As most clinicians are likely aware, rare diseases aren’t all that rare. Up to 10% of the U.S. population is thought to be affected by a rare disease, according to the National Organization for Rare Disorders.1 Still, there are more than 7,000 different rare diseases, and a variety of presentations for each one, making them extremely difficult for health care providers to recognize and rapidly diagnose, let alone treat. It’s not clear exactly what portion of rare diseases are hematologic in nature, but a U.S. Government Accountability Office report published in 2018 found that more than half of drugs that received the orphan designation to treat rare diseases were for hematologic disorders, suggesting that the proportion may be high.2
According to one survey, it takes an average of more than seven years to be diagnosed with a rare disease.3 Plus, 44% of patients with a rare disease are initially misdiagnosed, and many receive ineffective or even harmful treatments.4
ASH Clinical News spoke with several experts in rare diseases about how to diagnose and treat patients with such diseases and the resources available to help physicians do so.
When to Suspect a Rare Disease
Any time a patient’s labs or symptoms don’t seem to match up, doctors should suspect that the patient has a rare disease, experts said.
Rekha Parameswaran, MD, a hematologist/oncologist at Memorial Sloan Kettering Cancer Center in New York, typically works with patients who are already receiving chemotherapy but may also have paroxysmal nocturnal hemoglobinuria (PNH) or bone marrow failure.
“Patients can present with seemingly common problems, especially anemia. Initially, we have a fairly standard workup that we might do, but when somebody’s labs are more severe than you would expect for the chemotherapy that they’re receiving,” you might start to suspect a rare disease, Dr. Parameswaran said, adding that this is especially true if blood counts drop very early on during treatment.
Sometimes an existing diagnosis can tip a doctor off. Certain symptoms and characteristics are more likely than others to be associated with rare diseases. For example, “If you’re dealing with a bone marrow failure or a myelodysplastic syndrome, we know there’s a strong suggestion that that could be associated with a rare disease,” said Julian Martinez, MD, PhD, a clinical geneticist at the University of California, Los Angeles (UCLA). “It’s really important that that become part of the differential.”
He also encouraged physicians to think more broadly. “What ends up happening is that each specialist focuses on the particular area they want to focus on. In many ways, that reduces the likelihood of a successful diagnosis because no one’s really paying attention to the bigger picture and trying to put all those clues together to suggest particular rare disease etiology.” He emphasized that it’s important to consider the whole patient, even when a diagnosis has already been made.
Collaborating to Diagnose a Rare Disease
Because nearly three-quarters of all rare diseases are genetic, family history and genetic screening can play a major role in diagnosing them.5 “The challenge with rare diseases is that their etiologies are so multifactorial that many times, we rely on genomic tools or technologies to help us narrow down which exact diagnosis we’re dealing with,” Dr. Martinez said.
But it isn’t always as simple as just one round of genetic testing. Depending on the clinical presentation and previous labs, a doctor might need to take a biopsy from specific tissue. “It requires that expertise of knowing what the right tissue and the right test are and what technology would actually lead to the most effective diagnosis,” Dr. Martinez said.
He recommended that hematologists/oncologists try to build relationships with groups that have more specialists and resources. “When it comes to seeking out a specialist, I think once a hematologist/oncologist realizes that there’s a rare combination of phenotypes that could potentially suggest a rare disease that might be outside of his or her focus, then they might refer the patient to a well-established team at an academic center or to a local geneticist.”
Teaming Up Across the Country
In 2008, the Undiagnosed Disease Program launched. The program was so successful, explained Isaac Kohane, MD, PhD, principal investigator of the coordinating center for the Undiagnosed Diseases Network (UDN) at Harvard Medical School, that patients pressured Congress into expanding it and funding the UDN in 2013. The network includes 12 clinical sites across the country where physicians, clinical geneticists, researchers, and other experts work together to diagnose and treat patients with rare diseases. Patient data are uploaded into a secure cloud that only other practitioners in the network can access.
