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, Professor of Orthopaedic Molecular Medicine and Genetics and Co-Director of The 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.
Fibrodysplasia ossificans progressiva (FOP) is a very rare inherited connective tissue disorder characterized by the abnormal development of bone in areas of the body where bone is not normally present (heterotopic ossification), such as the ligaments, tendons, and skeletal muscles. Specifically, this disorder causes the body's skeletal muscles and soft connective tissues to undergo a metamorphosis, essentially a transformation into bone, progressively locking joints in place and making movement difficult or impossible. FOP is characterized by malformed big toes that are present at birth (congenital). Other skeletal malformations of the cervical spine and ribs and the abnormal development of bone at multiple soft tissue sites may lead episodically to stiffness in affected areas, limited movement, and eventual ankylosis of affected joints (neck, shoulders, elbows, hips knees, wrists, ankles, jaw, often in that order).
Episodic flare-ups (pre-osseous soft tissue swellings) of FOP usually begin during early childhood and progress throughout life. Most cases of FOP occur as the result of a sporadic new mutation. The genetic mutation that results in this disorder has been identified. FOP is caused by the mutation of a gene in the bone morphogenetic protein (BMP) pathway, which is important during the formation of the skeleton in the embryo and the repair of the skeleton following birth.
All individuals with classic FOP have malformations of the great toes and, in approximately 50% of patients, the thumbs. These changes in the skeleton are present at birth (congenital) and are the first clinical signs of this disorder. The most common malformation associated with FOP is a shortened great toe with a malformed distal first metatarsal and a missing or abnormal interphalangeal joint. Other malformations of the toes and fingers may include inward turning of the great toe toward the other toes (hallux valgus), abnormally short fingers and toes (microdactyly), and/or permanent fixation of the fifth finger in a bent position (clinodactyly). Other congenital signs of FOP include proximal medial tibial osteochondromas, malformation of the upper part of the spinal column (cervical vertebrae) and/or an abnormally short broad neck of the bone in the thigh that extends from the knee to the pelvis (femur).
Progressive bone formation in areas of the body where bone is not normally present (heterotopic ossification) usually occurs during early childhood, but can occur during adolescence, early adulthood, or throughout life. The abnormal development of bone may occur spontaneously, but most commonly follows an episode of soft tissue injury or a viral illness. The first sign of heterotopic ossification is the appearance of firm tender swellings on certain parts of the body, especially the back, neck, and/or shoulders. These soft tissue swellings mature through an endochondral pathway to form mature heterotopic bone. Bony growths usually involve tendons, ligaments, skeletal muscle tissue, and connective tissue such as fascia and aponeuroses. In some cases, pain and stiffness occurs in these areas. On some occasions, a low-grade fever may herald the development of these swellings. Although the swellings eventually regress, they also harden into mature bone as they decrease in size.
In the affected areas, bone slowly replaces connective tissue; in addition to skeletal muscle, bony growths also occur in various tendons, ligaments, and bands of fibrous tissue that support muscles (fascia). The neck, back, chest, arms, and legs are usually the first areas affected. The disease may eventually affect the hips, ankles, wrists, elbows, shoulders, and/or jaw as well as the abdominal wall. In some affected individuals, the progression of bone development may be rapid; in others, the process may be gradual. Even among identical twins, the disease progression may vary greatly, reflecting different traumatic episodes.
Chronic swelling in various parts of the body is a common physical characteristic of individuals with FOP. Swelling may occur along with the abnormal bone formation that characterizes FOP, or it may occur when newly-formed bone presses on lymphatic vessels, obstructing the flow of tissue fluid. In addition, swelling may also be caused by a lack of pumping action within the hardened (ossified) muscle and can cause blood and tissue fluids to pool in a limb (e.g., arms and/or legs).
Abnormal development of bone eventually leads to stiffness and limited movement of affected joints. If the jaw is involved, affected individuals may have trouble eating and/or speaking. In addition, abnormal development of bone may lead to progressive deformity of the spine including side-to-side (scoliosis) and, in some cases, front-to-back curvature of the spine (kyphosis). In some cases, the bone that develops in abnormal areas may fracture. As the disease progresses, individuals with FOP experience limited mobility that causes problems with balance, difficulty walking and/or sitting, and/or severely restricted movement.
FOP may eventually result in complete immobilization. Affected individuals may experience progressive pain and stiffness in affected areas, complete fusion of the spine, and/or pain in certain areas of the body caused by abnormal bony growths that compress the nerves in these areas (entrapment neuropathies). As mobility begins to deteriorate, affected individuals may exhibit an increased susceptibility to respiratory infection or right sided congestive heart failure. In some cases of FOP variants, individuals may exhibit hair loss or mild cognitive delay. Hearing impairment is seen in approximately 50% of affected individuals.
