Horses or Zebras

Horses and Zebras: Rare Conditions in Primary Care

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Of the myriad medical conditions you may see over the course of your professional practice, more than 6,000 of them are considered “rare.” We are pleased to offer you information and resources to help you better recognize and manage rare and unusual diseases.

Jumping Frenchmen of Maine may sound like an extreme sports team or a new-age rock band, but it’s neither. It’s the name of an unusual disorder that causes an extreme startle reaction to unexpected noises or sights[1] and is classified by the National Institutes of Health (NIH) as 1of 6,000 rare or “orphan” diseases. Some of these rare conditions carry strange names like Madelung’s Disease, which causes abnormal fat accumulation around the neck and shoulders, or Kufs Disease, a cerebroretinal degenerative condition. Others, such as multiple myeloma and cystic fibrosis, are more familiar but are also considered rare diseases—defined as affecting less than 200,000 people in the United States per year [Table 1]. To get an idea as to how infrequently these diseases occur, consider that 25.8 million people in the United States have type 2 diabetes and 16.3 million have coronary heart disease![2,3]

In the past, orphan diseases were overlooked by drug and medical device developers because they affected so few people. But in 1983, Congress enacted The Orphan Drug Act, which provided tax incentives and time-limited exclusive marketing to biotechnology and pharmaceutical companies that develop drugs to treat rare disorders. In the 10 years prior to passage of the Orphan Drug Act, only 10 new drugs for rare diseases were developed by the pharmaceutical industry. In the 28 years since the approval of the act, more than 300 new orphan drugs have been approved in the United States–an average of about 11 new drugs every year.[4] In the last decade, 148 orphan drugs received marketing approval, of which 26% were for pediatric diseases.[5]

Horses and Zebras

For medical students, one of the first lessons in identifying diseases is “When you hear hoof beats, think horses, not zebras!” In other words, most times the obvious answer is the correct answer and “common things are common.”

Consider a patient who comes in during flu season with a fever, headache, and a stiff neck. While these are the classic symptoms of bacterial meningitis, the flu is more likely. While there may be an eventual need for tests to rule out rarer and more serious illnesses, remembering that “common things are common” is a good starting point during flu season.

Most of the illnesses you treat are likely to be common conditions such as diabetes and hypertension. However, some patients will have a disease that is rare or presents in an unusual manner, and primary care includes the responsibility for recognizing these less common conditions and managing these patients, as well.[6,7] While it is virtually impossible for you to have the skill set and experience necessary to quickly identify all rare diseases or conditions that present in an atypical fashion, it is important to develop an “ear” for the unusual and the critical ability to move past the common and focus on the rare.[8]

Hunting Down the Zebras

Pay attention to your patients. No clinician wants to miss a zebra. Yet spotting them is becoming increasingly complicated. More than ever, sorting out the hoof beats requires keeping an open mind when a “horse” looks a little strange, doesn’t quite sound or smell right, or doesn’t fit the textbook description. It means not automatically discounting vague symptoms like “feeling weird.” And it means taking friends seriously when they say, “she’s acting strange.” If a patient doesn’t respond in a typical pattern to standard treatment, take note. Trust your instincts when you feel that a patient’s course is just not right. When you see patients with symptoms you don’t understand, look for patterns, consult colleagues, and search the recent literature. Talk with patients about their recent travels, their family history, and their work environment.

Think outside of the neighborhood. World travel and immigration trends can introduce diseases from other countries. An asymptomatic 15-year-old female presents to your office complaining of “red urine.” Her only laboratory abnormality is a urinalysis that reveals 20 to 50 RBCs. What is her likely diagnosis? If her surname is Smith and she has never left the United States, she might have a urinary tract infection, glomerulonephritis, or even idiopathic hematuria following her menstrual cycle. But what if her surname is Abdiraman and she recently moved to the United States from Sudan? In that case, the most likely diagnosis would be schistosomiasis hematobium, a common condition among those who have recently arrived from East Africa, with the infection rate in this population exceeding 40%.[9] If you were not aware of this patient’s ethnic background or country of origin, you’d be less likely to consider this zebra.

