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Periodic Fevers or Autoinflammatory Syndromes

These syndromes are rare, with a spectrum of features, characterised by fever and other features such as rash, joint pain or arthritis, abdominal pain, mouth ulcers, red eyes and neurological involvement. For some conditions, if untreated, there is an increased risk of amyloidosis, which is often fatal. The approach to a child with persistent fever is available. The periodic fever syndromes are a spectrum of conditions and with advances in understanding of the genetics and pathways of inflammation, more treatment options are becoming available.  Some of the periodic syndromes include:

  • Familial Mediterranean fever.
  • Hyperimmunoglobulinaemia D - also known as mevalonic kinase deficiency.
  • Tumor necrosis factor receptor-associated periodic syndrome (TRAPS).
  • The cryopyrinopathies (Familial cold auto-inflammatory syndrome), Muckle – Wells syndrome, chronic infantile neurologic cutaneous and articular syndrome (CINCA) and also known as neonatal onset multi-system inflammatory disease (NOMID).
  • Periodic fever with aphthous stomatitis, pharyngitis and adenitis (PFAPA).
  • Cyclic neutropenia.

There can be overlapping clinical features between various disorders and even heterogeneity among patients even with the same genetic disorder, making diagnosis often challenging. The differential must include infection and malignancy and can include extensive tests over a period of time. Genetic testing is available for some conditions. Support for the family is important and the role of the nurse specialist is highlighted in pmm-nursing. 

A summary of the autoinflammatory diseases is useful to demonstrate the overlap between the spectrum of disease currently identified. It is likely that more will be identified. Treatment options include biological agents for some of these conditions (e.g., IL1 blockade in Cryopyrinopathies) often with dramatic improvement in the quality of life for children.  Patients require long term specialist supervision. 

The autoinflammatory alliance provides more information and resources for families http://autoinflammatory.org

Chronic recurrent multifocal osteomyelitis (CRMO) is regarded as an autoinflammatory condition but as yet the aetiology is unclear. CRMO presents similarly to bacterial osteomyelitis with pain - often in multiple sites with bone or joint swelling - however by definition, the investigations for infection are negative and cultures are sterile. There are often multiple involved sites with recurring episodes of bone pain, sometimes with swelling. The most common affected areas are long bones (tibia), but ribs, clavicle, vertebrae or pelvis can be affected with some lesions being apparently asymptomatic and detected with imaging. Treatment is with NSAIDS for symptomatic relief and this may suffice for some patients at the mild end of the spectrum. Intravenous pamidronate (a biphosphonate treatment) is helpful to alleviate pain and reduce disease activity in CRMO. Systemic immunosuppression is used for refractory disease or where there is intolerance to pamidronate. Clinical trials are in progress. The emergence of bony swelling, with or without pain, is always a concern for red flag conditions; malignancy and infection must be excluded and multidisciplinary input is often needed to establish the correct diagnosis; children will often need extensive investigations including imaging and potentially biopsy of bone to establish the diagnosis. 

The photograph below shows expanded medial clavicle and sternoclavicular joint in a child ultimately diagnosed with CRMO

The photograph below shows severe swelling of both knees with marked muscle wasting in a child with untreated CINCA

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