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Hereditary Multiple Osteochondromas

Synonyms: Diaphyseal Aclasis, Multiple Cartilaginous Exostoses, Hereditary Multiple Exostoses. Includes: Hereditary Multiple Osteochondromatosis, Type I; Hereditary Multiple Osteochondromatosis, Type II

, PhD, , MD, , MD, and , MD, PhD.

Author Information
, PhD
Department of Medical Genetics
University and University Hospital of Antwerp
Antwerp, Belgium
, MD
Associate Professor, Department of Orthopaedics and Sports Medicine
University of Washington
Seattle, Washington
, MD
Professor, Department of Orthopaedics and Sports Medicine
University of Washington
Seattle, Washington
, MD, PhD
Professor, Department of Medicine
Division of Medical Genetics
University of Washington
Seattle, Washington

Initial Posting: ; Last Update: November 21, 2013.

Summary

Disease characteristics. The disorder hereditary multiple osteochondromas (HMO), previously called hereditary multiple exostoses (HME), is characterized by growths of multiple osteochondromas (benign cartilage-capped bone tumors that grow outward from the metaphyses of long bones). Osteochondromas can be associated with a reduction in skeletal growth, bony deformity, restricted joint motion, shortened stature, premature osteoarthrosis, and compression of peripheral nerves. The median age of diagnosis is three years; nearly all affected individuals are diagnosed by age 12 years. The risk for malignant degeneration to osteochondrosarcoma increases with age, although the lifetime risk of malignant degeneration is low (~1%).

Diagnosis/testing. The diagnosis of HMO is based on clinical and/or radiographic findings of multiple exostoses in one or more members of a family. The two genes in which mutations are known to cause HMO are EXT1 and EXT2. A combination of sequence analysis and deletion analysis of the entire coding regions of both EXT1 and EXT2 detects mutations in 70%-95% of affected individuals.

Management. Treatment of manifestations: Painful lesions in the absence of bone deformity are treated with surgical excision that includes the cartilage cap and overlying perichondrium to prevent recurrence; forearm deformity is treated with excision of the exostoses, corrective osteotomies, and ulnar-lengthening procedures; though uncomplicated resection of osteochondromas in growing children is frequently reported, there is a theoretic risk of growth abnormality resulting from resection of periphyseal osteochondromas; leg-length inequalities greater than 2.5 cm are often treated with epiphysiodesis (growth plate arrest) of the longer leg or lengthening of the involved leg; angular misalignment of the lower limbs may be treated with hemiepiphysiodeses (or osteotomies) at the distal femur, proximal tibia, or distal tibia; early treatment of ankle deformity may prevent or decrease later deterioration of function; sarcomatous degeneration is treated by surgical resection.

Surveillance: Monitoring of the size of exostoses in adults may aid in early identification of malignant degeneration, but no cost/benefit analyses are available to support routine surveillance; a single screening MRI of the spine in children with HMO has been recommended by some to identify spinal lesions that may cause pressure on the spinal cord and would warrant close clinical follow up with excision of those lesions that cause spinal cord impingement and/or symptoms.

Genetic counseling. HMO is inherited in an autosomal dominant manner. Penetrance is approximately 96% in females and 100% in males. In 10% of affected individuals HMO is the result of a de novo mutation. Offspring of an affected individual are at a 50% risk of inheriting the disease-causing mutation. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation in a family is known.

Diagnosis

Clinical Diagnosis

Hereditary multiple osteochondromas (HMO) are diagnosed clinically in individuals with the following:

  • Multiple osteochondromas (cartilage-capped bony growths) arising from the area of the growth plate in the juxtaphyseal region of long bones or from the surface of flat bones (e.g., the scapula)
    • The key radiographic and anatomic feature of an osteochondroma is the uninterrupted flow of cortex and medullary bone from the host bone into the osteochondroma.
    • Osteochondromas possess the equivalent of a growth plate that ossifies and closes with the onset of skeletal maturity.
    • Approximately 70% of affected individuals have a clinically apparent osteochondroma about the knee, suggesting that radiographs of the knees to detect non-palpable osteochondromas may be a sensitive way to detect mildly affected individuals.
  • Family history consistent with autosomal dominant inheritance (~10% of affected individuals have no family history of multiple osteochondromas)

Note regarding terminology: Osteochondromas were previously called exostoses; however, the term exostosis is no longer used to describe the lesions in HMO because the term osteochondroma specifies that these lesions are cartilaginous processes that ossify and not simply outgrowths of bone. The changed terminology has been adopted by the World Health Organization (WHO).

