Managing Patients with Rare Conditions

A survey of more than 1000 patients with rare diseases and their doctors ( estimated that it takes an average 7.6 years in the United States, and 5.6 years in the United Kingdom for a patient with a rare disease to receive a correct diagnosis. During that time, the average patient will be misdiagnosed 2 or 3 times while visiting 4 different primary care physicians and 4 different specialists.

A problem with these statistics, however, is that they assume all rare diseases are the same. Each disease is unique. Some are diagnosed quickly, while some take decades to be correctly diagnosed.

Delayed Diagnosis Is Common

Many factors contribute to the difficulty of diagnosing a rare disease— especially, a disease that develops slowly, or does not have symptoms known to be specific to it. Clinicians are trained to view a set of symptoms as the result of a more common ailment or combination of ailments (eg, allergies, asthma, cardiovascular problems, infection). In most cases, that is likely the correct assumption. A common story shared in the rare disease community begins with the notion that clinicians are taught in medical school to think like ranchers: if ranchers hear hoofbeats, they should assume that a horse is behind them, not a zebra. How does this apply to physicians? When physicians see a series of symptoms, they should assume they are related to a common ailment, not a rare one. As a result, a patient with a rare disease may see many doctors to obtain a second, third, and fourth opinion and receive multiple misdiagnoses that are geared toward more common conditions.

With more than 25 million Americans with rare diseases, it is likely that most clinicians will encounter several of them during their career. Because there are approximately 7000 rare diseases, however, it is difficult for clinicians to know when to look for a “zebra” and when to look for a “horse.” Unfortunately, no easy way exists to get around this problem, except through awareness and reminding physicians to consider rare conditions earlier in diagnostic testing instead of when all other common ailments have been ruled out.


The treatments for rare diseases are as variable as the diseases themselves. Treatments can range from specific FDA-approved orphan drugs to diet and lifestyle changes to surgical intervention, or all 3.

To date, approximately 500 orphan drugs have been approved for rare diseases. Many conditions, however, have multiple orphan drugs (see Appendix A). Almost half of the orphan drugs are for cancers and hematologic conditions (including blood cancers). The rare conditions with approved orphan drugs can be found listed in Appendix A.

Lifestyle Changes

Whereas most attention in the rare disease community is focused on orphan drug development, many rare diseases can be managed by surgery, diet, and lifestyle changes. For example, phenylketonuria—an inherited disorder causing toxic levels of phenylalanine—may be managed with a phenylalanine-restricted diet in some patients (these patients may also benefit from the orphan drug Kuvan). Xeroderma pigmentosum—an inherited condition characterized by extreme sensitivity to ultraviolet sunlight—is generally treated behaviorally, by avoiding direct exposure to the sun and by using sunscreens. Ménière’s disease is an abnormality of the inner ear leading to vertigo and dizziness. In most cases, a restrictive, no-salt diet, perhaps even antihistamines and/or diuretics, are used to manage the condition.


Surgery can also be the primary treatment. For example, a patient with Tetralogy of Fallot, a congenital heart defect, can be treated with openheart surgery, while a child with craniosynostosis can often lead a normal life following neurosurgery and plastic surgery early in development. Most rare diseases, however, do not have a treatment, and for those that do, whether it is surgery, a lifestyle change, or an orphan drug, the data on the safety and efficacy of that treatment are often limited.

Treatment versus Cure

Treatment options may be classified as (1) curative, (2) diseasemodifying, or (3) symptom- or function-modifying.

1. Curative Treatments
Although curative treatments are very uncommon for rare diseases, most rare infections (eg, Tropheryma whipplei) or rare poisonings (eg, from snakebites or cyanide) can be cured with treatment. Surgery can also “cure” many anatomical defects, such as craniosynostosis or coarctation of the aorta.

2. Disease-Modifying Treatments
These treatments may receive orphan drug approval to treat rare diseases. For example, enzyme replacement therapy for Gaucher disease may delay or stop the progression of the disease, but not cure it. Many patients can lead normal lives following treatment, but the underlying cause of the disease remains. For others, the treatment may delay progression but will not stop it.

3. Function-Modifying Treatments
These types of therapies may not be approved orphan drugs, but are necessary to treat the plethora of symptoms that result from a rare disease (eg, pain, nausea, gastrointestinal problems, anemia). A major concern with treating these symptoms is that the therapies may not be covered by insurance, which can lead to major financial setbacks for a family especially if surgery, complicated medical/communication devices, and/or physical therapy are necessary.

Long-Term Effects of Treatment

A common concern with many treatments for rare diseases is that we do not know the long-term effects of treatment or how treatment will need to change as a patient ages or as their disease progresses. Although the FDA makes every effort to approve drugs that are safe and effective, most clinical trials, that have led to orphan drug approval, have been limited in size and design. Only recently have we begun to address the natural history of these conditions, and how that history may change with improvements in medical care.

The long-term follow-up of patients through carefully designed and maintained patient registries is becoming increasingly important. Such registries can provide critical data on the natural history of a specific disorder and how a specific treatment changes this natural history. Increasingly, patient advocacy organizations are taking the lead in establishing registries. With the aid of the Internet and globalization of patient communities, foundations are becoming increasingly effective at encouraging participation in registries by their patient and family stakeholders.

Guidelines for Rare Diseases

There are increasing efforts to develop and publish international consensus documents regarding care guidelines and standards of care for specific rare disorders. However, these efforts have generally been limited to the most common of the rare disorders—the minority of these disorders—for which adequate data exist to develop guidelines. Websites of patient advocacy groups are often the entry point to determine whether guidelines exist and where they can be found (see Appendix B). Many patient advocacy groups have sections for healthcare professionals to learn more about the management of specific rare conditions. Many advocacy groups also highlight specialized clinics where the staff have experience in treating particular rare diseases.

As Treatments Improve Outcomes, They Also Create New Unknowns

Since many rare diseases occur in children, pediatricians often see them and may become at least somewhat familiar with their management. In contrast, physicians who treat adult patients are less likely to see rare diseases. Ironically, as the treatment of rare diseases has improved, many children with a rare disease live into adolescence and adulthood, only to find that their new treating physician is less familiar with the rare disease than they are. In other words, as patients age, they may be the ones providing their doctor with in-depth information about their condition. In addition, the lack of natural history studies for many diseases— especially in light of recent treatment advances—means that we often do not know how a disease will progress, or how a treatment will affect other body systems. Therefore, patients with rare diseases are encouraged to enroll in patient registries and/or natural history studies to help advance the medical community’s understanding of each rare disease.
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