Don’t discount family history. Approximately 80% of rare diseases are not acquired—they are the result of genetic defects or mutations. Specific inherited conditions are more common in some ethnic backgrounds than others, so it helps to know all you can about your patients’ family backgrounds. Patients of Eastern European Jewish origin have a much higher prevalence of Tay-Sachs disease and Niemann-Pick disease than other nationalities[10]; thalassemia is a blood disorder that mainly affects people of Mediterranean (Italian, Greek, North African), African, and Southern Asian descent[11]; and Maple Syrup Urine disease is a life-threatening inherited disorder that is more common in the Mennonite population[12] and is the most common inborn error of metabolism in babies born in the Phillipines.[13]

Where to Go for Help

While each specific rare disease affects less than 2,000 people, overall there are more than 10 million people in the United States suffering from these conditions. For one-third of people with a rare disease, getting an accurate diagnosis can take one to five years. On average, an accurate diagnosis takes nearly three years. So where do you—or a person or family with a rare or undiagnosed disease—turn for help?

The Internet is an excellent place to start. A 2011 survey by Wolters Kluwer Health suggests that 46% of clinicians “frequently” use a general browser such as Google or Yahoo to help diagnose and treat patients, and another 32% use the Internet as an occasional resource. Among respondents, 63% reported changing an initial diagnosis based on new information accessed via online resources/support tools.[14]

Aside from providing access to public agencies and organizations, the Internet is a valuable diagnostic tool. Clinicians adept at using the Internet can use a search engine such as Google to help them uncover a diagnosis for a difficult case. As described in the New England Journal of Medicine,[15] a doctor astonished her colleagues by correctly diagnosing IPEX (immunodeficiency, polyendocrinopathy, enteropathy, X-linked) syndrome, reporting that the diagnosis “popped right out” after she entered the salient features into Google. In another study, doctors in Australia identified 26 difficult diagnostic cases previously published in the New England Journal of Medicine.[16] The doctors, blinded to the correct diagnoses, selected three to five search terms from each case and did a Google search. They then selected and recorded the three diagnoses that were ranked most prominently by Google before comparing the results with the correct diagnoses as published in the journal. The Google searches yielded the correct diagnosis in 58% of the cases.

For clinicians, The Internet also provides access to three important online resources sponsored by the National Institutes of Health (NIH): the Office of Rare Diseases Research; the Undiagnosed Diseases Program; and the Rare Diseases Clinical Research Network. The Office of Rare Diseases provides information about more than 6,000 rare diseases, as well as links to clinical abstracts and patient support groups. In an effort to speed the process of diagnosing rare diseases, the NIH launched the Undiagnosed Diseases Program in May 2008 to which clinicians can refer patients. A panel of 25 NIH physicians from an array of specialties will review the cases and determine which patients should be assessed at the NIH Clinical Center. Those who are selected will undergo a week-long evaluation at the center, with their travel and treatment costs covered by the program, and any of dozens of specialists from the NIH may be called in to consult. But sometimes even those resources aren’t enough to uncover the cause of a patient’s symptoms. In a recent 60 Minutes interview, Dr. William Gahl, Director of the Underdiagnosed Diseases Program, cited the sobering statistic that despite the resources of his research team and his NIH colleagues, “we’ve only been able to give a complete diagnosis to 45 out of 450 patients.”[17]

The key Internet resource for patients is the National Organization for Rare Disorders (NORD). NORD is a vast, nonprofit, and physician support center that directs patients to more than 2,000 support groups and organizations for more than 1,100 rare diseases, as well as a free subscription database of rare diseases. Physicians with expertise in rare diseases can join the site as physician experts.

Another resource for patients and clinicians is the NIH-sponsored Genetic and Rare Diseases Information Center (GARD). GARD provides immediate, virtually round-the-clock access to experienced information specialists who can furnish current and accurate information in both English and Spanish about genetic and rare diseases. Another organization, In Need Of Diagnosis, Inc. (INOD), is a nonprofit organization that works with families and the community to assist and support individuals distressed with disorders that have eluded diagnosis and to identify and encourage the implementation of protocols that will facilitate quicker and more accurate diagnosis. INOD’s mission is to promote changes in the healthcare system to facilitate the prompt and accurate diagnosis of medical disorders, especially rare disorders, and to provide help and support to those who are in need of diagnosis. INOD provides tools and resources to patients to assist them in their quest for a diagnosis and to provide support along the way.