Molecular Genetic Testing

Genes. The two genes in which mutations are known to cause HMO are EXT1 and EXT2.

Evidence for locus heterogeneity. One group has suggested that a third gene, EXT3, maps to chromosome 19 [Le Merrer et al 1994]; this linkage association has not been corroborated and may represent a false positive.

Clinical testing. Sequence analysis of the entire coding regions of both EXT1 and EXT2 detects mutations in 70%-85% of affected individuals. Performing deletion/duplication analysis to detect exonic, multiexonic, and whole-gene deletions may increase the detection rate to as much as 85%-95% [Jennes et al 2009]. FISH analysis is not recommended (see Table 1).

Table 1. Summary of Molecular Genetic Testing Used in Hereditary Multiple Osteochondromas

Gene 1Proportion of HMO Attributed to Mutations in This GeneTest MethodMutations Detected 2Mutation Detection Frequency by Gene and Test Method 3, 4
EXT156%-78% 5Sequence analysis/mutation scanning 6Sequence variants 788%-93%
FISH 8Large deletions0%-8% 8
Deletion/ duplication analysis 9(Multi)exonic and whole-gene deletions7%-10%
EXT221%-44% 5Sequence analysis/mutation scanning 6Sequence variants 790%-100%
FISH 8Large deletions<1% 8
Deletion/duplication analysis 9(Multi)exonic and whole-gene deletions0%-8%

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Mutation detection frequency reflects a combined approach of sequence analysis and MLPA for both EXT1 and EXT2 [Jennes et al 2009].

5. For review see Jennes et al [2009].

6. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably between laboratories depending on the specific protocol used. See Wuyts et al [2005], Signori et al [2007].

7. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

8. Not recommended. FISH analysis alone can detect only large deletions and therefore cannot detect the single-exon deletions that cause HMO. Note: (1) FISH probes that are commonly used for diagnosis of Langer-Giedion syndrome (also known as trichorhinophalangeal syndrome type II (TRPS2) (OMIM 150230) are not recommended for HMO diagnosis. Langer-Giedion syndrome is a contiguous gene deletion syndrome that includes EXT1 as well as TRPS1, the gene in which mutation causes trichorhinophalangeal syndrome type I (TRPS1), and other genes responsible for intellectual disability located near, but outside, EXT1. (2) FISH probes used for diagnosis of the contiguous gene deletion syndrome known as Potocki-Shaffer syndrome (proximal 11p deletion syndrome; P11pDS; OMIM 601224) are not recommended for HMO diagnosis. P11pDS includes EXT2 and ALX4, the gene associated with enlarged parietal foramina/cranium bifidum type 2 (see Genetically Related Disorders).

9. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Testing Strategy

To confirm/establish the diagnosis in a proband

1.

Sequence EXT1 first because EXT1 mutations are more frequently detected than EXT2 mutations.

2.

If no mutation is detected in EXT1 by sequence analysis, EXT2 should be sequenced.

3.

If no mutation is identified in either EXT1 or EXT2 by sequence analysis, deletion/duplication analysis of both genes should be considered.

Prenatal diagnosis and preimplantation genetic diagnosis for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

The number of osteochondromas, number and location of involved bones, and degree of deformity vary. Osteochondromas grow in size and gradually ossify during skeletal development and stop growing with skeletal maturity, after which no new osteochondromas develop. The proportion of individuals with hereditary multiple osteochondromas (HMO) who have clinical findings increases from approximately 5% at birth to 96% at age 12 years [Legeai-Mallet et al 1997]. The median age at diagnosis is three years. By adulthood, 75% of affected individuals have a clinically evident bony deformity. Males tend to be more severely affected than females [Pedrini et al 2011]. Most individuals with HMO lead active, healthy lives.

The number of osteochondromas that develop in an affected person varies widely even within families. Involvement is usually symmetric. Most commonly involved bones are the femur (30%), radius and ulna (13%), tibia (20%), and fibula (13%). Hand deformity resulting from shortened metacarpals is common. Abnormal bone remodeling may result in shortening and bowing with widened metaphyses [Porter et al 2004].

