Hereditary multiple exostoses

views updated

Hereditary multiple exostoses


Hereditary multiple exostoses (HME) refers to a group of disorders characterized by abnormal bone growth. The major symptom is the development of nodules (bumps) on various bones of the body. Exostoses may produce pain and other complications by pressing on nearby tissue, they may limit movement of joints, and in some cases they must be surgically removed.


An exostosis is a benign (non-cancerous) bony growth. This does not refer to a normally shaped bone that has simply grown larger than normal. Rather, an exostosis is a bump, or nodule, on a bone, usually with overlying cartilage. That is why HME is sometimes referred to as the "bumpy bones" disease. Other names for the disorder include multiple hereditary exostoses (MHE), multiple cartilaginous exostoses, osteochondromatosis, and diaphyseal aclasis.

People with HME typically develop anywhere from several to many exostoses during their life, mostly during childhood and adolescence. Exostoses vary in size, and can develop on most bones in the body. An exostosis may present no problem, or it may cause pain and other complications by pressing on nearby soft tissue (nerves, blood vessels, tendons, internal organs), or on another bone at a joint. Exostoses that do cause problems are often surgically removed. HME can cause differences in the shape of bones, or reduce their growth rate. Thus, people with HME tend to be somewhat shorter than average and may have limited movement in certain joints. People with HME are not at risk for tumor development in other tissues.

HME is an autosomal dominant condition, and most people with the disorder have family members who are affected. A small percentage of people who carry an HME gene do not develop any recognizable exostoses. The vast majority of exostoses are benign growths, but a small percentage can become malignant (cancerous).

Genetic profile

Three different types of HME are known to exist—HME type I, HME type II, and HME type III. There appear to be no obvious differences in the presentation and course of the disorder between the three types. Instead, the designations correspond to the three genes—EXT1, EXT2, and EXT3 respectively—that have been linked to HME. The protein produced by the EXT1 gene on chromosome number 8 is called exostosin-1, and the EXT2 gene on chromosome number 11 produces exostosin-2. The EXT3 gene is located on chromosome number 19, but as of 2000, its protein product had not been identified.

As noted, HME is an autosomal dominant condition, which means any person who carries an HME gene has a 50% chance of passing it on each time they have a child. Ninety percent of people with HME have a positive family history. In the other 10% of cases, HME occurred in that person for the first time as the result of a new mutation in one of the EXT genes. Regardless of whether someone inherits HME from a parent or it occurs in them for the first time, each of their children is still at 50% risk.

A tumor is the result of cells that undergo uncontrolled replication/division. People often equate the word "tumor" with cancer . However, a tumor is simply a growth, and may be malignant (cancerous) or benign (non-cancerous). Technically exostoses are tumors, but they are nearly always benign.

EXT1 and EXT2 belong to a class of genes known as tumor suppressors. In normal circumstances, tumor suppressor genes prevent cells either from replicating at all, or from replicating too quickly. If both copies of a tumor suppressor gene are mutated (inactivated), control of cell replication/division is lost. A person who inherits HME type I or HME type II already has one EXT1 or EXT2 gene inactivated from the moment they are conceived. However, abnormal bone growth does not occur unless the other gene of the pair also becomes inactivated. This second gene mutation , called loss of heterozygosity (LOH), appears to be an unlikely, random event, which explains why there is not abnormal growth throughout all of the bones. Only the occasional bone cell that undergoes LOH has a chance of becoming an exostosis. Any person without HME can develop a single exostosis, and 2% of all people do. It is simply that exostosis development is much less likely when two random mutations of an EXT gene in a bone cell must occur, rather than just one.


The prevalence of HME is estimated at about 1 in 75,000. There does not appear to be any significant difference in prevalence between the major ethnic groups. Most studies have found that males with an HME gene tend to have more obvious and severe symptoms than females. The reason for this is unknown. This makes it appear as though males are more likely to inherit HME, when in fact they are just more likely to be diagnosed.

Most people with HME have either HME type I or HME type II. Apparently only a small percentage of HME cases are linked to the EXT3 gene. Further study of the HME genes should establish an accurate prevalence for each type.

Signs and symptoms

About half of all people with HME are diagnosed by the time they are three years old. Only 5% of newborns that carry an HME gene show some signs at birth, but 95% of all people with the condition show noticeable signs by the time they are 12 years of age.

Exostoses primarily develop during the period of rapid bone growth—from infancy through late adolescence. As noted, however, a small percentage of newborns already have noticeable exostoses at birth, and rare individuals with HME may develop exostoses as adults. The number of exostoses varies from person to person, even within families. However, the average affected person develops six exostoses during his or her life.

