You are in: eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases Hereditary Periodic Fever SyndromesArticle Last Updated: Oct 5, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 11
  Author: Marwan Shinawi, MD, Assistant Professor, Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital Marwan Shinawi is a member of the following medical societies: American College of Medical Genetics, American Medical Association, and American Society of Human Genetics Coauthor(s): Fernando Scaglia, MD, Assistant Professor of Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital Editors: Michael Fasullo, PhD, Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Leonard G Feld, MD, PhD, MMM, Chairman of Pediatrics, Carolinas Medical Center; Chief Medical Officer, Levine Children's Hospital, Carolinas Healthcare System; Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System; Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center Author and Editor Disclosure Synonyms and related keywords: hereditary autoinflammatory disorders, HPFS, familial Mediterranean fever, FMF, recurrent hereditary polyserositis, hyperimmunoglobulinemia D with periodic fever syndrome, HIDS, Tumor necrosis factor-receptor–associated periodic syndrome, TNF-receptor–associated periodic syndrome, TRAPS, Muckle-Wells syndrome, MWS, familial cold autoinflammatory syndrome, FCAS, chronic infantile neurologic cutaneous articular syndrome, CINCA, neonatal-onset multisystem inflammatory disease, NOMID, cryopyrin, NALP3, PYPAF1, PFAPA, MEFV, MVK, TNFRSF1, NALP3/CIAS1/PYPAF1, familial cold urticaria, FCU, acquired cold urticaria, ACU, mevalonic aciduria, MVA INTRODUCTIONSection 2 of 11
  Background Hereditary periodic fever syndromes (HPFSs) are rare and distinct heritable disorders characterized by short and recurrent attacks of fever and severe localized inflammation that occur periodically or irregularly and that are not explained by usual childhood infections. These attacks undergo spontaneous remission without antibiotic, anti-inflammatory, or immunosuppressive treatment. Between attacks, patients feel well and regain their normal daily functions until the next episode occurs. The episodes are usually associated with elevated serum levels of acute-phase reactants (eg, fibrinogen, serum amyloid A [SAA]), an elevated erythrocyte sedimentation rate (ESR), and leukocytosis. Six periodic fever diseases have been well characterized over the last few years, and considerable recent progress has been made in identifying causative genes and developing treatment options (McDermott, 2001 and 2002; Hull, 2003; Simon, Neurology, 2004). The 6 disorders listed below are addressed in separate subsections of this overview:
The differential diagnosis for periodic fever spectrum of diseases is wide and includes infectious, malignant, and autoimmune disorders, as well as factitious and iatrogenic fever. If these attacks persist for longer than 1 year and, especially if they are associated with a family history of periodic fever, the possibility of HPFS should be raised. Table 1 summarizes the gene symbols, chromosomal loci, protein products, and modes of inheritance of these diseases. Table 1. Summary of the Genes and Proteins of the HPFSs
General pathogenesis Cryopyrin, also called NALP3 or PYPAF1, is the product of the NALP3/CIAS1/PYPAF1 gene that is mutated in MWS, FCAS, and CINCA or NOMID. It contains an N-terminal pyrin domain (PD), a central nucleotide-binding oligomerization domain (NOD), and C-terminal leucine-rich repeats (LRRs). Cryopyrin is a member of the Apaf-1/Nod1-like protein family that regulates apoptosis and inflammation. The PD mediates protein interactions and is structurally related to the 6-helix bundle death domain (DD)-fold family that includes the caspase recruitment domain (CARD), the death effector domain (DED), and the DD. Cryopyrin and apoptosis-associated speck-like protein (ASC) form a PD-CARD–containing adaptor that was originally found in the subcytosolic fraction and referred to as the speck seen in cells undergoing apoptosis. They interact by means of the oligomerization of ASC to induce both apoptosis and activate nuclear factor (NF)-kappaB (McDermott, 2002; Dowds, 2003). NF-kappaB is a proinflammatory transcription factor. The interaction of NALP3 with ASC and caspase-1 causes a high pro-interleukin (IL)-1beta processing activity. On the other hand, pyrin-marenostrin, the product of the gene for FMF, interacts with ASC and disrupts the cryopyrin-ASC interaction and specifically inhibits apoptosis and NF-kappaB activation (Agostini, 2004). Mutations in pyrin-marenostrin can lead to autoinflammation by reducing the inhibitory pathway. Furthermore, pyrin interacts with proline-serine-threonine phosphatase-interacting protein (PSTPIP1, or CD2-binding protein 1 [CD2BP1]), a tyrosine-phosphorylated protein involved in cytoskeletal organization and thereby in immunologic cellular interactions (Shoham, 2003) (see Image 1). Why mutations in the MK gene, MVK, which is known to disturb cholesterol metabolism, can cause a disease featured by periodic inflammatory attacks (eg, HIDS) is unclear. Most mutations in TNFRSF1A mediate their effect by decreasing the shedding of TNFRSF1A. This effect decreases the amount of soluble receptor available to bind soluble TNF and to subsequently initiate and maintain the inflammatory responses. FAMILIAL MEDITERRANEAN FEVERSection 3 of 11
BackgroundFMF (MIM 249100), also known as recurrent hereditary polyserositis, is an autosomal recessive disease that affects people of Mediterranean ancestry, such as those of north-African (Sephardic), Iraqi Jewish, Arabic, Armenian, Turkish, or Italian descent. FMF is characterized by short febrile attacks caused by neutrophil-induced serosal inflammation and a gradual accumulation of amyloid in kidneys. Pathogenesis The biologic function of pyrin-marenostrin (FMF protein) is the subject of intensive research, and a consensus regarding its function is gradually being achieved (see Image 1). Pyrin-marenostrin contains at least 4 conserved domains that are found in a range of proteins, and it is thought to function in apoptotic and inflammatory signaling pathways by means of homotypic protein-protein interactions. Evidence that pyrin-marenostrin has an anti-inflammatory role comes from targeted disruption of pyrin in the mouse, which shows an increase in IL-1 processing and defective lipopolysaccharide (LPS) and IL-4–induced apoptosis in peritoneal monocytes (Chae, 2003). Frequency FMF is the most common disease among the HPFS, and it is common among Mediterranean people. Most cases occur in the following ethnic groups: Jews, Arabs, Armenian, and Turks. Carrier frequency of the defective gene is as high as 1:4 in these ethnic groups. Mortality and morbidity The most serious complication in FMF is renal amyloidosis. In the absence of early continuous treatment with colchicine, renal amyloidosis may develop over several years and progress to renal failure in many patients. In countries where dialysis and kidney transplantation are widely available, the outcome of patients who develop end stage renal disease due to FMF amyloidosis can be similar to that in the general transplant population (Sherif, 2003). Patients with FMF without amyloidosis are expected to have a normal life span. Race FMF affects people of Mediterranean extraction, such as North-African Jews, Arabs, Armenians, Turks, and Italians. However, many cases have been documented in the United States in other ethnic groups. In a survey of 100 American patients with FMF who were referred to the National Institutes of Health (NIH), 19% of those with mutations were of Italian ancestry, 21% were Ashkenazi Jews, 27% were Armenian, and 17% were Arabs; the rest were of non-Ashkenazi Jewish, Cuban, Turkish, and northern European heritage (Samuels, 1998). Sex The male-to-female ratio of cases has consistently been reported to be about 1.5-2.0:1.0, raising the possibility that the mutation has reduced penetrance in women. Many women report that attacks occur most commonly with menses; this pattern suggests that female sex hormones might influence the disease (Samuels, 1998). In addition, many women find that their pattern of attacks disappears during pregnancy, only to return after delivery. Furthermore, the risk of renal amyloidosis is higher in men than in women (Cazeneuve, 2000; Gershoni-Baruch, Arthritis Rheum, 2003). Age Approximately 90% of patients are younger than 20 years, and 60% of patients are younger than 10 years. Late-onset disease is usually more clinically benign than early-onset disease. Clinical detailsHistory The main complication in FMF is the development of renal amyloidosis. In the absence of early, continuous treatment with colchicine, may develop over several years and progress to nephrotic syndrome and renal failure in many patients. This complication results from the deposition of amyloid A protein, a cleavage product of SAA, and it occurs in more than 90% of patients of north-African Jewish descent but less often than this in other ethnic groups. Although this condition is mainly related to the M694V homozygous genotype, it is also reported in association with other genotypes that confer a relatively mild form of the disease. Furthermore, renal amyloidosis