Understanding the Past and Future of Multiple Hereditary Exostoses
Multiple Hereditary Exostoses (MHE) occurs when benign tumors grow out from the ends of long bones. The tumors are known collectively as exostoses, which is when a bone like tumor forms on top of a bone; individually they are exostosis. MHE is estimated to occur in about one in 50,000 (Pannier 46). This fits the classification of a rare disease, which requires a birth prevalence of around one in 1500. While the disease itself does not have a cure, there are treatment options emerging to deal with the disease. First, scientists have determined the cause of the disease: the disease is contracted either through genetics (about 70%) or through a random mutation (about 30%). On a genetic level, scientists have determined that it is autosomal dominant, meaning, that when a child is conceived and the genetic make-up is determined, there is a 50% chance of the disease being inherited. The disease is found in coding errors on the EXT1 and EXT2 genes, which both code for tumor suppression. MHE occurs because this coding error prevents the production of heparan sulfate, which then leads to the tumor growth failing to be capped and stopped (Pannier 49). MHE presents an interesting case study to explore because of its relationships with more well known diseases, like cancer, there is a significant amount research going into studying the rare disease.
In essence, exostoses, is a skeletal disease that causes benign tumors to arise from long bones. The disease appears to have first been mentioned by John Hunter in Lectures on the principles of surgery in 1786 and was named almost one hundred years later in 1876. Symptoms normally arrive in childhood and the disease can be diagnosed fairly early on. The exostoses grow from the end of long bones, particular the shoulders, knees, and ankles. The ribs, spine, scapula, and pelvis also tend to be affected but with nowhere near the frequency as in the legs, forearms, and hands (Pannier 48). Exostoses that grow out of long bones originate from the growth that takes place within growth plate (Ryckx 598). These exostoses can cause pain and varying degrees of deformity within the skeletal structure. Growth of the exostoses stops when the growth plates close after puberty, however, a surgically removed bone does have the possibility of growing back (Hennekam 262). MHE leads to patients having a shorter height, limitations in joint range, and deformities in the limbs (Ryckx 598). The major risk that can come from MHE is the possibility that the tumor becomes malignant at some point in the future after puberty. It is estimated that this happens in around 0.5% to 2% of patients (usually around age 30) (Hennekam 264).
Today, the main way to treat MHE is through surgical removal of the exostoses. Not every exostosis has to be removed; normally if a patient is experiencing pain, they will undergo an x-ray to determine which exostosis is causing the problem. Surgery is normally preformed for pain, growth issues, a loss of range of motion, deformities, and other major skeletal issues (Alvarez 122). With frequent doctor check-ups and x-rays any problematic exostoses can be identified and scheduled for removal. The possibility of a malignant change can be identified by looking at the amount of calcification on the tumors, which can be seen through looking at x-rays. Doctors can also identify through x-rays the possibility of tumors pressing against arteries, tendons, and nerves, all of which would need to be dealt with surgically (Hennekam 263). With MHE, any bone can be affected by the tumors, except for the facial bones. The bones within the face grow through intramembranous ossification, which is different from the other bones of the body that grow through the growth plate, this different type of growth prevents any exostoses from growing (Ryckx 598).
MHE is believed to be an autosomal dominant inherited disease, as mentioned before, this means that if one parent has the disease, a child has a 50% chance of inheriting it too. However, there are also cases where the disease has been spontaneously mutated without any prior family history. MHE has been identified on chromosomes 8 and 11, with the genes causing the disease known as EXT1 and EXT2 respectively. Formerly, it was believed that there was an EXT3 gene on chromosome 19p, but it is now considered only a minor contributor to the larger problems that would exist in EXT1 or EXT2 (Ryckx 600). The EXT1 and EXT2 genes when functioning properly lead to an increase in enzymatic activity to produce heparan sulfate, but when they do not function properly the heparan sulfate production decreases greatly. Heparan sulfate helps to cap tumor growth, preventing metastasis. The lack of heparan sulfate happens in MHE patients where a significant difference in glycosyltransferase activity has been recorded (601).
