When Joint Destruction Hurts Nothing: Rare Pain Gene Mutation Masqueraded as Childhood Arthritis

At first glance, the three children arriving at Vietnam National Children’s Hospital in Hanoi looked like textbook cases of juvenile idiopathic arthritis. A ten-year-old girl, a twelve-year-old girl, and an eight-year-old boy all presented with chronic, progressively worsening arthritis affecting the large joints of their lower limbs. Their magnetic resonance imaging scans revealed a pattern familiar to any pediatric rheumatologist: fluid accumulating inside the joint spaces, dramatic thickening of the synovial membrane that lines the joint, and extensive erosion of the subchondral bone just beneath the cartilage. Everything about the pictures pointed toward destructive oligoarticular juvenile idiopathic arthritis, the most common chronic rheumatic disease of childhood. Yet something was profoundly wrong with the clinical picture, and it was something the children themselves could not articulate, because they could not feel it.

The crucial clue was the absence of pain. In juvenile idiopathic arthritis, inflammation of the joints typically produces severe, persistent pain that dominates the child’s life and drives the diagnostic workup. These children, despite showing local signs of inflammation and despite radiographic evidence of severe, ongoing destruction of their joints, reported little to no pain at all. That striking mismatch between the extent of joint damage and the near-complete lack of discomfort prompted the clinical team, led by Ha Thu Thi Nguyen of the hospital’s Immunology, Allergy, and Rheumatology Center, to look beyond the immune system for an explanation. What they found, published as a case series in BMC Pediatrics, rewrites the diagnostic playbook for a vanishingly rare genetic condition that can wear the mask of a common autoimmune disease.

Whole-exome sequencing, a technique that reads the protein-coding portions of all genes simultaneously, revealed the same pathogenic homozygous variant in all three children: a splice-site mutation in the NTRK1 gene, designated c.1354+1G>T. Splice-site mutations disrupt the molecular punctuation marks that tell the cellular machinery where to cut and rejoin RNA transcripts, and this particular change at the boundary of an intron corrupts the production of the NTRK1 protein. The gene encodes TrkA, the tropomyosin receptor kinase A, a receptor tyrosine kinase that sits on the surface of developing sensory and sympathetic neurons and responds to nerve growth factor. When nerve growth factor binds TrkA, it triggers signaling cascades, including the mitogen-activated protein kinase pathway, that are essential for sensory neurons to survive, mature, and extend their fibers into tissues such as skin, bone, and joint capsules.

When both copies of NTRK1 carry loss-of-function mutations, as in these children who inherited one defective copy from each parent, the result is congenital insensitivity to pain with anhidrosis, also known as hereditary sensory and autonomic neuropathy type IV. The classical triad consists of an inability to feel pain and temperature, an inability to sweat, and intellectual disability. Because sensory neurons that normally transmit pain signals never develop properly, affected individuals live in a world without the protective alarm system that pain provides. They do not withdraw from hot surfaces, do not limp on fractured bones, and do not rest damaged joints. The anhidrosis arises because sympathetic neurons that innervate sweat glands also depend on the nerve growth factor–TrkA pathway and fail to function without it.

Musculoskeletal complications are among the most devastating consequences of this sensory deprivation. Without protective pain feedback, children subject their joints to repetitive microtrauma that goes unnoticed and untreated. The result is a destructive arthropathy known as a neuropathic joint, or Charcot joint, in which cartilage wears away, bone erodes, and the joint architecture collapses. The case series notes that synovial chondromatosis, a condition in which the joint lining produces nodules of cartilage, can occasionally be a primary manifestation, closely mimicking the oligoarticular form of juvenile idiopathic arthritis. In some reported patients, the joint destruction is compounded by osteomyelitis, an infection of the bone that develops because unnoticed injuries create entry points for bacteria and because the child never complains early enough to prompt treatment.

The diagnostic journey of the three Vietnamese children illustrates how easily this rare disease hides behind a common one. Two of the three patients received escalating immunosuppressive therapy, including biologic agents that target specific immune pathways, yet their joint devastation continued to progress. That therapeutic failure should itself have raised suspicion, because genuine juvenile idiopathic arthritis usually responds, at least partially, to modern immunosuppression. Instead, the children were cycled through treatments that could not possibly work, because the underlying driver of their joint destruction was not inflammation in the conventional sense but the mechanical consequences of a nervous system that could not feel or report injury. Every month of immunosuppression represented not only wasted resources but real risk, since these drugs carry infections and other side effects.