In a study of 46 kindreds in Washington State, 39% of individuals had a deformity of the forearm, 10% had an inequality in limb length, 8% had an angular deformity of the knee, and 2% had a deformity of the ankle [Schmale et al 1994]. Angular deformities (bowing) of the forearm and/or ankle are the most clinically significant orthopedic issues.

Hip dysplasia may result from osteochondromas of the proximal femur and from coxa valga. Decreased center-edge angles and increased uncovering of the femoral heads may lead to early thigh pain and abductor weakness and late arthritis [Malagon 2001, Ofiram & Porat 2004]. Femoral-acetabular impingement may also arise from proximal femoral osteochondromas, limiting hip motion [Shin et al 2009, Hussain et al 2010, Viala et al 2012].

It has been stated that 40% of individuals with HMO have "shortened stature.” Although interference with the linear growth of the long bones of the leg often results in reduction of predicted adult height, the height of most adults with EXT2 mutations and many with EXT1 mutations falls within the normal range [Porter et al 2004]. Shortened stature is more pronounced in persons with EXT1 mutations [Porter et al 2004, Pedrini et al 2011, Clement et al 2012].

Note: "Shortened stature" is used to indicate that although stature is often shorter than predicted based on the heights of unaffected parents and sibs, it is usually within the normal range.

Osteochondromas typically arise in the juxtaphyseal region of long bones and from the surface of flat bones (pelvis, scapula). An osteochondroma may be sessile or pedunculated. Sessile osteochondromas have a broad-based attachment to the cortex. The pedunculated variants have a pedicle arising from the cortex that is usually directed away from the adjacent growth plate. The pedunculated form is more likely to irritate overlying soft tissue, such as tendons, and compress peripheral nerves or vessels. The marrow and cancellous bone of the host bone are continuous with the osteochondroma.

Symptoms may also arise secondary to mass effect. Compression or stretching of peripheral nerves usually causes pain but may also cause sensory or motor deficits [Hattori et al 2006]. Spinal cord compression and myelopathy from cervical osteochondromas has been reported [Aldea et al 2006, Giudicissi-Filho et al 2006, Pandya et al 2006]. Mechanical blocks to motion may result from large osteochondromas impinging on the adjacent bone of a joint. Overlying muscles and tendons may be irritated, resulting in pain and loss of motion. Nerves and vessels may be displaced from their normal anatomic course, complicating attempts at surgical removal of osteochondromas. Rarely, urinary or intestinal obstruction results from large pelvic osteochondromas. Thoracic osteochondromas have been reported to lead to diaphragmatic rupture [Abdullah et al 2006].

The most serious complication of HMO is sarcomatous degeneration of an osteochondroma. Axial sites, such as the pelvis, scapula, ribs, and spine, are more commonly the location of degeneration of osteochondromas to chondrosarcoma [Porter et al 2004]. Rapid growth and increasing pain, especially in a physically mature person, are signs of sarcomatous transformation, a potentially life-threatening condition:

  • A bulky cartilage cap (best visualized with MRI or CT) thicker than 2.0 to 3.0 cm is highly suggestive of chondrosarcoma [Shah et al 2007].
  • After skeletal maturity, increased radionucleotide uptake on serial technetium bone scans may also be evidence of malignancy.
  • High metabolic activity in the cartilage as evidenced by uptake of gadolinum on T2 MRI may also be indicative of malignancy [De Beuckeleer et al 1996].
  • FDG-PET imaging may be useful in the workup for malignant transformation in HMO. An SUVmax of 2.0 has been reported as the cutoff above which chondrosarcomatous degeneration of an osteochondroma has likely occurred, although lesions with an SUVmax as low as 1.3 have been found in Grade I chondrosarcoma [Aoki et al 1999, Feldman et al 2005].

The reported incidence of malignant degeneration to chondrosarcoma, or less commonly to other sarcomas, has ranged from 0.5% to 20%, with many reports strongly favoring the lower estimates [Legeai-Mallet et al 1997]. However, in certain families, the rates of malignant degeneration have been reported to be as high as 6% [Porter et al 2004, Vujic et al 2004]. In a large cohort of 529 affected individuals, the rate of malignant transformation was calculated to be 5% [Pedrini et al 2011].

