Inside Pediatrics Winter 2015

Breaking the Code of Undiagnosed Diseases

Inside the Diagnosis

the patient’s current situation, what other specialties should be brought into the case and what additional testing needs to be conducted. “We see ourselves as the Supreme Court of medical evaluations,” Korf said. “We’re not a first step.” A high percentage of the patients seen in the undiagnosed diseases program need further, more complex evaluation, and that’s where the “new-fashioned” medicine plays a crucial role. Many of the diseases are genetic-based, so genome sequencing is conducted to identify them. “With genome sequencing, you’re looking at all genes, so you don’t have to know the answer in advance,” Korf said. “One test cancels the need for a lot of others.” The genome sequencing is done in collaboration with HudsonAlpha Institute for Biotechnology in Huntsville, Alabama, where Korf co-directs the UAB-HudsonAlpha Center for Genomic Medicine. In one-third to one-half of his patients who undergo genome sequencing, Korf finds the resulting diagnoses typically fall within three categories: (1) the diagnosis makes a lot of sense but is sometimes very rare and, thus, had previously gone unrecognized; (2) the diagnosis is rare, unknown or may not even have a name, so the referring physician would not have thought to test for it; or (3) the genomic findings reveal a possible diagnosis that has never been seen before. For patients, the benefits can be life-changing. “Genome sequencing cuts short the diagnostic odyssey and gives them answers that have been elusive for years and even decades,” Korf said. In children, a sure diagnosis provides peace of mind because it identifies the genetic foundation of the disease so parents know the risk of recurrence. It also may result in a new course of treatment that might not have been considered, eliminating the

Sometimes the most puzzling of medical mysteries can be solved by a delicate balance of the old and the new. That’s the foundation of the undiagnosed diseases program headed by geneticist Bruce Korf, M.D., Ph.D. By the time even his youngest patients meet Korf and his colleagues, they have assembled medical records with hundreds to thousands of pages reflecting the inconclusive results of testing that has cost a fortune by anyone’s standards. They have chronic major medical problems, but none of the specialists they’ve seen can confirm a definitive diagnosis. “They go from doctor to doctor, medical facility to medical facility, seeking answers no one can give them,” Korf said. “Tests are repeated, and there’s very little communication.” So two years ago, Korf, who served as chair of the external advisory committee for the Undiagnosed Diseases Program at the National Institutes of Health (NIH,) created a similar program at the University of Alabama at Birmingham (UAB.) It is one of the first university-affiliated programs to be developed on the NIH model. Within the next six months, the pediatrics arm of the program will be relocated to Children’s of Alabama. “It’s a powerful program. That’s why I wanted to start it here,” he said. “It’s a union of very old-fashioned medicine with very new-fashioned medicine.” Patients are typically referred when routine evaluations have not been effective. Upon the patient’s first visit, the “old-fashioned” aspect of medicine takes the lead as Korf and his team make every effort to gather as much information as possible through extensive conversations with the patient and his or her family to ensure a thorough understanding of the patient’s history and identify any gaps that exist in the work up. The team distills what they’ve learned and discusses ideas among themselves to determine next steps. Korf and his colleague Maria Descartes, M.D., then conduct an assessment of the patient to determine

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