can occur in asymptomatic individuals who do not have attacks of serositis (phenotype II) (Livneh, 1996). Patients with FMF have recurrent acute febrile painful attacks lasting 12 hours to 4 days. The pain usually involves 1 or 2 of the following sites at a time: abdomen, chest, joints, muscles, scrotum, and skin. The most common manifestation is abdominal pain. The underlying clinical picture is that of acute peritonitis. The acute abdominal attack of FMF is sometimes confused with the acute surgical abdomen caused by appendicitis. The utility of elective appendectomy to prevent misdiagnosis and the possible devastating consequences in emergency surgery is still undetermined (Reissman, 1994). Rare patients have a chronic abdominal disease caused by peritoneal adhesions due to recurrent inflammation of the peritoneal membranes. Brik and Litmanovitz et al (2001) reported a high frequency of MEFV mutations among Arab and Jewish children with functional abdominal pain that differs from the classical definition of FMF. The febrile joint attacks, which occur in 70% of patients of FMF manifest as recurrent episodes of nondestructive acute monoarthritis of short duration and most frequently involve the large joints of lower extremities (Brik and Shinawi, 2001). In about 1% of patients, arthritis is the sole disease manifestation. Myalgia is a frequent finding in FMF patients. The febrile myalgia syndrome is a severe, disabling, and painful attack that lasts weeks and responds only to treatment with corticosteroids and not colchicine, the basic treatment in FMF. The febrile chest attacks occur in about 40% of patients and manifest as pleuritis. Patients have unilateral chest pain that increases on inspiration. The pain is associated with shortness of breath, and rapid, shallow breathing. Patients who are homozygotes for the M694V mutation have considerably more episodes of pleuritis, cough, and rapid and shallow breathing than patients, who are either homozygotes for the V726A mutation or any other combination of mutations (Brik, 2003). The inflammation of the tunica vaginalis testis causes a picture of acute scrotum in about 5% of the patients. It usually results in self-limited, unilateral, red painful swelling of the scrotum. The skin also is involved in FMF, and the typical lesion is erysipelas-like erythema on the lower extremities. Furthermore, vasculitis emerges as an important yet not a widely recognized feature of FMF that may precede the classic manifestations of the disease. For examples, Henoch-Schönlein purpura (HSP) and polyarteritis nodosa (PAN) occur more commonly in patients with FMF than in the general population (Ozdogan, 1997; Gershoni-Baruch, J Pediatr, 2003). Other rare but well-documented manifestations include pericarditis, meningitis, headache during attacks, and infertility in women (due to defective ovulation and peritoneal pelvic adhesions) (Livneh, 1996). Until 1997, no specific laboratory test for FMF was available, and the diagnosis was based on clinical findings, including a favorable response to colchicine. Table 2 provides 1 set of diagnostic criteria used to diagnose FMF. The discovery of the gene for FMF has since changed the approach, and most cases are currently confirmed with molecular testing. Table 2. Diagnostic Criteria for FMF (Liyneh, 1997)
Note: A definitive diagnosis is based on 2 major or 1 major and 2 minor criteria. A probable diagnosis is based on 1 major and 1 minor criteria. Physical examination Patients are healthy between attacks. During attacks, they have fever and tachypnea. Abdominal examination reveals boardlike rigidity, rebound tenderness, reduced peristalsis. About one third of patients have splenomegaly. Lung examination shows unilateral diminished breath sounds and pleural friction rubs. Musculoskeletal examination reveals joint effusion, most commonly monoarthritis of knee, hip, and/or ankle, as well as muscle tenderness. The genitalia are notable for unilateral scrotal tenderness and swelling. Inspection of the skin reveals erysipelas-like erythema. The skin is tender, erythematous, and warm. Swollen areas 10-15 cm in diameter usually occur below the knee on the anterior part of the leg or on the dorsum of the foot (unilaterally or symmetrically), and purpuric lesions may occur in association with HSP. CausesInheritance and genes The mode of inheritance is autosomal recessive with reduced penetrance for certain mutations. The gene responsible for FMF (designated MEFV for Mediterranean fever) was localized by means of positional cloning to the short arm of chromosome 16 and cloned by 2 consortia: the International FMF Consortium (1997) and the French FMF consortium (1997) in 1997. It consists of 10 exons (cDNA of 3.5 kb) covering about 15 kb of genomic DNA. It encodes a protein of 781 residues that was named pyrin by the International Consortium and marenostrin by the French consortium. The protein is expressed mainly in granulocytes, which play an essential role in the normal and pathologic inflammatory response. Mutations in the MEFV gene have been identified in most patients. These include 4 conservative missense mutations (M680I, M694V, M694I, and V726A) clustered in exon 10, which, together with mutation E148Q in exon 2, account for the vast majority of FMF chromosomes identified in patients with the disease (Shinawi, 2000; Gershoni-Baruch, 2001; Touitou, Eur J Hum Genet, 2001). An updated list of mutations for FMF can be found online at the Infevers Web site, or the Repertory of Familial Mediterranean Fever (FMF) and Hereditary Autoinflammatory Disorders Mutations. Different affected populations harbor different MEFV mutations. For example, Gershoni et al (2001) analyzed the frequencies and distribution of these mutations in patients with FMF and in healthy individuals. In Ashkenazi Jews, only the V726A and E148Q mutant alleles were identified, whereas in Moroccan Jews, only the M694V and E148Q mutations were detected. Individuals of Muslim Arab origin have all of the common MEFV mutations, namely, M694V, V726A, M680I, M694I, and E148Q (Shinawi, 2000; Gershoni-Baruch, 2001). Gene product The MEFV product, pyrin-marenostrin, is expressed predominantly in granulocytes (the cell most frequently found in FMF inflammatory exudates) and in cytokine-activated monocytes (Centola, 2000). This observation suggests that pyrin plays an intrinsic role in regulating leukocyte function. Analysis of the newly discovered pyrin sequence failed to substantiate the hypothesis that the FMF protein might be a serine protease inhibitor of the fifth component of complement. Although the C-terminal half of pyrin is homologous to several transcription factors, transfected full-length pyrin colocalizes with the cytoskeleton (Mansfield, 2001). A potentially important clue to the function of pyrin was the elucidation that the 92 amino acids at the N-terminal compose the PD that has been found in several regulators of apoptosis and inflammation. LPS and proinflammatory cytokines induce ASC, which binds procaspase-1 by means of cognate CARD interactions and which leads to caspase-1 oligomerization and autocatalysis (Dowds, 2003). LPS, as well as antiinflammatory cytokines (eg, IL-4), induces pyrin in macrophages and monocytes, the predominant lineage in IL-1beta secretion. Pyrin binds and sequesters ASC, preventing caspase-1 activation (Chae, 2003; Dowds, 2003). Genotype-phenotype correlation Table 3 shows how the severity of FMF symptoms can be evaluated according to severity-scale scores. Table 3. FMF Severity Score (Pras, 1998)
The phenotypic variability of the disease is at least partly due to allelic heterogeneity. Mutations of M694V and the complex V726A-E148Q allele are associated with a severe phenotype (an early age of onset and a high frequency of arthritis and rash) and amyloidosis (Dewalle, 1998; Gershoni-Baruch, Eur J Hum Genet, 2002). Mutation M680I induces a moderate form of disease phenotype (Shinawi, 2000; Gershoni-Baruch, 2002). Mutations E148Q, K695R, and V726A have reduced penetrance, and many individuals who are either homozygous or compound heterozygous for these mutations remain asymptomatic (Aksentijevich, 1999; Gershoni-Baruch, 2001). This reduced penetrance might partially explain the difference between the estimated allelic frequency based on disease prevalence and the tested allelic frequency in certain populations, such as Arabs and Ashkenazi Jews. This allelic heterogeneity does not seem to account for all the clinical variability observed in FMF, and a role for additional genetic and/or environmental modifiers has been suggested. Polymorphisms at the SAA1 gene (alpha/alpha genotype is associated with severe phenotype and renal amyloidosis), and the major histocompatibility complex I chain-related gene A (MICA) plays a role as a modifier in FMF (Cazeneuve, 2000; Touitou, 2001; Gershoni-Baruch, Arthritis Rheum, 2003). Furthermore, the occurrence of arthritis attacks and male sex were significantly and independently associated with renal amyloidosis (Cazeneuve, 2000; Gershoni-Baruch, J Rheumatol, 2003). Because of the reduced penetrance of E148Q, patients with E148Q are frequently unidentified and therefore not treated with colchicine. The present authors know of no documented cases of amyloidosis in homozygotes for E148Q. When this mutation is part of the complex V726I-E148Q allele, the incidence of amyloidosis increases (Gershoni-Baruch, 2002). Animal models Evidence that pyrin-marenostrin has an antiinflammatory role comes from targeted disruption of pyrin in the mouse, which increases IL-1 processing and defective LPS and IL-4-induced apoptosis in peritoneal monocytes (Chae, 2003). This heightened sensitivity to endotoxin suggests that transient bacteremias might provoke exaggerated IL-1 alpha production and thereby a systemic inflammatory response to what is ordinarily an innocuous event. Such a defect in homeostasis might also extend to the stress hormone-induced IL-1 production and provide a mechanism for the often-reported association of physical or psychological stress with febrile episodes in FMF. Environmental causes Emotional stress, extreme physical exercise, and menses can trigger the inflammatory attacks of FMF. Differential diagnosisThe differential diagnosis of FMF includes the following:
Periodic episodes of high fever accompanied by aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) are characterized by an abrupt onset of fever, malaise, aphthous stomatitis, tonsillitis, pharyngitis, and cervical adenopathy. It occurs at intervals of 4-8 weeks, lasts for 4-6 days, and usually starts before the age of 5 years. Throat cultures are negative, but levels of acute-phase reactants are elevated. The attacks resolve spontaneously, but a single dose of prednisone 2 mg/kg given orally (PO) at the beginning of the attack is abortive (Padeh, 1999). The condition completely resolves in most patients. PFAPA is sporadic, and no ethnic predilection has been found. WorkupLaboratory studies During attacks, laboratory studies show elevation in the total white blood cells (leukocytosis) with increased proportion of circulating immature neutrophil cells in the peripheral blood, an elevated ESR, and increased levels of acute-phase reactants (C-reactive protein [CRP], SAA, fibrinogen, haptoglobin, C3, and C4). Urinalysis demonstrates transient albuminuria and microscopic hematuria during the episodes. If amyloidosis develops, proteinuria is the first sign that can progress to the proteinuria in the nephritic range. Anemia of chronic disease may be present. The synovial fluid is cloudy, filled with polymorphonuclear (PMN) cells, and sterile. Histology Amyloidosis results in a characteristic apple-green appearance when samples are stained with Congo red and viewed under polarized light. Erysipelas-like skin lesions manifests as edema and hyperemia of the dermis with PMN infiltration. Imaging studies Upright abdominal radiographs may show air-fluid levels (peritonitis). Chest radiographs may show a small effusion in the costophrenic angle or atelectasis (pleuritis) and/or enlargement of the cardiac silhouette (pericarditis, amyloid cardiomyopathy). Radionuclide scintigraphy (acute scrotum evaluation) usually shows increased perfusion (ie, inflammation that needs only conservative treatment). In rare cases, perfusion is decreased (and indicates torsion that needs emergency surgical exploration). Other tests ECG may show elevation of the ST segment (pericarditis), and echocardiography may show pericardial fluid (pericarditis). Regarding lumbar puncture (LP), few reports describe increased levels of protein and leukocytes in the CSF during attacks. TreatmentMedical care Treatment with colchicine reduces the number and severity of the FMF inflammatory attacks in 95% of patients. About 65% of patients have complete remission, and 30% have clinically significant improvement. However, about 5% are nonresponders partly because of noncompliance. Because colchicine is also effective in preventing amyloidosis, lifelong treatment has been recommended for all patients with FMF (including nonresponders). Colchicine is an alkaloid that interferes with microtubule formation and affects mitosis and other microtubule-dependent functions. Its bioavailability is 25-50% when administered PO. Colchicine and its metabolites are excreted through the urinary and biliary tracts. It may be used during breastfeeding; however, amniocentesis should be performed when it is used in pregnancy (Ben-Chetrit, 1998). At low doses, colchicine is a relatively safe medication, with GI manifestations being the most common adverse effects. Treatment with colchicine is started with 1 mg/day regardless of the patient's age or body weight. This dosage can be increased until remission is achieved. Some physicians prescribe 1 tablet (ie, 0.5-0.6 mg) per day for children younger than 5 years. This dosage may be sufficient to prevent attacks, but it may not prevent amyloidosis (Livneh, 1996). When the dosage is > 1 mg/day, it should be divided for twice-daily administration. Colchicine treatment based on genotype has been suggested (see Familial Mediterranean Fever on the GeneTests Web site). However, the authors know of no controlled studies that have been conducted to evaluate this approach. Spondyloarthropathy and diffuse myalgia responds to nonsteroidal anti-inflammatory drugs (NSAIDs) but not to colchicine. The episodes of febrile myalgia syndrome respond only to corticosteroids and not colchicine. Medications The drug of choice for medical therapy is colchicine. In the United States, colchicine is an investigational drug used in the management of FMF (off label). It prevents febrile attacks in 65% of patients and reduces the severity and frequency of attacks in another 30%. About 5% of patients are nonresponders partly because of noncompliance. Colchicine is not effective in aborting an established attack, and NSAIDs can be used for this purpose. Administer the tablet PO with water and maintain adequate fluid intake. Tablets are available in 0.6 or 0.5 mg. The adult dosage for prophylaxis is 2-4 tablets daily in divided doses. Patients should usually start with 2 tablets per day. If they have no response, the dosage may be increased to 4 tablets up to 3 mg/day, if tolerated. For prophylaxis in children, the starting dosage is 2 tablets in 2-3 divided doses, which can be increased to 3 tablets as needed. Contraindications include the following conditions: hypersensitivity to colchicine or any component of the formulation; severe renal, GI, hepatic, or cardiac disorders; blood dyscrasias; and pregnancy (parenteral). The most common adverse events are GI: nausea, vomiting, diarrhea, abdominal pain. Cardiovascular adverse events include hypotension, sinus bradycardia, and vasculitis. CNS effects include confusion, delirium, and seizures. Dermatologic effects are rash, alopecia, bullous skin disease, toxic epidermal necrolysis, urticaria, pruritus, axonopathy, licheniform eruptions, and exanthema. Endocrine and metabolic effects are dehydration. Genitourinary effects include azoospermia. Hematologic effects are neutropenia, agranulocytosis, thrombocytopenia, aplastic anemia, methemoglobinemia, and megaloblastic anemia. Hepatic effects include hepatotoxicity. Neuromuscular and skeletal effects are myopathy, peripheral neuritis, paralysis, and rhabdomyolysis. Ocular effects include diplopia. Renal effects are hematuria, and acute tubular necrosis. Respiratory effects are apnea, respiratory depression, and respiratory collapse. Miscellaneous adverse effects include aneuploidy induction and fixed drug eruption. Signs and symptoms of overdose (usually associated with intravenous [IV] treatment) include the following: apnea, bradycardia, diabetes insipidus, diarrhea, fever, hematuria, hypernatremia, hyperthermia, hypocalcemia, hypothermia, leukocytosis, myasthenia gravis (exacerbation or precipitation), myoglobinuria, nausea, nephritis, oligospermia, polyuria, ptosis, purpura, rhabdomyolysis, sexual dysfunction, and vomiting. Colchicine is a substrate of cytochrome P450 (CYP) 3A4 (major), and it induces CYP2C8/9 (weak), CYP2E1 (weak), CYP3A4 (weak). Concurrent use of cyclosporine with colchicine may increase the toxicity of colchicine. CYP3A4 inhibitors may increase the levels and/or effects of colchicine. Examples of inhibitors are azole antifungals, ciprofloxacin, clarithromycin, doxycycline, erythromycin, imatinib, and isoniazid. Colchicine is pregnancy category C (PO formulation) or D (parenteral formulation). Colchicine is known to arrest mitotic and meiotic chromosomal segregation in vitro; therefore, birth defects are a potential concern if the drug is used during pregnancy. However, none of the studies to date has conclusively demonstrated that colchicine is responsible for chromosomal abnormalities or other birth defects (Livneh, 1996). Amniocentesis is still suggested to screen for chromosomal defects if either parent is taking the drug. Lactation enters breast milk; therefore, use caution in breastfeeding patient; the American Academy of Pediatrics rates this as compatible. Use with caution in debilitated or elderly patients, as well as in patients with mild-to-moderate cardiac, GI, renal, or liver disease. Dosage reduction is recommended in patients who develop weakness or GI symptoms (anorexia, diarrhea, nausea, vomiting) related to drug therapy. Surgical Care Elective or emergency appendectomy might be indicated. Hemodialysis and renal transplantation may prolong the lives of patients with amyloidosis, as long as colchicine is used