Malignant degeneration can occur during childhood or adolescence, but the risk increases with age. The prevalence of chondrosarcoma in the general population is approximately one in 250,000 to one in 100,000; however, 5% of those with a chondrosarcoma have HMO. Based on a study of HMO in Washington State (USA), it was estimated that HMO increases the risk of developing a chondrosarcoma by a factor of 1000 to 2500 over the risk for individuals without HMO.

Note: It is difficult to estimate the actual risk because so many published studies are series from the surgical literature. In the approximately 20 studies over the last 25 years that included affected family members of probands (i.e., those who did not themselves present for medical treatment), the rates of sarcomatous degeneration averaged approximately 2%-5%. However, no longitudinal studies have addressed the issue of lifetime risks.

Genotype-Phenotype Correlations

Most studies have identified a higher burden of disease in persons with EXT1 mutations than in those with EXT2 mutations:

  • See findings reported by Francannet et al [2001].
  • In a study of 172 individuals from 78 families, Porter et al [2004] identified more severe disease in individuals with mutations in EXT1 than in EXT2 on the basis of shortened stature, skeletal deformity (shortened forearm or bowing, knee deformity), and function (elbow, forearm, and knee range of motion). The risk of chondrosarcoma may also be higher in individuals with an EXT1 mutation [Porter et al 2004].
  • Persons with EXT1 mutations were found to have a greater number of exostoses, a greater incidence of limb malalignment with shorter limb segments and height, and more frequent pelvic and flat bone involvement than those with EXT2 mutations [Alvarez et al 2006].
  • Pedrini et al [2011] suggested a clinical classification system based on the presence or absence of deformities and functional limitations (adapted in Mordenti et al [2013]). In 529 individuals with multiple osteochondromas (MO) a more severe MO phenotype was found to be associated with mutation in EXT1 and male sex.

Other studies note no difference in phenotype associated with mutations in EXT1 versus EXT2 but often these studies are limited in study population size [Jennes et al 2008]. Therefore, the severity of HMO phenotype cannot yet be predicted based on the EXT1/EXT2 genotype, as there are other genetic factors that influence the final clinical outcome [Jennes et al 2012].

Penetrance

The penetrance is estimated to be 96% in females and 100% in males. Most published instances of reduced penetrance have occurred in females. However, comprehensive skeletal radiographs have not been performed in most of these instances.

Nomenclature

"Multiple osteocartilaginous exostoses" was used to convey the observation that the growths are composed primarily of cartilage in the child and ossify as skeletal maturity is reached.

In the United States, the terms “exostosis” and “hereditary multiple exostoses” have been used to denote the growths and the disorder, but the World Health Organization (WHO) has selected the nomenclature “osteochondromas” for exostoses and “multiple osteochondromas” for the disorder [Bovée & Hogendoorn 2002]. These latter terms are preferable as they more precisely describe the lesions as cartilaginous in origin. However, hereditary multiple exostoses (HME) and multiple hereditary exostoses (MHE) are still frequently used as abbreviations for this disorder, and the genes are named exostosin-1 (EXT1) and exostosin-2 (EXT2).

Prevalence

The reported prevalence of HMO ranges from as high as one in 100 in a small population in Guam to approximately one in 100,000 in European populations [Krooth et al 1961, Hennekam 1991]. The prevalence has been estimated to be at least one in 50,000 in Washington State [Schmale et al 1994].

Differential Diagnosis

Solitary osteochrondroma. Skeletal surveys suggest that a solitary osteochondroma, a common benign bone tumor, can be found in 1%-2% of the population. Solitary osteochondromas demonstrate growth patterns similar to those of multiple osteochondromas. Conditions that may be confused with a solitary osteochondroma include juxtacortical osteosarcoma, soft tissue osteosarcoma, and heterotopic ossification. Plain radiographs or CT are often helpful in distinguishing these lesions from osteochondromas. Typically, none of these conditions displays the continuity of cancellous and cortical bone from the host bone to the lesion characteristic of hereditary multiple osteochondromas (HMO).