Retrospective history-taking proved equally revealing. Once the clinicians knew what to ask, they confirmed that the children had shown subtle autonomic symptoms since early childhood, particularly anhidrosis, which the families had initially overlooked or attributed to other causes. In hot climates such as Vietnam’s, children who cannot sweat face recurrent, unexplained fevers, and episodes of hyperthermia are a recognized feature of the condition that can be life-threatening. Other subtle clues in affected children often include self-mutilating behaviors such as biting the tongue or fingertips, painless fractures, patches of skin that fail to heal, and intellectual disability of varying degree. None of these features is specific on its own, and families frequently normalize them, which is precisely why the diagnosis is so often delayed until catastrophic joint damage forces medical attention.

The MRI findings themselves deserve careful attention from diagnosticians. While the combination of intra-articular effusion, severe synovial hypertrophy, and extensive subchondral osteolysis superficially resembles aggressive juvenile idiopathic arthritis, the authors emphasize that the disparity between this severe osteoarticular destruction and the patient’s painlessness is the discriminating feature. A joint that looks catastrophically destroyed on imaging but belongs to a child who walks in without a limp of complaint is a biological contradiction in any pain-intact patient. Electromyography, which measures the electrical activity of nerves and muscles, can support the diagnosis by demonstrating the absence of sensory nerve action potentials, but genetic confirmation through sequencing of NTRK1 remains the definitive test, and whole-exome sequencing proved sufficient to identify the homozygous splice-site variant in all three cases.

The implications of this case series extend well beyond three patients in Hanoi. Congenital insensitivity to pain with anhidrosis is extremely rare, but destructive arthritis in a child who does not hurt is a presentation that any clinician, anywhere, can learn to recognize in seconds once it has been named. The authors distill the lesson into a practical algorithm: when severe joint destruction coexists with painlessness, and especially when aggressive immunosuppressive therapy fails, clinicians should suspect an underlying neuropathic disorder, take a careful history for autonomic symptoms such as absent sweating since infancy, and pursue genetic testing. Early recognition matters because management of the two conditions diverges completely. Children with NTRK1 mutations do not need stronger immunosuppression; they need protective strategies to prevent injury, vigilant surveillance of skin and bones, prompt treatment of occult fractures and infections, careful temperature management to prevent hyperthermic crises, and family counseling about the autosomal recessive inheritance pattern, which carries a 25 percent recurrence risk for each pregnancy of carrier parents.

The report also highlights the growing role of genomic medicine in pediatric rheumatology. Conditions that once defied classification, presenting as atypical or treatment-refractory arthritis, are increasingly resolved by sequencing technologies that were unavailable to previous generations of clinicians. For the three children in this study, the molecular diagnosis ended a cycle of ineffective therapy and finally explained a lifetime of strange, disconnected symptoms, from the fevers without sweat to the joints that fell apart without complaint. Their story is a reminder that the most important diagnostic instrument in medicine remains the clinician’s attention to what does not fit, and that sometimes the loudest clue a patient can offer is silence where pain should be.

Subject of Research: NTRK1 mutations causing congenital insensitivity to pain with anhidrosis misdiagnosed as juvenile idiopathic arthritis

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

Article References: Nguyen, H. T. T., Le, C. Q., Hoang, L. T., Nguyen, T. H. T., Nguyen, Q. T., Nguyen, V. H., Nguyen, M. P. T., & Ang, E. Y. (2026). Lessons from arthritis and osteomyelitis mimicking juvenile idiopathic arthritis: painlessness as an important clue to NTRK1 mutations. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07592-x

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07592-x

Keywords: NTRK1, congenital insensitivity to pain, anhidrosis, juvenile idiopathic arthritis, CIPA, hereditary sensory and autonomic neuropathy, whole-exome sequencing, pediatric rheumatology, neuropathic arthropathy, TrkA, nerve growth factor, genetic diagnosis