to prevent amyloid from depositing in the grafts. Consultations Consultations with the following specialists may be helpful: rheumatologist, nephrologist, surgeon (in cases of acute abdomen), urologist (in cases of an acute scrotum), dermatologist, and infectious disease specialist (in cases of periodic fever or fever of unknown origin). Follow-upTests Routine urinalyses are imperative for patients with FMF because albuminuria appears early in the course of renal amyloidosis. In patients with confirmed proteinuria, renal or rectal biopsy is required to confirm the diagnosis. Complications M694V and the complex V726A-E148Q alleles in both the homozygous and heterozygous state is significantly associated with amyloidosis, as demonstrated in several studies. However, previous reports have described amyloidosis in patients with other mutations. Therefore, the risk of amyloidosis must be considered, even when the M694V mutation is not detected. Rare extrarenal manifestations of amyloidosis include cardiomyopathy, goiter, and malabsorption caused by mucosal infiltration of small bowel; these complications should also be considered. Prognosis Amyloidosis determines the prognosis and is the main cause of death among patients with FMF before the introduction of colchicine in 1972. Life expectancy is normal without amyloidosis. Patient education Continuous daily treatment is needed to prevent amyloidosis and attacks (and not for the treatment of acute attacks). Compliance is important, and the discontinuation of colchicine may result in an attack within a few days. Educate patient about the potential adverse effects of colchicine. Medicolegal pitfallsContinuous daily treatment is urged for the prevention of amyloidosis. Patients with FMF who already have proteinuria should still be given colchicine to stabilize or decrease the amount of protein loss. Patients receiving renal transplants should also be given a daily colchicine regimen to prevent graft amyloidosis. Nonresponders should continue colchicine treatment to prevent amyloidosis. The adverse affects of colchicine can be reduced by gradually increasing the dose. Failure to counsel the patient about the mode of inheritance and the risk of recurrence is another pitfall. HYPERIMMUNOGLOBULINEMIA D WITH PERIODIC FEVER SYNDROMESection 4 of 11
BackgroundIn 1984, van der Meer et al first described HIDS (MIM 260920), also known as MK deficiency (MKD), in 6 patients of Dutch ancestry. The patients had a long history of recurrent attacks of fever of unknown cause, as well as high serum immunoglobulin D (IgD) levels and numerous plasma cells with cytoplasmic IgD in the bone marrow. Clinical symptoms of during the attacks were lymphadenopathy, abdominal pain, diarrhea, headache, hepatomegaly and/or splenomegaly, arthralgia and/or arthritis, and skin lesions. Patients may have no symptoms between attacks. However, in some patients, the attacks may be so frequent that the symptoms persist. Pathophysiology HIDS is caused by mutations in the MVK gene that results in a depressed enzymatic activity, which has been confirmed in fibroblasts from patients with HIDS (Drenth, 1999; Houten, 1999). MK, a homodimeric enzyme, is found mainly in peroxisomes and catalyzes an early step in the mevalonate pathway that produces cholesterol and other important molecules, including dolichol, and ubiquinone, by means of the farnesyl-PP intermediate (see Image 2). This pathway is also responsible for isoprenylation, a posttranslational modification of proteins that causes them to become membrane bound. Why a disorder in the cholesterol metabolism can cause a disease featured by periodic inflammatory attacks, such as HIDS, is unclear. Frequency The carrier frequency of MVK mutations in the Dutch population was recently calculated to be 1:65. The predicted disease incidence is far more than actually observed, suggesting reduced penetrance of the most common mutation (V377I) (Houten, 2003) Mortality and morbidity Patients have a good prognosis because amyloidosis has not been reported in any patient with this syndrome. No apparent neurologic or morphologic abnormalities occur, and, between febrile attacks, patients are remarkably free of symptoms. Race Most of the patients initially described were from European countries, with a clear preponderance for the Netherlands or the north of France. Later, the disease was identified in patients from other European countries such as England, Germany, Italy, Turkey, and the Czech Republic, as well as the United States and in Japan (Simon, 2003). As of May 2003, the hyper-IgD syndrome registry in Nijmegen, the Netherlands, had clinical data on 193 patients, mostly from western European countries. (See the Hyper-IgD and periodic fever syndrome [HIDS] Web site.) Sex The male-to-female ratio was equal in 1 study (Cuisset, 2001) but about 3:2 in another large series (Simon, 2001); this last finding raises the possibility of reduced penetrance in women. Age The disease has an early age of onset. Most patients have attacks before the end of their first year of life (median, 0.5 y). The attacks persist throughout life, though patients have a reduction in intensity and frequency of attacks after adolescence. Clinical detailsHistory Patients have a long history of episodic attacks of fever that occur every 4-8 weeks and that may last 3-7 days, though individual variability is considerable. Attacks manifest as high, spiking fever is preceded by chills in 76% of patients (Drenth, 1994). During the attacks, 72% of patients complained of abdominal pains, 56% of vomiting, 82% of diarrhea, and 52% of headache. Joint involvement is common in the hyper-IgD syndrome with polyarthralgia in 80% and a nondestructive arthritis in 68% of patients. About 82% of patients reported skin lesions with some attacks. Serositis has been seen in only a minority of patients. Of surprise, amyloidosis has not been recorded in any of the patients with this syndrome. Diagnostic criteria for HIDS are as follows (Drenth, 1994):
Drenth and van der Meer recommended the following diagnostic strategy (2001):
Physical examination Patients may have a high, spiking fever. About 94% of patients have lymphadenopathy. Other findings may include splenomegaly, arthritis mainly of the large joints, eg, knee and ankle), skin lesions (erythematous macules and papules and sometimes petechia and purpura), and aphthous ulcers in the mouth or vagina. CausesGenetic causes HIDS is inherited as an autosomal recessive disease, and about one half of patients have a positive family history. The clues to genetic basis for this disease were increased concentrations of mevalonic acid in the urine of patients during severe episodes of fever but not between crises. A reduced activity of MK (encoded by MVK), a key enzyme of isoprenoid biosynthesis, was found in cells from patients with HIDS. Sequence analysis of MVK cDNA showed different mutations, of which V377I is most common (Drenth, 1999; Houten, 1999). Genomic analysis of MVK revealed that it is 22 kb long and that is contains 11 exons of 46-837 bp and 10 introns of 379 bp to 4.2 kb (Houten, 2001). Gene product MK, a homodimeric enzyme, is present in the peroxisomes of every mammalian cell and follows 3-hydroxy-3-methylglutaryl-CoA reductase in the cholesterol synthesis and converts mevalonate into 5-phosphomevalonate. Mutations in the MVK gene result in depressed enzymatic activity, which is mainly due to reduced protein levels. Of interest, MK activity in peripheral blood mononuclear cells decreases 2- to 8-fold when patients with HIDS have febrile attacks. A similar phenomenon occurs in vitro, when HIDS cell lines were cultured at 39°C. MK activity decreased, and MK were progressively rate limiting. These results led Houten et al (2002) to hypothesize that minor elevations in temperature can set off a chain of events, with MVK becoming progressively rate limiting. The events lead to a temporary deficiency of isoprenoid end-products, which induces inflammation and fever. Genetic heterogeneity Simon et al (2001) examined 54 patients who met the criteria for HIDS and identified 2 groups: 41 patients with MK mutations (classic-type HIDS) and 13 patients without mutations (variant-type HIDS). Patients with classic-type HIDS had a low MK enzyme activity, high IgD levels, and additional symptoms with attacks. The IgD level was not correlated with disease severity, MK enzyme activity, or genotype. Aggravating factors Vaccinations precipitate attacks in 54% of patients. Minor trauma, surgery, and stress are other known aggravating factors. Differential diagnosisMevalonic aciduria (MVA, MIM 610377) is typically a disease of infantile onset. It is characterized by psychomotor retardation, ataxia, failure to thrive, cataracts, and dysmorphic features (Schafer, 1992; Hoffmann, 1993; Prietsch, 2003). Patients also have periodic fever attacks that are similar to but more severe than in HIDS. In general, they die in early childhood. Patients have dysmorphic features that include microcephaly, triangular face, and hypoplastic alae nasi (Tsimaratos, 2001). The residual MK activity in patients HIDS is 1-7%, whereas residual MK activity in almost every patient with MVA is undetectable ( <0.5%) (Houten, 2001). In HIDS, the mutations are located along the