Overview
Definition:
Periodic fever syndromes (PFS) are a group of rare, inherited autoinflammatory disorders characterized by recurrent episodes of fever and inflammation affecting various organs, including joints, skin, serosa, and the gastrointestinal tract
These are primarily genetic conditions.
Epidemiology:
The prevalence of individual PFS varies significantly
Familial Mediterranean fever (FMF) is the most common globally, particularly in Mediterranean and Middle Eastern populations
Other conditions like PFAPA (Periodic Fever, Aphthous stomatitis, Pharyngitis, Adenitis) are more common in pediatric populations worldwide, while TRAPS (Tumor Necrosis Factor Receptor-Associated Periodic Syndrome), HIDS/MVK (Hyperimmunoglobulin D Syndrome/Mevalonate Kinase Deficiency), and CAPS (Cryopyrin-Associated Periodic Syndromes) are rarer.
Clinical Significance:
Accurate and timely diagnosis of PFS is crucial as delayed or missed diagnosis can lead to significant morbidity, including chronic inflammation, organ damage (amyloidosis in FMF), and impaired quality of life
Genetic testing has revolutionized the diagnostic approach, enabling definitive diagnosis and guiding targeted therapies.
Clinical Presentation
Symptoms:
Recurrent episodes of fever, typically >38.5°C
Systemic inflammation: serositis (pleuritis, peritonitis), arthritis/arthralgia, skin rash (erythema, urticaria-like lesions, livedo reticularis)
Mucocutaneous manifestations: aphthous ulcers, pharyngitis, adenitis (prominent in PFAPA)
Abdominal pain
Myalgia
Fatigue
Specific to syndromes: conjunctivitis, hearing loss, neutrophil infiltration, neutrophilic skin lesions.
Signs:
Fever during episodes
Localized inflammation: joint swelling and tenderness, abdominal tenderness, skin lesions
Pharyngeal erythema and tonsillar exudates (PFAPA)
Lymphadenopathy (PFAPA)
Neurological signs can occur in some specific syndromes.
Diagnostic Criteria:
No single universal set of criteria exists due to the heterogeneity of PFS
Diagnosis often relies on a combination of clinical suspicion, response to treatment trials (e.g., colchicine for FMF, steroids for PFAPA), family history, and specific laboratory findings
For some, genetic testing confirms the diagnosis
Established criteria exist for specific syndromes (e.g., Tel Hashomer criteria for FMF).
Diagnostic Approach
History Taking:
Detailed fever pattern: frequency, duration, severity, triggers, periodicity
Associated symptoms during febrile episodes: pain location and character, rashes, oral ulcers, joint swelling, abdominal complaints
Past medical history: previous diagnoses, treatments and responses
Family history: similar episodes in relatives, consanguinity, known genetic disorders
Travel history
Dietary history
Red flags: severe abdominal pain, chronic joint swelling, unexplained rash, family history of amyloidosis.
Physical Examination:
General examination: vital signs, alertness, hydration
Detailed examination of affected systems: skin (lesions, erythema), joints (swelling, tenderness, range of motion), oropharynx (ulcers, tonsillar appearance), abdomen (tenderness, organomegaly), lymph nodes
Assessment of neurological status.
Investigations:
Initial investigations: Complete blood count with differential (leukocytosis, neutrophilia)
Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) (elevated during flares)
Blood biochemistry: liver and renal function tests, electrolytes, albumin
Urinalysis
Blood cultures to rule out infection
Inflammatory markers: serum amyloid A (SAA) (markedly elevated in FMF)
Immunoglobulins (IgD and IgA elevated in HIDS)
Ferritin (can be elevated)
Specific autoantibodies (ANA, RF) are typically negative, aiding in differentiating from autoimmune diseases
Genetic testing: Targeted gene sequencing for mutations in MEFV (FMF), TNFRSF1A (TRAPS), MVK (HIDS), NLRP3 (CAPS), PSTPIP1 (PAPAS), CECR1 (ADA2 deficiency), etc
Panel testing or whole exome sequencing may be considered for undiagnosed cases.
Differential Diagnosis:
Infectious causes of fever (bacterial, viral, fungal)
Other autoinflammatory syndromes not fitting classical descriptions
Autoimmune diseases (e.g., SLE, JIA)
Malignancy
Familial Mediterranean fever (FMF)
Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS)
Hyperimmunoglobulin D Syndrome (HIDS) / Mevalonate Kinase Deficiency (MKD)
Cryopyrin-Associated Periodic Syndromes (CAPS)
PFAPA (Periodic Fever, Aphthous stomatitis, Pharyngitis, Adenitis)
Deficiency of ADA2 (DADA2)
Familial cold autoinflammatory syndrome (FCAS), Chronic infantile neurological cutaneous and articular (CINCA)/Neonatal-onset multisystem inflammatory disease (NOMID).
