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 &

The patients whom we see have already been through major medical centers, and the obvious and even the not-so-obvious studies have been performed, so I would expect us to have a lower success rate based on that. In fact, one of the things that we have to accept is failure. If we agree to pursue the most difficult cases, we and the patients have to accept the fact that we will often fail.

We don't really have the resources to keep good track of everything. We have a database in which we can look things up, but it would be better if we had the time and the money to review all of our cases every year or so. Instead we do it in an ad hoc fashion. But we are academic. We read the literature, and if we read about a new disease, we actually remember patients because they were with us for a week, and we say, "You know, so-and-so may have had such-and-such disease," and then we can look for the particular gene that has been described in the literature. But it's possible that our database can be made more sophisticated and we can have more resources to search it more often.

Medscape: You often include other family members in the evaluation. Have you ever found a disorder that had been unrecognized in a patient's family member?

Dr Gahl: Yes. That can happen because of decreased expressivity. When that happens, we actually like to bring in the other family member and do an evaluation. Even when other family members have no signs of disease whatsoever, they are almost always extremely cooperative in terms of consenting to provide history and DNA to help their loved ones reach a diagnosis.

Medscape: You have said that patients with acute illness aren't accepted into the UDP. Do patients with chronic disorders receive any treatment or counseling while they are in the Clinical Center?

Dr Gahl: They do receive genetic counseling and often other treatment as well. Our team is made up of physicians and nurse practitioners who are clinical caregivers, so there are always two aspects to our evaluation and our diagnostic process. One is what the patient might have and how we can pursue finding out what that is. The second aspect is how the patient can deal with the existing problems caused by the disorder—in other words, symptomatic care. We will recommend adjustments to medications, and we will recommend further consultations at home. Our Rehabilitation Medicine Department will not only recommend but often provide resources for skills, such as putting on your socks, or exercises and physical therapy. Occasionally we will even recommend some disease-specific therapies that can be pursued by the treating physician in the community. We really do take care of the patient as much as we possibly can.

Medscape: Do you ever try out different treatments as part of the diagnostic evaluation while the patient is in the Clinical Center?

Dr Gahl: By and large, there are very few cases in which we do what we call diagnostic therapeutic interventions. There are cases in which we first make a diagnosis of a symptom—not necessarily the basic disease but a symptom such as parkinsonism, and we can provide some therapy for that based upon that symptomatic diagnosis.

We had a patient who had necrosis and severe inflammation of his skin and soft tissue. His soft tissue was falling off. He had open wounds that would become infected. On imaging, we found calcification right under the skin. One of our consultants suggested a treatment, sodium thiosulfate. We put him on sodium thiosulfate, and over the next 6-8 months it has allowed his skin to heal, with only a few residual lesions. That helps us somewhat with the diagnosis. Calcium phosphate is incredibly insoluble and causes an inflammatory reaction. That's what he had before. Now we give him sodium thiosulfate, and the thiosulfate salt of calcium is much more soluble than the phosphate salt of calcium, so it removes the inflammation. It has turned his life around. He now has a chance to cure his soft tissue. We don't have a diagnosis but we can put a name on it—something like tumoral calcinosis, although that is just a descriptive term.


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