protein; this differs from MVA, in which the MK mutations are mainly clustered to the same region of the protein (Cuisset, 2001). The most common MVK mutation, V377I (1129G>A), is identified exclusively in HIDS patients. Other common mutations have been associated with both HIDS and MVA. Of interest, the results of genotype analysis alone do not explain the remarkable variability in phenotype, and genetic or environmental factors have to be considered to explain the phenotypic variability. In fact, the clinical presentation of MKD represents a phenotypic continuum from MVA to HIDS instead of 2 separate phenotypic entities. The identification of adult patients with phenotypic overlap between these syndromes supports this continuum (Simon, Neurology, 2004). WorkupLaboratory studies The most typical finding is the consistently elevated serum IgD level (>100 U/mL comparable to 141 mg/L), though patients can have normal IgD levels. The IgD level is not correlated with disease severity, MK enzyme activity, or genotype (Simon, 2001). Approximately 82% also have elevated serum IgA levels (Klasen, 2001). During attacks, an acute-phase response occurs, with high CRP levels, increased ESR, and leukocytosis. Symptomatic episodes are associated with increased concentrations of inflammatory mediators (TNF-alpha, IL-6, interferon [IFN]-gamma) and anti-inflammatory compounds (IL-1 receptor antagonist and soluble TNF receptors p55 [sTNFr p55] and sTNFr p75]) (Drenth, 1995). Increased urine concentrations of mevalonic acid are found during severe episodes of fever but not between crises (as measured on mass spectrometry or proton nuclear magnetic resonance [NMR] spectroscopy). In addition, increased urinary excretion of neopterin is correlated with disease activity. Mutation analysis reveals mutations in the gene for MK in 76% of clinically affected patients (Simon, 2001). Approximately 90% of patients are compound heterozygous. About 80% of mutations are missense. In HIDS, the mutations are along the area that encodes for the protein, whereas in MVA, the MK mutations are mainly clustered to the same region of the protein. V377I and I268T are the most common mutations (Cuisset, 2001). These mutations cause a moderate (5-15%) functional defect of MVK, as tested in cultured fibroblasts or lymphocytes compared with undetectable findings in MVA. Histology Histologic examination of skin lesions may reveal vasculitis. TreatmentMedical care The treatment of HIDS is largely supportive because various standard anti-inflammatory drugs (including colchicine and steroids) fail to suppress the attacks. In a randomized double-blind placebo-controlled trial, thalidomide resulted in a nonsignificant decrease of acute phase protein synthesis but without an effect on the attack rate (Drenth, 2001) MK follows 3'-hydroxy-3'-methylglutaryl-coenzyme A (HMG-CoA) reductase in the isoprenoid pathway. A preliminary study showed that simvastatin (an inhibitor of HMG-CoA reductase) may ameliorate the inflammatory attacks in the hyper-IgD syndrome. This effect was tested in 6 patients with hyper-IgD syndrome and proven MKD who were followed up for 2 treatment periods with simvastatin 80 mg/d or placebo for 24 weeks, separated by a 4-week washout period in a double-blind fashion. Simvastatin resulted in a decrease in the urinary mevalonic acid concentration in all patients and decreased the number of febrile days in 5 of 6 patients. No adverse effects were observed (Simon, Clin Pharmacol Ther, 2004). Consultations Consultations with the following specialists may be helpful: dermatologist, rheumatologist, and infectious disease specialist (to evaluate periodic fever). Follow-upPatients with the hyper-IgD syndrome have febrile attacks throughout their lives, with a slight decrease after adolescence. Amyloidosis has not been reported in with this disease. Medicolegal pitfallsA normal IgD level does not exclude the diagnosis. A failure to consider the diagnosis in patients from outside the Netherlands or France is a pitfall. TUMOR NECROSIS FACTOR-RECEPTOR&NDASH;ASSOCIATED PERIODIC SYNDROMESection 5 of 11
BackgroundTRAPS (MIM 142680), or familial Hibernian fever, is a disorder that was first reported in 1982 in a large family of Irish-Scottish ancestry (Williamson, 1982). TRAPS is a dominantly inherited disorder characterized by episodic attacks of fever, abdominal pain, severe myalgia, and painful erythema on the trunk or extremities usually lasting for longer than 1 week. Attacks tend to last longer in TRAPS than in hyper-IgD syndrome or FMF. Pathogenesis TRAPS is caused by mutations in TNFRSF1A, the gene that encodes the receptor for TNF (McDermott, 1999). TNF-alpha activates TNFRSF1A, the extracellular portion of the gene undergoes cleavage and subsequent shedding from the cell membrane. This process is thought to contribute to the clearance of TNFRSF1A from the membrane and produces a pool of soluble receptors that may attenuate the inflammatory response by competing with membrane-bound receptors (Hull, Medicine, 2002). Most mutations in TNFRSF1A mediate their effect via decreased shedding of TNFRSF1A, thereby decreasing the amount of soluble receptor available to bind soluble TNF and subsequently initiate and maintain the inflammatory response. Defective shedding only partially explains the pathophysiologic mechanism of TRAPS because some mutations have normal shedding (Aksentijevich, 2001). The dramatic response for etanercept (see the Treatment section below), an anti-TNF agent, suggests that TNF plays a critical role in the inflammatory process of this disease. Frequency To the authors' knowledge, no systematic studies have been conducted to ascertain the frequency of the disease in different ethnic groups. Among Caucasians and African Americans, 2 TNFRSF1A mutations, R92Q and P46L, have been found to occur in more than 1% of chromosomes (Aksentijevich, 2001). This high carrier frequency might reflect a combination of underdiagnosis, reduced penetrance, and variable expressivity. Mortality and morbidity The prognosis for patients with the TRAPS mainly depends on amyloidosis. The medical literature does not provide clear mortality data. Race Most patients are of northern European descent. Although TRAPS was originally described in patients of Irish or Scottish ancestry, mutations have been reported among patients from different ethnicities, including African American, French, Belgian, Dutch, Arab, Jewish, and many other ethnicities (Hull, Medicine, 2002). Sex A male-to-female ratio of 3:2 is reported (Hull, Medicine, 2002). The reason that women are more protected than men is still unknown. Age The median age of onset is 3 years, with the age at initial presentation ranging from 2 weeks to 53 years. The age of onset varies within and among families. Clinical detailsHistory The rate and duration of the inflammatory attacks vary greatly. On average, they occur once every 6 weeks and last longer than 1 week. Few patients have daily pain without a clear resolution of symptoms. Sterile inflammation of the serosal membrane cause abdominal and chest pain, which occur in 90% and 60% of patients, respectively. Arthralgia of the large joints is common, but arthritis is rare. Painful unilateral or bilateral conjunctivitis and periorbital edema are also common and characteristic findings. In men, scrotal pain during attacks is reported, and the incidence of inguinal hernia is increased, for unknown reasons. The myalgias are severely disabling and are a constant feature; myalgias usually start the attacks of TRAPS and migrate centrifugally over the course of the attack. About 84% of patients have tender, migratory erythematous patches, which typically overlie areas of myalgia and lasting for 4-21 days (Toro, 2000). The following clinical characteristics suggestive of TRAPS may serve as guidelines or indications for ordering genetic testing (Hull, Medicine, 2002):
