Pursuing Elusive Diagnoses for Rare Diseases

Undiagnosed Diseases Program

Laura A. Stokowski, RN, MS; William A. Gahl, MD, PhD


February 26, 2015

Editorial Collaboration

Medscape &

Medscape: You have written in the past about the difficult relationship that can develop between clinician and patient when the clinician can't give the patient a definitive diagnosis. Can you explain this?

Dr. Gahl: Patients relate that it is very difficult to have a mysterious illness without a name. They sense doubt from friends and family, and even their physicians will sometimes become distant or even resentful. It's an awkward situation. It's human nature to want to help, and it's uncomfortable to fail. The physician is confronted with the failure to make a diagnosis or to even help the patient much at all. We feel that all the time, so the referring physician must feel that too.

Medscape: You have also found, through your experiences of the past 6 years, that the care of patients applying to the program had often been overseen by a single specialist, and that may have limited the focus in seeking a diagnosis for some patients. Would you expand on this?

Dr Gahl: Of course this isn't universal, but there are some instances in which a patient has a multisystemic disorder, and one of the systems involved is, for example, gastrointestinal (GI), so the patient has been seeing a gastroenterologist. The gastroenterologist turns out to be the most sympathetic and most willing to take on the entire patient. Therefore, the GI symptoms are managed, and the patient falls into a routine of seeing only the gastroenterologist. That particular specialist, however, might not address the slow progression of a neurologic aspect of the patient's disorder. Or a patient might have undergone a workup of pulmonary symptoms 5 years earlier, but the pulmonary disease is never revisited. We find patients who have fallen into these situations.

Medscape: You have also observed that very few patients had experienced a true multidisciplinary evaluation before they came to you. What would you suggest to providers in the community to improve this aspect of care for patients with undiagnosed diseases?

Dr Gahl: I see it as a referral issue. If you are in a midsized or small-town practice, even though different specialists are available, they may not all get together to discuss a case, whereas that is the purpose of some of these tertiary care centers. You expect that from Mayo Clinic, the Cleveland Clinic, or Johns Hopkins. Referral to a tertiary care center is what physicians with really tough cases need to do. The center may not always provide a multidisciplinary evaluation. We did an informal analysis and came up with the opinion that if a patient has been to even a single tertiary care center and doesn't have a diagnosis, then it's time to go to a UDP. That is based partly on finances. It costs so much for these folks to keep going to doctors, that it's probably worth the cost to the system of an UDP evaluation.

Medscape: Do you foresee being able to develop a model for an approach to these patients that could be followed in the community or in an academic medical center?

Dr Gahl: Yes. In a way, this new network really is that model. We have a 100-page manual of operations, and there are lists of tests that can be done and places to have these tests done. The Undiagnosed Diseases Network is the embodiment of that model.

There is a strong academic spin to this approach. In the community, it can be difficult to get exomes done or find someone to analyze the results of exome tests. The other problem is, who is going to pay for it? The UDP is funded to have experts to consider these cases thoroughly, something that is very time-consuming. It is unlikely to happen in a community where the physician has to see a patient every 15 minutes.

Medscape: What type of genetic testing should be done for some patients with undiagnosed diseases that isn't being done now?

Dr Gahl: We are talking about agnostic genetic testing, which means that you are not looking for a specific gene having a mutation. Agnostic testing is looking at all the genes and then figuring out which one might be the most likely to be causing the disease. That is exome sequencing or genome sequencing, and it is becoming part of our armamentarium, especially in pediatrics. That's partly because kids have a whole family who can be used for next-generation sequencing, and partly because there are more geneticists in the pediatrics community than in the adult community. Eventually exome sequencing is going to be used more and more.

Medscape: You have mentioned plans to set up a Web portal that would be accessible to worldwide experts, where de-identified patient case information could be posted, allowing others to contribute to "solving" these cases. Has this happened?

Dr Gahl: Yes. The issue is that we have to select those cases very carefully. This is largely for researchers who may have an interest in a specific gene, or for academic clinicians who may have a very unusual case that matches the case that we put on the Web. That will be part of the network too—the sharing of both phenotypic and sequence data for the purpose of finding other cases that are similar.

Medscape: What else have you learned through the first years of the UDP that you can share with clinicians?

Dr Gahl: There are personal and human issues here. These patients are incredibly desperate. We often find that patients are happy to have a diagnosis even if it's a bad diagnosis. The need to know is a primal requirement for human beings. These patients and families are in a wondering-and-wandering mode that lasts for years. It is very, very difficult. They are desperate and they are anxious to share their stories, and that sometimes comes into conflict. There is some tension with our society's interest in privacy.

The rare disease and the undiagnosed disease communities are in a position to change the way people think about the sharing of public information. That is going to be one of the goals of the Undiagnosed Disease Network: shared, private information which the families and the patients agree to by consent. Sharing information is important to the families. The other point I would make is that the UDP patients have a mortality rate of about 5% (or a little bit higher), and that's the mortality rate of war. This is a big deal for these individuals.

More information about the UDP and how to refer patients to the program can be found here.


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