Progressive Osseous Heteroplasia (POH)

Progressive Osseous Heteroplasia (POH)

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Progressive Osseous Heteroplasia (POH) is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • POH

Disorder Subdivisions

  • None

General Discussion

Progressive osseous heteroplasia (POH) is an extremely rare disorder characterized by abnormal development of bone in areas of the body where bone is not normally present (heterotopic ossification). The disorder first appears as areas of patchy bone formation (ossification) in the skin during infancy; heterotopic ossification progresses to involve superficial and deep connective tissues, areas of fat beneath the skin (subcutaneous fat), muscles, tendons, ligaments, and the sheets of fibrous tissue that envelop muscle (fascia). This abnormal formation of bone may restrict the movement of affected joints and/or hinder the growth of affected limbs. The course of the disease is unpredictable; some areas of the body may become severely affected while others may remain unaffected.

Symptoms

The symptoms of POH are usually present at birth (congenital) or within the first few weeks of life, and they tend to progress slowly and asymmetrically as an affected individual grows older. Infants with POH typically have a maculopapular rash (with the appearance of patchy areas of bone within the dermis). Initially, affected skin may feel abnormally rough.



The major finding in infants with POH is the development of bone in areas of the body where bone is not normally present (heterotopic ossification). Initially, bone growth may develop within the skin (osseous nodules or plaques called osteoma cutis). These areas may become progressively widespread and may grow together (coalesce) to form even larger areas of hardened and thickened skin (dermal ossification). As the disease progresses, these bony growths may extend into the deeper layers of the skin (subcutaneous layers). Eventually, abnormal bony growths occur in various connective tissues of the body such as fascia and skeletal muscle.



As the abnormal development of bone progresses, it may restrict movement in certain joints and eventually lock the joints (ankylosis), such as the knees and ankles. POH may also restrict movement in the hips, wrists, jaw, shoulders, and/or other areas of the body. Affected arms and legs may become malformed and not grow to full length. This can occur on one side of the body and lead to unequal growth; one leg or one arm may become shorter than the other, for example. Some areas of the body may be severely affected, while other areas may remain unaffected. In some patients, lesion formation occurs predominantly or exclusively on one side (either left or right) of the body (hemimelic progressive osseous heteroplasia).



Children with POH may also have sharp, needle-like projections of bone (spicules) that break through the surface of the skin, causing irritation or superficial infection. In addition, when bone growth occurs around the spine, some affected individuals may develop an abnormal sideways curvature of the spine (scoliosis).



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. .

Bone formation in POH tends to be more intramembranous than endochondral in nature, and no inflammatory component has been identified. Histologically, bone can be seen to arise directly from adipose stromal tissue although the exact cell(s) of origin remain unknown.

Causes

Most cases of POH occur randomly (sporadically) as the result of a spontaneous genetic change (i.e., new mutation) of a specific gene. This mutation can be inherited as an autosomal dominant trait indicating that only one of the two copies of a gene in a cell needs to be mutated in order to cause the disease.



Investigators have determined that some cases of POH may be caused by disruption or changes (mutations) of the GNAS gene located on the long arm (q) of chromosome 20. Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q." About three-fourths of examined POH patients have inactivating GNAS gene mutations.



The GNAS (Guanine Nucleotide-Binding Protein, Alpha-Stimulating Polypeptide) gene contains instructions for creating (encoding) a protein that researchers believe may be involved in suppressing the activity of proteins (created by other genes) that promote bone growth. Mutation of the gene results in deficiency or dysfunction of this protein. However, the exact manner in which mutations of the GNAS gene bring about the symptoms of POH is not yet known.



A specific process associated with POH is known as genetic imprinting. Everyone has two copies of every gene (except those genes on X and Y chromosomes) - one received from the father and one received from the mother. In most cases, both genes are "turned on" or active. However, some genes are preferentially silenced or "turned off" based upon which parent that gene came from (genetic imprinting). Genetic imprinting is controlled by chemical switches through a process called DNA methylation. Proper genetic imprinting is necessary for normal development. Defective imprinting has been associated with several human diseases including POH. In individuals with POH, the defective copy of the GNAS gene is inherited from the father. If a defective GNAS gene is inherited from the mother, individuals typically develop related, yet clinically distinct, disorders known as Albright hereditary osteodystrophy and/or pseudohypoparathyrodism type 1a (PHP1a).

Affected Populations

More than 50 cases of progressive osseous heteroplasia have been identified around the world. Although the majority of the cases reported initially occurred in females, the disorder appears to affect males and females in equal numbers. Because POH often goes unrecognized or misdiagnosed, determining the true frequency of the disorder in the general population is difficult. In the most severe cases, symptoms are usually apparent at birth or within the first few weeks of life. Symptoms usually progress as affected individual's age.



POH was first described in 1994.

Standard Therapies

Diagnosis

The diagnosis of progressive osseous heteroplasia may be confirmed by a thorough clinical evaluation, characteristic physical findings, and tests that demonstrate the presence of heterotopic ossification (e.g., x-ray and roentgenograms) with characteristic appearance for POH. An additional test may include the removal and testing of tissues (biopsy). In some cases, there may be temporarily (transient) increased levels of alkaline phosphatase in the blood serum



Treatment

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. Occupational therapy evaluations and appropriate assistive devices for activities of daily living may be helpful for those in whom POH involves the upper limbs. Immunizations should be given on areas of the skin that are unaffected by the bony growths that are prevalent with this disorder.