Physical examination Patients may have fever, tachypnea, and tender and warm areas of involved muscles. These findings are often associated with erythematous patches, monoarthritis of the large joints (most commonly the hips, knees, and ankles), signs of acute abdomen, and lymphadenopathy (in some patients). CausesGenetics TRAPS is an autosomal dominant disease caused by mutations in the TNFRSF1A gene. The gene is composed of 10 exons. So far, 58 mutations have reported in patients (see the Infevers Database for TRAPS mutations.) Most mutations described to date are missense mutations that affect the first 2 cysteine-rich domains of the extracellular portion of the receptor, and some of these alleles encode proteins with disrupted disulfide bonds. Carriers of cysteine mutations are most severely affected and most prone to develop life-threatening amyloidosis (Aksentijevich, 2001). Many of these mutations are missense mutations in exons 2, 3, and 4 that involve highly conserved cysteine residues of the extracellular portion of TNFRSF1A. Genotype-phenotype correlation Mutations that result in cysteine substitutions are associated with increased penetrance of the clinical phenotype (93% vs 82% for noncysteine residue substitutions), and they also increase the probability of life-threatening amyloidosis (24% vs 2% for noncysteine residue substitutions) (Aksentijevich, 2001). The R92Q and P46L mutations are low-penetrant mutations that also occur in a small percentage of healthy individuals. Aggravating factors Patients usually report an increased severity with physical or emotional stress or after physical trauma. Differential diagnosisOther HPFS, especially FMF should be considered (Dode, Arthritis Rheum, 2002). Acute peritonitis is another differential diagnosis. A substantial number of patients undergo explorative laparotomy and appendectomy because of signs of acute abdomen. (See also the Differential diagnosis section for FMF.) WorkupLaboratory studies As in other HPFS, levels of acute-phase reactants (SAA, CRP, fibrinogen, haptoglobin, ferritin) are high, and ESR is elevated during attacks and even between attacks in many patients. The blood count may reveal anemia of chronic disease, leukocytosis, and thrombocytosis. The IgD level may be elevated (<100 IU/mL), and levels of soluble TNFRSF1A in the serum may be reduced during and between attacks. Polyclonal gammopathy may also be present. Histology Polarized light microscopy of Congo red-stained samples obtained from renal biopsy shows deposition of amyloid fibrils. Skin lesions may show a superficial and deep perivascular and interstitial infiltrate of lymphocytes and monocytes. Muscle biopsy may reveal monocytic fasciitis or lymphocytic vasculitis (but not myositis) (Hull, Arthritis Rheum, 2002). TreatmentMedical care Conventional treatment includes NSAIDs that relieve symptoms of fever; however, these are not effective in relieving musculoskeletal and abdominal symptoms. Glucocorticoids decrease the severity of symptoms in most patients. Neither of these treatments alters the frequency of attacks in most patients. Preliminary results in controlling the acute symptoms and reversion of amyloidosis with etanercept (Enbrel) have been reported. Etanercept, an anti-TNF agent, is a dimeric recombinant fusion protein consisting of the extracellular domain of the type 2 TNF-alpha receptor, linked by the Fc portion of immunoglobulin G (IgG)-1. It binds to TNF and attenuates its biologic effects. Standard doses of etanercept administered subcutaneously (SC) twice a week decrease the frequency, duration, and severity of attacks (Hull, Medicine, 2002). One study showed that etanercept does not abort inflammatory attacks but improves disease activity allowing for a reduction of corticosteroids (Drewe, 2003). The authors concluded that etanercept may be clinically useful in replacing or reducing steroid requirements in the treatment of TRAPS. In addition, etanercept may reverse or slow the progression of systemic AA amyloidosis in patients with TNFRSF1A mutations. However, treatment may need to be continued, possibly for the patient's life time, to prevent end-stage disease (Drewe, 2004). Although these preliminary results suggest that etanercept may provide a safer and more effective alternative to conventional therapies, long-term double-blind studies are needed to establish its role in clinical management of this disease and to evaluate its effect on AA amyloidosis. Medications Medications used to treat TRAPS include etanercept and prednisone. Etanercept (Enbrel) binds to TNF and blocks its interaction with cell-surface TNF receptors, rendering TNF biologically inactive. IT modulates biologic responses that TNF induces or regulates. The adult dosage is 50 mg SC given once weekly or 25 mg given twice weekly. Individual doses should be separated by 72-96 hours. In children age 4-17 years, once-weekly dosing is 0.8 mg/kg SC (not to exceed 50 mg/dose), and twice-weekly dosing is 0.4 mg/kg SC (not to exceed 25 mg/dose). As in adults, individual doses should be separated by 72-96 hours. Contraindications are hypersensitivity to etanercept or any component of the formulation, sepsis, and active infections (including chronic or local infection). Etanercept may interact with anakinra. An increased rate of serious infections has been noted with concurrent therapy. Live vaccines should not be given during therapy. In addition, etanercept is pregnancy class B. Developmental toxicity studies performed in animals have revealed no evidence of harm to the fetus. However, no studies have been performed pregnant women; this drug should be used during pregnancy only if it is clearly needed. Adverse effects may occur with slightly increased rates in pediatric patients. Adverse effects include headache, dizziness, nausea, injection-site reaction, respiratory tract infection, rhinitis, sinusitis, positive antinuclear antibodies (ANAs) and antidouble-stranded DNA antibodies; rash, abdominal pain, dyspepsia, vomiting, and weakness. Rare events include lymphadenopathy, malignancies (including lymphoma), membranous glomerulopathy, myocardial infarction, mouth ulcer, multiple sclerosis, myocardial ischemia, pancreatitis, polymyositis, pulmonary embolism, renal calculus, sarcoidosis, thrombophlebitis, vasculitis (cutaneous), and pancytopenia. Regarding precautions, safety in patients with immunosuppression or chronic infections has not been evaluated. Rare cases of tuberculosis have been reported. Discontinue administration if the patient develops a serious infection. Use caution in patients predisposed to infection, (eg, those with poorly controlled diabetes), in patients with preexisting or recent-onset demyelinating CNS disorders, in patients with CHF, and in patients with a history of clinically significant hematologic abnormalities. The effect on the development and course of malignancies is not fully defined. The long-term immunogenicity, carcinogenic potential, or effects on fertility are unknown. Allergic reactions may occur (<2%), but anaphylaxis has not been observed. If an anaphylactic reaction or other serious allergic reaction occurs, the administration of etanercept should be discontinued immediately, and appropriate therapy initiated. The patient's vaccinations should be made current before they start therapy. Prednisone decreases inflammation by suppressing the migration of PMN leukocytes, by reversing increased capillary permeability, and by suppressing the immune system (by reducing the activity and volume of the lymphatic system). Prednisone is available as tablets of 1, 2.5, 5, 10, 20, or 50 mg. The adult dosage is 5-60 mg/day PO in divided doses given 1-4 times/day. The pediatric dosage is 0.05-2 mg/kg/day PO divided 1-4 times/day. Prednisone should be administered with meals to decrease GI upset. Contraindications include hypersensitivity to prednisone or any component of the formulation, serious infections (except tuberculous), meningitis, systemic fungal infections, and varicella. The drug is a substrate of CYP3A4 (minor), and it induces CYP2C19 (weak), 3A4 (weak). Decreased effect may be observed with barbiturates, phenytoin, and rifampin. Prednisone decreases the effectiveness of corticosteroids, salicylates, and vaccines and toxoids. It increases the effect and/or toxicity of NSAIDs. Concurrent use of prednisone may increase the risk of GI ulceration. Prednisone is pregnancy class B; available evidence suggests that it is safe to use during pregnancy. Regarding lactation, the drug enters the breast milk and is considered compatible. Adverse effects include edema, hypertension, QT prolongation, cardiomegaly, cardiomyopathy, dizziness, seizures, psychosis, pseudotumor cerebri, headache, memory disturbance, mania, insomnia, nervousness, acne, purpura, skin atrophy, angioedema, acanthosis nigricans, Cushing syndrome, pituitary-adrenal axis suppression, amenorrhea, growth suppression, glucose intolerance, hypokalemia, alkalosis, peptic ulcer, nausea, vomiting, increased appetite, indigestion, aplastic anemia (1:3600-5000 patients), leukemoid reaction, fatal hepatotoxicity (1:24,000-32,000 patients), osteoporosis, fractures, weakness, cataracts, and glaucoma. Signs and symptoms of overdose include cognitive dysfunction, dementia, depression, mania, GI bleeding, hirsutism, hyperglycemia, hypertrichosis, hyperuricemia, hypokalemia, increased intraocular pressure, leukocytosis, lymphopenia, and eosinopenia. Withdraw therapy with a gradual tapering of the dose. The drug may retard bone growth. Use with caution in patients with hypothyroidism, cirrhosis, CHF, ulcerative colitis, and thromboembolic disorders, as well as in patients at increased risk for peptic ulcer disease. Corticosteroids should be used with caution in patients with diabetes, hypertension, osteoporosis, glaucoma, cataracts, or tuberculosis. Use caution in hepatic impairment. Because of the risk of adverse effects, systemic corticosteroids should be used cautiously in the elderly, in the smallest possible dose, and for the shortest possible time. Consultations Consultations with the following specialists may be helpful: nephrologist, rheumatologist, dermatologist, surgeon, urologist, and infectious disease specialist (to evaluate periodic fever). Follow-upComplications Amyloidosis is the most serious long-term complication of TRAPS. About 14% of patients with TRAPS develop amyloidosis, which has a strong predilection for those with mutations that result in cysteine substitutions. Approximately 24% patients with TRAPS and cysteine mutations (substitutions) develop amyloidosis versus 2% of patients with noncysteine mutations (Aksentijevich, 2001). Activity Physical or emotional stress can provoke the inflammatory symptoms. Prognosis Amyloidosis determines the prognosis. Without amyloidosis, the patient's life expectancy is normal. Medicolegal pitfallsA failure to follow-up for the development of proteinuria is a pitfall. Normal levels of TNFRSF1A in the serum do not rule out the diagnosis. Reasons include the possibility of nonshedding mutations and normal levels during attacks. In addition, renal amyloidosis impairs TNFRSF1A clearance by the kidney. Not all individuals with mutations have symptoms. MUCKLE-WELLS SYNDROMESection 6 of 11
