Synovial chondromatosis is a benign condition characterized by metaplasia of synovial cells forming cartilaginous bodies and intra-articular loose subsynovial tissue bodies especially in large joints (knees, hips and shoulders). It’s rare in childhood (prevalence of 1/100,000) in which may mimic oligoarticular JIA [15]. It’s considered as a benign tumor and retrospective studies from adults describe a low risk of developing in chondrosarcoma. Plain radiography and MRI imaging are considered the gold standard for diagnosis; however, they can be initially negative because of the same signal intensity between fluid and non-mineralized synovium [16]. The response to NSAIDs is reported only in the early phases, while surgical arthroscopy remains the best treatment available with good clinical outcome.

A previously healthy 3-year-old child was evaluated for a 3-month history of asthenia, left limping and bilateral knees effusion, more evident on the left. A progressive increase in child’s abdominal circumference was also reported. Her family history was remarkable for Hodgkin lymphoma in her mother and cardiomyopathy in her first cousin. On physical examination, a mild tachycardia (heart rate 135–140 bpm) was detected. Heart and lung examination were unremarkable; the abdomen was distended, not painful, with palpable liver and broad tympany on percussion. Swelling of the knees without other inflammatory signs and bilateral congenital trigger fingers of the hands were reported. Blood tests showed neutrophilic leukocytosis and thrombocytosis (WBC 12.520/mmc, PLT 500.000/mmc) with mild increase in gamma- glutamyl transferase. All other laboratory exams, including coagulation, electrolytes, CRP, ESR, and renal function were normal. The abdominal US showed an intrabdominal effusion and the chest X-Ray reveled an increase in cardiothoracic ratio (Fig. 5). For this reason, an echocardiography was performed and restrictive cardiomyopathy due to pericardial effusion was found. The complexity of the clinical picture led to perform genetic analysis, that reveled a mutation in the PRG4 gene and diagnosis of Camptodactyly- arthropathy-coxa vara-pericarditis (CACP) syndrome was made. A mild bilateral coxa vara was highlighted by a pelvis and lower limbs X-Ray, performed after the outcome of the genetic investigations. The patient was therefore referred to the cardiology department and ibuprofen was prescribed in associations with intensive physiotherapy.

Chest x-ray: flask appearance of the cardiac shadow due to pericardial effusion

CACP syndrome is a rare recessive disorder (prevalence of < 1/1,000,000) caused by a mutation in the PRG4 gene coding for a lubricating proteoglycan of the surface of articular cartilage. The loss of function mutation causes progressive joints deformity due to a hyperplasic process of the synoviocytes, responsible for the typical features (camptodactyly, arthropathy and coxa vara). In about 20% of cases, in addition to joint involvement, pericardial involvement is described, suggesting that CACP syndrome may also be due to a regulatory dysfunction in the proliferation of serosal cells [17]. This condition is likely underdiagnosed and sometimes misdiagnosed as polyarticular or systemic JIA when pericardial involvement is present. However, in contrast to JIA, there is no joint inflammation, and therefore, there is little response to anti-inflammatory therapy; In addition, MRI allows to find the typical acetabular cysts [18]. The therapeutic management is only symptomatic in association with physiotherapy and multidisciplinary approach [19].

A previously healthy 16-year-old boy was evaluated for 6-month history of left limping with recurrent left knee arthritis treated with intra-articular corticosteroid injection with transient benefit but, afterwards, swelling recurrence. His past medical history and familiar history were unremarkable. He was evaluated at our Institute during the third episode of swollen knee, 2 months after the first episode. Despite the swelling, he did not report morning stiffness or joint pain. The physical examination was unremarkable except for a warm, swallen right knee with limited ROM. CBC, ESR, CRP and autoantibody profiles (ANA and anti-DNA) were normal. Knee US showed significant intra-articular effusion and synovial thickening, with no positivity to color-doppler signal. Oligoarticular JIA was suspected and a knee arthrocentesis was performed with 270 ml of bloody fluid drained (Fig. 6). Synovial fluid analysis showed a mild increase in WBC count (20.267cells/uL), with negative bacterial culture. One month after arthrocentesis, the joint picture appeared to have improved; however, slight intra- articular effusion persisted on US. Based on the pattern of recurrent arthritis, although the boy denied any travel to endemic areas or tick bites, second level analysis were performed that showed seropositivity for Borrelia Burgdorferi, confirmed by positive immuno-blot; diagnosis of Lyme arthritis (LA) was made and antibiotic therapy with Amoxicillin 50 mg / kg/ day for 28 days was started.

270 cc of blood serum from knee arthrocentesis performed after 2 months of limping

LA is a manifestation of infection with Borrelia burgdorferi spirochete. It’s widespread in North America, but it’s infrequent in Europe, although an increase in its incidence has also been recorded, ranging from 0.14 to 1.4 cases/1000 habitants/year, due to the greater diffusion of the vector [20]. Lyme disease usually begins with an expanding skin lesion, known as erythema migrant (stage 1) that, if untreated, can be followed within days to weeks, by early disseminated infection, responsible for neurological and cardiac involvement (stage 2). Late infection occurs after months and it’s characterized by arthritis or acrodermatitis chronica atrophicans (stage 3). However, LA may be not associated with a history of tick bite and / or erythema migrant, so arthritis can be the first manifestation. At the onset, LA usually affects large joints with recurrent swelling often associated with limited ROM but little or no pain and the knee is the most affected joint. The ankle is the second one and the picture may mimic an oligoarticular JIA [21]. Serological testing is the only available method to support a diagnosis of Lyme borreliosis and it’s based on a 2- step test using serological screening and confirmation with immunoblot or Polymerase Chain Reaction. Although a course of oral antibiotics leads to resolution in over 70% of cases, in a smaller proportion of patients, an immunological mechanism leads to chronic arthritis, indistinguishable from JIA [22].

