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Hereditary Multiple Osteochondromas

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Copyright 1993, 2000, 2008, 2012

NORD is very grateful to Wim Wuyts, PhD, Department of Medical Genetics, University and University Hospital of Antwerp, Belgium, for assistance in the preparation of this report.

Synonyms of Hereditary Multiple Osteochondromas

Disorder Subdivisions

General Discussion

Summary
Hereditary multiple osteochondromas (HMO) is a rare genetic disorder characterized by multiple benign (noncancerous) bone tumors that are covered by cartilage (osteochondromas), often on the growing end (metaphysis) of the long bones of the legs, arms, and digits. These osteochondromas usually continue to grow until shortly after puberty and may lead to bone deformities, skeletal abnormalities, short stature, nerve compression and reduced range of motion. Hereditary multiple osteochondromas is inherited as an autosomal dominant genetic condition and is associated with abnormalities (mutations) in the EXT1or EXT2 gene.

Introduction
Hereditary multiple osteochondromas was formerly called hereditary multiple exostoses.

Symptoms

Hereditary multiple osteochondromas is a rare disorder that affects bone growth. Bony tumors (exostoses or osteochondromas), covered with cartilage, typically appear in the growth zones (metaphyses) of the long bones adjacent to the areas where tendon and muscles attach to the bone. These growths vary in size and number among affected individuals, even within the same family. Some individuals will present with a few large "lumps" while others will show several small growths. The median age of diagnosis is three years and almost all affected individuals are diagnosed by 12 years of age.

In many cases, no treatment is required. If the exostoses are small, they may have little or no effect on the patient. However, in more severe cases, the growths may cause deformities of the forearm, knees, ankles, spine and/or pelvis. They may impose upon nerves, tendons and/or blood vessels, and interfere with movement or circulation, causing substantial pain as a result of pinched nerves or compressed tendons.

Bones that develop exostoses most often are the upper arm (humerus), forearm, knee and shoulder blades (scapulae). Bowing of the forearm and ankle are the problems that most often require surgical correction.

Approximately 40 percent of affected individuals have mild short stature as a result of shortened and/or bowed legs. If the vertebrae are affected, spinal cord compression may result, causing numbness and/ or paralysis. Urinary obstruction has been observed due to exostoses of the pelvic area.

The bony growths that characterize this disorder continue to grow until shortly after puberty at which time normally new growth no longer develops. The risk for development of malignant (cancerous) tumors, mostly chondrosarcomas, is approximately 1 to 5%.

Causes

Hereditary multiple osteochondromas is inherited as an autosomal dominant genetic condition. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation in the affected individual. Approximately 10% of cases of HMO are thought to be the result of new mutations. At present two genes, EXT1 and EXT2, are known to show mutations in HMO patients and it is thought that these genes function as tumor suppressors. For some affected individuals no mutation in either gene is detected. In almost all these cases, the "mutation negative" patients do not have a familial history for exostoses. Most likely, they have an EXT1 or EXT2 mutation in only part of their body cells and the mutation is absent or undetectable in blood cells, which are usually used for DNA analysis. Data indicates that individuals with EXT1 mutations may have more severe effects than those with EXT2 mutations. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.

Affected Populations

The prevalence of HMO has been estimated to be about 1 of 50,000 live births. A high prevalence of this disorder has been reported in some isolated communities. Hereditary multiple osteochondromas is a disorder that affects males and females in equal numbers but in general males tend to be more severely affected.

Related Disorders

Symptoms of the following disorders can be similar to those of hereditary multiple exostoses. Comparisons may be useful for a differential diagnosis.

Metachondromatosis is a very rare autosomal dominant genetic disorder characterized by both enchondromatosis and multiple exostoses. Enchondromatosis is characterized by slow growing tumors of cartilage cells near the ends of the long bones. The multiple exostoses associated with this condition occur mostly in the digits and do not lead to deformity of the long bones or joints. This condition is caused by a mutation in the PTPN11 gene.

Langer-Giedion syndrome, also known as trichorhinophalangeal syndrome type II (TRPS2), is an extremely rare inherited multisystem disorder. TRPS2 is characterized by fine, thin hair; unusual facial features; progressive growth retardation resulting in short stature (dwarfism); abnormally short fingers and toes (brachydactyly); "cone-shaped" formation of the "growing ends" of certain bones (epiphyseal coning); and/or development of multiple bony growths (exostoses) projecting outward from the surfaces of various bones of the body. In addition, affected individuals may exhibit unusually flexible (hyperextensible) joints, diminished muscle tone (hypotonia), excess folds of skin (redundant skin), and/or discolored elevated spots on the skin (maculopapular nevi). Affected individuals may also exhibit mild to severe mental retardation, hearing loss (sensorineural deafness), and/or delayed speech development. The range and severity of symptoms varies greatly from case to case. TRPS2 is due to the absence of genetic material (chromosomal deletions) on chromosome 8. The size of the deletion varies from case to case but includes the EXT1 gene. (For more information on this disorder, choose "trichorhinophalangeal syndrome type II " as your search term in the Rare Disease Database.)

