A Diagnostic Dilemma: Sometimes You’ll Never Know

Patient Presentation
A 9-year-old male came to clinic with a 1 month history of painful joint swelling. One month ago he started having right ankle pain that was intermittent but consistent. One day ago his right wrist, right ankle and bilateral knees had some swelling but no erythema or warmth. He says that he has pain in them when he moves but not when he is resting and he denies any joint stiffness or gelling. He also had 1-2 days of multiple red skin lesions on his extremities and trunk, not overlying the affected joints. The skin lesions do not come and go and do not itch. They are mainly discrete circular lesions with no central clearing and did not change since they noticed them. The father and patient deny any recent infections but his sibling had a strep throat a few weeks ago. They had used ibuprofen and diphenhydramine orally once each without any symptom changes. They denied any contact with animals, ticks bites or non-city water supply. They deny any travel or contact with others from oversees, military personnel or institutionalized persons. They denied any history of trauma, no medication or other drug use and the child was not under unusual stress.

In the review of systems he denies any fever, chills, no eye changes, muscle aches, no pain in general and sore throat or ear pain specifically, and weight changes or clothing fitting differently. He has no problems with breathing or swallowing, problems on exertion, heart palpitations, syncope or any gastrointestinal or genitourinary complaints including colors in stool or urine color. He denied any bleeding but had some bruising of his shins from playing. He has been sleeping, eating and acting normally. The past medical history is positive for mild intermittent asthma but no allergies. The family history is positive for a maternal grandmother with arthritis and psoriasis.

The pertinent physical exam overall looked well. He had a heart rate of 88 beats/minutes, respiratory rate of 20 breaths/minute, blood pressure of 96/62, and temperature of 37.2°C. His weight was 75% and height was 50% and were tracking. He did not have generalized edema. HEENT specifically showed no facial swelling, eye or pharynx changes. Heart examination showed a new musical systolic II/VI murmur best at the mid left sternal border. Lungs and abdomen were normal. Genitorurinary examination showed no mucosal changes of the urethra or anus. He had some shotty anterior cervical and inguinal adenopathy. There were no posterior, occipital, axillary, elbow, or knee adenopathy. Tonsils were 2+ and his spleen and liver were normal sized. His musculoskeletal examination showed his right wrist, right ankle and bilateral knees had some swelling with the right ankle and bilateral knees being more prominent and slightly warmer. There was no overlying erythema but the right ankle and bilateral knees had some warmth. He complained of pain with movement of these joints, but was not able to say if it felt to be the joint itself or the swelling around it. He denied any pain in actual muscles upon palpation. He had no pain in small joints including the hands, feet and temporomandicular joint. His skin examination revealed 1-3 mm erythematous plaque-like lesions with a uniform but slightly serpigenous border that were slightly-raised across the entire lesion, reddened without scale and had no specific central-clearing. They were not painful nor pruritic and these could not be elicited with palpation or stroking. He also had 2-3 similar lesions on his shins that were more nodular in the center with slight darkening of skin laterally.

The diagnosis at this time included possibly rheumatic fever (possible new heart murmur, possible erythema marginatum, joint swelling and subcutaneous nodules), Lyme disease (rash and joint swelling), erythema multiforme (rash but without target lesions), atypical urticaria (swelling of areas of the body but without pruritis), arthritis (juvenile idiopathic arthritis or psoriatic), other autoimmune disease, and viral syndrome including it causing idiopathic localized edema. There were no obvious signs of acute infectious problems, no history of trauma, no drugs and specific stressful social situations so problems related to those were not considered as likely. Atypical Kawasaki Disease was contemplated but the patient had no history of fever or mucositis. Occult malignancy was considered. The resident was unclear as to how to proceed and the supervising attending also had another faculty member look at the physical findings who also agreed with that general differential diagnosis.

Because of the concern for rheumatic fever and the patient had a laboratory evaluation that included a complete blood count that was normal except slightly large platelets. Urinalysis and culture, rapid streptocococcal testing, complete metabolic panel, erythrocyte sedimentation rate and creatinine kinase were normal. C-reactive protein was 0.8 mg/dl (normal < .05 mg/dl) The electrocardiogram was negative.

The patient clinically was started on diphenhydramine and ibuprofen around the clock with clinic for possible urticaria or rheumatological disease with followup in 2 days. Telephone contact the next day revealed that the patient was about the same to slightly better. The family did not show up for clinic the next day, but notes from an emergency room visit the previous evening showed that they had been worried that the swelling had gone away in the wrists and most of the knees, and now his left foot was swollen. The emergency room also wasn’t sure what this was but thought that some of the skin lesions had migrated and may look more “hive-like.”

