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Last updated: September 28, 2020
Years published: 1991, 1996, 1998, 1999, 2002, 2014, 2017, 2020
NORD gratefully acknowledges Frederick Singer, MD, Director, Endocrine/Bone Disease Program, John Wayne Cancer Institute, for assistance in the preparation of this report.
Summary
Fibrous dysplasia (FD) is a rare bone disorder. Bone affected by this disorder is replaced by abnormal scar-like (fibrous) connective tissue. This abnormal fibrous tissue weakens the bone, making it abnormally fragile and prone to fracture. Pain may occur in the affected areas. As children grow, affected bone may become misshapen (dysplastic). FD may only affect one solitary bone (monostotic disease) or the disorder can be widespread, affecting multiple bones throughout the body (polyostotic disease). The severity of the disorder can vary greatly from one person to another. Any part of the skeleton can be affected, but the long bones of the legs, the bones of the face and skull (craniofacial area), and the ribs are most often affected. FD is usually diagnosed in children or young adults, but mild cases may go undiagnosed until adulthood. In some cases, FD may not require treatment; in other cases, certain medications and surgical procedures may be recommended.
Introduction
FD was first described in the medical literature in 1938 by Dr. Lichtenstein and in 1942 by Drs. Lichtenstein and Jaffe. Fibrous dysplasia can occur as part of a larger disorder such as McCune-Albright syndrome (fibrous dysplasia-cafรฉ au lait spots-endocrine dysfunction) or Mazabraud syndrome (fibrous dysplasia-myxomas). The term Jaffe-Lichtenstein syndrome is sometimes used synonymously with monostotic FD or to denote cases of polyostotic FD with cafรฉ au lait spots, but no endocrine dysfunction. These disorders most likely represent a spectrum of disease associated with activating mutations of the GNAS1 gene.
The severity and specific symptoms of FD can vary greatly from one person to another. Most affected individuals only have one bone involved and often there are no associated symptoms (asymptomatic). Many times, FD is discovered incidentally when x-rays are performed for another reason. Conversely, some affected individuals can have multiple bones affected and develop severe and potentially disabling or disfiguring symptoms. In most affected individuals, onset of symptoms is usually in childhood; it is unusual for the onset of the disorder to occur after 10.
FD is a benign (noncancerous) disorder and does not spread. The bone or bones that are affected by the disorder are usually established early in life and it is very rare for new areas to become affected. The areas affected may be described as lesions. FD lesions may progressively grow and expand until an affected bone finishes growing. These lesions can eventually cause affected bones to become abnormally weakened, misshapen, and prone to facture. Bone pain can also occur and may be severe in some patients.
Specific symptoms associated with FD depend upon the specific bones involved. Any part of the skeleton can potentially be affected, but the long bones of the arms and legs, the bones of the face and skull (craniofacial area), and the ribs are most often affected. Monostotic FD often presents as a painless swelling on the ribs. FD affecting the spine can cause abnormal curvature of the spine (scoliosis). When the long bones of the legs are affected, this can lead to frequent fractures due to weight bearing when walking or standing. Additionally, the long bones can eventually become bowed. In children, their legs may not be of equal length (limb length discrepancy). Eventually, this can affect a personโs ability to walk, causing an abnormal gait (e.g. walking with a limp).
FD of the craniofacial region can cause a variety of symptoms depending on the type and specific location of the lesions(s). Such symptoms can include pain, nasal congestion, misaligned or displaced teeth, uneven jaws, and facial asymmetry, in which one side of the face does not match the other side. FD in the craniofacial region can alter the facial features resulting in an abnormally prominent forehead (frontal bossing), bulging eyes (proptosis), and difference in the vertical positions of the eyes so that the eyes are uneven (vertical dystopia). The degree of facial abnormality can vary greatly from one person to another. The shape of the skull may be altered in certain cases.
FD can potentially cause a variety of neurological symptoms as areas of abnormal tissue development can compress nearby nerves. Specific symptoms are related to the specific nerves involved. For example, vision loss and hearing impairment can occur because of compression of optic and auditory nerves in the skull. However, vision loss and hearing impairment only occur in rare instances.
The abnormal structure of affected bone can lead to degenerative arthritis in adjacent joints.
Women with FD may be at risk of increased pain during pregnancy because of the estrogen receptors found in FD.
Although the term tumor may be used to describe FD lesions, these growths are benign (non-cancerous). Only in extremely rare cases do FD lesions become cancerous (malignant transformation). These malignant tumors developed in individuals who had been radiated for bone pain; a treatment option that has been abandoned.
