Treating zebras: Healthcare’s response to rare disease

When you hear hoofbeats, don’t think of a zebra. This motto is drummed into U.S. medical students, and for good reason. The logical fallacy of base-rate neglect underlines the importance of understanding fundamental distribution levels. It makes sense to investigate the most likely outcomes — the horses — before moving on to less-common diseases.

But zebras do exist, and the last day of February — on leap years, the rarest day on the calendar — is set aside to acknowledge this fact. World Rare Disease Day is meant to draw attention to the more than 7,000 diseases classified as rare.

The diseases themselves range from kidney cancer to chromosome deletions, but one thing they have in common is an arduous diagnostic journey. According to the rare disease advocacy organization Global Genes, patients with rare diseases see an average of 10 specialists over eight years before they are correctly diagnosed — and most of these patients have been misdiagnosed three times along the way.

As a case-sharing platform used every day by doctors, nurses, and medical students around the world, Figure 1 aims to help shorten that diagnostic journey. Our Figure 1 Rare account highlights these diseases, expanding on real medical cases shared on our network. Think of it as a place to see zebras in captivity.

This year, to mark World Rare Disease Day, we asked our community to describe the experience of treating rare disease. Here are some of their stories.

The frustration of misdiagnosis

I had a patient with an insulinoma, a pancreatic tumour. She had to see several endocrinologists to believe the humble general practitioner. She did very well post-excision of her tumour. The frustration was knowing her, her very specific hypoglycaemic episodes both witnessed and just described by the patient, and it still being labeled “reactive hypoglycaemia” for months while she worsened.
- General practitioner, Australia

A condition rarely seen

I was a part of a team in a developing country treating a 30-year-old woman who had pentalogy of Fallot, a rare heart condition. With the advent of better medicinal practices, research, and techniques, these patients are rare but do exist; they live longer and therefore present at varying stages of the illness with “new” symptoms. The major downfall is that there was not a lot of literature that exists in the proper management of this condition, especially as the patient increases in age, therefore making it increasingly difficult to properly manage them. She was eventually treated for right-sided heart failure with pulmonary hypertension, diuresed, given antihypertensives, oxygen initially and weaned off, then discharged on medication.
- Medical student, Jamaica

One in a million

Our pediatric palliative care facility has dozens of stories of children we have cared for with rare/orphan diseases. We learn so much from the parents/caregivers of these special kids. These parents share the useful routines that have helped their children live comfortably. Pain and symptom management can be complicated by the unique responses that some of these children have to traditional therapies. I am so grateful for the wealth of knowledge, love, and hope they share with the team. These patients are one in a million to their families.
- Pediatric nurse, United States

A hard time giving up control

I have taken care of many pediatric patients with rare disease diagnoses. The major challenge from a nursing perspective is that parents sometimes have a hard time giving up control and letting the staff take over. Because there are so many rare diseases, sometimes diagnosis can be delayed.
- Registered nurse, United States

The general surgeon had never seen a case like this

Patient with sclerosing peritonitis (a rare complication of peritoneal dialysis) presented with symptoms of bowel obstruction that was difficult to see on CT and had a high mortality risk if operated on due to stretched mesentery. I was simply the ER nurse for this patient. The general surgeon hadn’t ever seen a case like this and apparently had a hard time finding anyone who had experience managing a similar case locally.
- Registered nurse, United States

The treatment cost $624K a year

One of the childcare workers that helped with the care of my children just didn’t look good one day. She ended up in the hospital that I work for and was soon in full-blown renal failure with no known cause. She endured dialysis, both hemo and peritoneal, for weeks until a rare diagnosis of atypical hemolytic uremic syndrome (aHUS) was made. She ended up being cured by a drug called Soliris which costs $26,000 every 2 weeks in the U.S. — and she will most likely need this forever. My concern is she is still under her parents’ insurance, but not for much longer. Wondering how she will manage this disease without that coverage.
- Registered nurse, United States

Nurse, mother, advocate

I am a pediatric registered nurse, and parent of a child with a rare autoinflammatory disease. Our challenges to get him diagnosed properly and treated, and hearing stories from other patients that had struggled for years undiagnosed, inspired me to start a non-profit organization for autoinflammatory diseases.
From 1999–2003 I spent a lot of time on PubMed and at the medical school library after reviewing my child’s full medical chart. I kept taking him to specialists, and giving them information about periodic fever syndromes. I ended up finding a lab that offered genetic testing for autoinflammatory diseases in late 2002, not long after the genetic panel became available, and got a doctor to order the test (his pediatrician was willing to order the test when we did not have luck with our rheumatologist at the time.) There was a certain disease on the panel that seemed likely, but I also felt that it was possible that we could again get no results from the test, but that it would still be worth it to test him.
Three months later, in January 2003 we got genetic confirmation that he did have that exact disease that we had suspected, which was a bittersweet moment. Knowing the cause changes everything, and allowed us to narrow in on what to chase for getting him help. But at the same time, he had a disease that patients were quite debilitated from since there was no targeted treatment. I had to seek specialists, and found other patients online that led me to clinical research at the National Institutes of Health (NIH). My son started a clinical trial in January 2004 with a medication that was found to target his condition, and it changed his life. We noted dramatic improvement within the first 24 hours on the medication. After a few weeks he was growing again, after no growth in over 18 months, and not suffering anymore from severe pain, fatigue, and inflammation from his brain to his ankles.
Had I not known how to do our own research, and seek out testing and specialists to help my child, it is likely that his diagnosis would have taken more years, and he would have sustained more permanent damage. He had some serious complications while undiagnosed that were life-threatening, so we are lucky he made it to be able to start medication that changed his life. Our non-profit organization, the Autoinflammatory Alliance helps many patients, and also many medical professionals, with resources and connects them to specialists to help with these diseases and clinical trials.
One of the biggest issues is getting doctors to consider the possibility of a rare disease when presented with certain symptoms. For example, we have found a number of patients that went undiagnosed and untreated for years with symptoms such as hearing loss, rash, fevers, and other things that are classic symptoms of Cryopyrin-Associated Periodic Syndrome (CAPS). However, some doctors never connected the possibility that hearing loss could be connected to the other symptoms as one disease, and treated things separately. It is important to look at everything, and see if there could be a connection, especially when dealing with unusual cases. It is especially a challenge for many autoinflammatory diseases that present with recurrent fevers, rashes, and other symptoms that can be mistaken for more common conditions. We developed a comparative chart with medical experts, that included photos in 2013, and expanded it into an online searchable, comparative database for autoinflammatory diseases in 2015, at autoinflammatory-search.org so doctors could compare symptoms, and consider these diseases. Within a month of our release of the chart at a few medical conferences, including ACR, we had a great increase in doctors globally contacting us with cases that they felt may be autoinflammatory, and patients. This has continued for the past few years.
Our goal is to help get information out there for patients and doctors so people can get diagnosed and onto treatment sooner, since earlier diagnosis and treatment can greatly improve the quality of life, and in some cases spare patients from lifelong permanent damage due to their disease.
- Registered nurse, United States

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