Step 3: Syndrome Description

So far, we have gathered information about the effects of chromosome changes through (a) a literature review, and (b) a thorough series of clinical assessments. Now, it is time to pull together a syndrome description. This description is a comprehensive collection of all the different things that we’ve found in a group of people with a particular chromosome change. Some things might be quite common, such as strabismus in people with tetrasomy 18p. Other things might be seen in a minority of individuals, such as holoprosencephaly in people with 18p-. Other things might only be reported once, and it is unclear whether it is a consequence of the chromosome change, or perhaps it is completely unrelated to the chromosome change.

Once we’ve got the syndrome description, what do we do with it? Well, the first thing we want to do is share our description with others. We can do this in a couple of different ways. We write scientific papers for publication in medical journals to share information. We make presentations at various scientific conferences. We also share information with patient advocacy groups. In our case, this is mainly through the Chromosome 18 Registry’s website as well as at the annual Registry meeting.

The syndrome description gives families and providers an idea of what kinds of issues and concerns may arise in someone with a particular chromosome change. This gives them an opportunity to screen for problems, prepare for various possible outcomes, and just have a better idea of what kinds of things might pop up as a person ages. However, as most parents will tell you, a syndrome description is useful, but it most certainly is not the end-all, be-all. Although we are able to describe the different features that have been seen in people with chromosome changes, we cannot predict precisely who will get which features. There are still several steps that must be completed before we are able to provide personalized information based on a person’s specific genetic change.

Once we are able to fully describe the range of features that are associated with a condition, we can then start to figure out which ones are associated with different breakpoints. For example, we can ask questions such as, “What is different between people who have a breakpoint in 18q23.1 versus those with a breakpoint in 18q12.3?” In fact, this question leads us directly into the next step on the path to treatment: gene identification.

Step 2: Clinical and Molecular Assessments

Once we have completed the literature review, we can move on to the next step in the process: the clinical and molecular assessments.

Clinical Assessments. Using the information from the literature review, we can design a series of evaluations aimed at clarifying and expanding our understanding of the condition. The ultimate goal of this step is to understand how, precisely, the chromosome change affects a person. How does it affect development? What about bone structure? Does the chromosome change lead to any hormonal issues? How about vision? And hearing?

The information gathered in the literature review is critical in helping us with this step. Because we have been able to identify gaps in knowledge about the conditions, we can design assessments to fill in those gaps! Thanks to the literature review, we also know which features have already been described but still require additional investigations. For example, thanks to the literature review, we recognized that many people with distal 18q- have short stature. This led us to question WHY they have short stature. Is it because of a change in their bones? Is it because they are missing certain growth factors? We developed assessments that would help us answer these questions. We included bone surveys and growth hormone testing. We learned that many people with distal 18q- often have growth hormone deficiency! With that knowledge, we were able to start treating people, which, in many cases, led not only to an improvement in growth, but also an improvement in cognitive ability!

As you might have guessed from the example above, the phrase “clinical assessments” may refer to a pretty wide range of possible evaluations. It might involve an examination by a medical professional, such as a geneticist or an ophthalmologist. It might involve imagine studies, such as x-rays or an MRI. It could involve some blood work to look at different hormones and other substances in the blood. Surveys might be used to determine whether behavior and intelligence are affected by the chromosome change.

In addition to deciding which assessments to complete, it is also important to determine who will perform those assessments. Obviously, we want only highly-qualified professionals performing these evaluations. They should have advanced training in their area of expertise, and they should also have experience in working with people with intellectual or physical challenges. This is where our team of clinical investigators comes in. We have assembled a team of professionals who help us design informative evaluations.

In addition to designing the evaluations, our team of clinical investigators is also responsible for performing those evaluations. It is very important that every person we see is evaluated using the same protocols; ideally, the same professional would perform the evaluation as well! This is important because we want to make sure that any differences that we identify between study patients are not due to different procedures. In other words, by ensuring that every study patient goes through the same evaluation process completed by the same clinical investigator, we ensure that we are collecting the most reliable data!

One last word about our team of clinical investigators. All of our clinical investigators collaborators have one very important quality: the ability to think outside of the box. In addition to performing evaluations and making treatment recommendations, our clinical investigators must also be able to take their findings and move them to the next level. In other words, they need to understand underlying biological and molecular mechanisms and use that knowledge to identify novel treatments. This requires them to keep abreast of all the latest developments and technologies in addition to seeing patients, interpreting complex data, and writing manuscripts! No small feat!

Molecular Assessments.

While our clinical investigators are busy evaluating patients and interpreting clinical data, our laboratory technicians are busy examining the molecular basis of the chromosome 18 conditions. The molecular assessments we complete in the laboratory are focused on chromosome 18 and provide us with more data than tests run in clinical laboratories. This is important for two reasons.

First, we must confirm that everyone in a particular study group has the same chromosome change. We have to make sure, for example, that individuals in the 18p- study group do not also have a duplication or deletion on another chromosome. If there are other non-18 chromosomes involved, it is more difficult to determine the effects of a chromosome 18 change. For example, if a child with a heart defect has both a deletion on chromosome 18 as well as a duplication on chromosome 6, we would not be able to determine whether the heart defect is due to the missing genes on chromosome 18, the extra genes on chromosome 6, or a combination of the two!

The second reason that a molecular assessment is so important is that it allows us to determine which genes are involved in the chromosome 18 change. We use the latest technology to identify the precise locations of the breakpoints involved in a deletion or duplication. This is a critical step in understanding which genes lead to a medical or developmental problem. This in turn will tell us about the underlying biology of those problems, which will hopefully lead us to treatment and prevention options.

Once we have thoroughly assessed and evaluated many people with the same condition, it is time to pull all of our data together to create a syndrome description. This is the next step along the pathway to treatment.