Familial fever disorders represent a group of rare genetic conditions characterized by recurrent episodes of fever and inflammation, often without an identifiable infectious cause.
These syndromes are inherited and involve dysregulation of the immune system's inflammatory response, leading to periodic fever attacks that can significantly impact quality of life.
What Are Familial Fever Disorders?
Familial fever disorders, also known as hereditary periodic fever syndromes or autoinflammatory diseases, involve genetic mutations that cause abnormal activation of the innate immune system. Unlike common fevers triggered by infection, these disorders produce fever episodes due to inappropriate inflammation caused by genetic defects in molecules regulating immune signaling pathways.
Common Types and Genetic Causes
Familial Mediterranean Fever (FMF)
The most common hereditary fever disorder predominantly affecting people of Mediterranean descent. FMF is caused by mutations in the MEFV gene, which encodes the protein pyrin—an important regulator of inflammation. Patients experience recurrent episodes of fever, severe abdominal pain, chest pain, and sometimes joint inflammation.
Mevalonate Kinase Deficiency (MKD) / Hyperimmunoglobulinemia D Syndrome (HIDS)
Caused by mutations in the MVK gene encoding mevalonate kinase, an enzyme involved in cholesterol and isoprenoid biosynthesis. This deficiency leads to reduced enzyme activity and recurrent fever attacks associated with rash, abdominal pain, and lymphadenopathy. This condition shows autosomal recessive inheritance.
Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS)
Caused by mutations in the TNFRSF1A gene affecting the tumor necrosis factor receptor important for controlling inflammation. TRAPS presents with prolonged fever episodes, muscle pain, rash, and abdominal discomfort.
Cryopyrin-Associated Periodic Syndromes (CAPS)
These include familial cold autoinflammatory syndrome and Muckle-Wells syndrome, caused by mutations in the NLRP3 gene encoding cryopyrin, a component of the inflammasome complex regulating interleukin-1 beta production.
Pathophysiology: Genetic Disruption of Immune Regulation
The hallmark of familial fever disorders is the dysregulation of pro-inflammatory cytokines, especially interleukin-1 (IL-1), leading to self-sustained systemic inflammation. Mutations result in defective control over innate immunity elements such as pyrin or inflammasomes, which normally act as checks to prevent excessive immune activation. The resulting overproduction of cytokines causes the inflammatory fever episodes and associated symptoms.
Diagnosis and Challenges
Diagnosis is often delayed due to the rarity of these conditions and symptom overlap with infectious or autoimmune diseases. Identification relies on clinical history of periodic fever episodes and targeted genetic testing to confirm mutations. Early diagnosis is crucial to prevent complications such as amyloidosis, especially in FMF patients, where untreated inflammation can cause damage.
Dr. Hal M. Hoffman, a leading authority on autoinflammatory diseases, notes, "Familial fever syndromes highlight the importance of genetic regulators in controlling innate immunity. Precision diagnosis allows targeted therapies that can drastically improve patient outcomes".
Similarly, Dr. Raphaela Goldbach‑Mansky, a leading clinician‑scientist in autoinflammatory diseases, states, "Recognizing familial fever disorders in adults and children requires awareness of their genetic basis and clinical pattern. Timely intervention can prevent severe morbidity associated with chronic inflammation."
Treatment and Management
Management typically involves suppressing the inappropriate inflammatory response. For FMF, colchicine remains the mainstay to reduce the frequency and severity of attacks and prevent amyloidosis. Biologic therapies targeting IL-1 (like anakinra) or TNF inhibitors are effective in other syndromes like CAPS or TRAPS. Regular monitoring and supportive care are essential to address symptoms and prevent long-term complications.
Familial fever disorders are genetically inherited syndromes characterized by recurrent, unexplained fever episodes resulting from defects in immune system regulation. Clinical recognition combined with genetic testing facilitates proper diagnosis and treatment, preventing serious complications linked to chronic inflammation.
