Super Sleuths to Unravel Perplexing Pediatric Cases in Undiagnosed Diseases Network

By Sharlene George

Dealing with a mystery illness that doesn’t appear to match any conditions described in medical textbooks can entangle families on a diagnostic odyssey for years and even decades. Dozens of examinations, a barrage of tests, multiple misdiagnoses, and trips in and out of hospitals can leave them exhausted and no closer to knowing what is wrong with their child.

Those struggling to find a diagnosis can now turn to a new team of super sleuths from Children’s Hospital of Philadelphia and the Hospital of the University of Pennsylvania who are ready to unravel these perplexing diseases, in both children and adults. The two institutions received $2.5 million in research grants from the National Institutes of Health as a newly designated Undiagnosed Diseases Network (UDN) site.

The UDN research study was developed to improve and accelerate the diagnosis of conditions that are rarely seen, have not previously been described, or are unrecognized forms of more common diseases. Since the UDN launched in 2015, the network has diagnosed more than 200 cases that had long confounded the medical community, yet many more remain unexplained. By expanding the network, the UDN will enhance its diagnostic expertise and give more patients the opportunity to participate.

Kathleen Sullivan, MD, PhD, chief of the Division of Allergy and Immunology at CHOP and Reed Pyeritz, MD, PhD, the William Smilow Professor of Medicine and professor of Genetics at Penn, will act as co-directors for the joint CHOP/Penn site. On a regular basis, they will assemble experienced, knowledgeable clinician-scientists to leverage their collective brainpower and tackle the toughest of these tough cases.

“When a patient comes through the program and are accepted to the CHOP/Penn site, they will be seen by a committee of the best and the brightest specialists who will sit together, think together, and plan the approach on how best to diagnose the patient,” Dr. Sullivan said. “In the end, we will deliver the news about the diagnosis and, importantly, how that is going to change and customize their therapy — how that is going to help them be healthier.”

Dr. Sullivan expects about 15 pediatric patients will be assigned this year to the CHOP/Penn site through an online patient application portal called the UDN Gateway. Their cases will be scrutinized by a core group of CHOP experts including Edward Behrens, MD, chief of the Division of Rheumatology and the Joseph Lee Hollander chair of pediatric rheumatology; Matthew Deardorff, MD, PhD, associate medical director of the Roberts Individualized Medical Genetics Center; Marni Falk, MD, executive director of the Mitochondrial Medicine Frontier Program; Adeline Vanderver, MD, program director of the Leukodystrophy Center and Jacob A. Kamens Endowed Chair in Neurologic Disorders and Translational Neurotherapeutics; and Zhe Zhang, PhD, bioinformatics scientist in the Department of Biomedical and Health Informatics. The team will consult with ad hoc members — Dr. Sullivan called them “superstars” of their specialties — to shed light on each patient’s condition from multidisciplinary perspectives.

In some cases, they may need a more complete genetic picture of the patient, so they will use sophisticated whole exome sequencing to rapidly sequence large amounts of DNA and catalog all of the protein-coding genes in a child’s genome. Combing through this large amount of data can produce valuable clues to possible disease-causing mutations, but they’re not always obvious, especially if the team isn’t aware of any other patient cases involving the same genetic variants and similar clinical presentations. In these unusual cases, the team will reach out across the globe to help narrow down an answer. 

Using crowdsourcing research tools, the UDN team can input a short description of the patient’s genotype and phenotype — without using personal identifiers — and query international scientists to see if they have encountered a patient who is comparable. If they find a “match,” the scientists can be more confident in going back to their labs to conduct more research that could allow them to ascribe a particular gene to the patient’s illness.

“I love the idea of invoking the entire world to come together and say, we have something that looks like this, and let’s move together to help all of our patients,” Dr. Sullivan said. “I think that is really beautiful. The idea that you can crowdsource information does not feel very high tech, but when you’re talking about rare diseases, it may be the only way.”

Strength in numbers is the underpinning of the UDN, which has the vision statement: Solving medical mysteries through team science. The network includes a dozen clinical sites, a coordinating center, a sequencing core, a metabolomics core, two model organisms screen centers, and a central biorepository that allow investigators to interrogate the most challenging undiagnosed diseases from various dimensions.

Arriving at an accurate diagnosis is like finding a key to that could unlock treatment possibilities. In some fortunate cases that the UDN deciphers, a drug already on the market for another condition may be useful; however, the National Human Genome Institute reports that about 95 percent of rare disorders do not even have one treatment approved by the Food and Drug Administration.

If an effective treatment doesn’t already exist, more research will be needed to identify novel therapeutic approaches. CHOP Research Institute has an ideal bench-to-bedside infrastructure that will expedite the UDN team’s ability to successfully engage with basic science researchers who are eager to participate in projects that eventually could change children’s lives, Dr. Sullivan said.

Over her 25 years at CHOP, starting at the 22q and You Center and then continuing to help families with rare pediatric autoimmune diseases such as very early onset inflammatory bowel disease, Dr. Sullivan has recognized that every patient is on a unique journey; patients with the same disease can manifest symptoms in dissimilar ways, so clinicians need to respect their individuality and tailor diagnosis and treatment accordingly.

“One of the things I’ve learned is it’s really hard to predict what you’re going to find,” Dr. Sullivan said. “It’s humbling and exciting that we’re at the forefront of learning about different types of diseases and what the diseases look like in different patients. I hope we can help in some way all of the families who come to us through the network and are desperate for the right answer.”

The UDN estimates that overall one in 10 people have a rare disease. Those without an explanation for their symptoms may wrongly be labeled as having psychiatric conditions, which can delay proper diagnose and leave families demoralized. Dr. Sullivan anticipates that finally knowing the root cause of their child’s illness not only will bring profound relief, but also opportunities to connect with other families who have experienced their same challenges and can join together to accelerate future research for rare pediatric diseases.