Three inherited conditions in which multiple osteochondromas occur:

  • Metachondromatosis is inherited in an autosomal dominant manner. In contrast to HMO, metachondromatosis is characterized by both osteochondromas and intraosseous enchondromas. The osteochondromas of metachondromatosis occur predominantly in the digits and, unlike those of HMO, point toward the nearby joint and do not cause shortening or bowing of the long bone, joint deformity, or subluxation. Metachondromatosis is caused by mutations in PTPN11 [Bowen et al 2011].
  • Langer-Giedion syndrome (OMIM 150230) is a contiguous gene deletion syndrome involving EXT1. Affected individuals have intellectual disability and characteristic craniofacial and digital anomalies. Skeletal abnormalities result from haploinsufficiency of TRPS1, the gene responsible for trichorhinophalangeal syndrome type I (TRSP1).
  • 11p11 deletion syndrome (formerly known as DEFECT 11 or Potocki-Shaffer syndrome) (OMIM 601224) is a contiguous gene deletion syndrome involving EXT2 and ALX4 (OMIM 168500). Deletion of ALX4 results in parietal foramina and ossification defects of the skull (see Enlarged Parietal Foramina/Cranium Bifidum). As-yet unidentified genes are responsible for the craniofacial abnormalities, syndactyly, and intellectual disability seen in some cases [Romeike & Wuyts 2007].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with hereditary multiple osteochondromas (HMO), the following evaluations are recommended:

  • Detailed history of symptoms from osteochondromas
  • Physical examination to document location of osteochondromas, functional limitations, and deformity (shortness of stature, forearm bowing and shortening, knee and ankle angular deformities)
  • Medical genetics consultation

Treatment of Manifestations

Osteochondromas require no therapy in the absence of clinical problems.

Angular deformities, leg-length inequalities, and pain resulting from irritation of skin, tendons, or nerves often require surgery. Most individuals with HMO have at least one operative procedure and many have multiple procedures [Porter et al 2004]:

  • Painful lesions without bony deformity can be treated with simple surgical excision. Excision of osteochondromas may also slow the growth disturbance and improve cosmesis and must include the cartilage cap and overlying perichondrium to avoid recurrence.
  • Surgery for forearm deformity may involve excision of the osteochondromas, corrective osteotomies, and/or ulnar lengthening procedures that may improve pronation, supination, and forearm alignment [Matsubara et al 2006, Shin et al 2006, Ishikawa et al 2007, Watts et al 2007]; however, adults with HMO and untreated forearm deformities describe few functional limitations.
  • Though uncomplicated resection of osteochondromas in growing children is frequently reported [Fogel et al 1984, Danielsson et al 1990, Shin et al 2006, Ishikawa et al 2007], there is a theoretic risk of growth abnormality resulting from resection of periphyseal osteochondromas.
    • Abnormal growth and development of the forearm and leg in untreated individuals with HMO is common, including both proportionate and disproportionate shortening of the two bones of the forearm or leg, producing shortened and angulated limbs, respectively.
    • Waiting to resect osteochondromas until they have migrated away from the physis would decrease the risk of injury to the physis, as well as potentially limiting the likelihood of recurrence of lesions [Chin et al 2000, Shin et al 2006]. However, numerous studies suggest that early treatment (in individuals age <10 years) of forearm deformities via resection of distal osteochondromas may decrease proportionate shortening and bowing of the forearm [Masada et al 1989, Ishikawa et al 2007] as well as deformity about the ankle [Chin et al 2000].
  • Leg-length inequalities greater than 2.5 cm are often treated with epiphysiodesis (growth plate arrest) of the longer leg.
  • Angular misalignment of the lower limbs may be treated with hemiepiphysiodeses (or osteotomies) at the distal femur, proximal tibia, or distal tibia [Ofiram et al 2008, Boero et al 2011, Rupprecht et al 2011, Tompkins et al 2012, Driscoll et al 2013].
  • Early surgical treatment of tibio talar tilt may prevent or decrease the incidence of late deterioration of ankle function; long-term follow-up studies are needed [Noonan et al 2002].
  • Surgical resection is the treatment for sarcomatous degeneration. Adjuvant radiotherapy and chemotherapy are controversial for secondary chondrosarcoma, but are often used in the setting of a secondary osteosarcoma.

Surveillance

Monitoring of the size of adult osteochondromas, in particular those involving the pelvis or scapula, may aid in early identification of malignant degeneration, but no cost/benefit analyses are available to support routine surveillance.