“The patient data follow the patient, which doesn’t happen that often in medicine,” Dr. Kohane said. “That way, that patient could be seen anywhere in the network.”
Dr. Kohane emphasized that the network is a tool for doctors and their patients and there’s no additional cost to the patients to be a part of it.
Europe has its own rare disease diagnosis network, known as Solve-RD. The European Union funded the project, which includes 300 clinicians, scientists, and patients in 15 European countries, in 2018.
Dr. Martinez, who also serves as a leader of the UDN site at UCLA, explained that in recent years, more and more multidisciplinary clinics have been doing outreach, such as advertising at conferences, to let physicians know they are available and willing to collaborate to treat patients with rare diseases.
Unfortunately, Drs. Martinez and Kohane said, patients often don’t get a diagnosis, even after they find specialists and have a thorough workup with a variety of genetic screenings. “Sadly, we only diagnose somewhere between 30% to 40% of the patients,” Dr. Kohane said.
However, research is ongoing, and as new screening tools are developed, the UDN annually revisits cases the team wasn’t initially able to diagnose, Dr. Kohane said. “Because medicine keeps moving forward, we learn more about the genome every year,” he explained. “Even patients who have been previously undiagnosed are revisited every year to see if we know new things about the genome so we can maybe provide a diagnosis.” Dr. Kohane estimated that about 5% of the 5% to 10% of previously undiagnosed cases are getting diagnosed.
Getting Support and Treatment
In the best scenarios, geneticists or multidisciplinary clinics manage to find a definitive diagnosis for a rare disease and a patient can start an off-the-shelf treatment right away. If the patient was diagnosed by a group such as the UDN, the team will transition the patient back to his or her local doctor or to a more specialized local team that can provide expert treatment. “Trying to figure out a way to have the expertise local to the patient is a big priority,” Dr. Martinez said.
One group of underserved patients, Dr. Parameswaran explained, is those who were diagnosed with a rare disease in childhood but are now young adults transitioning out of pediatric care. This is something her clinic sees often.
“If they’ve grown up with a rare disorder, they may have come to view pediatric nurses at the infusion centers as extended family. The clinic is a home away from home,” Dr. Parameswaran said. “So, one way to help the patients moving to the adult clinics is trying to make sure we transition to be part of the extended family too.” She added that patient advocacy groups can play a major role here. It’s important for patients to know they’re not alone, she said.
Sometimes, a patient gets a diagnosis, but no treatment is available. In these cases, the UDN can connect the individual to researchers and companies working on clinical trials.
The Role of Technology
It’s well known that telemedicine surged during the COVID-19 pandemic, with patients and doctors becoming more accustomed to the setup. A McKinsey analysis found that health care providers are seeing between 50 and 175 more patients via telehealth than they did before the pandemic.6
Specialists hail this as a major benefit for patients with rare diseases. Not only does it save patients time and money by providing access to geneticists and rare disease specialists without forcing them to spend a day traveling and taking time off work, but it also allows for smoother visits.
“We’re able to see patients in their own environment. For patients who have neurodevelopmental differences, it’s hard to have them come to a very scary clinic where there are loud noises and doctors in white coats. With telehealth, we can see them in their home, with their parents, in a very comfortable environment,” said Dr. Martinez.
That doesn’t mean that all patients can see a specialist through their computer screen, however. Many patients are without internet or don’t have access to telehealth. “For those patients, we try to find other resources that the health system has to try and help with transportation so they can come in person,” Dr. Martinez said.
While more advanced gene sequencing is frequently increasing the number of patients whose diseases can be diagnosed, experts said there is still a long way to go. In addition to genomic testing, scientists say practitioners should consider using metabolomics, proteomics, methyl profiling, and a variety of other more specialized molecular tests to help diagnose patients.7
Over the last six or seven years, when scientists have identified a mutation but are not positive that the mutation is the cause of a patient’s symptoms, teams have started to use gene-editing technologies to create animal models with the same mutations to see if they develop the same symptoms as the patient, Dr. Kohane said. “That gives us much more confidence that we found the right mutation,” he said.
