To the Editor:

Calcium pyrophosphate dihydrate (CPPD) crystal deposition may cause acute arthritis (pseudogout), cartilage degeneration identified radiographically as chondrocalcinosis (CC), and other chronic degenerative joint changes in patients aged > 60 years. The few reported cases of CPPD disease in younger patients have been associated with underlying genetic or metabolic conditions.1,2 We report the first case of a patient with CPPD crystals on synovial fluid analysis with underlying Wilson disease (WD).

A 13-year-old male patient presented to an outside emergency department with multiple weeks of left knee swelling and pain. He had a prominent effusion by exam and radiography; orthopedics performed joint arthrocentesis and recommended laboratory evaluation that included elevated C-reactive protein (0.9 [ref < 0.3 mg/dL]), elevated transaminases (aspartate aminotransferase [AST] 41 [ref 15-37] U/L; alanine aminotransferase [ALT] 108 [ref 24-68] U/L), and synovial fluid analysis notable for 27,050/mm3 white blood cells, 91% polymorphonuclear neutrophils, 9% mononuclear cells, no bacteria, and presence of intra- and extracellular CPPD crystals. Lyme serology was positive for 10/10 IgG bands; the patient was treated with doxycycline for 28 days.

The patient presented to our pediatric rheumatology clinic in the 10th week of illness, 2 weeks after doxycycline completion. Physical exam re-demonstrated left knee arthritis. Given the rarity of CPPD crystals in pediatric populations, and the lack of complete improvement on antibiotics, Lyme arthritis, chronic idiopathic arthritis, CPPD arthritis, or an underlying metabolic disease were considered. Laboratory tests were notable for a further increase in transaminases (AST 133, [ref 0-35] U/L; ALT 304 [ref 0-50] U/L). Blood counts, inflammatory markers, electrolytes, magnesium level, thyroid and parathyroid hormone testing, and iron panel were normal. The CPPD crystal findings and uptrending transaminases prompted us to evaluate serum ceruloplasmin, which returned at 3 (ref 20-60) mg/dL. For the lingering arthritis, a second course of 28 days of doxycycline was prescribed, which completely resolved his arthritis.

Given the low ceruloplasmin, a gastroenterology referral was placed. Additional laboratory tests were significant for positive antinuclear antibody (1:160, speckled), elevated 24-hour urine copper (182 mcg [ref 10-30] mcg), negative liver kidney microsomal and F-actin antibodies, and negative HBsAg and anti-HepC serologies. Liver ultrasound showed hepatomegaly with normal Doppler flow. Ophthalmology evaluation found cortical and zonular cataracts bilaterally. Liver biopsy demonstrated portal fibrosis and patchy lymphocytic infiltrates with early portal-portal bridging fibrosis, noted by the pathologist as “changes that can be seen in WD.” The early diagnosis of WD prompted by CPPD crystal identification allowed for early management with a copper-limited diet without need for copper chelation therapy.

CPPD disease is rare in patients aged < 40 years.1 Acute CPPD disease can occur spontaneously and be idiopathic, or be related to joint trauma, medical illness, or surgery.2 In younger adults with CPPD disease, metabolic disorders are often identified, including disorders that either stimulate excess generation (gain-of-function ANKH mutations) or decreased breakdown (inherited defects of alkaline phosphatase or hypophosphatasia) of pyrophosphate; conditions that result in the loss of magnesium (a co-factor of alkaline phosphatase); or diseases that increase concentrations of calcium, iron, and copper, each of which are alkaline phosphatase inhibitors.1,2

To our knowledge, this highlights the first reported case of CPPD crystal identification in synovial fluid related to WD, a rare genetic disorder that is characterized by excess copper storage. Limited reports have evaluated associated boney or articular disease in patients with WD. Bone loss, osteomalacia, arthralgias, or arthritis are common in WD.3,4 Chondrocalcinosis (CC) may occur, principally in knees and wrists.4,5 Although copper deposition has been observed on synovial tissue biopsies in patients with WD and arthritis,4,6,7 CPPD on fluid analysis was either not reported or not present. The presence of CC and copper deposition in tissue biopsies in patients with WD with arthritis suggests a mechanistic role by which excess copper can cause joint pathology. Whether CPPD crystals are pathogenic is unclear.

We posit that our patient’s monoarticular arthritis was due to Lyme infection rather than WD-related arthritis, as evidenced by symptomatic improvement following antimicrobial therapy that preceded a copper-limited diet. However, whether the CPPD crystals were due to his underlying WD, provoked by infection, or simply an incidental finding is unknown. In our pediatric rheumatology clinic, we have evaluated 4 adolescent patients in the last year, each referred for articular symptoms along with CPPD crystals on synovial fluid analysis. One was diagnosed with Lyme arthritis (this case), one with Helicobacter pylori-associated reactive arthritis, and two with juvenile idiopathic arthritis. Notably, repeat synovial fluid analysis was conducted in only one of these patients who still had active arthritis, and the CPPD crystals resolved, suggesting that the previously identified CPPD crystals in this child were not pathogenic. We hypothesize that infection, inflammatory arthritis, or metabolic disorders may perturb local synovial fluid mineral composition, predisposing to CPPD formation.8,9 Further research is needed to clarify whether CPPD crystals are incidental findings or whether CPPD crystal deposition precipitate or worsen arthritis in a previously healthy adolescent.