Radiography, CT scanning, MRI, positron emission tomography and technicium-99 radionuclide imaging can be used to evaluate centrally located osteochondromas, but it is not known whether the benefits outweigh the risks of irradiation and the potential for false positive results that lead to unnecessary interventions. In addition, optimal screening intervals have not been determined.

A single screening MRI of the spine in children with HMO has been recommended by some [Roach et al 2009] to identify spinal lesions that may cause pressure on the spinal cord. The presence of osteochondromas in the canal would then warrant close clinical follow up; encroaching lesions and those causing symptoms may merit excision.

Evaluation of Relatives at Risk

Presymptomatic testing is not warranted because the clinical diagnosis is evident at an early age and because no precipitants, protective strategies, or specific nonsurgical interventions are known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

The disorder hereditary multiple osteochondromas (HMO) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Approximately 90% of individuals with HMO have an affected parent; approximately 10% have a de novo mutation.
  • Recommendations for the evaluation of parents of an individual with simplex HMO (i.e., a single occurrence in a family) include physical examination, radiographs, and/or molecular genetic testing if a mutation has been identified in the proband.

Note: Although 90% of individuals diagnosed with HMO have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members and/or decreased penetrance.

Sibs of a proband

  • The risk to sibs depends on the genetic status of the parents.
  • Because most probands have a parent with the altered gene, the sibs of a proband with HMO usually have a 50% chance of inheriting the gene alteration; sibs who inherit the alteration have a 95% chance of manifesting symptoms.
  • When the parents are clinically unaffected or the disease-causing mutation cannot be detected in the DNA of either parent, the risk to the sibs of a proband appears to be low. However, germline mosaicism has been described for this disorder and should be taken into account [Szuhai et al 2011].

Offspring of a proband. The offspring have a 50% chance of inheriting the mutant allele.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected or has a disease-causing mutation, his or her family members are at risk.

Related Genetic Counseling Issues

Consideration in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, parental mosaicism needs to be considered; possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks' gestation) or chorionic villus sampling (usually performed at ~10-12 weeks' gestation). The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like HMO) do not affect intellect or life span and for which some treatment exists are not common. Differences in perspective may exist among medical professionals and families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • MHE and Me
    14 Stony Brook Drive
    Pine Island NY 10969
    Phone: 845-258-6058
    Email: mheandme@yahoo.com
  • MHE Research Foundation
    149 - 16th Road
    Whitestone NY 11357
    Phone: 877-486-1758
    Email: sarahziegler@mheresearchfoundation.org
  • MHE Coalition
    6783 York Road
    #104
    Parma Heights OH 44130-4596
    Phone: 440-842-8817
    Email: CheleZ1@aol.com

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Hereditary Multiple Osteochondromas: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Hereditary Multiple Osteochondromas (View All in OMIM)

133700EXOSTOSES, MULTIPLE, TYPE I
133701EXOSTOSES, MULTIPLE, TYPE II
608177EXOSTOSIN GLYCOSYLTRANSFERASE 1; EXT1
608210EXOSTOSIN GLYCOSYLTRANSFERASE 2; EXT2

Molecular Genetic Pathogenesis

Both EXT gene (EXT1, EXT2) products are involved in the biosynthesis of heparan sulfate. EXT1 and EXT2 encode glycosyltransferases that interact as heterooligomeric complexes [McCormick et al 2000]. Pathogenic variants in EXT1 or EXT2 cause cytoskeletal abnormalities that include actin accumulation, excessive bundling by alpha-actinin, and abnormal presence of muscle-specific alpha-actin [Bernard et al 2000]. Some evidence suggests that EXT1 and EXT2 may have tumor suppressor activity [Hecht et al 1997].

A two-hit mutation model was proposed for EXT1 and EXT2 in the formation of osteochondromas, based on the observation of loss of heterozygosity in chondrosarcomas [Hecht et al 1997, Philippe et al 1997] and the identification of homozygous EXT1 deletions in solitary osteochondromas [Hameetman et al 2007]. Osteochondroma mouse models [Jones et al 2010, Matsumoto et al 2010] have shown that complete inactivation of both Ext1 alleles in a small fraction of chondrocytes is sufficient for the development of osteochondromas and other skeletal defects associated with MHO and that osteochondromas are composed of a mixture of EXT+/- and EXT-/- cells. The failure to identify mutations in both alleles of EXT1 and/or EXT2 or loss of heterozygosity in osteochondromas of individuals with hereditary multiple osteochondromas (HMO) in some studies [Hall et al 2002, Zuntini et al 2010] may be caused by the limitations of sensitivity of the detection test used or may suggest alternative mechanisms for osteochondroma formation. Epigenetic loss of EXT1 activity through hypermethylation has been observed in leukemias and other cancers, further supporting a tumor suppressor role for this gene product [Ropero et al 2004].

