Periodic fever syndrome

Overview

Periodic fever syndrome refers to a group of rare, autoinflammatory disorders characterized by recurrent episodes of fever and systemic inflammation that occur at regular or irregular intervals without evidence of infection. Unlike autoimmune diseases, these syndromes result from innate immune system dysfunction rather than autoantibody production. Periodic fever syndromes often begin in childhood and can vary widely in presentation, frequency, and severity. Common examples include Familial Mediterranean Fever (FMF), TNF Receptor-Associated Periodic Syndrome (TRAPS), Hyper-IgD Syndrome (HIDS), and Cryopyrin-Associated Periodic Syndromes (CAPS). These conditions are genetically driven and may involve additional symptoms such as rash, joint pain, abdominal discomfort, or mouth ulcers.

Causes

Periodic fever syndromes are primarily caused by inherited genetic mutations that affect the regulation of the innate immune system, particularly pathways involved in inflammation and cytokine release. These mutations lead to inappropriate or exaggerated inflammatory responses, resulting in recurrent fever and other systemic symptoms.

Some of the most recognized genetic causes include:

• MEFV gene mutations: Associated with Familial Mediterranean Fever (FMF)

• TNFRSF1A gene mutations: Associated with TRAPS

• MVK gene mutations: Associated with Hyper-IgD Syndrome (HIDS)

• NLRP3 gene mutations: Associated with Cryopyrin-Associated Periodic Syndromes (CAPS)

• Unknown genetic factors: In some cases, the underlying mutation may not be identified

Most periodic fever syndromes are inherited in an autosomal recessive or autosomal dominant pattern, depending on the specific condition. De novo (spontaneous) mutations can also occur.

Symptoms

While symptoms vary by syndrome, the hallmark feature is recurrent fever episodes that last several days and are not caused by infection. Common associated symptoms may include:

• Fever: Occurs periodically, typically lasting 1–5 days depending on the syndrome

• Abdominal pain: Common in FMF and other syndromes involving peritonitis-like symptoms

• Joint pain or arthritis: Especially in TRAPS and CAPS

• Skin rashes: Urticarial or maculopapular rashes in CAPS and other variants

• Mouth ulcers or sore throat: Seen in PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis) syndrome

• Swelling around the eyes: Especially characteristic of TRAPS

• Headache and fatigue: May accompany each febrile episode

Episodes may occur at predictable intervals (cyclic) or may be triggered by stress, infection, or other environmental factors. Some syndromes, like CAPS, may have near-continuous symptoms with periodic exacerbations.

Diagnosis

Diagnosing periodic fever syndromes involves a detailed clinical history, physical examination during and between episodes, and targeted laboratory and genetic testing. Because these conditions can mimic infections or autoimmune diseases, diagnosis is often delayed.

Key diagnostic steps include:

• Clinical evaluation: Assessing the pattern, frequency, and duration of fever episodes and associated symptoms

• Family history: Exploring any known familial occurrence of similar symptoms

• Laboratory tests:

  • Elevated inflammatory markers (ESR, CRP, serum amyloid A) during flares

  • Normal cultures and absence of infection or autoimmune markers

• Genetic testing: Confirms diagnosis by identifying pathogenic variants in relevant genes

• Exclusion of other conditions: Such as infections, malignancy, or systemic autoimmune diseases

For some syndromes like PFAPA, diagnosis is based primarily on clinical criteria, as no definitive genetic test is available.

Treatment

Treatment of periodic fever syndromes aims to reduce the frequency and severity of episodes, manage systemic inflammation, and prevent long-term complications like amyloidosis. Therapeutic options depend on the specific syndrome and patient response.

Pharmacologic therapies include:

• Colchicine: First-line treatment for FMF; reduces attack frequency and prevents amyloidosis

• NSAIDs: Used to control pain and inflammation during attacks

• Corticosteroids: Effective in PFAPA and some other syndromes for aborting episodes

• Biologic agents:

  • Anakinra (IL-1 receptor antagonist): Used in CAPS and some TRAPS patients

  • Canakinumab (IL-1β monoclonal antibody): Long-acting biologic approved for CAPS and FMF

  • Etanercept or Infliximab (anti-TNF agents): Sometimes used in TRAPS

• Immunosuppressants: Occasionally used in resistant cases, though less common

Regular monitoring is essential to adjust therapy, manage side effects, and track inflammatory markers.

Prognosis

The prognosis of periodic fever syndromes varies depending on the specific disorder, severity, and response to treatment. Many patients with well-controlled disease can lead normal lives with appropriate therapy. However, untreated or poorly controlled disease can lead to serious complications, including:

• AA (secondary) amyloidosis: A life-threatening complication from chronic inflammation, particularly in FMF and TRAPS

• Growth delay: In children with frequent episodes and systemic inflammation

• Organ dysfunction: In long-standing, poorly managed disease

With early diagnosis, individualized treatment plans, and multidisciplinary care, most individuals achieve good control of symptoms and avoid long-term damage. Genetic counseling is recommended for affected families to understand inheritance patterns and future reproductive risks.