Febrile SyndromesDz

Last updated: November 5, 2014

Synonyms: Periodic fever, hereditary periodic fever.

ICD-9 Code: Periodic Fever, 277.3; cyclic neutropenia, 288.0.

Definition: Several distinct diseases all associated with joint pain and fever, among other symptoms, have been shown to relate to defects in single genes. These include FMF; TNF receptor–associated periodic syndrome (TRAPS); hyperimmunoglobulinemia D (Hyper IgD) with periodic fever syndrome; familial cold autoinflammatory syndrome; Muckle-Wells syndrome; neonatal-onset multisystem inflammatory disease (NOMID); periodic fever with aphthous stomatitis, pharyngitis, and adenitis (or Marshall syndrome); and Blau syndrome. These disorders are characterized by recurrent febrile episodes with systemic inflammation commonly affecting the joints.

Etiology: FMF (autosomal recessive) relates to defects in a 10-exon gene on the short arm of chromosome 16, MEFV, that encodes pyrin, a 781-amino-acid protein that associates with the cytoskeleton of neutrophils and activated monocytes. TRAPS (autosomal dominant), which had been known as familial Hibernian fever before the discovery of the genetic defect, related to defects in the gene encoding p55 TNF receptor type I (CD120a). Hyperimmunoglobulinemia D with periodic fever syndrome (autosomal recessive) relates to defects in the gene encoding mevalonate kinase, an enzyme central to cholesterol synthesis. Blau syndrome (autosomal dominant) relates to mutations in NOD2, a gene also associated with susceptibility to Crohn’s disease. Familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and NOMID (autosomal dominant) all relate to mutations in a single gene, CIAS1, that encodes cryopyrin, a protein similar to pyrin that is also expressed primarily in neutrophils and monocytes.

Incidence: These disorders are rare but are more common with some ages and ethnicities.

Cardinal Findings: FMF is a prototype for these disorders and is characterized by several-day episodes of fever, monarticular arthritis, rash, and abdominal pain. Many of these disorders also manifest rash, mucosal inflammation, adenopathy, and serositis, and thus the diagnosis may rest with age, demographic features, or genetic testing. These disorders are characterized below.
—TNF receptor–associated periodic syndrome (Hibernian fever): Characterized by fever, arthralgia, myalgia, migratory rash, and abdominal pain lasting a week or longer (as long as 6 weeks). Primarily described in those of Irish, Scottish, and Australian ancestry.
—Hyperimmunoglobulinemia D with periodic fever syndrome: The usual onset is before 1 year of age. Symptoms last 3 to 7 days and may include recurrent fever, abdominal pains, arthralgia or arthritis, rash, diarrhea, headaches, and elevated ESR/CRP. Hyper IgD syndrome primarily affects those of Dutch, French, or Western European ancestry.
—Familial cold autoinflammatory syndrome: Characterized by the infantile onset of 1- to 3-day episodes of urticaria with fever, arthralgia, or conjunctivitis and may be induced by cold.
—Muckle-Wells syndrome: This syndrome has its onset by adolescence and is associated with fever arthralgia, urticaria, conjunctivitis, sensorineural hearing loss, hypergammaglobulinemia, and an intense acute-phase response. Amyloidosis may complicate Muckle-Wells syndrome.
—Neonatal-onset multisystem inflammatory disease: It is also known as chronic infantile cutaneous and articular disorder and has symptoms similar to those of Muckle-Wells syndrome on a more chronic basis.
—Periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA or Marshall syndrome): Usually has its onset before age 5 years and remits spontaneously within 4 to 8 years. Symptoms include periodic fevers >40°C at fixed intervals every 2 to 8 weeks and usually resolve within 4 days. Aphthous ulcers, pharyngitis, and adenitis are seen in 70% to 90%. Periodic fever with aphthous stomatitis, pharyngitis, and adenitis is not familial and without diagnostic tests. Short doses of corticosteroids are recommended.
—Cyclic neutropenia: This is a disorder of recurrent fever (every 15–35 days) lasting as long as 14 days and coincides with episodic neutropenia (polymorphonuclear leukocytes >500/mm3). Patients complain of malaise, pharyngitis, mouth ulcers, and lymphadenopathy. This is an autosomal dominant disorder wherein a stem cell regulatory defect results from a mutation of neutrophil elastase gene and apoptosis of polymorphonucleocyte precursors. Treatment options include steroids, cyclosporine, and granulocyte colony-stimulating factor.
—Relapsing fever is not a genetic defect but rather to a tick-borne infection with the spirochete Borrelia recurrentis. It manifests as headache, fever, myalgia, arthralgia, photophobia, and abdominal pains. Episodes occur every 10 to 14 days. Diagnosis is by serology. It may give false-positive results for tests for Lyme disease.

Keys to Diagnosis: The diagnosis of these conditions is still largely made on clinical grounds. FMF testing for mutations in the MEFV gene are available. TRAPS may be screen for by MEFV gene testing (to exclude FMF) and serum p55 TNF receptor levels (low). Genomic DNA sequencing for mutations of p55 TNF-R1 testing are not routinely available but may be necessary to confirm the diagnosis.

Differential Diagnosis: Other causes of fever of unknown origin should be considered including lymphoma, thromboembolic disease, endocarditis, polymyalgia rheumatica, temporal arteritis, Still’s disease, occult abscess, drug fever, and factitious fever (e.g., thermometer manipulation, self-injection of pyrogenic material). Also, there are numerous febrile arthritis-dermatitis syndromes, including lupus, DM, psoriatic arthritis, sarcoidosis, Behçet’s syndrome, erythema nodosum, leukocytoclastic vasculitis, PAN, cryoglobulinemia, hepatitis B or C, inflammatory bowel disease, intestinal bypass arthritis, Lyme disease, rheumatic fever, reactive arthritis, gonococcal or meningococcal arthritis, Parvovirus B19, rubella, SAPHO syndrome, and Sweet’s syndrome.

Therapy: Colchicine has been the mainstay of treatment for FMF for many years and hence has been tried in Muckle-Wells and other syndromes as well. NSAIDs are commonly tried, and corticosteroids may be used intermittently for severe cases. Recently, there has been success using cytokine directed biologic agents, particularly soluble forms of the TNF receptor (etanercept) for TNF receptor–associated periodic syndrome or neonatal-onset multisystem inflammatory disease and IL-1 inhibitor (anakinra) for familial cold autoinflammatory syndrome and Muckle-Wells syndrome.

Hoffman H, Patel D. Genomic-based therapy: targeting interleukin-1 for autoinflammatory diseases. Arthritis Rheum 2004;50:345–349.PMID:14872474
Kastner DL. The hereditary periodic fevers. In: Hochberg MC, Silman AJ, Smolen JS, et al., eds. Rheumatology, 3rd ed. Edinburgh: Mosby, 2003:1717–1734.

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