11p11 deletion syndrome is a condition caused by a deletion of adjacent genes on chromosome 11 (contiguous gene syndrome) including the EXT2 gene. This condition is characterized by ossification defects of the skull, multiple exostoses and sometimes craniofacial abnormalities and mental retardation.

Standard Therapies

The diagnosis of HMO is based on clinical features, X-ray findings and family history. Molecular genetic testing of the EXT1 and EXT2 genes is available to confirm the diagnosis.

Treatment
Surgery may be required to relieve pain, improve movement, restore normal circulation, or for cosmetic reasons. Malignant degeneration of a tumor is treated surgically, possibly in combination with chemotherapy and radiation therapy.

Most of the malignant degenerations to cancers are to cartilage tumors or chondrosarcomas, which are slow growing and generally insensitive to chemotherapy.

Monitoring the size of affected bones by annual scans to screen for malignant degeneration is sometimes recommended. Rapid growth and increased pain are signs of a possible malignant change.

Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

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 National Institutes of Health (NIH) 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

Contact for additional information about hereditary multiple osteochondromas:

Wim Wuyts, PhD
Department of Medical Genetics
University and University Hospital of Antwerp
Prins Boudewijnlaan 43
2650 Edegem
Belgium
Phone: 32-3-275.97.06
Fax: 32-3-275.97.23

Hereditary Multiple Osteochondromas Resources

Organizations:

References

JOURNAL ARTICLES
Bowen ME, Boyden ED, Holm IA, et al. Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome. PLoS Genet. 2011; 7(4):e1002050.

Pedrini E, Jennes I, Tremosini M, et al. . Genotype-phenotype correlation study in 529 patients with multiple hereditary exostoses: identification of "protective" and "risk" factors. J Bone Joint Surg Am. 2011;93(24):2294-302.

Jones KB, Piombo V, Searby C et al. A mouse model of osteochondromagenesis from clonal inactivation of Ext1 in chondrocytes. Proc Natl Acad Sci U S A. 2010;107(5):2054-2059.

Jennes I, Pedrini E, Zuntini M et al.Multiple osteochondromas: mutation update and description of the multiple osteochondromas mutation database (MOdb). Hum Mutat. 2009;30(12):1620-16277.

Bovée JV. Multiple osteochondromas. Orphanet J Rare Dis. 2008;3:3.

Alvarez CM, De Vera MA, Heslip TR, Casey B. Evaluation of the anatomic burden of patients with hereditary multiple exostoses. Clin Orthop Relat Res. 2007;462:73-79.

Jaeger M, Westhoff B, Portier S, et al. Clinical outcome and genotype in patients with hereditary multiple exostoses. J Orthop Res. 2007;25(12):1541-1551.

Stieber JR, Dormans JP. Manifestations of hereditary multiple exostoses. J Am Acad Orthop Surg. 2005;13(2):110-120.

Porter DE Lonie L, Fraser, M, et al. Severity of disease risk of malignant change in hereditary multiple exostoses. A genotype-phenotype study. J Bone Joint Surg Br. 2004;86:1041-1046.

Ropero S, Setien F, Espada J, et al. Epigenetic loss of the familiar tumor-suppressor gene exostosin-1 (EXT1) disrupts heparan sulfate synthesis in cancer cells. Hum Mol Gent. 2004;13:2753-2765.

Noonan KJ, Feinberg JR, Levanda A, et al. Natural history of multiple hereditary osteochondromatosis of the lower extremity and ankle. J Pediatr Orthop. 2002;22 :120-4.

Bernard MA, Hall CE, Hogue DA, et al. Diminished levels of the putative tumor suppressor proteins EXT1 and EXT2 in exostoses chondrocytes. Cell Motil Cytoskeleton. 2001;48:149-162.

Francannet C, Cohen-Tanugi A, Le Merrer M, et al. Genotype-phenotype correlation in hereditary multiple exostoses. J Med Genet. 2001;38:430-434.

Bernard MA, Hogue DA, Cole WG, et al. Cytoskeletal abnormalities in chondrocytes with EXT1 and EXT2 mutations J Bone Miner Res. 2000;15:442-450.

McCormick C, Duncan G, Goutsos KT, et al. The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate. Proc Natl Acad Sci USA. 2000;97:668-673.

Wicklund Cl, Pauli RM, Johnson D, et al. Natural history study of hereditary multiple exostoses. Am J Med Genet. 1995;55:43-46.

Schmale GA, Conrad EU 3rd, Raskind WH. The natural history of hereditary multiple exostoses. J Bone Joint Surg Am. 1994;76:986-992.

INTERNET
Schmale GA, Wuyts W, Chansky HA, Raskind WH. (Updated September 5, 2008). Hereditary Multiple Osteochondromas. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2012. Available at http://www.genetests.org. Accessed September 19, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Exostoses, Multiple, Type I. Entry No: 133700. Last Edited June 1, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed September 19, 2012.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Exostoses, Multiple, Type II. Entry No: 133701. Last Edited December 8, 2009. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed September 19, 2012.

Report last updated: 2012/09/19 00:00:00 GMT+0