Both the locations and sizes of exostoses vary. The most commonly affected bones are those of the arms (humerus, radius, and ulna), legs (femur, tibia, and fibula), hands (carpals and metacarpals), and feet (tarsals and metatarsals). Exostoses on the arm or leg nearly always develop near the joints (elbow, wrist, knee, or ankle), rather than in the middle of the long bones. About 70% of people with HME have an exostosis or bone deformity around the knee. Flat bones, such as the scapula (shoulder blade) and pelvis, may be affected. The ribs and bones of the shoulder girdle occasionally develop growths, but exostoses are hardly ever seen on the spine or bones of the skull. Some exostoses under the skin may be barely noticeable to the touch (less than 1 cm in height), while others produce a noticeable bump (1-2 cm in height). Growths on the flat bones may be somewhat larger.

The most common problem in HME is exostoses that cause compression and irritation of adjacent soft tissue, such as skin, nerves, and blood vessels. These types of growths can cause chronic pain until they are removed, and accidentally hitting them against something solid can be especially painful. Exostoses that grow near the ends of long bones may interfere with normal movement of a joint. Many children with HME have difficulties with their knees, both in range-of-motion and with angular deformities ("knock-kneed"). An uncommon, but more complicated problem is a large exostosis on the inside of the pelvis that results in compression of the intestine or urinary tract.

HME affects the growth centers of bones (metaphyses and epiphyses), which can result in abnormal modeling (structure) of the affected bones. Reduction in size and bowing of bones are the most frequent structural anomalies seen. Consequently, people with HME tend to be somewhat shorter than average—final height in men averages 170 cm (66 in), while the average height in women is 160 cm (62 in). Differential rates of growth between a child's legs or arms can result in leg- or arm-length discrepancy, sometimes reaching 2 cm (1 in) or more. Leg-length discrepancy can result in hip pain and problems with walking caused by tilting of the pelvis.

The most serious complication in HME is the progression of a benign exostosis to a malignant (cancerous) state, known as a chondrosarcoma . This happens in slightly less than 1% of all people with the condition. Chondrosarcomas can develop in children, but those few cases that do occur are usually in adults. An undetected bone malignancy always presents a risk for metastasis—spreading of cancerous cells elsewhere in the body—which is one of the most dangerous complications of any cancer. Most chondrosarcomas should be detected and treated early, however, because they are usually associated with rapid growth of an exostosis accompanied by pain.


The diagnosis of HME is usually made when noticeable exostoses first appear. Any person who is at risk for the condition because of a family history is more likely to be accurately diagnosed at a younger age. As noted, the occurrence of a single exostosis in an otherwise healthy person is not rare. Therefore, two or more exostoses must be present in order to make the diagnosis of HME (although a single exostosis detected in someone who is known to be at 50% risk for HME is highly suggestive of the diagnosis).

Exostoses are not always detectable by physical examination. Consequently, an x-ray study of the commonly affected bones (skeletal survey) in questionable cases is the best method of confirming or excluding the diagnosis. This is especially true in cases where a child is known to be at risk for HME (positive family history).

Unlike some genetic disorders where many people with the condition have the same gene mutation, most individuals/families with HME tested so far have had different mutations in either EXT1 or EXT2. Therefore, while predictive or confirmatory genetic testing might be possible within a family (assuming the gene mutation is detectable), direct testing of EXT1/EXT2 in a person with a negative or uncertain family history is not yet reliable enough to use as a diagnostic tool.

Treatment and management

The only treatment for exostoses that present problems is to remove them surgically. In those instances where the exostosis is easily accessible, surgical removal is straightforward and carries very little risk. On the other hand, an exostosis that involves one of the joints or is less accessible—somewhere on the inner surface of the pelvis, for instance—may require involved surgery. A few people with HME will never require surgical intervention, but most have at least one surgery and some will have many. A child who is noted to have uneven or accelerated growth of a long bone in the arm or leg may be offered a procedure to straighten the bone or reduce its growth rate.

No external factors are known to cause or prevent the growth of exostoses. Those persons diagnosed with HME, as well as children at risk, must be taught to monitor themselves for unusual changes in bone growth.

Anyone with HME should have lifelong, periodic examinations by an orthopedic surgeon to look for and address any problematic exostoses, and to screen for chondrosarcoma. Since exostoses and other bone-growth problems occur primarily in childhood, special attention, care, and education about their disorder is often needed for children with HME. A support group especially for children, called MHE and Me, has special materials and a Web site devoted to issues of particular importance to kids (see Resources below).


The majority of people with HME lead active lives, and their lifespan is not reduced. Surgery to remove problematic exostoses will likely remain the primary method of treatment for some time. The hope is that further analysis of the EXT genes and their protein products will lead at some point to a more targeted approach at reducing or eliminating abnormal bone growths altogether.



MHE and Me—A Support Group for Kids with Multiple Hereditary Exostoses. 14 Stony Brook Dr., Pine Island, NY 10969. (914) 258-6058. <>.

Multiple Hereditary Exostoses Coalition. 8838 Holly Lane, Olmstead Falls, OH 44138. (440) 235-6325. <>.

Multiple Hereditary Exostoses Family Support Group. 5316 Winter Moss Court, Columbia, MD 21045. (410) 922-5898. <>.

Scott J. Polzin, MS, CGC