A young patient walks into the clinic complaining of facial swelling that has persisted for the past few days. Upon examination, the patient’s face appears bloated and asymmetrical. At this point, a physician should be thinking of a list of potential differential diagnoses—lipoma, allergy, abscess, mumps, and salivary gland tumors, among others. 

The whole point of having a list of differential diagnoses in mind is so that clinicians can quickly rule out unlikely diagnoses and investigate those deemed most likely. Physicians are trained to list their differential diagnoses in the order of most likely to least. Including a rare disease high on the list without justification is frowned upon, as it uses diagnostic resources and is unlikely to be the final diagnosis (hence, its rarity). 

The problem is that rare diseases, like hereditary angioedema (HAE), do occur; general practitioners and pediatricians know this. It is the job of a general practitioner to be calm, methodical, and rational in his or her clinical decision-making, which usually means investigating more common, benign diagnoses before making a referral to a specialist. In this sense, the local clinic functions as an outpatient triage center in which patients are seen for their concerns, and serious cases are separated from those that can be fully managed onsite. 

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Diagnosing and Treating a Rare Disease

It has been said that medicine is method. Common diseases are considered common because multiple epidemiological studies deem them to be. Rare diseases are considered rare for a number of reasons: certain diseases are more common in some parts of the world than others (such as dengue fever in tropical climates), whereas others are more common among particular people groups than others (celiac disease, for example, disproportionately affects Caucasians). 

Read more about HAE etiology 

However, it would be improper if a correct diagnosis does not even make it onto the list of differentials simply because of its rarity. This can have far-reaching consequences: time is bound to be wasted, patients tend to grow frustrated, the disease continues to progress unhindered, and prognosis worsens. 

Let us return to the example given in the first paragraph—that of a pediatric patient presenting with facial swelling. Proper history-taking and a physical examination will yield more information. A succession of quick laboratory tests and imaging studies should clarify the picture greatly. 

Let us assume that this child is having a manifestation of HAE. Once a pediatrician hits a roadblock in their diagnostic efforts, what should they do? Should they ascribe the condition to a disorder that is likely but not definitive? Should they try to manage the patient symptomatically? Should multidisciplinary discussions take place? 

Increasing Awareness of HAE

This is the fascinating question explored in a study by Chong-Neto and colleagues, aptly titled “Are pediatricians familiar with hereditary angioedema?” and published in the World Allergy Organizational Journal. 

“As a rare condition, hereditary angioedema is unknown to many healthcare professionals and often underdiagnosed,” the authors wrote. 

Studies around the world indicate that the median delay in diagnosis is far too long for a disease that can potentially be fatal. In Iran, the median delay is around 3 years; in Brazil, it is approximately 4 years. In India, the median diagnostic delay from symptomatic onset is a staggering 6 years. 

The longer HAE remains undiagnosed, the more likely that the worst-case scenario might happen: laryngeal edema resulting in airway obstruction and early death. Although edema attacks on other sites of the body can be painful, it is typically airway obstruction that kills. 

To gauge pediatrician knowledge about this condition, the research team sent out questionnaires that included various domains regarding HAE care, including previous experiences with the disorder and specific knowledge regarding this disease. All pediatricians chosen were from the Brazilian Society of Pediatrics. A total of 455 (2.6%) responded to the survey. 

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The median number of correct answers among specialists in allergy and immunology was merely 7/12 (58.3%), whereas the number among nonspecialists was 3/12 (25%). The questions focused on the clinical manifestations, diagnosis, and treatment of HAE. 

These figures alone offer a sober reality-check about pediatrician readiness when it comes to diagnosing and treating HAE. The researchers assumed that physicians who had been in practice longer would have more limited knowledge regarding this disorder compared with younger graduates. However, this was not shown to be the case. In short, the overall understanding of hereditary angioedema among this cohort was poor.

“Brazilian pediatricians presented, in general, a low level of knowledge about hereditary angioedema, even when allergy/immunology board-certification were considered,” the authors concluded. 

Clinical bodies must therefore make it their urgent task to educate physicians about HAE—how it manifests and how it is managed. Granted, this disease remains rare. But for that one child who receives the timely care that he/she deserves, the upside is immeasurable.


Chong-Neto HJ, Aroni BP, Mansour E, et al. Are pediatricians familiar with hereditary angioedema? World Allergy Organ J. 2023;16(6):100783. doi:10.1016/j.waojou.2023.100783

Agrawal A, Singh V, Kumar P, Bhagol A, Narwal A, Singh I. Unilateral swelling of cheekNatl J Maxillofac Surg. 2017;8(2):157-161. doi:10.4103/0975-5950.221703