The underlying cause of FD is not fully understood. Researchers believe that the disorder is caused by a change (mutation) in a gene called GNAS1. This gene mutation occurs after fertilization of the embryo (somatic mutation) and is therefore not inherited, nor will affected individuals pass the mutation on to their children. Affected individuals have some cells with a normal copy of this gene and some cells with the abnormal gene (mosaic pattern). The variability of symptoms of FD is due, in part, to the ratio of healthy cells to abnormal cells. Researchers do not know why these somatic mutations occur; they appear to develop randomly for unknown reasons (sporadically).
The GNAS1 gene creates (encodes) a protein known as a G-protein. In FD, a gain-of-function mutation in the GNAS1 gene results in the overproduction of this G-protein. In turn, this results in the overproduction of a molecule known as cyclic adenosine monophosphate (cAMP), which is involved in the change (differentiation) of osteoblasts in bone. Osteoblasts are bone-forming cells that form new bone. The human skeleton is living tissue that is constantly changing (remodeling). It is believed that FD involves increased bone turnover. Bone turnover is a normal process in which bone gradually breaks down (bone resorption) and then reforms. Bone turnover involves osteoblasts and cells that control bone resorption (osteoclasts). The interaction between osteoclasts and osteoblasts determines how bone reforms. The interaction is a complex process that involves many factors. Improper differentiation of osteoblasts due to mutation of the GNAS1 gene is believed to contribute to the development of FD. The activity of the osteoclasts in removing bone probably allows skeletal progenitor cells including immature osteoblasts and fibrous tissue to have more space to grow and multiply.
When other cells such as endocrine or skin cells are involved in addition to osteoblasts, McCune-Albright syndrome develops.
Fibrous dysplasia affects males and females in equal numbers. The disorder is diagnosed earlier in children and young children. The exact incidence and prevalence of the disorder is unknown. Mild cases may go undiagnosed, making it difficult to determine the true frequency of FD in the general population. The monostotic form is more common than the polyostotic form; according to some reports by a ratio of 4:1.
A diagnosis of fibrous dysplasia is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Individuals with mild forms of monostotic FD may be diagnosed incidentally when receiving an x-ray for another reason.
Clinical Testing and Workup
Specialized imaging techniques may be used to evaluate bone. Such imaging techniques include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. The abnormal tissue in FD resembles ground glass when seen on x-ray. These tests may be used to determine how extensively bones are affected.
A bone scan, also known as bone scintigraphy, is used to determine the extent of bone disease and may be used when a solitary FD lesion is found to confirm a diagnosis of monostotic FD or to discover whether additional affected areas are present (polyostotic FD). During this test, a harmless radioactive dye is injected into an arm vein. A special camera that can track the dye as it travels through bone is used to create a picture of the skeleton and determine all affected areas.
Bone biopsy is the surgical removal and microscopic examination of a small sample of affected tissue. A bone biopsy can reveal characteristic changes to bone that occur in individuals with FD and may be necessary to distinguish a FD lesion from other types of growths or tumors if it is unclear after an x-ray.
A highly sensitive, specific form of polymerase chain reaction (PCR) has been used to detect somatic mutations of the GNAS1 gene that characterize FD. PCR is a laboratory test that has been described as a form of โphotocopying.โ It enables researchers to enlarge and repeatedly copy sequences of DNA. As a result, they are able to closely analyze DNA and more easily identify genes and genetic changes (mutations). In FD, a specific form of PCR testing can detect activating mutations of GNAS1 in peripheral blood cells.
Treatment
The treatment of FD is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, general internists, orthopedic surgeons, endocrinologists, and other healthcare professionals may need to systematically and comprehensively plan an affect childโs treatment. Psychosocial support for the entire family is essential as well.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease progression; size of the lesion(s); the presence or absence of certain symptoms; an individualโs age and general health; and/or other elements. Decisions concerning the use of particular drug regimens, surgical treatments and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors. Being seen by a physician(s) with familiarity in treating individuals with FD is recommended.
In many cases, FD lesions do not cause any symptoms (asymptomatic). In such cases, observation and patient education may be all that is needed. Follow up x-rays every six months are recommended to determine whether the lesion has progressed.
Individuals with FD have been treated with drugs known as bisphosphonates such as pamidronate or alendronate. These drugs reduce bone turnover by inhibiting bone resorption. Calcium and vitamin D may be given along with the drug. Some affected individuals respond favorably to such therapy with the main benefit being decreased bone pain. Other affected individuals do not respond to therapy with bisphosphonates or relapse after an initial period of improvement. Relapse of bone pain is more common in individuals with polyostotic FD. The most potent bisphosphonate intravenous zoledronic acid may be used in such cases and is the most effective in improving bone pain.