BackgroundMWS (MIM 191900) was first described as a rare hereditary disorder with an autosomal dominant mode of inheritance (Muckle, 1962). Since then, most published studies have focused on kindreds from northern Europe. Patients with autosomal dominant MWS have acute febrile attacks with abdominal pain, arthritis, and urticaria. The disease is sometimes complicated by progressive nerve deafness and multiorgan AA-type amyloidosis. Pathogenesis Mutations in the NALP3/CIAS1/PYPAF1 gene are associated with the autoinflammatory diseases MWS, FCAS, and CINCA/NOMID syndrome (see Image 1). The gene product, cryopyrin, interacts with ASC, leading to the activation of caspase-1 and the subsequent release of IL-1, as well as the activation of NF-kappaB, which results in the release of many proinflammatory cytokines. IL-1 is a key proinflammatory cytokine that has many actions, including a contribution to increased synthesis of SAA by hepatocytes during the acute-phase response; SAA accumulates in different organs, causing amyloidosis. Frequency MWS is a rare disease, and the exact frequency is unknown. Mortality and morbidity Amyloidosis is the main factor that determines the prognosis of patients with the MWS. No clear mortality data are reported in the medical literature. Race No clear data are reported in the medical literature. Sex Males and females are equally affected. Age MWS manifests at birth or in early infancy. Clinical detailsHistory The disease is characterized by acute febrile inflammatory attacks lasting 24-72 hours and commonly manifest in childhood. The episodic attacks result in abdominal pain, polyarthralgias or arthritis, myalgia, urticaria, and conjunctivitis. Late in the course of the disease, sensorineural deafness occurs; this feature distinguishes MWS from other inflammatory disorders. After several years, amyloidosis of the AA type develops. Physical examination Finding findings may include arthritis (mostly of the large joints such as the knees, ankles, and shoulders), urticaria (mostly on the trunk and extremities), and conjunctivitis. CausesGenetics MWS is caused by mutations in a gene called CIAS1, NALP3, or PYPAF1, which encodes a protein known as NALP3, cryopyrin, or PYPAF1. This protein is a member of the pyrin superfamily of DD-fold proteins (Hoffman, Nat Genet, 2001; Dode, Am J Hum Genet, 2002). The NALP3/CIAS1/PYPAF1 gene is expressed in PMNs, monocytes, and chondrocytes. It contains a nucleotide-binding site (NACHT), a C-terminal domain containing 7 LRRs, and an N-terminal PD (PyD) (Tschopp, 2003). The PD of cryopyrin/NALP3/PYPAF1 is thought to interact with another PD protein, ie, ASC, leading to the signaling of NF-kappaB. Then, by activating caspase-1, ASC increases IL-1 beta production, which is thought to be an important mediator of inflammation in patients with NALP3/CIAS1/PYPAF1 mutations (Wang, 2002; Agostini, 2004; Hawkins, 2004). Specific inhibitors may control the function of cryopyrin/NALP3/PYPAF1, and mutations of the NACHT domain have been proposed to affect the binding of such inhibitors, resulting in the spontaneous activation of caspase-1 and the production of IL-1 with fever (see Image 1). As an alternative, this protein may be proinflammatory, and mutations might increase functional activity with unprovoked attacks of inflammation. NALP3/CIAS1/PYPAF1 mutations were initially identified in patients with MWS and FCAS disorders (Hoffman, Nat Genet, 2001). Since then, 52 mutations in this gene have been found, as listed in the Infevers Database of CAPS mutations. Of interest, some mutations in this gene are associated with different phenotypes in different families. The clinical features of patients with NALP3/CIAS1/PYPAF1 mutations overlap more than previously recognized, and that the correlation of phenotype and NALP3/CIAS1/PYPAF1 genotype is broad in terms of disease characteristics, penetrance, and severity. The clinical features of the various syndromes associated with mutations in the NALP3/CIAS1/PYPAF1 gene may overlap more than previously recognized (Hawkins, 2004). Aggravating factors Cold, dampness, and stress trigger cutaneous symptoms. Differential diagnosisMWS is an autosomal-dominant periodic fever syndrome with a phenotype similar to that of FCAS except that symptoms are not precipitated by cold exposure and that sensorineural hearing loss is frequently present. However, exacerbations of the disease manifestations after exposure to cold have been reported (Haas, 2004; Hawkins, 2004). In fact, cold-induced skin lesions in MWS represent typical generalized inflammatory reactions to cold air or win, as is also observed in familial cold urticaria (FCU) (Haas, 2004). The differential diagnosis also includes other HPFSs, Alport syndrome (which has the common features of renal, ear, and ocular involvement), amyloidosis, conjunctivitis, and arthritis. WorkupLaboratory studies Laboratory testing may show an acute-phase response during attacks, as well as leukocytosis. Other tests Results of hearing tests and cold-contact tests (with an ice cube and a cold-arms bath) are negative. To date, all mutations in FCAS have been identified in exon 3 of the NALP3/CIAS1/PYPAF1 gene (which has 9 exons). In the United States, GeneDx DNA Diagnostic Experts currently performs mutation testing by means of complete, bidirectional sequential analysis of exon 3 of the CAIS1 gene. For an update on the laboratories that perform the test, visit the GeneTests Web site funded by the NIH. Histology Microscopic features are similar to those observed in other types of urticaria. Few minutes after cold provocation, skin lesions show dermal edema with dilatation of the small vessels. The upper and mid dermis are marked infiltrated with a primarily neutrophilic infiltrate admixed with few eosinophils and mononuclear cells (but no signs of leukocytoclastic vasculitis) (Haas, 2004). TreatmentMedical Care Until recently, no treatment has been proved to be beneficial for MWS, though data suggest that colchicine and high-dose corticosteroids exert a favorable effect on the intensity and recurrence of attacks. The rarity of MWS and the lack of long-term observation leave unresolved the issue of prevention of amyloidosis with protracted colchicine treatment. Treatment with low-dose corticosteroids, chlorambucil, antihistamines, dapsone, azathioprine, mycophenolate mofetil, and infliximab have been unsuccessful, as determined with clinical measures and monthly estimates of the plasma concentration of SAA protein. In 2003, Hawkins et al reported a favorable response to a recombinant human IL-1 receptor antagonist (rHuIL-1Ra, anakinra) in 2 patients with MWS complicated by amyloidosis. Inflammatory symptoms ceased within hours of the first injection, and plasma concentrations of SAA protein decreased to normal baseline values within 3 days and remained normal on frequent testing for 6 months with diminished amyloid-related proteinuria (Hawkins, 2003). This remarkable response suggests that IL-1 has a role in the pathogenesis of inflammation associated with NALP3/CIAS1/PYPAF1 mutations. Although the long-term effect of this treatment is unknown, anakinra has the potential to be life saving in patients with MWS complicated by AA amyloidosis. A dramatic response to anakinra has also been seen in 3 more patients with MWS who are members of a British family (Hawkins, 2004). UV radiation may be administered to treat skin lesions. Consultations Consultations with the following specialists may be helpful: otolaryngologist (to evaluate hearing loss), dermatologist, rheumatologist, nephrologist, and infectious disease specialist (to evaluate periodic fever). Medications The drug of choice for the medical therapy of MWS is a selective recombinant IL-1 receptor antagonist. Anakinra (Kineret) is given in an adult dosage of 100 mg SC once daily or a pediatric dosage of 1 mg/kg SC once daily (currently not FDA approved for use in children in the United States). Contraindications are hypersensitivity to Escherichia coli–derived proteins, anakinra, or any component of the formulation, as well as active infections (including chronic or local infections). Anakinra can interact with etanercept. Concurrent use has been associated with an increased risk of serious infection. Use caution with other drugs known to block or decrease the activity of TNF, including infliximab and thalidomide. Anakinra is pregnancy class B; that is, no evidence suggests impaired fertility or harm to fetus in animal models. However, no controlled trials have been conducted in pregnant women. Regarding lactation, excretion in breast milk is unknown; use caution. Anakinra may affect defenses against infections and malignancies. Safety