In 2006, scientists at the University of British Columbia did research into the differences between the EXT1 and EXT2 gene expression in people that had MHE (Alvarez 123). The research was done by collecting blood samples for DNA; the DNA was then scanned to look for the EXT1 or EXT2 mutation and any person with both mutations was thrown out of the study. Next, the patients were sorted according to their phenotypes, which were categorized by the number of and location of the tumors they had (126). The results were interesting. First they confirmed that the phenotype expression for MHE patients can vary greatly from case to case. Their data also confirmed that the MHE patients that were suffering from the EXT1 mutation had greater strain being placed on their body as a result of MHE in comparison to those that had the EXT2 mutation (128). For reasons that were not completely clear, men tended to have more complicated cases of MHE. The authors theorized that this may be due to hormonal and growing differences between pubescent males and females, impacting how and for how long the tumors grow. Finally, younger MHE patients tended to be less affected by MHE overall; scientists believe younger MHE patients have simply had less growth and thus less time for the tumors to manifest (129). Genetically, there appears to be two main causes of MHE, known as EXT1 and EXT2, and while there are differences in the severity based on the gene, the patient’s gender, and the patient’s age they all are still classified as having MHE.
For years, the barrier to MHE research was the inability to replicate the disease in mouse models. With the creation of the knockout mouse, this has finally changed. A study from 2009 by researchers at the University of Utah deactivated EXT1 in knockout mice, mimicking the effects of MHE in humans. Their goal was to show that the deactivation of the EXT1 gene at low prevalence led to mice having symptoms similar to the human phenotype, therefore helping to confirm that the disease did originate there (Jones 2054). Their results showed that a spontaneous loss of heterozygosity between EXT1 and EXT2 did not do a sufficient job to model MHE, so they moved on to direct inactivation of EXT1, which was able to mimic the human MHE with low penetrance (2057).
Another example of recent research involved the possibility of synthesizing heparan sulfate in the body to help to decrease the effects of MHE. Scientists at the University of California-San Diego theorized that returning the heparan sulfate levels back to normal in the Chinese hamster ovary cells would descrease the effects of the disease. They found that Chinese hamster ovary cell lines show only a 10-30% reduction in the production of heparan sulfate due to mutations in the EXT1 gene. This reduction suggests that there are druggable molecules in MHE patients, leading to an increase in the growth factors that helped to produce heparan sulfate. The next line in their study is to try and replicate these results where the tumors are actually being formed. If this treatment works, it would identify the location of tumor development in MHE patient, which could also lead to a possible cure for MHE sometime down the line through the production of heparan sulfate in the affected areas (Seamen 1569).
In today’s funding driven world, research into rare diseases creates problems and questions that are difficult to answer. Scientists have to decide how much time, effort, and money should be devoted to research into diseases that affect such a small portion of the population that it is difficult to see the investment ever being fully returned. As mentioned earlier, to be considered a rare disease, about 1 in 1500 people or less must have it. This leads to a lack of demand in the market, and so research is less likely to happen into these diseases. This does not even mention the fact that even if someone did have the time, money, and effort to do research into a disease, they still will struggle to find human test subjects (Alvarez 129). This has made things difficult for researchers in the past, but there are ways that are being exploited to decrease the amount of inefficiency within science research. For years, patients with rare diseases have been turning to communities online in order to find support, stories, and the latest news relating to their respective diseases. Researches have now started to tap into these congregated patients through social media and are using these groups to find willing study participants much easier than they have in the past (Pharmacy 100). As this practice and trend continues to grow larger, it will help decrease the difficulty that some scientists have in finding test subjects for the studies and will help lead to more efficient research with cheaper to find patients.
Future MHE research is going to focus on how molecules work at the growth plate in order to help this tumor growth, this will hopefully lead to a better understanding of heparan sulfate and its exact role in tumor suppression. It is easy to see a larger proportion of funding being devoted to MHE over other diseases because there is a belief among scientists that an understanding of the genetics and tumors in MHE can lead to a cancer therapy (Ryckx 604). Cancer is one of the most pressing issues medically at the moment and the cure for it is a challenge that many scientists are undertaking. MHE has the potential of leading to a cure, as the tumors are similar, just not malignant. The research into MHE is extremely important and could impact the understanding of a lot of different diseases, including cancer.
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