Surgery is often used to treat individuals with FD, although most physicians recommend a conservative strategy. Surgery should be undertaken only for lesions that causing difficulty in some way. Surgery may be undertaken to correct disfigurement or deformity, to correct limb length discrepancy, to eradicate symptomatic lesions (e.g. those causing pain and/or compressing a nerve), to treat specific complications such as scoliosis, or to prevent fracture. Standard surgical procedures are effective in most adults with monostotic FD.
The drug tocilizumab is being studied as a potential therapy for FD. Tocilizumab is a drug that works by blocking the activity of interleukin-6 (IL-6), a specialized protein (cytokine) that stimulates bone resorption. Affected bone cells in FD release excess levels of interleukin-6 and researchers believe inhibiting IL-6 will decrease bone resorption.
Additional drugs are being study as potential therapies for FD. Such drugs include denosumab, a monoclonal antibody currently approved to treat osteoporosis and pregabalin, which is effective at treating neuropathic pain. More research is necessary to determine the long-term safety and effectiveness of experimental medications for the treatment of individuals with FD.
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:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Lietman SA, Levine MA. Fibrous dysplasia. Pediatr Endocrinol Rev. 2013;10:389-396. https://www.ncbi.nlm.nih.gov/pubmed/23858622
Lee JS, FitzGibbon EJ, Chen YR, et al. Clinical guidelines for the management of craniofacial fibrous dysplasia. Orphanet J Rare Dis. 2012;7(Suppl 1):S2. https://www.ncbi.nlm.nih.gov/pubmed/22640797
Collins MT, Singer FR, Eugster E. McCune-Albright syndrome and the extra skeletal manifestations of fibrous dysplasia. Orphanet J Rare Dis. 2012;7:S4. https://www.ncbi.nlm.nih.gov/pubmed/22640971
Chapurlat RD, Gensburger D, Jimenez-Andrade JM, et al. Pathophysiology and medical treatment of pain in fibrous dysplasia of bone. Orphanet J Rare Dis. 2012;7:S3. https://www.ncbi.nlm.nih.gov/pubmed/22640953
Stanton RP, Ippolito E, Springfield D, et al. The surgical management of fibrous dysplasia of bone. Orphanet J Rare Dis. 2012;7:S1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3359959/
Boyce AM, Chong WH, Yao J, et al. Denosumab treatment of fibrous dysplasia. J Bone Miner Res. 2012;27:1462-1470. https://www.ncbi.nlm.nih.gov/pubmed/22431375
Moseley JN, Friedrich JB. Monostotic fibrous dysplasia of the distal radius metaphysis: case report. Hand (NY). 2011;6:224-227. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3092897/
Regard JB, Cherman N, Palmer D, et al. Wnt/B-catenin signaling is differentially regulated by Ga proteins and contributes to fibrous dysplasia. Proc Natl Acad Sci USA. 2011;108:20101-20106. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250124/
DiCaprio MR, Enneking WF. Fibrous dysplasia. Pathophysiology, evaluation, and treatment. J Bone Joint Surg Am. 2005;87:1848-1864. https://www.ncbi.nlm.nih.gov/pubmed/16085630
Lietman SA, Ding C, Levine MA. A highly sensitive polymerase chain reaction method detects activating mutations of the GNAS gene in peripheral blood cells in McCune-Albright syndrome or isolated fibrous dysplasia. J Bone Joint Surg Am. 2005;87:2489-2494. https://www.ncbi.nlm.nih.gov/pubmed/16264125
Weinstein LS, Shenker A, Gejman PV, et al. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl Med. 1991;325:1688-1695. https://www.ncbi.nlm.nih.gov/pubmed/1944469
INTERNET
Boyce AM. Fibrous Dysplasia. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Available from Endotext.org. Updated March 27, 2019. https://www.ncbi.nlm.nih.gov/books/NBK326740/ Accessed Sept 28, 2020.
Vargas B, Clayer M. Orthopedic Surgery for Fibrous Dysplasia.Medscape. Updated: Dec 10, 2018. Available at: https://emedicine.medscape.com/article/1255262-overview Accessed Sept 28, 2020.
NIH/Osteoporosis and Related Bone Diseases ~ National Resource Center. Fibrous Dysplasia Overview. Last Update Dec 2018. Available at: https://www.niams.nih.gov/Health_Info/Bone/Additional_Bone_Topics/fibrous_dysplasia.asp Accessed Sept 28, 2020.
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