Patients with undiagnosed or rare diseases often remain without a diagnosis for many years. Many are misdiagnosed or treated symptomatically without having an identified underlying disease process. Health care providers in general practice and subspecialists are equipped to diagnose diseases commonly seen. Most practitioners are unlikely to be familiar with uncommon manifestations of a common disorder and have little or no experience with rare diseases. Multidisciplinary teams are effective in reviewing patients with undiagnosed and rare diseases and in developing a new diagnostic strategy for appropriate evaluation. A medical librarian and an access coordinating navigator are essential members of the team.
Key points
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Patients with undiagnosed and rare diseases (URDs) are often misdiagnosed.
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A team approach to the appropriate diagnosis of patients with URDs has been successful.
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Parents appreciate the team approach and ability to have the evaluation at one institution.
None of us is as smart as all of us .
Patients with URDs may be on a diagnostic odyssey for years or even decades. (See Robert M. Kliegman and colleagues’ article, “ How Doctors Think Common Diagnostic Errors in Clinical Judgment—Lessons from an Undiagnosed and Rare Disease Program ,” in this issue.) Many have complex symptoms that do not suggest an obvious diagnosis, whereas a significant number have been misdiagnosed and inappropriately treated for a disease they do not have. The process of diagnosing and appropriately managing URDs is fraught with challenges. Most patients begin the diagnostic odyssey for their complex medical condition under the care of a single physician but eventually seek further evaluation via referrals to multiple individual subspecialists. These referrals may lead to fragmenting of the medical record across various health care systems or even misalignment of diagnostic impressions and evaluation strategies within the same health care system. An additional challenge in pediatrics is that disease progression or developmentally related changes in the patient’s physiology, such as the onset of puberty, may alter a patient’s phenotype over time. Furthermore, most children, independent of their underlying pathophysiology, undergo developmental changes in their ability to communicate their symptoms, leading to a dynamically evolving understanding of their phenotype. Finally, patients who remain undiagnosed or misdiagnosed for many years often develop adverse behavioral or psychological reactions to their chronic medical condition or may acquire unintended or unrecognized side effects of inappropriate treatments that complicate the diagnostic evaluation.
Common medical disorders comprise most patient encounters in both general and subspeciality practices. The traditional diagnostic approach of an individual physician taking a history, conducting a physical examination, generating a differential diagnosis, and obtaining any indicated laboratory and imaging studies frequently yields a diagnosis for most patients presenting with common ailments. Undiagnosed diseases may represent atypical or poorly recognized manifestations of a common disease or, as often noted in pediatric patients, the presentation of a rare and often genetic disorder. (See Robert M. Kliegman and colleagues’ article, “ How Doctors Think Common Diagnostic Errors in Clinical Judgment—Lessons from an Undiagnosed and Rare Disease Program ,” in this issue.) For the physician who cares for patient after patient with the more common disorders in general practice, the usual response to a patient’s complaint is to consider that complaint within the scope of their practice. Uncomplicated disorders, such as the common cold, headaches, asthma, abdominal pain, or constipation, are readily recognized and diagnosed by a single physician familiar with both the patient and the management of common ailments. When a diagnosis fails to fit the usual pattern of disease, however, because of duration, the unanticipated involvement of other organ systems, abnormal responses to therapy, or additional atypical features, the patient may be referred to a specialist. This specialty referral may result in an appropriate diagnosis but may also be subject to the cognitive biases inherent within that medical specialty. Within each specialty, there is often a comfort zone in managing that specialty’s organ-specific symptoms; there may be less familiarity when symptoms do not fit. Each practice has an experiential proficiency with the diseases that are highly prevalent within their specialty. In contrast, individual rare disorders have a very low prevalence, and many practitioners may not have ever cared for or even read about patients with rare disorders. (See Robert M. Kliegman and colleagues’ article, “ How Doctors Think Common Diagnostic Errors in Clinical Judgment—Lessons from an Undiagnosed and Rare Disease Program ,” in this issue.) Cumulatively, there are too many individual rare disorders for any single practitioner to be aware of, let alone be able to diagnose, without the help of a team. When the traditional approach to medical diagnosis leaves patients undiagnosed, they require a team-based approach exemplified by the Japanese proverb, “None of us is as smart as all of us.”
Team dynamics
The authors’ URD team includes providers from most pediatric subspecialties, including hospitalists, geneticists, radiologists, and pathologists. Other essential health professionals on the team include a medical librarian and an access-coordinating specialist. Each subspecialist brings to the evaluation experience and expertise as both a pediatrician and a subspecialty physician and is instrumental in providing insights into the nuances associated with particular symptoms or the disease processes considered in the differential diagnosis. For example, although arthritis is a criterion in the recently modified Jones criteria for rheumatic fever, the observation that the arthritis is migratory, polyarticular, and exquisitely tender may not be discussed in published articles or textbooks or even in the criteria themselves. Such subtleties are frequently observed, however, in patients with URD, and awareness of these clinical pearls improves the diagnostic process.
