What is periodic fever syndrome in children?

Periodic Fever Syndrome in Children

Periodic fever syndromes in children are a group of autoinflammatory diseases characterized by recurrent, unexplained episodes of fever (typically lasting days) that occur at regular or irregular intervals, accompanied by systemic inflammation affecting the peritoneum, pleura, joints, and skin, with symptom-free intervals between attacks. 1, 2

Definition and Core Features

Periodic fever syndrome is defined by three or more febrile episodes occurring within six months, with each episode separated by at least seven days 3. These are distinct from common childhood infections because:

• Episodes recur in a predictable or semi-predictable pattern
• Fever resolves spontaneously without treatment
• Patients are completely asymptomatic between attacks
• No infectious cause can be identified despite thorough evaluation
• Inflammatory markers (CRP, ESR) are elevated during attacks but normalize between episodes

Pathophysiology

The underlying mechanism involves dysregulation of the innate immune system - specifically involving neutrophils, monocytes, and macrophages 3. The immune response is either:

• Overly sensitive to minor stimuli, or
• Fails to turn off appropriately after activation 4

Inflammasomes (intracellular proteins) activate pro-inflammatory cytokines, particularly IL-1β and IL-18, driving the recurrent inflammatory episodes 1, 4. Other cytokines involved include TNF-α, interferons, IL-2, IL-12, and IL-23 3.

Major Types of Periodic Fever Syndromes

Monogenic (Hereditary) Forms:

1. Familial Mediterranean Fever (FMF)

• Most common hereditary periodic fever
• Autosomal recessive (MEFV gene)
• Prevalent in Mediterranean and Middle Eastern populations
• Episodes last 1-3 days
• Features: peritonitis, pleuritis, acute synovitis (knee, ankle, hip), erysipelas-like rash 5, 6

2. TNF Receptor-Associated Periodic Syndrome (TRAPS)

• Autosomal dominant (TNFRSF1A gene)
• Longer fever attacks (average 21 days)
• Associated with ocular involvement and centrifugal erythematous patches
• Often starts in childhood with strong family history 5, 6

3. Mevalonate Kinase Deficiency (MKD)/Hyper-IgD Syndrome

• Autosomal recessive (MVK gene)
• Characterized by elevated IgD levels
• Variable fever duration 7, 6

4. Cryopyrin-Associated Periodic Syndromes (CAPS)

• Autosomal dominant (NLRP3 gene mutations)
• Spectrum from mild (FCAS) to severe (NOMID/CINCA)
• Can present in neonatal period 7, 8

Non-Hereditary Form:

5. PFAPA Syndrome (Periodic Fever, Aphthous stomatitis, Pharyngitis, Adenitis)

• Most common in children under age 5
• Sporadic (not inherited)
• Extremely regular fever cycles with oral ulcers, pharyngitis, cervical adenopathy
• Self-limited, typically resolves by age 7-8 years
• Diagnosis of exclusion 9, 10

Clinical Presentation

Key distinguishing features to identify:

• Fever pattern: Duration, frequency, regularity of episodes
• Age of onset: Most hereditary forms start in early childhood or infancy
• Family history: Critical for monogenic forms
• Ethnic background: FMF more common in Mediterranean/Middle Eastern populations
• Associated symptoms during attacks:
  • Abdominal pain (peritonitis)
  • Chest pain (pleuritis, pericarditis)
  • Joint pain/swelling
  • Skin rashes (type and distribution matter)
  • Oral ulcers
  • Lymphadenopathy
  • Ocular symptoms

Diagnostic Approach

Critical pitfall: These syndromes are easily overlooked when investigating recurrent fevers, as they are rare outside specific populations 2.

Evaluation must include:

1. Detailed fever diary: Document exact duration, frequency, and associated symptoms
2. Laboratory testing during attacks: Elevated acute phase reactants (CRP, ESR, ferritin), leukocytosis
3. Laboratory testing between attacks: Should normalize completely
4. Genetic testing: When clinical suspicion exists for specific hereditary syndromes 6
5. Rule out infectious causes: If symptoms persist beyond 3 months, viral syndromes are excluded 5
6. Rule out malignancy: Leukemia, lymphoma can mimic these syndromes 5

Complications

AA amyloidosis is the most feared complication - can occur in untreated or poorly controlled disease, leading to:

• Renal failure
• Cardiac involvement
• Significant morbidity and mortality 2, 11

Cardiovascular risks include:

• Pericarditis (most common cardiac manifestation)
• Early atherosclerosis from chronic inflammation
• Cardiac amyloidosis 11

Treatment Principles

Treatment varies by syndrome type 3:

• Colchicine: First-line for FMF, showing promise in other syndromes
• Corticosteroids: Effective for acute PFAPA flares
• IL-1 blockade: Life-changing for CAPS, TRAPS, and severe cases
• Anti-TNF therapy: Used in selected cases
• Cimetidine: Shown promise in trials for certain syndromes 1

Before starting biologic therapy, screening must exclude tuberculosis, HIV, hepatitis B and C 3.

Prognosis

• PFAPA: Excellent - self-resolves by age 7-8 years 10
• Hereditary forms: Variable, but effective IL-1 blockade has dramatically improved outcomes 7
• Without treatment: Risk of amyloidosis and chronic complications increases significantly 2

Ongoing monitoring required for disease activity, organ involvement, treatment adverse effects, and inflammatory biomarkers 3.