Rare Gastroenterology News

Disease Profile

Progressive osseous heteroplasia

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

Infancy

ageofonset-infancy.svg

ICD-10

M61.5

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

rnn-autosomaldominant.svg

Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

no.svg

X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

no.svg

X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

no.svg

Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

no.svg

Not applicable

no.svg

Other names (AKA)

POH; Familial ectopic ossification; Ectopic ossification familial type

Categories

Congenital and Genetic Diseases; Musculoskeletal Diseases; Skin Diseases

Summary

Progressive osseous heteroplasia (POH) is a progressive bone disorder in which bone forms (ossifies) within skin and muscle tissue.[1] It usually becomes apparent in infancy with skin (cutaneous) ossification, which progresses to involvement of subcutaneous and deep tissues, including muscle.[1][2] In some cases, it first becomes apparent later in childhood or in early adulthood.[1] Ossification may cause pain and open sores (ulcers) in affected areas of the body. Joints may become involved over time, causing impaired mobility.[1] POH is caused by a mutation in the GNAS gene and is inherited in an autosomal dominant manner.[1][2] 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.[3] 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.[2]

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.[2]

Symptoms

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.[4]

Parents may first notice small rice-sized particles of bone in the skin, causing the skin to feel rough and thick.[4][3] As affected children age, bone formation may progress to subcutaneous tissue and into deeper structures including muscles, tendons and ligaments.[4] It may cause pain and the development of open sores (ulcers) in affected areas of the body.[1] Joints may become involved over time, causing impaired mobility.[1]

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.[3]

In some individuals, the condition affects a small area of the body; in others, large areas of the body are affected.[4] The rate of progression also varies greatly among affected individuals and is unpredictable.[4] However, most individuals experience a gradual progression of the condition.[3]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Bone pain
0002653
Ectopic calcification
0010766
Limitation of joint mobility
Decreased joint mobility
Decreased mobility of joints
Limited joint mobility
Limited joint motion

[ more ]

0001376
Subcutaneous nodule
Firm lump under the skin
Growth of abnormal tissue under the skin

[ more ]

0001482
30%-79% of people have these symptoms
Ectopic ossification in muscle tissue
Calcification of muscle tissue
0011987
5%-29% of people have these symptoms
Abnormality of the parathyroid gland
0000828
Brachydactyly
Short fingers or toes
0001156
Hypermelanotic macule
Hyperpigmented spots
0001034
Osteoarthritis
Degenerative joint disease
0002758
Papule
0200034
Sarcoma
Cancer of connective tissue
Malignant connective tissue tumor

[ more ]

0100242
Percent of people who have these symptoms is not available through HPO
Abnormality of the musculature
Muscular abnormality
0003011
Ankylosis
0031013
Autosomal dominant inheritance
0000006
Growth delay
Delayed growth
Growth deficiency
Growth failure
Growth retardation
Poor growth
Retarded growth

[ more ]

0001510
Infantile onset
Onset in first year of life
Onset in infancy

[ more ]

0003593
Juvenile onset
Signs and symptoms begin before 15 years of age
0003621
Osteoma
0100246
Osteoma cutis
0025027
Progressive
Worsens with time
0003676
Variable expressivity
0003828

Cause

The genetics of progressive osseous heteroplasia (POH) is complex and may not yet be fully understood.[5] 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.[1]

Diagnosis

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:

  • 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[2]

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

    Treatment

    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).[2]

    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.[2]

    Important conservative approaches include physical therapy to preserve movement, and meticulous skin care to prevent the breakdown of skin.[2] 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.[3]

    Organizations

    Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

    Organizations Supporting this Disease

      Social Networking Websites

        Learn more

        These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

        Where to Start

        • MedlinePlus Genetics contains information on Progressive osseous heteroplasia. This website is maintained by the National Library of Medicine.
        • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

          In-Depth Information

          • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
          • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
          • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
          • PubMed is a searchable database of medical literature and lists journal articles that discuss Progressive osseous heteroplasia. Click on the link to view a sample search on this topic.

            References

            1. Progressive osseous heteroplasia. Genetics Home Reference. January 2009; https://ghr.nlm.nih.gov/condition/progressive-osseous-heteroplasia.
            2. Pignolo RJ, Ramaswamy G, Fong JT, Shore EM, Kaplan FS. Progressive osseous heteroplasia: diagnosis, treatment, and prognosis. Appl Clin Genet. January, 2015; 8:37-48. https://www.dovepress.com/progressive-osseous-heteroplasia-diagnosis-treatment-and-prognosis-peer-reviewed-fulltext-article-TACG.
            3. Progressive Osseous Heteroplasia. NORD. 2014; https://rarediseases.org/rare-diseases/progressive-osseous-heteroplasia/.
            4. About POH Disease. POHA: Progressive Osseous Heteroplasia Association. https://www.pohdisease.org/ABOUT_POH_DISEASE/.
            5. Happle R. Progressive osseous heteroplasia is not a Mendelian trait but a type 2 segmental manifestation of GNAS inactivation disorders: A hypothesis.. Eur J Med Genet. May, 2016; 59(5):290-294.
            6. Frederick S. Kaplan, Eileen M. Shore, Rachel B. Wagman, Sandra Roth, Fred B. Gardner. What is POH? A Guidebook for Families. POHA: Progressive Osseous Heteroplasia Association. 2002; https://www.pohdisease.org/files/1804/File/pohGuidebook-English.pdf.

            Rare Gastroenterology News