Genetic counseling will be of benefit for affected individuals and their families. A team approach for infants with this disorder will be of benefit and may include special social, educational, and medical services. Other treatment is symptomatic and supportive.

Investigational Therapies

Surgery, radiation therapy, and several different types of drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs), have been used in the past to treat disorders involving the abnormal development of bone (heterotopic ossification). Surgery may be considered because of the complications associated with improper bone growth (e.g., stiffening of affected joints), but extreme caution is advised as operative procedures often exacerbate bone growth in POH. Surgical removal of improper bone growth has provided temporary relief in some cases; in other cases, the improper bone growth has recurred massively after the surgery. In some disorders of improper bone growth, surgery may hasten the progression of the disorder or result in other complications. Extreme caution should be used in considering surgery for individuals affected by POH. It is rarely indicated. More research must be conducted to determine the effectiveness of radiation and various drug therapies when used to treat POH.



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:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

References

TEXTBOOKS

Kaplan, F.S. and E.M. Shore (2008). Fibrodysplasia (myositis) ossificans progressiva. In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, Seventh Edition. C. Rosen, Editor. ASBMR, Washington, DC.



Shore EM, Kaplan FS. Progressive Osseous Heteroplasia. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:203-204.



REVIEW ARTICLES

Shore EM, Kaplan FS. Inherited human diseases of heterotopic bone formation. Nat Rev Rheumatol 2010:6; 518-527.



Shore, E.M. and F.S. Kaplan (2008). Insights from a rare genetic disorder of extra-skeletal bone formation, fibrodysplasia ossificans progressiva (FOP). Bone 43, 427-433.



Shore E.M. and F. S. Kaplan (2005). FOP and POH: Two Genetic Disorders of Heterotopic Ossification. Clinical Reviews in Bone and Mineral Metabolism: 3: (3-4), 257-260.



Kaplan FS, Shore EM. Progressive osseous heteroplasia. J Bone Miner Res. 2000;15:2084-94.



Stoll C, Javier MR, Bellocq JP. Progressive osseous heteroplasia: an uncommon cause of ossification of soft tissues. Ann Genet. 2000;43:75-80.



JOURNAL ARTICLES

Pignolo RJ, Xu M, Russell E, et al.Heterozygous inactivation of Gnas in adipose-derived mesenchymal progenitor cells enhances osteoblast differentiation and promotes heterotopic ossification. J Bone Miner Res. 2011;26(11):2647-55.



Schimmel RJ, Pasmans SG, Xu M, Stadhouders-Keet SA, Shore EM, Kaplan FS, Wulfraat NM. GNAS-associated disorders of cutaneous ossification: two different clinical presentations. Bone 2010: 46; 868-872.



Adegbite, N.S, M. Xu, F.S. Kaplan, E.M. Shore, R.J. Pignolo (2008). Clinical features, GNAS mutational analysis, and diagnostic criteria for progressive osseous heteroplasia (POH) and POH-like syndromes. Amer. J. Med. Genet. 146A(14): 1788-1796.



Gelfand, I., R.S. Hub, E.M. Shore, F.S, Kaplan, L.A. DiMeglio (2007). Progressive Osseous Heteroplasia-Like Heterotopic Ossification in a Male Infant with Pseudohypoparathyroidism Type Ia: A Case Report. Bone 40, 1425-1428.



Kaplan FS, Glaser DL, Hebela N, Shore EM. Heterotopic ossification. J Am Acad Ortho Surg. 2004;12:116-125.



Faust, R.A., E.M. Shore, C.E. Stevens, M. Xu, S. Shah, C.D. Phillips, and F.S. Kaplan (2003). Progressive osseous heteroplasia in the face of a child. Amer. J. Med. Genet. 118A, 71-75.



Shore EM, Ahn J, Jan de Beur S, et al. Paternally inherited inactivating mutations of the GNAS1 gene in progressive osseous heteroplasia. N Engl J Med. 2002;346:99-106.



Rosenfeld SR, Kaplan FS. Progressive osseous heteroplasia in male patients: Two new case reports. Clin Orthop. 1995;317:243-45.



Kaplan FS, Hahn JV, Zasloff MA. Heterotopic ossification: two rare forms and what they can teach us. J Am Acad Orthop Surg. 1994;2:288-96.



Schmidt AH, Vincent KA, Aiona MD. Hemimelic progressive osseous heteroplasia: a case report. J Bone Joint Surg Am. 1994;76:Pp. 907-12.



Athanasou NA, Benson MK, Brenton BP, Smith R. Progressive osseous heteroplasia: a case report. Bone. 1994;15:471-75.



Kaplan FS, Craver R, MacEwen GD, et al. Progressive osseous heteroplasia: a distinct developmental disorder of heterotopic ossification. Two new case reports and follow-up of three previously reported cases. J Bone Joint Surg Am. 1994;76:425-36.



INTERNET

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 166350; Last Edit:6/17/09.

Resources

NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases

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Progressive Osseous Heteroplasia Association

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