The diagnosis of a genetic condition can be devastating. After patients are suddenly faced with medical decisions, they usually want to know how this condition will affect their future. Clinicians can provide information about pathophysiology, inheritance patterns, interventions, and the technical aspects of surgical procedures. Support groups help patients deal with practicalities of daily life and to navigate the increasingly complex medical system. In the process, patients and families find commonality and comfort by knowing they are not unique.

While Stephen C. Groft, PharmD, director of the NIH’s Office of Rare Diseases, encourages patients to use the Internet to find information, he also warns that it is dangerous to rely solely on the computer for medical advice. “Be cautious about unproven remedies and miracle cures being touted over the Internet,” he says.[1] Too often misleading or inaccurate information is given out that can do more harm than good. In addition, one person’s experience may vary greatly from another’s. The Internet, he adds, should complement the communication between patients and their doctors, not replace it.

 

Jill Shuman, MS, ELS
Updated June 5, 2012

A version of this article appeared in print in the February 2009 Primary Issues newsletter.

 

References

  1. Howard R, Ford R. From the jumping Frenchmen of Maine to post-traumatic stress disorder: the startle response in neuropsychiatry. Psychol Med. 1992;22(3):695-707.
  2. Diabetes Statistics. American Diabetes Association. http://www.diabetes.org/diabetes-basics/diabetes-statistics/. 2011. Accessed May 31, 2012.
  3. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation. 2012;125(1):e2-e220.
  4. Seoane-Vazquez E, Rodriguez-Monguio R, Szeinbach SL, Visaria J. Incentives for orphan drug research and development in the United States. Orphanet J Rare Dis. 2008;3(1):33.
  5. Thorat C, Xu K, Freeman SN, et al. What the Orphan Drug Act has done lately for children with rare diseases: a 10-year analysis. Pediatrics. 2012;129(3):516-521.
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  9. Miller JM, Boyd HA, Ostrowski SR, et al. Malaria, intestinal parasites, and schistosomiasis among Barawan Somali refugees resettling to the United States: a strategy to reduce morbidity and decrease the risk of imported infections. Am J Trop Med Hyg. 2000;62(1):115-121.
  10. Weinstein LB. Selected genetic disorders affecting Ashkenazi Jewish families. Fam Community Health. 2007;30(1):50-62.
  11. Cunningham MJ. Update on thalassemia: clinical care and complications. Hematol Oncol Clin North Am. 2010;24(1):215-227.
  12. Morton DH, Strauss KA, Robinson DL, et al. Diagnosis and treatment of maple syrup disease: a study of 36 patients. Pediatrics. 2002;109(6):999-1008.
  13. Lee JY, Chiong MA, Estrada SC, et al. Maple syrup urine disease (MSUD)—clinical profile of 47 Filipino patients. J Inherit Metab Dis. 2008;31(Suppl 2):S281-S285.
  14. Wolters Kluwer Health 2011 Point-of-Care Survey. How physicians get information to diagnose and treat patients. Wolters Kluwers Health. http://www.wolterskluwerhealth.com/News/Documents/White%20Papers/Wolters%20Kluwer%20Health%20Survey%20Executive%20Summary-Media.pdf. Accessed May 31, 2012.
  15. Greenwald R. … And a diagnostic test was performed. N Engl J Med. 2005;353(19):2089-2090.
  16. Tang H, Ng JH. Googling for a diagnosis—use of Google as a diagnostic aid: Internet based study. BMJ. 2006;333(7579):1143-1145.
  17. Hard cases: investigating rare & tough diseases. 60 Minutes Website. http://www.cbsnews.com/8301-18560_162-57437577/hard-cases-investigating-rare-tough-diseases/?pageNum=2&tag=contentMain;contentBody. Published May 20, 2012. Accessed May 30, 2012.