The composition of a team is aided in great part by the incorporation of established members whose regular participation in multiple patient case team reviews over time has led to the development of a group thought process. The authors make a conscious effort to recognize common cognitive errors and are highly suspicious of authoritative statements, such as, “It cannot be this disease,” “In my experience I have never seen this,” “We have already ruled out this disease,” or “It must be this disease.” In addition to recognizing errors or biases in the diagnostic process by working together to review many complex URD patients, the team has developed the ability to collectively recognize unusual or rare patterns of disease manifestations. Most general physicians use pattern recognition to diagnose common disorders, such as swollen edematous eyes, thought to represent an ocular allergy. But sometimes these swollen eyes are a manifestation of nephrotic syndrome ( Table 1 ). Members of the URD team have developed sensitivity to uncommon manifestations of common or even rare diseases, such as neurologic symptoms associated with familial hemophagocytic lymphohistiocytosis, Langerhans cell histiocytosis, autoimmune encephalitis, lupus, neurosarcoidosis, Wilson disease, or other inborn errors of metabolism.
| Presentation | Initial Diagnosis | Final Diagnosis |
|---|---|---|
| Weakness and fatigue | Chronic Lyme disease | Addison disease |
| Periorbital edema | Allergy | Nephrotic syndrome |
| Cervical lymphadenopathy | Bacterial adenitis | Kawasaki disease Cat-scratch disease Branchial cleft cyst |
| Weight loss | Anorexia nervosa | IBD Celiac disease |
| Thrombocytopenia | ITP | SLE ALL ALPS |
| Red urine | Nephritis | Autoimmune hemolytic anemia Rhabdomyolysis |
| Extremity pain | Sprain | Osteomyelitis Osteosarcoma |
| Joint or bone pain | JIA | ALL Lymphoma Neuroblastoma Scurvy |
| Aseptic meningitis | Viral meningitis | ADEM Autoimmune encephalitis Parameningeal infection Tuberculosis |
| Tachypnea | Pneumonia | DKA Salicylate toxicity Pulmonary embolism |
| Pallor, fatigue, microcytosis | Iron deficiency anemia | Crohn disease |
| Facial swelling | Cellulitis | Cold panniculitis Mosquito hypersensitivity Tooth abscess Poison ivy |
| Drop attacks | Seizures | Dysrhythmia Narcolepsy |
| Emesis | Gastroenteritis | Increased ICP Pancreatitis UTI Poisoning |
| Recurrent emesis | Gastroenteritis | Inborn errors of metabolism Malrotation |
| Jaundice | Hepatitis | Autoimmune hemolytic anemia HUS |
| Abdominal pain | Constipation | UTI HSP IBD Lower lobe pneumonia Testicular/ovarian torsion Pancreatitis Hepatitis |
| Dysuria | UTI | Peritonitis (ruptured appendix) |
| Pharyngitis | Group A streptococcus | Mononucleosis Lemierre disease |
After careful review of all the available medical records and team-based discussions, the authors are able to identify misdiagnosed patients who have been treated inappropriately for many years; for example, the misdiagnosis of chronic Lyme disease instead of Addison disease or anorexia nervosa instead of celiac disease (see Table 1 ).
Although common things do happen commonly, and when you hear hoof beats you should initially think of horses, the patients the authors see with URDs are often zebras (uncommon manifestations of a common disease or a poorly recognized manifestation of a rare disease). Team members may be considered “zebra hunters.”
Team dynamics
The authors’ URD team includes providers from most pediatric subspecialties, including hospitalists, geneticists, radiologists, and pathologists. Other essential health professionals on the team include a medical librarian and an access-coordinating specialist. Each subspecialist brings to the evaluation experience and expertise as both a pediatrician and a subspecialty physician and is instrumental in providing insights into the nuances associated with particular symptoms or the disease processes considered in the differential diagnosis. For example, although arthritis is a criterion in the recently modified Jones criteria for rheumatic fever, the observation that the arthritis is migratory, polyarticular, and exquisitely tender may not be discussed in published articles or textbooks or even in the criteria themselves. Such subtleties are frequently observed, however, in patients with URD, and awareness of these clinical pearls improves the diagnostic process.
The composition of a team is aided in great part by the incorporation of established members whose regular participation in multiple patient case team reviews over time has led to the development of a group thought process. The authors make a conscious effort to recognize common cognitive errors and are highly suspicious of authoritative statements, such as, “It cannot be this disease,” “In my experience I have never seen this,” “We have already ruled out this disease,” or “It must be this disease.” In addition to recognizing errors or biases in the diagnostic process by working together to review many complex URD patients, the team has developed the ability to collectively recognize unusual or rare patterns of disease manifestations. Most general physicians use pattern recognition to diagnose common disorders, such as swollen edematous eyes, thought to represent an ocular allergy. But sometimes these swollen eyes are a manifestation of nephrotic syndrome ( Table 1 ). Members of the URD team have developed sensitivity to uncommon manifestations of common or even rare diseases, such as neurologic symptoms associated with familial hemophagocytic lymphohistiocytosis, Langerhans cell histiocytosis, autoimmune encephalitis, lupus, neurosarcoidosis, Wilson disease, or other inborn errors of metabolism.