Researchers are also using artificial intelligence (AI) to help diagnose and manage rare diseases. For example, a team at the University of Pennsylvania and University of Florida are working on an AI algorithm that will help them predict who is most at risk of developing certain types of rare diseases such as vasculitis.8
While expert rare disease clinics have been doing more and more outreach as of late, they are struggling to reach one particular group of patients: those with a misdiagnosis. Patients who are undiagnosed and searching, along with their doctors, for an explanation for their symptoms are likely to seek help from outside sources and look for teams that might offer expertise. However, if someone already has a diagnosis but is not having the expected response to treatment, then both the patient and doctor are less likely to seek out alternative diagnoses.
“A lot of patients are given a diagnosis like diabetes or inflammatory bowel disease, where perhaps they don’t respond to the available medications,” Dr. Kohane said. “And the way the medical system works is that we say this patient doesn’t respond to therapy. That’s technically true, but it may also be that a fraction of those patients don’t have the disease we think they do.” Finding those patients, he said, will require a new way of mining data like hospital and insurance records. Plus, “many treatments that are intended for more common presentations might actually be harmful to patients with rare diseases,” Dr. Martinez said.
One of the biggest open questions, Dr. Kohane said, is how environmental exposures can lead to disease. “We want to look beyond genetic causes to environmental causes, so rare causes of diseases that have been undiagnosed and may relate to exposures. Frankly, that’s a lot harder to analyze, but it’s a big part of the disease burden.”
Dr. Kohane also hopes doctors will be better able to coordinate records in the future. “This country has a very fractured health record system, so getting a comprehensive view of patients, treatments, and clinical history is hard. We always worry that we’re missing key facts.”
With these challenges in mind, Dr. Parameswaran highlighted the importance of taking a patient-centric approach when treating rare diseases. “We talk a lot about patient-centered care, and I think taking care of patients with rare disorders really epitomizes patient-centered care. So much of it is really listening to the patient, keeping your clinical skills alert for thinking more deeply about a patient whose medical course is not going the way you expect it to.”
- National Organization for Rare Diseases. Rare disease facts & statistics. Accessed December 18, 2023. https://rarediseases.org/understanding-rare-disease/rare-disease-facts-and-statistics/.
- U.S. Government Accountability Office. Orphan drugs: FDA could improve designation review consistency; rare disease drug development challenges continue. November 30, 2018. Accessed December 28, 2023. https://www.gao.gov/products/gao-19-83.
- Shire. Rare disease impact report: insights from patients and the medical community. 2013. Accessed December 18, 2023. https://globalgenes.org/wp-content/uploads/2013/04/ShireReport-1.pdf.
- Vandeborne L, van Overbeeke E, Dooms M, et al. Information needs of physicians regarding the diagnosis of rare diseases: a questionnaire-based study in Belgium. Orphanet J Rare Dis. 2019;14(1):99.
- Nguengang Wakap S, Lambert DM, Olry A, et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet. 2020;28:165-173.
- Bestsennyy O, Gilbert G, Harris A, et al. Telehealth: a quarter-trillion-dollar post-COVID-19 reality? McKinsey & Company. McKinsey & Company. 2020. Accessed December 18, 2023. https://www.mckinsey.com/~/media/McKinsey/Industries/Healthcare Systems and Services/Our Insights/Telehealth A quarter trillion dollar post COVID 19 reality/Telehealth-A-quarter-trilliondollar-post-COVID-19-reality.ashx.
- Marwaha S, Knowles JW, Ashley EA. A guide for the diagnosis of rare and undiagnosed disease: beyond the exome. Genome Med. 2022;14:23.
- Tonnessen D. Researchers will use AI to predict who may develop certain rare diseases. University of Florida Health. October 25, 2022. Accessed December 18, 2023. https://ufhealth.org/news/2022/researchers-will-use-ai-predict-who-may-develop-certain-rare-diseases.