Lessons from arthritis and osteomyelitis mimicking juvenile idiopathic arthritis: painlessness as an important clue to NTRK1 mutations

Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare disorder that is caused by autosomal recessive mutations in the Neurotrophic Receptor Tyrosine Kinase (NTRK1) gene. The disease typically presents with a triad of insensitivity to pain and temperature, anhidrosis, and intellectual disabilities. Musculoskeletal symptoms are occasionally a primary manifestation, particularly synovial chondromatosis, mimicking oligoarticular juvenile idiopathic arthritis (JIA). The disparity between severe osteoarticular destruction and painlessness is an important clue to consider underlying neuropathy-related disorders. We herein report three cases initially misdiagnosed with oligoarticular JIA, who were subsequently identified to carry the same pathogenic NTRK1 mutations. A 10-year-old girl, a 12-year-old girl, and an 8-year-old boy presented with a chronic progressive oligoarthritis in the large joints of the lower limbs. Musculoskeletal magnetic resonance imaging (MRI) showed the same patterns of intra-articular effusion, severe synovial hypertrophy, and extensive subchondral osteolysis, which are characteristic of destructive JIA. In two of the patients, joint devastation progressed despite multiple immunosuppressive agents, including biologic therapies. On examination, the absence of severe pain in spite of the local inflammatory signs and severe osteoarticular damage, suggested underlying neuropathy-related disorders in these cases. We further confirmed the past medical history of subtle autonomic symptoms, particularly anhydrosis since childhood, which the families had initially overlooked. Genetic investigation using whole-exome sequencing (WES) ultimately identified the same pathogenic homozygous NTRK1 splice-site variant (c.1354 + 1G > T) in all three patients. NTRK1-related disease occasionally presents primarily with destructive arthritis, which is easily misdiagnosed as JIA. The significant discrepancy between severe osteoarticular damage and painlessness, along with a poor response to aggressive immunosuppressive therapy, are important clues to raising suspicion of an underlying neuropathic disorder. Early recognition of subtle autonomic symptoms, such as anhidrosis, and genetic confirmation are crucial to prevent delayed diagnosis and unnecessary escalation of treatment.