Tender, warm, poorly demarcated subcutaneous nodules. Acutally a panniculitis. Classically on the shins but can be widespread.
Mostly caused by Group A strep or drugs, but can be a clue to:
NSAIDs effective. Potassium iodide used in chronic/recurrent cases (can cause hyperthyroidism)!
Steroids should rarely be considered.
A Cryopyrin disorder, found in Northern Europeans. Cryopyrin triggers an IL-1 dominated inflammatory response, and is coded for by the Cold-Induced Autoinflammatory Syndrome 1 (CIAS1) gene, also known as the NLRP3, NALP3 or PYPAF1 gene.
Attacks of periodic fever are very brief eg 1-2 days – apart from fever, an urticarial rash is sometimes seen, limb pain/arthralgia occurs. Abdominal pain and arthritis occur rarely. Sensorineural hearing loss is characteristic.
Amyloidosis affects 25%, which is high cf other periodic syndromes.
Diagnosis is by genetics.
Steroids are often used but benefit is inconsistent; interleukin 1 (IL-1) receptor antagonist Anakinra shows promise.
Familial cold autoinflammatory syndrome (FCAS) is a similar condition, also related to Cryopyrins. Cold induced obviously, but without the deafness, and amyloidosis is rare.
NOMID/CINCA are also related – the names say it all: Neonatal onset multisystem inflammatory disorder, and chronic infantile neurological cutaneous and articular syndrome. Papilloedema and uveitis potentially leading to blindness occur; there is epiphyseal bone formation; hepatosplenomegaly; and a chronic meningitis with deafness. There is no known treatment, sadly.
Mostly Dutch and French. Not to be confused with Hyper IgE syndrome or Hyper IgM syndrome. Big database in Nijmegen. A genetic syndrome (autosomal recessive, explained by MVK (mevalonate kinase) gene mutations on chromosome 12p – see Omim) with recurrent febrile attacks starting under 1yr of age.
Attacks last 3-7 days, so may or may not be shorter than TRAPS, occur every 4-8 weeks. Features are:
Diagnosis is by finding of high IgD (>100U/ml); most also have high IgA (with or without raised IgG and IgM), which is an important clue.
Increased Mevalonic acid in urine during fever.
Febrile attacks in response to immunizations often reported, so may be another clue.
Attacks tend to diminish with age without completely disappearing; amyloidosis seems to occur only rarely (cf TRAPS). Simvastatin is supposed to help!
First described in a family of Irish descent, hence “Hibernian”, now called TRAPS (TNF receptor assoc periodic syndrome), and now described in a wide range of different ethnicities.
Various mutations of TNF-Receptor Super Family 1A (TNFSF1A) seen, on chromosome 12p (same as HIDS but different gene). These mutations are dominant and penetrate poorly, with only a small proportion developing disease.
Onset is typically around 3yrs of age but varies widely. Periodicity also varies widely: typically every 5-6 weeks. Fever for 3 days heralds onset of other symptoms, which then last for usually 5 days or more (cf Familial Mediterranean Fever):
About 14% develop amyloidosis.
Diagnosis is mainly clinical. Must have at least 6/12 history of recurrent inflammatory symptoms, with at least one of the above features, episodes must last at least 5/7 on average (even if variable), with response to steroids but not colchicine. Other affected family members will obviously increase your suspicion. Ethnic group does not seem to have any bearing.
Steroids reduce severity but not frequency of attacks. NSAIDS help fever. Etanercept appears to prevent; colchicine does not (hence one of the diagnostic criteria above!).
[Medicine 2002;81(5):349-68 PMID 12352631]
Short attacks of fever, usually lasting 1-3 days, recurring at varying intervals (periodic), cf Behcet’s.
Most children develop severe abdominal pain with the episodes, due to sterile peritonitis.
Pleuritis, leading to chest pain, arthritis, myalgia and skin rashes may also occur.
Most cases are from Arabic Turkish, Armenian or Jewish background. Inheritance is autosomal recessive. The gene has been cloned and four mutations have been identified.
Colchicine is the treatment of choice. Some patients may develop amyloidosis; certain mutations are at higher risk.
Recurrent fever and aphthous stomatitis, mostly. However, there is no regular periodicity of the symptoms, and episodes of fever may last for weeks.
Traditionally associated with Mediterranean or Eurasia but in UK mostly white Caucasian.
Other features –
BPSU study found 1 case every 2 weeks in the UK. Median age of onset was 6yrs – but diagnosis 11yrs!
Colchicine as regular preventive treatment, else immunosuppressive treatment. Topical steroids or short courses oral steroids.
=periodic fever, aphthous stomatitis, pharyngitis, adenitis.
Fever every 4-6 weeks (periodic). Neutrophil count normal, cf cyclical neutropenia.
Besides mouth ulcers, sore throat and cervical lymphadenopathy, headache, musty smell (!), abdo pain.
Affected children continue to grow normally, are well between attacks, and do not suffer long-term sequelae.
Treatment with steroids or with cimetidine has been effective, and some children have had no further attacks following tonsillectomy (which suggests some relationship with strep infection but not clear).
=elastase defect.
Regular pattern of fever (periodic), approximately three-weekly, perhaps associated with malaise, periodontitis, aphthous ulceration, impetigo, sore throat and enlarged lymph glands.
But by the time the child presents, the neutrophil count may have returned to normal (although unlikely to be high).
Check FBC twice weekly for 4-6 weeks to demonstrate the fluctuation of the neutrophil (and monocyte) count.
Important not to miss, as children can develop severe bacterial sepsis while neutropaenic (mortality rate of up to 10%).
Need antimicrobial prophylaxis, and possibly GCSF.
Differential is PFAPA (periodic fever, aphthous stomatitis, pharyngitis, adenitis)
| Infectious causes |
| Mycobacteria (TB and non-tuberculous disease) |
| Borrelia |
| Leptospira |
| Streptobacillus moniliformis (rat bite fever) |
| Hepatitis B |
| Orbivirus |
| Rickettsea (typhus) |
| Entamoeba histolytica |
| Others |
| Cyclical neutropoenia |
| PFAPA |
| Behcet’s |
| Hyper IgD (HIDS) |
| Familial Mediterranean fever |
| Familial Hibernian fever/TRAPS |
| Cryopyrin disorder |
Periodic fevers are defined as uniform periods of fever that recur regularly in individuals who are healthy between attacks. Parents may organize life eg holidays around expected attacks and don’t have any concerns otherwise cf child with recurrent respiratory and gastrointestinal infections after starting nursery who “always has something”.
Recurrent bacterial infections esp recurrent/chronic pneumonia or otitis media may indicate a humoral immune defect. Similarly, recurrent documented viral or fungal infections may indicate a cell mediated immune defect.
Arbovirus, spread by ticks, big problem in forested regions of Europe and vaccine available.
In Scotland, “Louping ill” is tick born encephalitis affecting sheep – v rarely humans too.
Since 2019, 3 cases of TBE in England (virus had been found in ticks in Southern England before), and recently 1 in Scotland. Patient had a dozen or so ticks that were only removed after a day.
Lyme disease is the other important tick borne infection.