HEREDITARY PERIODIC FEVER SYNDROMES

Hereditary Periodic Fever Syndromes — recurrent inflammation from genetic inflammasome dysregulation, where gene-specific IL-1 or TNF-targeted biologics transform the disease course once the correct diagnosis is made.

Whole genome sequencing evaluates MEFV, MVK, TNFRSF1A, NLRP3, NOD2, and all additional autoinflammatory genes — resolving the diagnostic uncertainty that leads to years of misdiagnosis as infection, autoimmune disease, or psychosomatic illness.

CLIA CertifiedCAP AccreditedISO 15189 Medical LabACMG ClassifiedHIPAA & GDPR100,000+ Genomes Sequenced

About this condition

Hereditary Periodic Fever Syndromes

Hereditary periodic fever syndromes are a group of monogenic autoinflammatory disorders characterized by recurrent episodes of systemic inflammation — fever, serositis, rash, arthralgia, and elevated acute-phase reactants — without autoantibodies or infectious etiology. The major conditions include familial Mediterranean fever (FMF, MEFV), TNF receptor-associated periodic syndrome (TRAPS, TNFRSF1A), hyper-IgD syndrome/mevalonate kinase deficiency (HIDS/MKD, MVK), and cryopyrin-associated periodic syndromes (CAPS — encompassing FCAS, Muckle-Wells syndrome, and NOMID/CINCA, all caused by NLRP3 variants).

These conditions share the clinical pattern of recurrent, self-limited episodes of systemic inflammation separated by symptom-free intervals — but each has distinct gene-specific features. FMF episodes last 1-3 days with serositis (peritonitis, pleuritis) and are prevented by colchicine. TRAPS episodes last 1-4 weeks with migratory rash and periorbital edema. HIDS episodes last 4-7 days with lymphadenopathy and aphthous ulcers. CAPS varies from cold-triggered urticaria (FCAS) to destructive arthropathy and sensorineural hearing loss (Muckle-Wells) to severe neonatal-onset multisystem inflammation (NOMID). The most feared long-term complication, shared across syndromes, is AA amyloidosis from chronically elevated serum amyloid A — which can cause nephrotic syndrome and renal failure.

Targeted biologic therapy has transformed outcomes. Colchicine remains first-line for FMF. IL-1 inhibitors (anakinra, canakinumab) are the treatment of choice for CAPS and colchicine-resistant FMF. TRAPS responds to IL-1 blockade and, in some cases, etanercept (TNF inhibition). HIDS/MKD responds to IL-1 inhibitors and appears to respond to statins (simvastatin) through an unknown mechanism. The specific gene diagnosis determines the targeted biologic, enables monitoring for gene-specific complications, and prevents the AA amyloidosis that develops from undertreated chronic inflammation.

AA amyloidosis — the most feared complication of all periodic fever syndromes — is preventable with adequate anti-inflammatory therapy. Molecular diagnosis enables early treatment that prevents this irreversible organ damage.

Gene locus
MEFV (16p13.3), TNFRSF1A (12p13.31), MVK (12q24.11), NLRP3 (1q44), NOD2 (16q12.1)

Recurrent fevers of unknown origin have a long differential diagnosis. Molecular testing for the autoinflammatory gene panel resolves diagnostic uncertainty and directly identifies the targeted biologic therapy.

Average diagnostic delay for periodic fever syndromes is 5-10 years — WGS ends the odyssey of misdiagnosis

Patients with periodic fever syndromes typically undergo years of repeated evaluations for infection, malignancy, and autoimmune disease before the autoinflammatory diagnosis is considered. During this diagnostic delay, chronic subclinical inflammation accumulates serum amyloid A, progressing toward AA amyloidosis. WGS evaluates all autoinflammatory genes simultaneously from a single sample, providing the specific gene diagnosis that identifies the targeted biologic and prevents long-term amyloid organ damage.

The specific gene determines which biologic to use — colchicine, IL-1 inhibitors, or TNF blockade are not interchangeable

FMF responds to colchicine in approximately 95% of patients — making it first-line therapy. CAPS requires IL-1 inhibition (anakinra or canakinumab) because colchicine is ineffective. TRAPS may respond to IL-1 blockade or etanercept, but infliximab (anti-TNF) worsens TRAPS. These gene-specific treatment responses mean that empirical biologic therapy without molecular diagnosis risks using the wrong drug. WGS identifies the causative gene, enabling immediate initiation of the correct targeted therapy.

Others in Autoimmune & Inflammatory

Browse all conditions →

One test. A lifetime of answers.

One kit, sent to your home. Your entire genome sequenced at the clinical standard used for diagnostic decisions. 200+ physician-ready reports delivered to your Genome Manager in 6–8 weeks — permanent and updated as science advances.

From $449

Ships within 48 hours · Results in 6–8 weeks

Get my Genome Test