Hereditary multiple osteochondromas

Alternate names

HMO; Hereditary multiple exostoses; Hereditary multiple exostosis; Multiple exostoses

Definition

Hereditary multiple osteochondromas (HMO), also called hereditary multiple exostoses, is a genetic disorder that causes the development of multiple, cartilage-covered tumors on the external surfaces of bones (osteochondromas).

Onset

The osteochondromas typically become apparent during childhood or adolescence, and the number, size and location of osteochondromas varies from person to person.

Epidemiology

The incidence of hereditary multiple osteochondromas is estimated to be 1 in 50,000 individuals. This condition occurs more frequently in some isolated populations: the incidence is approximately 1 in 1,000 in the Chamorro population of Guam and 1 in 77 in the Ojibway Indian population of Manitoba, Canada.

Cause

• Mutations in the EXT1 and EXT2 genes cause hereditary multiple osteochondromas.
• The EXT1 gene and the EXT2 gene provide instructions for producing the proteins exostosin-1 and exostosin-2, respectively.
• The two exostosin proteins bind together and form a complex found in a cell structure called the Golgi apparatus, which modifies newly produced enzymes and other proteins.
• In the Golgi apparatus, the exostosin-1 and exostosin-2 complex modifies a protein called heparan sulfate so it can be used by the cell.

Gene mutations

When there is a mutation in exostosin-1 or exostosin-2, heparan sulfate cannot be processed correctly and is nonfunctional. Although heparan sulfate is involved in many bodily processes, it is unclear how the lack of this protein contributes to the development of osteochondromas.

• Researchers estimate that about 15 percent of people with hereditary multiple osteochondromas have no mutation in either the EXT1 or the EXT2 gene. It is not known why multiple osteochondromas form in these individuals.

Types

• If the condition is caused by a mutation in the EXT1 gene it is called hereditary multiple osteochondromas type 1.
• A mutation in the EXT2 gene causes hereditary multiple osteochondromas type 2.
• While both type 1 and type 2 involve multiple osteochondromas, mutations in the EXT1 gene likely account for 55 to 75 percent of all cases of hereditary multiple osteochondromas, and the severity of symptoms associated with osteochondromas seems to be greater in type 1.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

Signs and symptoms

• Signs and symptoms may include pain, decreased range of motion, nerve impingement, deformity, differences in limb length, short stature, and fractures.
• Osteochondromas of the ribs may cause complications such as a collapsed lung (pneumothorax), hemothorax, or pericardial effusion.
• Osteochondromas typically grow throughout childhood and stop growing when the growth plates close. However, they do recur later on in some people.
• While the vast majority of osteochondromas are benign (noncancerous), they may become malignant (cancerous) in adulthood in 2% to 5% of people with HMO.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormality of the humerus
• Abnormality of tibia morphology(Abnormality of the shankbone)
• Failure to thrive(Faltering weight)
• Multiple exostoses

30%-79% of people have these symptoms

• Abnormality of femur morphology(Abnormality of the thighbone)
• Abnormality of the dentition(Abnormal dentition)
• Abnormality of the metaphysis(Abnormality of the wide portion of a long bone)
• Anteverted nares(Nasal tip, upturned)
• Avascular necrosis(Death of bone due to decreased blood supply)
• Bone pain
• Cranial nerve paralysis
• Genu valgum(Knock knees)
• Hypoplasia of the ulna(Underdeveloped inner large forearm bone)
• Madelung deformity
• Micromelia(Smaller or shorter than typical limbs)
• Muscle weakness (Muscular weakness)
• Radial bowing(Bowing of outer large bone of the forearm)
• Short stature(Decreased body height)

5%-29% of people have these symptoms

• Abnormal pericardium morphology
• Abnormal pyramidal sign
• Chondrosarcoma
• Dilatation(Wider than typical opening or gap)
• Elbow dislocation(Dislocations of the elbows)
• Hemiplegia/hemiparesis(Paralysis or weakness of one side of body)
• Osteoarthritis(Degenerative joint disease)
• Osteolysis(Breakdown of bone)
• Pelvic bone exostoses
• Recurrent fractures(Increased fracture rate)
• Scoliosis
• Synostosis of joints(Fusion of joints)

Diagnosis

Hereditary multiple osteochondromas (HMO) should be suspected in individuals with the following radiographic features and family history:

• 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.

The clinical diagnosis of HMO can be established in a proband with characteristic clinical features (see Suggestive Findings). If clinical features are inconclusive, a molecular diagnosis can be established in a proband by the identification of a heterozygous pathogenic variant in EXT1 or EXT2 by molecular genetic testing.

Treatment

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 osteochondromas, 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; angular misalignment of the lower limbs may be treated with hemiepiphysiodeses (or osteotomies) at the distal femur, proximal tibia, or distal tibia; 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; early treatment of ankle deformity may prevent or decrease later deterioration of function; sarcomatous degeneration is treated by surgical resection. [1].

NIH genetic and rare disease info

• NIH info on Hereditary multiple osteochondromas

Hereditary multiple osteochondromas is a rare disease.

Hereditary multiple osteochondromas Resources
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