Clinical features of autoinflammatory periodic fever syndromes

Gattorno, 2019

Note: Most children with recurring fevers do not have an autoinflammatory periodic fever syndrome.

Autoinflammatory periodic fever syndromes are very rare and it must be noted that most children with recurring fevers do not have an autoinflammatory periodic fever syndrome. Healthy toddlers have an average of 6 febrile infective episodes per year and that number is significantly higher for those who attend institutional day careGray, 2012.

A broad list of differential diagnoses (mimics) should be considered for people with recurring fevers. This includes:

infections (eg recurring viral infections, occult bacterial infection)
malignancy (eg leukaemia, lymphoma, neuroblastoma)
immunodeficiency (eg cyclical neutropenia)
autoimmune conditions (eg systemic lupus erythematosus, inflammatory bowel disease).

One of the more common autoinflammatory periodic fever syndromes, familial Mediterranean fever, can present with severe abdominal pain that can mistakenly be diagnosed as acute appendicitis or testicular torsion, putting patients at risk of unnecessary surgery. Chest pain and arthritis are also common in familial Mediterranean fever and severity of symptoms is not reliable to differentiate these conditions from other serious causes.

Clinical assessment, both when people are well and during an episode, is helpful to characterise their clinical signs. Clinical features suggestive of an autoinflammatory periodic fever syndrome lists some of the clinical features that may be suggestive of an autoinflammatory periodic fever syndrome.

Figure 1. Clinical features suggestive of an autoinflammatory periodic fever syndrome

Clinical features suggestive of an autoinflammatory periodic fever syndrome include:

stereotypical episodes with consistent clinical features
absence of any concurrent infective symptoms such as cough or coryza
intervals between fever episodes are often consistent (although not necessarily true of all periodic fever syndromes)
clinical features include rash, peritonitis (eg acute abdominal or testicular pain), chest pain, aphthous stomatitis, arthralgia or arthritis
investigations typically show marked elevation of acute phase reactants including serum C-reactive protein (CRP) concentration and erythrocyte sedimentation rate (ESR)
complete resolution of all features between episodes.

There are many clinically and genetically defined autoinflammatory periodic fever syndromes. Periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) is the most common autoinflammatory periodic fever syndrome, with an estimated yearly incidence of 2 per 10 000 children under the age of 5 yearsHashkes PJ, 2019. Familial Mediterranean fever is the most common genetically defined autoinflammatory disease. It is rare on a global scale but affects as many as 1 per 500 people among certain ethnic groups of Mediterranean ancestryHashkes PJ, 2019. Most of the other autoinflammatory periodic fever syndromes are very rare. The more common conditions and their specific features are detailed in Common features of specific autoinflammatory periodic fever syndromes.

Table 1. Common features of specific autoinflammatory periodic fever syndromesGattorno, 2019
periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) familial Mediterranean fever (FMF) tumour necrosis factor receptor–associated periodic syndrome (TRAPS) hyperimmunoglobulin D syndrome (HIDS) / mevalonate kinase deficiency (MKD) familial cold autoinflammatory syndrome (FCAS) Muckle-Wells syndrome (MWS) neonatal-onset multisystem inflammatory disease (NOMID)
periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA)
Age at onset	early childhood
Duration or frequency of episodes	3 to 6 days every 4 to 6 weeks often very consistent intervals between episodes
Key features	fever aphthous ulcers pharyngitis adenitis
Inheritance	reported AD pattern inheritance but not completely understood
Common ethnicity	any
Gene or protein	unknown
Treatment	spontaneously improves in most patients and they do not require any treatment corticosteroids tonsillectomy colchicine
familial Mediterranean fever (FMF)
Age at onset	most in early childhood
Duration or frequency of episodes	12 to 72 hours with varying intervals weekly or a few times per year
Key features	fever peritonitis arthralgia arthritis erysipelas-like rash on trunk or limbs amyloidosis
Inheritance	AR, but carriers can have milder symptoms
Common ethnicity	Armenian Arabic Turkish Italian Jewish
Gene or protein	MEFV (gene), pyrin (protein)
Treatment	colchicine IL-1 antagonists (eg anakinra, canakinumab)
TNF receptor–associated periodic syndrome (TRAPS)
Age at onset	early childhood, but can rarely present in adulthood
Duration or frequency of episodes	days to weeks at varying intervals
Key features	fever peritonitis myalgia painful rash conjunctivitis periorbital oedema arthritis
Inheritance	AD
Common ethnicity	Irish Scottish
Gene or protein	TNFRSF1A
Treatment	corticosteroids IL-1 antagonists (eg anakinra, canakinumab) TNF inhibitors (less effective)
hyperimmunoglobulin D syndrome (HIDS) / mevalonate kinase deficiency (MKD)
Age at onset	infancy
Duration or frequency of episodes	4 to 6 days at varying intervals
Key features	abdominal pain diarrhoea maculopapular rash lymphadenopathy aphthous stomatitis myalgia
Inheritance	AR
Common ethnicity	any
Gene or protein	MVK (protein)
Treatment	NSAIDs corticosteroids IL-1 antagonists (eg anakinra, canakinumab)
familial cold autoinflammatory syndrome (FCAS)
Age at onset	usually infancy, but can be later in life
Duration or frequency of episodes	12 to 24 hours or longer often occurs shortly after exposure to cold
Key features	cold-induced urticaria headache arthralgia
Inheritance	AD
Common ethnicity	any
Gene or protein	NLRP3 (gene), cryopyrin (protein)
Treatment	IL-1 antagonists (eg anakinra, canakinumab)
Muckle-Wells syndrome (MWS)
Age at onset	infancy
Duration or frequency of episodes	variable and can be continuous
Key features	urticarial rash arthralgia hearing loss
Inheritance	AD
Common ethnicity	any
Gene or protein	NLRP3 (gene), cryopyrin (protein)
Treatment	IL-1 antagonists (eg anakinra, canakinumab)
neonatal-onset multisystem inflammatory disease (NOMID)
Age at onset	infancy
Duration or frequency of episodes	continuous
Key features	urticarial rash destructive arthritis aseptic meningitis hearing loss optic neuritis
Inheritance	AD
Common ethnicity	any
Gene or protein	NLRP3 (gene), cryopyrin (protein)
Treatment	IL-1 antagonists (eg anakinra, canakinumab)
Note: AD = autosomal dominant; AR = autosomal recessive; IL-1 = interleukin-1; MEFV = Mediterranean fever gene; MVK = mevalonic kinase; NSAID = nonsteroidal anti-inflammatory drug; TNF = tumour necrosis factor; TNFRSF1A = TNF-receptor super-family member 1A