and efficacy in patients with immunosuppression or chronic infections have not been evaluated. Discontinue administration if patient develops a serious infection. Do not start drug administration in patients with an active infection. Patients with asthma may be at an increased risk of serious infections. The drug should not be used in combination with TNF antagonists, unless no satisfactory alternatives exist, and then, it should be used only with extreme caution. The patient's vaccinations should be made current before they start therapy. No data are available concerning the effects of anakinra on vaccination. Live vaccines should not be given concurrently. No data are available concerning secondary transmission of live vaccines in patients receiving anakinra. Hypersensitivity reactions may occur. Discontinue if signs and/or symptoms of hypersensitivity reaction are observed. The safety of anakinra has not been studied in children younger than 18 years. Dosage adjustment may be needed in renal impairment. Neutrophil counts should be assessed before the start of treatment and repeated every month for the first 3 months of treatment and then quarterly up to 1 year. Adverse reactions include headache, injection-site reaction, infection, nausea, diarrhea, abdominal pain, leukopenia, sinusitis, and flulike symptoms. Follow-upComplications Approximately 26% of patients have renal amyloidosis. AA amyloidosis is not required for the diagnosis of MWS, it does not occur in every patient, it can be delayed in the course of the disease, or it can be clinically latent. Nerve deafness is another complication. Prognosis Systemic amyloidosis is a complication of this condition, and amyloid nephropathy is a frequent cause of death FAMILIAL COLD AUTOINFLAMMATORY SYNDROMESection 7 of 11
BackgroundFCAS (MIM 120100) is also known as FCU, familial polymorphous cold eruption, and cold hypersensitivity. FACS is an autosomal dominant and systemic inflammatory disease that was first described in 1940. The patient develops urticaria, arthralgia, conjunctivitis, and fever after an exposure to cold. FCAS differs from other HPFS in that cold is a consistent trigger, the age of onset is usually less than 6 months, and the episodes usually last less than 24 hours (Hoffman, J Allergy Clin Immunol, 2001). Pathogenesis Mutations in the NALP3/CIAS1/PYPAF1 gene are associated with the autoinflammatory diseases MWS, FCAS, and CINCA/NOMID syndrome. The gene product, cryopyrin, interacts with ASC, leading to the activation of caspase 1 and the subsequent release of IL-1. In addition, activation of NF-kappaB results in the release of many proinflammatory cytokines. IL-1 is a key proinflammatory cytokine that has many actions, including a contribution to increased synthesis of SAA by hepatocytes during the acute-phase response; SAA accumulates in different organs, causing amyloidosis. Frequency FCAS is a rare disease, and the exact frequency is unknown. Mortality and morbidity Amyloidosis determines the prognosis. Without amyloidosis, the patient's life expectancy is normal. Race Most of the reported cases are from Europe and North America, but data from other areas are unclear. Sex Males and females are equally affected. Age Attacks start within the first 6 months of life in 95% of affected subjects and within the first few days of life in 60% (Hoffman, J Allergy Clin Immunol, 2001). The mean age at presentation is 47 days, with a range of 2 hours to 10 years. Symptom severity does not appear to vary with the age of onset. The urticaria is maximal in early adult life. Clinical detailsHistory The recurrent urticarial rash is the most consistent trait occurring in all affected subjects. Additional recurrent and common symptoms include fever and chills (93%), polyarthralgia (96%), and conjunctivitis (84%). Other commonly reported symptoms after exposure to cold include profuse sweating (78%), drowsiness (67%), headache (58%), extreme thirst (53%), nausea (51%), and myalgia (Hoffman, J Allergy Clin Immunol, 2001). Arthritis was not reported as a feature of this disease. The mean duration of cold exposure required to provoke symptoms is 52 minutes (range, 5 min to 3 h), with symptoms appearing after a shorter exposure in cold temperatures than in warm temperatures and increased severity after long cold exposure than after short exposure. The average length of an attack is 12 hours (range, 30 min to 72 h); about 94% of subjects report that most attacks last less than 24 hours. The clinical diagnostic criteria for FCAS that Hoffman et al proposed are listed below (Hoffman, J Allergy Clin Immunol, 2001). When these criteria were applied in 1 study, 41% of affected subjects met all 6 criteria for FCAS, 90% met 5 criteria, and 100% met 4 criteria. None of the unaffected subjects met more than 2 criteria (Johnstone, 2003). Proposed diagnostic criteria for FCAS are the following (Hoffman, J Allergy Clin Immunol, 2001):
Physical examination Patients may have fever, profuse sweating, conjunctivitis, and urticaria (mostly on the extremities and face). CausesFCAS is caused by heterozygous mutations in NALP3/CIAS1/PYPAF1 gene (Hoffman, Nat Genet, 2001; Dode, Am J Hum Genet, 2002). (For more details, see the Causes section for MWS.) The L353P CIAS1 mutation is present in more than 90% of North American patients (Hoffman, 2003; Hoffman, Lancet, 2004). Cold is a consistent trigger of the attacks. The temperature that is required to induce symptoms varies widely, but colder temperatures produced more severe reactions than did warmer temperatures. Many subjects report more severe symptoms on damp and windy days and on exposure to an air conditioner than in other situations. Experimental general exposure to cold can reproduce the symptoms. Differential diagnosisAcquired cold urticaria (ACU) is 1 of the most common forms of physical urticaria. The pathophysiology of ACU involves mast-cell degranulation and histamine effects. Unlike FCAS, ACU typically occurs in adulthood and resolves spontaneously. The clinical presentations of the 2 entities also differ: ACU develops within minutes of direct contact with cold; it resolves within hours; and it can be accompanied by angioedema, wheezing and hypotension. Other HPFS, especially MWS should be considered. Involvement of the CNS (eg, chronic aseptic meningitis, sensorineural hearing loss, optic-nerve elevation) is observed in MWS and in CINCA syndrome but not in the FCAS. The musculoskeletal system is differently involved in these 3 diseases. The main rheumatologic problems are arthralgia in FCAS, synovitis in MWS, and premature patellar and epiphyseal long-bone ossification and bone overgrowth in CINCA syndrome. At present, these 3 diseases are considered to reflect a spectrum of illnesses, with FCAS at the mild end and CINCA syndrome at the severe end. Of interest, few NALP3/CIAS1/PYPAF1 mutations are found in more than 1 disorder in which genetic and environmental modifiers play a role in determining the disease phenotype. Other differential diagnoses are cryoglobulinemia and urticaria. WorkupLaboratory studies Laboratory studies may reveal elevated levels of acute-phase reactants, an elevated ESR, and leukocytosis during attacks. Serum IL-6 concentrations may be high. Numbers of mast cells and tissue histamine levels are normal. Histology Skin biopsy samples obtained during attacks show an intense inflammatory infiltrate around dilated blood vessels. This infiltrate includes neutrophils, eosinophils, and lymphocytes, with moderate edema in the upper part of the dermis. Chronic perivascular inflammation with interstitial neutrophils and mononuclear cells has also been reported as the main histologic finding (Shpall, 2004.) Other tests The ice cube test is performed by placing an ice cube directly on the skin for 5 minutes. Patients with the disease have no urticaria in response. Regarding genetic testing, all mutations in FCAS have been identified in exon 3 of the NALP3/CIAS1/PYPAF1 gene, which has 9 exons. In the United States, GeneDx DNA Diagnostic Experts currently performs mutation testing by means of complete, bidirectional sequential analysis of exon 3 of the CAIS1 gene. For an update on the laboratories that perform the test, visit the GeneTests Web site funded by the NIH. TreatmentMedical care Anti-inflammatory agents provide a benefit in selected patients. Among patients recruited to a pilot study, IL-1 receptor agonist administered before a cold challenge blocked symptoms (eg, rash, arthralgia, and fever) and increased WBC counts and serum IL-6 concentrations (Hoffman, 2004). Medications The drug of choice for medical therapy is a selective recombinant IL-1 receptor antagonist (eg, anakinra), see discussion under MWS. Consultations Consultations with the following specialists may be helpful: dermatologist, rheumatologist, and nephrologist. Follow-upPrevention Patients should avoid exposure to cold. Complications Systemic amyloidosis is a complication, and amyloid nephropathy is a frequent cause of death. Prognosis Unlike ACU, FCAS occurs early in life, and no cases of spontaneous remission have been reported. Medicolegal pitfallsFailure to give proper genetic counseling and advice about the mode of inheritance is a pitfall. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||