A 14-year-old boy was referred to our Service for a 3-year history of swollen right knee unresponsive to intra-articular corticosteroid injections. His past medical history and his family history were unremarkable. The physical examination was unremarkable except for swelling of the right knee. The laboratory tests revealed always normal CBC and negative inflammatory markers and secondary analysis showed RF, ANA, HLA- B27 and Lyme disease, negative results. A knee MRI showed a large effusion and hyperplasia of the synovium, with no bone erosions or lytic lesions (Fig. 7). The arthrocentesis performed resulted in aspiration of a small quantity of bloody fluid. The presence of a monoarticular arthritis, unresponsive to therapy, with no bone erosions despite the long history, led us to perform an arthroscopy with synovectomy. On histological examination, proliferation of mononuclear cells, multinucleated giant cells and macrophages overloaded with hemosiderin were noted and diagnosis of Pigmented Villonodular Synovitis (PVS) was made.

MRI of the right knee with proton density-weighted axial view showing hyperplasia of the synovium and low signal intensity indicating hemosiderin (arrow)

PVS is a synovial proliferative lesion rare in children but more frequent in young adults with a prevalence of 1.8/1,000,000, in which there is often a monoarticular knee involvement with a marked swelling without pain or inflammation. Pathogenesis is unknown, but it results in a synovial hyperplasia and accumulation in the synovia of histiocytes, multinucleated giant cells, and macrophages overloaded with hemosiderin. This accumulation gives a typical picture on MRI, which represents the gold standard for the diagnosis showing focal irregular high signal intensity lesions on T2-weighed images [23]. However, the slow growth and low intensity of pain at early-stage may lead to a delayed diagnosis or a misdiagnosis with JIA or other rheumatologic disorders [24]. Diagnostic confirmation is by histology after total synovectomy, which represents the main treatment [25].

A 2-year-old girl presented with a right limping. Her past medical history and her family history were unremarkable. The physical examination was unremarkable except for a swollen, painful right knee with a limitation of ROM. Laboratory exams showed an increase in ESR (40 mm/h) with normal CRP, CBC, liver and renal function and a positive for ANA 1:1280. Oligoarticular JIA was suspected and clinical remission after intra-articular corticosteroid injection was achieved. However, the child presented a relapse of arthritis in the following months, in her left ankle and left knee for which medicated arthrocentesis was performed and therapy with methotrexate was started with subsequent clinical remission.

JIA is the most common rheumatologic disease in children, with a prevalence ranging from 3.8 to 400/100,000 [3]. Limping could be a symptom of JIA in children, especially in females. The most frequently affected joints are the knees and ankles with swelling, local warmth, and a limited ROM on physical examination [26]. Diagnosis is clinical, and laboratory tests are usually normal. ANA may be normal and they are used for uveitis risk stratification. NSAIDs and corticosteroid joint injections are the main treatment for JIA. Second level drugs such as DMARDs or biologic agents for example anti-TNF drugs, are indicated in children that have severe or progressive arthritis [27].

In this article, we described some important causes of chronic limping, that, although rare, clinicians must suspect in presence of specific symptoms and signs (Table 1) and a more common case, the JIA. However, a persistent limping is not necessarily a sign of JIA, and the differential diagnosis involves a broad spectrum of rheumatic and non-rheumatic diseases (Table 2). An early onset arthritis with systemic involvement and a positive family history could be secondary to genetic conditions (case 1 and case 5), while a history of recurrent monoarticular arthritis should arouse suspicion of LA (case 6), even in the absence of tick bite history. Except in the systemic onset, laboratory tests including blood cell counts and inflammatory markers are usually normal in JIA. An alteration in laboratory tests, such as anemia can be found in presence of malignancy. It’s imperative to remember that tumors may have bone involvement, as in the case of neuroblastoma metastases (case 2) and that the lesions may initially not be evident and blood tests may be normal. Additional testing, such as Lyme serology or tumor markers may be considered, based on the potential differential diagnosis. Furthermore, the diagnostic approach on a limping child often include plain inferior limb X-Rays and joint US for the detection of focal anomalies or articular effusion respectively. Sometimes, repeating an X-Ray is mandatory in frequent relapse (case 3). However, if there is discrepancy between important symptoms and mild clinical signs of arthritis considers malignancy even if X-Ray is negative and, in that case, consider MRI (case 2). MRI plays a major role for diagnosis of potential underlying etiologies (cases 3 and 4). Finally, the arthrocentesis is a procedure that may be necessary for some conditions thanks to its diagnostic and therapeutic value. Macroscopically, synovial fluid analysis can provide information in terms of quantity, the possible presence of hemarthrosis and its viscosity (cases 6 and 7). Moreover, an analysis of cellularity is useful to investigate an inflammatory condition and also a histological analysis of synovial tissue may help to orientate in specific diagnosis (case 7). In conclusion, we suggest thinking about alternative diagnoses, although rare, when you are in presence of persistent limping and atypical JIA.