Right Ankle Pain and Swelling in a 16-Year-Old Boy

A 16-year-old male patient of Pacific Island and Asian ethnicity presents to the primary care office for nonurgent evaluation of a 4-day history of gradual onset of right ankle pain. There has been no trauma or injuries. His mother reports recurrent monthly episodes lasting 2 days for the past few years. Records show that he first presented for the recurrent right ankle pain 3 years prior and visited with a specialist who did not document a specific diagnosis. Ibuprofen provides relief of his pain and walking makes it worse. There is no subjective fever or local erythema. There is no prior workup, and the family is not aware of any triggers. His medical history includes body mass index (BMI) over the 95th percentile since age 2, blood pressure over the 95th percentile since age 13, and mild intermittent asthma. Without his parent present, he reports never having been sexually active. One year ago, he denied alcohol use during a screening physical. His mother and father have metabolic syndrome. His diet is devoid of vegetables and is high in processed food. He is not physically active.Physical examination reveals blood pressure at the 96th percentile (139/91), pulse 93, temperature 37.1 °C, height 65” (165 cm), weight 176 lb (80 kg), and BMI at the 96th percentile (29.3). His pain level is 6/10. His skin is without ecchymosis, purpura, or acanthosis nigricans. There is no cardiac murmur. He has marked bilateral pes planus, visible swelling of the anterior right ankle joint, slight warmth to palpation without erythema, resistance to motion of the right ankle, and no tenderness of the medial or lateral malleolus.An ankle radiograph reveals no abnormal bony or joint findings, and ultrasonography of the right ankle in the dorsiflexed position shows a hypoechoic pocket of fluid without echogenic debris. An arthrocentesis is performed.Ankle pain and swelling may be caused by injuries, infections, autoimmune processes, and long-term bony alignment issues causing joint inflammation and degeneration. Infections include septic arthritis including gonococcal arthritis, occurring as a complication of disseminated gonococcal infection. Septic arthritis is marked by a purulent-appearing aspirate. This patient has a yellow cloudy specimen as opposed to a gray or purulent appearance. The nature of his aspirate, recurrent monoarticular involvement, and lack of fever points away from septic arthritis as the likely cause. Autoimmune causes such as juvenile idiopathic arthritis (JIA) and reactive arthritis are considered. JIA is a diagnosis of exclusion with no one definitive serologic test given the heterogeneity of subtypes.1 Onset most often occurs between ages 2 and 11 with a 2:1 predilection for girls vs boys.1 Symptoms are commonly observed as insidious with episodes of joint pain lasting weeks at a time.1 The patient’s pattern of sudden-onset, short-duration flares of joint pain are not the usual presentation for JIA or for reactive arthritis. The classic presentation of Reiter syndrome with arthritis, conjunctivitis, and urethritis occurs 1 month after a bacterial intestinal infection. The absence of a preceding acute illness makes reactive arthritis less likely. This patient has pes planus, which could contribute to issues throughout the anatomic chain of ambulation; however, the pain associated with pes planus is typically in the heel or arch and would likely exist bilaterally with his symmetric anatomy. Pseudogout is caused by the deposition of calcium pyrophosphate dihydrate (CPPD) crystals in joint fluid, and although it has a similar presentation to this patient’s diagnosis, pseudogout is associated with aging and the increases of CPPD deposition over many decades.2 The classic diagnostic laboratory finding of pseudogout is positively birefringent crystals in the joint fluid.3 His joint fluid findings lead to his actual diagnosis.Arthrocentesis yields 3 mL of cloudy synovial fluid, which is transported in a sterile specimen cup to the laboratory for a cell count with differential and crystal examination. Evaluation shows 3000 red blood cells/mL (3.0 × 109/L), 34 370 white blood cells (WBC)/mL (34.37 × 109/L) with a neutrophilic predominance, and the presence of negatively birefringent crystals. The WBC count in his synovial fluid is consistent with inflammation. His recurrent acute monoarticular joint pain, BMI over the 95th percentile, and the presence of negatively birefringent crystals in the synovial fluid lead to a diagnosis of gout, a diagnosis that is not frequently considered in adolescents. The presence of these crystals under polarized microscopy in a symptomatic joint meets the diagnostic criteria.4Gout is rare in childhood, occurring at a rate of 1/5000 to 1/300 000 adolescents.5 Acute gout often presents with monoarticular arthritis. The metatarsophalangeal joint is the most commonly affected joint, but other joints, including the ankle, can be affected with a high frequency.6 Gout is associated with hyperuricemia, but most individuals with hyperuricemia do not develop gout. Acute flares of arthritis can be induced by dehydration, microtrauma associated with activity, and other stressors to joint function.2Gout is seen in children with conditions that result in excessive production of uric acid from purine nucleic acids and in conditions associated with a decreased renal excretion of uric acid. Overproduction of uric acid occurs in Lesch-Nyhan syndrome, tumor lysis syndrome, malignancies