Genetic Testing Approach
Indications For Testing:
Strong clinical suspicion based on recurrent fever and inflammatory symptoms
Failure to respond to empiric treatments
Positive family history
To confirm a diagnosis and guide specific therapy
For prenatal or preimplantation genetic diagnosis in affected families.
Gene Panel Selection:
For suspected FMF: targeted sequencing of MEFV gene
For suspected TRAPS: TNFRSF1A gene
For suspected HIDS: MVK gene
For suspected CAPS: NLRP3 gene
For undiagnosed recurrent fevers with multisystem inflammation: consider a broader autoinflammatory gene panel covering common and rarer syndromes
Next-generation sequencing (NGS) based panels are highly efficient.
Interpretation Of Results:
Identification of known pathogenic variants in relevant genes strongly supports the diagnosis
Variants of uncertain significance (VUS) require careful correlation with clinical phenotype and family segregation studies
Understanding genotype-phenotype correlations is key
Absence of identified pathogenic variants does not entirely rule out a PFS, especially if clinical suspicion remains high, as novel mutations or atypical presentations can occur.
Limitations And Challenges:
Cost of testing
Availability of specific genetic tests
Interpretation of VUS
Genotype-phenotype variability
Not all recurrent fevers are genetically explained
Need for specialized genetic counseling and interpretation by experienced clinicians.
Management
Medical Management:
Targeted therapy based on the specific genetic diagnosis
FMF: Colchicine is the first-line treatment, aiming to prevent flares and amyloidosis
TRAPS: Corticosteroids (short-term), Anakinra, Etanercept, Canakinumab
HIDS: Anakinra, Etanercept, Canakinumab, high-dose IVIG, statins
CAPS: Canakinumab, Rilonacept, Anakinra
PFAPA: Short courses of corticosteroids, tonsillectomy in refractory cases
DADA2: Anti-TNF agents like Infliximab, Adalimumab.
Supportive Care:
Symptomatic relief during flares: antipyretics, analgesics
Hydration
Nutritional support if indicated
Management of complications like amyloidosis or arthritis
Regular monitoring of inflammatory markers and organ involvement.
Monitoring And Follow Up:
Regular clinical assessment to evaluate disease activity and response to treatment
Monitoring of inflammatory markers (ESR, CRP)
Periodic assessment for complications (e.g., renal function for amyloidosis)
Genetic counseling for affected families
Long-term follow-up is essential to adjust treatment and monitor for evolving phenotypes or complications.
Prognosis
Factors Affecting Prognosis:
Specific syndrome diagnosed
Genetic mutation
Timeliness and efficacy of treatment
Adherence to medication
Development of complications (e.g., amyloidosis, chronic arthritis).
Outcomes:
With appropriate targeted therapy, most PFS can be managed effectively, leading to significant reduction in flares and prevention of long-term organ damage
FMF treated with colchicine has an excellent prognosis, preventing amyloidosis in most cases
CAPS treated with IL-1 inhibitors have a dramatically improved prognosis
However, some individuals may have refractory disease or develop complications despite treatment.
Follow Up:
Lifelong follow-up is generally recommended, especially for conditions like FMF where amyloidosis is a risk
Frequency of follow-up depends on disease activity, treatment response, and presence of complications
Regular clinical assessment, laboratory monitoring, and genetic counseling are key components of long-term care.
Key Points
Exam Focus:
Recognize the clinical hallmarks of common periodic fever syndromes (FMF, PFAPA, TRAPS, HIDS, CAPS)
Understand the role of genetic testing in confirming the diagnosis and guiding therapy
Differentiate PFS from infectious and autoimmune conditions
Know the first-line treatments for major PFS.
Clinical Pearls:
Always consider PFS in children with recurrent fevers of unknown origin, especially if associated with systemic inflammatory signs
A detailed family history is paramount
Negative autoantibodies (ANA, RF) are a strong clue against autoimmune disease
Genetic testing should be guided by clinical suspicion and phenotype.
Common Mistakes:
Attributing recurrent fevers solely to infections without thorough investigation
Delayed genetic testing leading to prolonged undiagnosed periods
Misinterpreting VUS without clinical correlation or family studies
Inadequate treatment leading to chronic organ damage.