EXT1 and EXT2 are related to the EXTL family of genes by sequence homology. At present the EXTL family consists of three members (Table 2) but to date these genes have not been shown to be involved in osteochondroma development.

Not only do EXT1 and EXT2 code for transmembrane glycoproteins that together form a heterooligomeric heparan sulfate polymerase: the protein product also participates in cell signaling and chondrocyte proliferation and differentiation [McCormick et al 2000, Senay et al 2000, Bernard et al 2001, Hall et al 2002]. Study of heparan sulfate proteoglycan (HSPG) synthesis in Drosophila suggests that a parallel signaling pathway may exist in humans [Bellaiche et al 1998].

EXT1

Normal allelic variants. EXT1 contains 11 exons spanning 250 kb.

Pathogenic allelic variants. More than 400 different mutations have been described in EXT1, listed in the Multiple Osteochondromas Mutation Database (Modb) [Jennes et al 2009]. These mutations are dispersed throughout the entire gene and most are predicted to result in premature termination of the gene product. Only a few of the mutations have been identified in more than one family. There are several relative hot spots for mutations. Exons 1 and 6 contain one and two polypyrimidine tracts, respectively, which are often sites of frameshift mutations. Missense mutations cluster in codons 339 and 340. Mutations in the carboxy-terminal region are relatively sparse. Whole-gene, partial-gene, and single-exon deletions have been described but there are no recurrent break points [Jennes et al 2009, Jennes et al 2011].

Normal gene product. Exostosin-1 comprises 746 amino acids and is involved in heparan sulfate synthesis. It is a type II transmembrane glycoprotein that localizes to the endoplasmic reticulum [McCormick et al 2000]. Exostosin-1 and exostosin-2 form a heterooligomeric complex that accumulates in the Golgi apparatus and has substantially higher glycosyltransferase activity than exostosin-1 or exostosin-2 alone [McCormick et al 2000].

Abnormal gene product. Nonsense and splice-site mutations have also been observed. Most of the missense mutations detected occur in residues that are highly conserved evolutionarily and are thought to be crucial for the activity of the protein. The clinical significance of missense mutations affecting residues that are not as highly conserved is uncertain, as they may be rare normal variants.

EXT2

Normal allelic variants. EXT2 contains 14 exons plus two alternative exons spanning 110 kb.

Pathogenic allelic variants. More than 200 pathogenic allelic variants have been found in EXT2, listed in the Multiple Osteochondromas Mutation Database (Modb) [Jennes et al 2009]. The pathogenic allelic variants are mainly located in the first eight exons and are mainly loss-of-function mutations (frameshift, in-frame deletion, nonsense, and splice site). Few missense mutations have been reported in EXT2. Some missense mutations occur in evolutionarily conserved residues, have been seen in more than one family with HMO, and are likely to be pathogenic allelic variants. Very few pathogenic allelic variants have been found in the carboxy-terminal region of the gene.

Normal gene product. The protein comprises 718 amino acids. Like exostosin-1, exostosin-2 is a type II transmembrane glycoprotein that localizes to the endoplasmic reticulum and is involved in heparan sulfate synthesis [McCormick et al 2000]. Exostosin-1 and exostosin-2 form a heterooligomeric complex that accumulates in the Golgi apparatus and has substantially higher glycosyltransferase activity than exostosin-1 or exostosin-2 alone [McCormick et al 2000].

Abnormal gene product. The frameshift, nonsense, and splice-site mutations are predicted to result in premature chain termination and loss of gene function.

References

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Chapter Notes

Revision History

  • 21 November 2013 (me) Comprehensive update posted live
  • 5 September 2008 (me) Comprehensive update posted live
  • 20 September 2005 (me) Comprehensive update posted to live Web site
  • 2 July 2003 (me) Comprehensive update posted to live Web site
  • 3 August 2000 (me) Review posted to live Web site
  • 22 March 2000 (hc) Original submission
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