NORD gratefully acknowledges Frederick S. Kaplan, MD, Isaac & Rose Nassau Professor of Orthopaedic Molecular Medicine; Chief, Division of Orthopaedic Molecular Medicine and Director, Center for Research in FOP & Related Disorders, The Perelman School of Medicine at The University of Pennsylvania and Eileen M. Shore, PhD, Cali/Weldon Professor of FOP Research, Departments of Orthopaedic Surgery and Genetics, and Co-Director, Center for Research in FOP & Related Disorders, The Perelman School of Medicine at The University of Pennsylvania, for assistance in the preparation of this report.
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.
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.
Most cases of POH occur randomly as the result of a spontaneous (sporadic) 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 regulating the activity of proteins (created by other genes) that promote bone growth and direct cell fate decisions. Mutation of the gene results in deficiency or dysfunction of this protein. The exact manner in which mutations of the GNAS gene bring about the symptoms of POH is not yet known, however recent evidence implicates activation of the “hedgehog” signaling pathway in this process.
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).
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.
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
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.
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.
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