such as leukemia, trisomy 21, hypoxemic asthma, congenital heart disease, and glycogen storage diseases.3,5 Other than mild intermittent asthma, the patient is not known to have any of these associated conditions. Underexcretion of uric acid can be caused by kidney disease and has been reported in autosomal dominant tubulointerstitial kidney disease.7 There are many gene variants associated with increased uric acid levels, and risk of gout, and the prevalence of these variants differs by racial group.8 Certain Asian ethnocultural groups exhibit a higher genetic risk than people of European descent.8,9Genetic susceptibility to gout is synergistic with lifestyle contributions including excess weight, diet content, and high-fructose corn syrup intake.10 Although adolescent gout is a product of the interplay of genetics and environment, genetic predisposition may be a larger contributor to the occurrence of gout in adolescents as opposed to adults.6 Uric acid gradually increases with age into adolescent years. Gender differences begin to appear at age 12 with boys developing higher levels.5,11 Uric acid levels reflect increases of BMI, and rising levels are associated with adolescent hypertension.5,6,12,13 In adolescents, a 1-mg/dL increase in uric acid level is associated with a 54% increased prevalence of metabolic syndrome.5Serum uric acid may or may not be elevated during acute attacks. An elevated serum uric acid level is not required for the diagnosis but may be helpful in monitoring response to uric acid level–lowering therapy.2 Arthrocentesis findings include a leukocyte count of 5000 to 80 000 WBC/mL (5–80 × 109/L) with a neutrophil predominance. There is significant overlap of cell count findings in gout with that of septic arthritis. Gram stain and culture are encouraged to rule it out. In this case, our clinical judgment was that septic arthritis was much less likely than gout and so the limited amount of aspirate was used for crystal analysis. The urate crystals of gout are thin, rod-shaped, and negatively birefringent under polarized microscopy.2,3 They are more likely to be observed during an acute attack as opposed to a senescent period.3Nonsteroidal anti-inflammatory drugs, colchicine, and steroids may be considered for treatment of gout flares or with initial induction of urate-lowering treatment. There are many dosing regimens.14Long-term management involves a healthy diet, physical activity to lower BMI, and uric acid–lowering medications. The xanthine oxidase inhibitor allopurinol lowers uric acid levels and has been directly associated with lowering systolic and diastolic blood pressure in adolescents with hypertension and prehypertension as elevated uric acid levels activate the renin-angiotensin system.12,13 Risks associated with its use include multiple delayed-type hypersensitivity reactions including Stevens-Johnson syndrome (SJS), fixed drug eruption, and drug rash with eosinophilia and systemic symptoms (DRESS).2,15 DRESS is a delayed T-cell hypersensitivity reaction against medications and their metabolites, marked by fever, diffuse erythematous rash, and internal organ involvement.1,8 The risk of DRESS with the use of allopurinol has been shown to be associated with the HLA-B*58:01 genotype at rates of at least 34 times those without the genotype.15 The HLA-B*58:01 genotype occurs a rate of 7% to 20% in those of Southeast Asian descent vs less than 2% in Europeans.13,15,16 Testing for this may be considered prior to prescribing allopurinol and is a conditional recommendation for care of those of Southeast Asian descent.17 Although DRESS is reversible with discontinuance of the offending medication, it carries risks for morbidity and mortality.2,15,18 Patients and families should be cautioned on the risks of SJS and the early symptoms of DRESS including lymphadenopathy and measles-like rash to prompt early medication discontinuance.At follow-up to discuss his results, the patient and family were advised of the diagnosis of gout, and a family-based referral to nutrition counseling was provided to help with the entire family’s health. His blood pressure was again elevated at 147/89, which is receiving ongoing attention. The affected right ankle effusion was smaller than on presentation and was still slightly warm to palpation. Ibuprofen and a short course of colchicine were prescribed to ameliorate gout flares. A complete blood cell count, creatinine to assess his glomerular filtration rate, serum uric acid level, and HLA-B*58:01 genotype were ordered to evaluate for underlying causes of gout as well as to assess whether he has an increased risk of DRESS related to the use of allopurinol given his reported ethnicities. The patient and family have not followed up on these tests; however, efforts continue to address this and his overall health.Gout and hyperuricemia should be considered in adolescents with high BMI and hypertension, who present with recurrent monoarticular pain.Assessing sexual history and consideration of septic arthritis are important elements in working up monoarticular arthritis.In patients with symptoms consistent with gout, arthrocentesis that yields synovial fluid containing negatively birefringent crystals is the definitive method of diagnosing gout.The HLA-B*58:01 genotype is associated with the delayed hypersensitivity DRESS reactions to allopurinol. Consider testing for it prior to instituting urate-lowering therapy in patients with higher rates of carriage such as those of Southeast Asian lineage.