Most cases of FOP occur sporadically. Where a familial pattern has been identified, FOP is inherited as an autosomal dominant trait with complete penetrance.
In April 2006, an international team of researchers led by Eileen M. Shore, PhD, and Frederick S. Kaplan, MD, of the University of Pennsylvania, published results of research identifying the genetic mutation that causes FOP. The team found that FOP is caused by a mutation of a gene on chromosome 2 (2q23-24) for a receptor in the BMP signaling pathway called ACVR1.
Bone morphogenetic proteins are regulatory proteins involved in the embryonic formation and after-birth (post-natal) repair of the skeleton. The gene identified as the FOP gene encodes a BMP receptor called Activin Receptor Type IA, or ACVR1, one of four known BMP Type I receptors. BMP receptors help determine the fate of the stem cells in which they are expressed. Classic FOP occurs when a particular amino acid in the ACVR1 protein is substituted for another amino acid at a specific location. In 2012, an ACVR1 knock-in mouse was reported with the same phenotype as human FOP. Extremely rare and illustrative phenotypic and genotypic variants of FOP have been reported, but in all patients, heterozygous activating mutations are present in the ACVR1 gene.
Chromosomes, present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22, and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome, and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further subdivided into many numbered bands, which specify the location of the thousands of genes that are present on each chromosome. For example, chromosome 2q23-24 refers to a location between bands 23 and 24 on the long arm of chromosome 2.
Genes are on the chromosomes that are inherited from the father and the mother. Phenotypic variation (including genetic diseases) is determined by the genes that specify a particular trait.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy, regardless of the sex of the resulting child.
FOP is a very rare inherited connective tissue disorder that was first identified in the 17th century. Of an estimated 3000 affected individuals worldwide, there are approximately 800 known patients. This disorder affects both genders and all ethnicities.
Malformations of the toes and fingers may be present at birth (congenital); abnormal development of extra-skeletal bone usually occurs during early childhood. In some rare cases, onset of abnormal bone growth may not occur until late adolescence or early adulthood. Affected individuals may have periods of time where they are free of new episodes of bone growths. However, new bone growth may begin at any time for no apparent reason (spontaneously).
Misdiagnosis of FOP is common but can be avoided simply by examining the individual’s toes for the characteristic feature, short great toes. The diagnosis may be confirmed by a thorough clinical evaluation, characteristic physical findings, and sequencing of the ACVR1 gene.
Biopsies should be avoided because the tests may result in rapid bone formation in those areas where tissue is removed. Intramuscular injections (e.g., immunizations) must be avoided, and dental therapy should preclude injections of local anesthetics and stretching of the jaw. In addition, individuals should avoid any situations, such as falls, that may cause blunt trauma, since trauma may cause abnormal bone development in most cases. Various viral illnesses including influenza and influenza-like illnesses may provoke flare-ups of the condition.
In affected individuals with an increased susceptibility to respiratory infections due to progressive mobility impairment, certain steps may be taken to prevent such infection, such as preventative (prophylactic) antibiotic therapy.
There are no known effective treatments for FOP. Certain types of drugs have been used to relieve pain and swelling associated with FOP during acute flare-ups (most notably corticosteroids) and non-steroidal anti-inflammatory medication between flare-ups.
Affected individuals may benefit from occupational therapy. Special shoes, braces, and other devices that assist in walking and weight-bearing have been used to help people with FOP. Affected individuals may have their physicians contact an occupational therapist who can help obtain special devices or tools to assist them in daily activities.
Genetic counseling may be of benefit for families with the hereditary form of FOP. A team approach for infants with this disorder will also be of benefit and may include special social, educational, and medical services. Other treatment is symptomatic and supportive.
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 website.
For information about clinical trials being conducted at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
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For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
It is hoped that the discovery of the FOP gene and the mutation that causes FOP will lead to future research on possible ways to treat the disease itself, and not just its symptoms.
Investigational therapies for FOP might include antiangiogenic agents, retinoic acid receptor gamma-selective agonists and BMP antagonists. Corticosteroids, cox-2 inhibitors, leukotriene inhibitors, and thalidomide have also been explored.
Contacts for additional information about fibrodysplasia ossificans progressiva:
Eileen M. Shore, PhD
Professor, Departments of Orthopaedic Surgery and Genetics
Perelman School of Medicine
University of Pennsylvania
424 Stemmler Hall
3450 Hamilton Walk
Philadelphia, PA 19104-6081
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