereditary causes. POH is among several related genetic disorders, including Albright hereditary osteodystrophy (AHO), pseudohypoparathyroidism (PHP), and primary osteoma cutis, which share the common features of superficial ossification and association with mutations in the GNAS gene. These disorders are characterized by additional features that are not associated with POH.

POH is diagnosed on the basis of three major criteria:

  • superficial HO that progresses to deep connective tissue;
  • two or fewer AHO features, excluding HO; and
  • no parathyroid hormone (PTH) resistance (as in PHP)

In addition to these key diagnostic criteria, there are several findings that support the diagnosis of POH. These include:

  • a GNAS mutation identified with genetic testing (present in almost two-thirds of POH patients)
  • evidence for paternal inheritance
  • a specific pattern of ossification seen on radiographic imaging
  • a history of intrauterine growth retardation
  • leanness
  • age of onset younger than 1 year

Last updated on 05-01-20

What is the chance that a woman with progressive osseous heteroplasia will have children with this condition?

In those with progressive osseous heteroplasia, the defective copy of the GNAS gene is inherited from the father. If a defective GNAS is inherited from the mother, individuals typically develop the related, yet distinct, disorder known as pseudohypoparathyrodism type 1a (PHP1a), which is usually seen in association with Albright's hereditary osteodystrophy (AHO). Thus, women with progressive osseous heteroplasia have a 50% chance of having children with PHP1a and AHO. To read more about these conditions, click on the links above.

Last updated on 05-01-20

How is progressive osseous heteroplasia inherited?

Progressive osseous heteroplasia (POH) is described as an autosomal dominant trait. This means that having a change (mutation) in only one copy of the responsible gene in each cell is enough to cause features of the condition. In most cases, the mutation occurs randomly (sporadically) for the first time in a person without a family history of POH. While a mutation that causes POH can be inherited, familial cases of POH are extremely rare.

People normally inherit one copy of each gene from each parent. For most genes, both copies are active, or "turned on." For some genes, however, only one of the two copies is active - either the maternal copy or the paternal copy. These differences in activation based on the gene's parent of origin are caused by a phenomenon called genomic imprinting. The gene responsible for POH (the __GNAS __gene _ ) has a complex genomic imprinting pattern. In some cells the maternal copy is active, while in others the paternal copy is active. _Progressive osseous heteroplasia is thought to occur when mutations affect the paternally inherited copy of the gene.

People with POH can conceive and have children. However, because it is an autosomal dominant condition, each child of a person with POH has a 50% chance to inherit the mutation that causes the condition. While POH occurs only when the mutated gene is inherited from the father, Albright's hereditary osteodystrophy (AHO) features can be associated with mutations inherited from either parent, and pseudohypoparathyroidism type 1A and/or AHO-associated obesity can occur when the mutated gene is inherited from the mother.

Due to the complexity of the genetics of POH and related conditions, people with questions about the genetics and inheritance of POH are encouraged to speak with a genetics professional.

Last updated on 05-01-20

What is progressive osseous heteroplasia?

Progressive osseous heteroplasia (POH) is a progressive bone disorder in which bone forms (ossifies) within skin and muscle tissue. It usually becomes apparent in infancy with skin (cutaneous) ossification, which progresses to involvement of subcutaneous and deep tissues, including muscle. In some cases, it first becomes apparent later in childhood or in early adulthood. Ossification may cause pain and open sores (ulcers) in affected areas of the body. Joints may become involved over time, causing impaired mobility. POH is caused by a mutation in the GNAS gene and is inherited in an autosomal dominant manner. In most cases, the mutation occurs randomly in a person with no family history of POH. In some cases, the mutation is inherited from a parent. There are currently no effective treatments for POH, and surgery to remove widespread lesions often results in recurrences or complications. However, well-circumscribed lesions can often be removed with successful, long-term results.

POH is thought to be part of a spectrum of related genetic disorders which include Albright hereditary osteodystrophy, pseudohypoparathyroidism, and primary osteoma cutis. These disorders share the features of superficial ossification and being caused by mutations affecting the GNAS gene.

Last updated on 05-01-20

What is the long-term outlook for people with progressive osseous heteroplasia?

Because progressive osseous heteroplasia (POH) is so rare, there is limited information about long-term outlook (prognosis). The progression of POH is highly variable even among members of the same family. In some individuals, it may progress extremely slowly; in others it may progress more rapidly. Most individuals experience a gradual progression of the condition. The degree of morbidity depends on the location and extent of abnormal bone formation, and in some cases, the condition results in severe disability. The condition may be associated with restricted movement of the arms and legs caused by "locking" of joints (ankyloses), pain, and secondary osteoporosis. POH may also restrict movement in the hips, jaw, shoulders, and/or other areas of the body. Despite the morbidity associated with POH, there is no known effect on the life span of affected individuals as it does not directly affect the internal organs.

Last updated on 05-01-20

How many people have progressive osseous heteroplasia?

Progressive osseous heteroplasia (POH) is a very rare condition. A rare disease is a disease or condition affecting fewer than 200,000 persons in the United States. Reportedly, as of 2002, approximately 40 patients had been identified worldwide. It is possible that there are more people with POH who have been misdiagnosed as having other conditions.

Last updated on 05-01-20

How might progressive osseous heteroplasia be treated?

At this time, there are no effective treatments or prevention for progressive osseous heteroplasia (POH). Surgery to remove diffuse lesions usually leads to recurrences or complications, but areas of well-circumscribed lesions can often be removed, with successful long-term results. Unfortunately, amputations are sometimes needed when there is severe growth retardation and functional ankylosis (locking of joints).

One case report on the use of the bisphosphonate pamidronate in POH suggested stabilization of the condition, but it is unclear how applicable this may be to preventing new skin lesions. Treatment with a bisphosphonate is unlikely to have an effect on preexisting bone formation.

Important conservative approaches include physical therapy to preserve movement, and meticulous skin care to prevent the breakdown of skin. Special shoes, braces, and other devices to assist in walking and weight- bearing have been used to help people with POH involving the lower limbs.

Last updated on 05-01-20

Name: International Fibrodysplasia Ossificans Progressiva Association 1520 Clay Street, Suite H2
North Kansas City, MO, 64116, United States
Phone: 407-365-4194 Fax : 407-365-3213 Email: Url:
Name: Progressive Osseous Heteroplasia Association 5327 Westpointe Plaza Drive, #113
Columbus, OH, 43228 , United States
Phone: 614-887-POHA (7642) Email: Url:
Name: International Osteoporosis Foundation 9, rue Juste-Olivier CH-1260 Nyon
Phone: +41 22 994 0100 Fax : +41 22 994 0101 Email: Url:

Connect with other users with Progressive osseous heteroplasia on the RareGuru app

Do you have information about a disease, disorder, or syndrome? Want to suggest a symptom?
Please send suggestions to RareGuru!

The RareGuru disease database is regularly updated using data generously provided by GARD, the United States Genetic and Rare Disease Information Center.

People Using the App

Join the RareGuru Community

To connect, share, empower and heal today.

People Using the App