Laboratory testing now returned showing a normal anti-streptolysin O but abnormal anti-DNase B antibodies of 1350 (normal 0-310 U/ml). An infectious disease consultant said these levels could last for a long time and felt that with the other testing and history this was not rheumatic fever but recommended a Lyme titre be completed. A rheumatology consultant felt that at this time a vasculitis could be the cause and recommended to monitor the patient while continuing the ibuprofen, do an ultrasound of the joints to see where the actual swelling was if the patient came in, and schedule an appointment with rheumatology in the next few days. Serum ferritan and Lyme titres were eventually negative. On the telephone later that day the parents reported that the swellings and skin lesions were resolving. The joint pain had gone away and maybe one or two of the skin lesions were now slightly pruritic. They also now remembered that he had a significant fall on the playground 1 month ago and had been complaining of the right ankle pain before the current episode. He returned for his health maintenance examination 5 days later and all symptoms had resolved so no further evaluation was completed. It was thought this was most likely a hive reaction to an unrecognized virus.

It can be difficult to consider what is the problem when a health care provider is presented with a group of seemingly disparate signs and symptoms with a history and time course that do not match classic (or commonly atypical) disease presentations. Common things happen commonly, so when symptoms occur without the usual co-occurring symptoms, unusual symptoms or time courses, it can be challenging. The provider must develop a reasonable differential diagnosis and balance how far to go with the evaluation against how much to monitor the patient for new signs or symptoms which can provide new information. Patient safety and the natural time course of diseases have to be considered. Providers also recognize that well-appearing individuals with acute onset of problems usually have a common problem such as a viral syndrome and have to balance that knowledge. The judicial use of laboratory testing and other health care providers’ expertise to help clarify some of the confounding problems, and give guidance and reassurance for the provider as he/she works through a diagnostic dilemma.

The provider was presented with chronic joint pain with acute swelling. While this could be a virus, occult trauma, malignancy, rheumatological disease or even an unusual infection such as tuberculosis are potential considerations.
A differential diagnosis of leg pain can be found here. Early symptoms of rheumatological disease can overlap with many common illnesses. A review of juvenile rheumatoid arthritis can be found here

The provider was also presented with a rash that had characteristics of several different rash types. These characteristics are less likely to be an acute infectious rash but idiopathic urticaria or a vasculitis are potential possibilities.
A differential diagnosis of rash can be found here

With potential subcutaneous nodules, especially on the shins, trauma is very common, but rheumatic fever and erythema nodosum are also considerations.
Causes of erythema nodsum can be reviewed here

Allergic symptoms are known to cause common or unusual swelling of various body parts but normally pruritis accompanies the lesions and the lesions usually will change shape more quickly.
A differential diagnosis of acute urticaria can be found here

Often patients have functional murmurs that may not be documented or they are documented during a hypercatabolic state such as when a patient is febrile. However with a new murmur other diseases must be considered such as rheumatic heart disease or other valve issues, cardiomyopathy, or arrhythmia.
A differential diagnosis of heart failure can be found here – along with sudden death here

Occult malignancy is a diagnosis no clinician want to consider but like many of the problems listed above, early signs can overlap with many other diseases.
A review of leukemia can be found here

Learning Point
In evaluating a diagnostic dilemma, starting the laboratory evaluation helps to begin the process of trying to find an answer and can also help the families as “something is being done.” Watchful waiting is appropriate in many circumstances but can be difficult for the health care provider as well as the families. First symptoms are sometimes just that, first symptoms. It takes time for other features of a disease process to become manifest.

Families will often be quite concerned and support for them is also necessary and close communication and followup is appropriate. Families are trying to give good information but sometimes it is not available them. Sometimes new information becomes available after parents talk with other family members (common for family history) or other people such as teachers or child care professionals may also have additional history to offer. Use symptom diaries gathers important data and engages the family in “doing something.” The symptom diaries can be very important tools in understanding and sorting out the timing, duration, severity, aggravating and elevating factors of the patient’s symptoms.

Health care providers themselves can be concerned that they are “missing something” or possibly overlooking something else in the differential diagnosis (rare diseases or new diseases do occur). Careful attention to the timing of history, physical examination and laboratory findings is always important. With diagnostic dilemmas, it may just “take more time” and clinicians and families have to be patient, or the symptoms may go away, and everyone may “never know what happened.” Sometimes patients have to be admitted to hospital for closer monitoring and evaluation.

Questions for Further Discussion
1. What are indications for admitting to the hospital for further evaluation?
2. What types of common problems are diagnostic dilemmas?

Related Cases

    Disease: Diagnostic Dilemma | Hives

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Hives

Information prescriptions for patients can be found at MedlinePlus for these topics: Topics and Topics.

and at Pediatric Common Questions, Quick Answers for this topic: Topic

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Khanna K, Liu DR. Acute Rheumatic Fever: An Evidence-Based Approach To Diagnosis And Initial Management. Pediatr Emerg Med Pract. 2016 Aug;13(8):1-23.

Pattanaik D, Lieberman JA. Pediatric Angioedema. Curr Allergy Asthma Rep. 2017 Aug 8;17(9):60.

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa