Introduction are young children, usually presenting with

Introduction

Juvenile idiopathic arthritis (JIA) is the most common childhood chronic inflammatory arthritis; typically, arthritis of unknown origin begins before the age of 16 years and persists for at least 6 weeks. The nomenclature and classification of JIA based on the International League of Association for Rheumatology (ILAR) criteria (1, 2). JIA is a diagnosis of exclusion and represents a phenotypically heterogeneous group. However, they have similar inflammatory articular changes. It is crucial to recognize arthritis which is a clinical finding manifested as stiffness particularly in the morning, effusion/ swelling and limited range of motion of the affected joints (3).

Many children referred to pediatric rheumatology clinics with musculoskeletal manifestations such as joint contracture, swelling or deformity without signs of inflammation. A spectrum of systemic noninflammatory disorders may masquerade as JIA (4). Patients with noninflammatory disorders have arthropathy rather than arthritis. Arthropathy can arise from bony dysplasia, thickened synovium or noninflammatory effusion (5, 6). Unfortunately, it is not uncommon that the presence of noninflammatory arthropathy mimics juvenile arthritis delays the correct diagnosis and the appropriate management (7, 8).

We believe that a complete history with emphasis on the family history and thorough musculoskeletal examination supported by basic laboratory tests including acute phase reactants and proper imaging studies are sufficient to identify such disorders and eventually initiate the proper management and avoidance of unnecessary treatment (9).

This review highlights selected noninflammatory disorders often presented with articular manifestations; it is not uncommon to mislabel such disorders as JIA. The focus is on the clinical, biochemical and imaging features of these disorders.

Idiopathic multicentric osteolysis

Idiopathic osteolysis is a rare inherited heterogeneous group of disorders. The exact etiology and pathogenesis are not well identified. There are different forms with different terms; the frequency of these disorders worldwide is unknown (10, 11). The affected patients are young children, usually presenting with limitation of the wrist and ankle joints simulating arthritis but with rapid progressive resorption of carpal and tarsal bones ended with severe deformities and functional disabilities (12, 13). Patients had pain due to severe osteoporosis rather than synovitis.

The initial presentation mimics arthritis; so, it is not uncommon to mislabel such conditions as JIA (14, 15). However, careful clinical assessment demonstrated that those patients do not have morning stiffness or joint effusion. Plain radiography of the hands and feet revealed early destructive osteolytic changes of the carpal and tarsal bones, which are not consistent with inflammatory arthritis. Furthermore, the inflammatory markers including erythrocyte sedimentation rate and C-reactive protein are typically within normal limits.

We described a large cohort of one of the idiopathic multicentric osteolysis disorders; named nodulosis, arthropathy, and osteolysis (NAO) syndrome (16). NAO syndrome results from a mutation in the gene encoding the matrix metalloproteinase 2 gene (MMP-2), at 16q 12-21 loci. Mutational inactivation of MMP-2 creates an imbalance between bone synthesis and resorption (17).  The main clinical findings are arthropathy in form of limitation of motion with contractures and deformities affecting both hands and feet in addition to nodular lesions in both palmar and plantar surfaces (Figure I) (Add photo of hands and feet). Few patients had other joints involvement including elbow, knees and hips. Radiography of the hands and feet showed advanced osteolytic changes (Figure II) (Hand X-ray).

Unfortunately, there is no available effective treatment for these disorders. Supportive treatment in form of calcium and vitamin D supplement in addition bisphosphonate might improve the bone density but do not change the disease course (18, 19). 

Mucopolysaccharidosis

Mucopolysaccharidosis (MPS) are a heterogeneous group of inborn metabolic disorders of glycosaminoglycan. There are different phenotypes depending on certain gene mutations encoding glycosaminoglycan-degrading enzymes, resulting in the inability to metabolize certain glycosaminoglycan. Overall the frequency of MPS varies in each population but the most common form is MPS type-I (20, 21). Patients usually look normal at birth. However, as they get older, they show progressive clinical features affecting multiple organ systems. Severe MPS phenotypes are typically under the care of medical genetic specialists. Diagnostic approach and management of MPS is beyond this review. However, a general pediatrician or other specialist may suspect or see mild cases initially. Accordingly, he can refer the patient to medical genetic specialist for more confirmatory testing and management.

 MPS type-I has historically been delineated into three separate subtypes, Hurler syndrome (severe), Hurler-Scheie syndrome (intermediate) and Scheie syndrome (mild). Musculoskeletal manifestations such as stiffness and joint contractures are prominent in all forms of MPS; these manifestations include joint complaints that may mimic inflammatory arthritis seek rheumatologist consultation (7, 22). The milder phenotypes are more likely to be missed; unfortunately, diagnostic delays occur frequently in these patients. Rheumatologists and other specialists should be aware of the musculoskeletal manifestations of MPS. The proper history and physical examination should help in recognizing these cases. MPS should be considered a differential diagnosis in children with joint contractures in the absence of sings of inflammation (23). Furthermore, certain radiographic findings such as characteristic dysplasia and dysostosis multiplex should raise the consideration of MPS (24, 25) (Figure III) (X-ray).

Early diagnosis and management are necessary to improve the outcome in affected patients.  Enzyme activity assays based on cultured fibroblasts, leucocytes, plasma or serum are considered the gold standard for diagnosis of MPS. Certain MPS disorders can be treated with hematopoietic stem cell transplantation and those for which enzyme replacement therapy is available (25, 26).

Camptodactyly-arthropathy-coxa vara-pericarditis syndrome

Camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome is a rare autosomal inherited disorder affecting mainly the joints. Usually, the affected individual did not complain of joint pain or morning stiffness. Typically, the manifestations started in the infancy period as camptodactyly of the fifth fingers. However, the hallmark features like swelling of interphalangeal joints, wrists, and knees developed in early childhood. The swollen joints are due to the synovial thickening and effusion, which often associated with limited motion but without redness, tenderness or hotness (8, 27). One of the important components of this disorder is femoral   dysplasia; patients usually developed progressive coxa vara deformity, some have other radiological findings such as acetabular cysts (Figure IV- hip X-ray). Ultrasonography is probably beneficial in differentiating CACP syndrome from inflammatory arthritis; CACP syndrome patients had prominent synovial proliferation with normal synovial vascularity (28, 29).  

Some patients may present with pericarditis, occasionally associated with effusion requiring pericardiocentesis.

All these manifestations are due to noninflammatory process. Characteristically, the inflammatory markers are normal. The synovial pathology described as proliferative synovium with hypercellularity by infiltrating macrophages with a contribution by proliferating fibroblastic synoviocytes (30).  CACP syndrome occurred because of the defect in the main surface lubricant for the joints and tendons; this defect caused by different mutations in the proteoglycan-4 (PRG-4) gene, which is located on chromosome 1q25-31. There are several pathogenic mutations have been reported in this gene. However, till date, no reports elucidate the genotype-phenotype association of this rare syndrome (31, 32). Because of multiple joint swollen and presence of joint effusion, the CACP syndrome may be diagnosed inaccurately as JIA, which causing a delay in the diagnosis and management (9, 33).    

Unfortunately, there is no available effective treatment for this rare disorder. It is worth mentioning, most CACP syndrome patients as they were labeled incorrectly with JIA, received traditional and biological disease-modifying antirheumatic drugs during their disease course with no beneficial therapeutic results. 

Progressive pseudorheumatoid dysplasia

Progressive pseudorheumatoid dysplasia (PPRD) is an autosomal recessive disorder characterized by progressive arthropathy involving the small peripheral joints. Patients usually present in early childhood with progressive stiffness and flexion contractions of the interphalangeal joints associated with metaphyseal bony overgrowth of the metacarpal and phalanges.  However, other musculoskeletal features gradually develop with time, patients had abnormal posture, disproportionate short stature, kyphoscoliosis and hyperlordosis abnormal gait due to axial skeleton involvement and hip joint deformity and stiffness (34, 35).

PPRD is a rare skeletal disorder frequently diagnosed among Arabs; it is attributed to the loss of function in WNT1-inducible signaling pathway protein3 (WISP3), this gene is essential for normal growth and function of joint cartilage (35- 37). All musculoskeletal changes result without evidence of inflammation. Typically, inflammatory markers are within normal and radiological findings showed dysplastic rather than arthritic changes; the characteristic findings include epimetaphyseal expansion and platyspondyly (Figure V- hand X-ray).

Despite the joint involvement is noninflammatory in nature, PPRD is frequently misdiagnosed as JIA, particularly in the early stages of the disease (38).

Unfortunately, no cure for this disorder, it is only supportive treatment. Occasionally, patients required analgesics or anti-inflammatory drugs, especially, for patients with osteoarthritis like pain due to joint degeneration and bony dysplasia.

Conclusion

 

JIA is the most common chronic childhood arthritis; it is a diagnosis of exclusion. Unfortunately, no available diagnostic tool but the comprehensive history including family history and complete physical examination are the most helpful tools in sorting out the various causes of articular disorders in children. Genetic musculoskeletal disorders mimic chronic polyarthritis should be considered in the differential diagnostics of JIA. Normal inflammatory markers and characteristic radiological features are able to distinguish these disorders from JIA. However, molecular genetic findings are the confirmatory test. Timely diagnosis of these disorders is crucial to offer the family the proper genetic counseling and avoid inappropriate therapy.

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