What are the other Names for this Condition? (Also known as/Synonyms)

• Ectopic Ossification, Familial type
• Familial Ectopic Ossification
• POH (Progressive Osseous Heteroplasia)

What is Progressive Osseous Heteroplasia? (Definition/Background Information)

• 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
•  Progressive Osseous Heteroplasia 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

(Source: Progressive Osseous Heteroplasia; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Who gets Progressive Osseous Heteroplasia? (Age and Sex Distribution)

• Progressive Osseous Heteroplasia (POH) is a very rare condition
• 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

(Source: Progressive Osseous Heteroplasia; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

What are the Risk Factors for Progressive Osseous Heteroplasia? (Predisposing Factors)

• A positive family history may be an important risk factor, since Progressive Osseous Heteroplasia is an inherited condition

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Progressive Osseous Heteroplasia? (Etiology)

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

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 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

(Source: Progressive Osseous Heteroplasia; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Autosomal dominant: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

What are the Signs and Symptoms of Progressive Osseous Heteroplasia?

Symptoms of Progressive Osseous Heteroplasia (POH) usually are apparent within the first few months of life, and may be present from birth.

• The condition does not affect the formation of any portions of the normal skeleton at birth. Most affected children are diagnosed before the age of ten
• Parents may first notice small rice-sized particles of bone in the skin, causing the skin to feel rough and thick
• As affected children age, bone formation may progress to subcutaneous tissue and into deeper structures including muscles, tendons and ligaments
• It may cause pain and the development of open sores (ulcers) in affected areas of the body
• As the condition progresses, it may cause restricted mobility of various joints, eventually "locking" the joints (ankylosis)
• Affected arms and legs may become malformed and may not grow their full length. If bone growth occurs around the spine, scoliosis may develop
• In some individuals, the condition affects a small area of the body; in others, large areas of the body are affected

The rate of progression also varies greatly among affected individuals and is unpredictable. However, most individuals experience a gradual progression of the condition.

• Joints may become involved over time, causing impaired mobility
• Abnormality of the musculature
• Abnormality of the skin
• Growth delay
• Osteoma

Very frequently present symptoms in 80-99% of the cases:

• Bone pain
• Ectopic calcification
• Limitation of joint mobility
• Subcutaneous nodule

Frequently present symptoms in 30-79% of the cases: Ectopic ossification in muscle tissue.

Occasionally present symptoms in 5-29% of the cases:

• Abnormality of the parathyroid gland
• Brachydactyly
• Hypomelanotic macule
• Osteoarthritis
• Papule
• Sarcoma

 (Source: Progressive Osseous Heteroplasia; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

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

(Source: Progressive Osseous Heteroplasia; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Progressive Osseous Heteroplasia?

The complications of Progressive Osseous Heteroplasia may include:

• Severely affected quality of life
• Immobility

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Progressive Osseous Heteroplasia 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

(Source: Progressive Osseous Heteroplasia; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How can Progressive Osseous Heteroplasia be Prevented?

Currently, Progressive Osseous Heteroplasia may not be preventable, since it is a genetic disorder.

Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy

If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child

Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of Progressive Osseous Heteroplasia? (Outcomes/Resolutions)

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 lifespan of affected individuals as it does not directly affect the internal organs

(Source: Progressive Osseous Heteroplasia; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Additional and Relevant Useful Information for Progressive Osseous Heteroplasia:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/