eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Hereditary Periodic Fever Syndromes

Author: Marwan Shinawi, MD, Assistant Professor, Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine
Coauthor(s): Fernando Scaglia, MD, FACMG, Associate Professor of Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital
Contributor Information and Disclosures

Updated: Nov 19, 2009

Introduction

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.^1,2,3,4 The 6 disorders listed below are addressed in separate subsections of this overview:

• Familial Mediterranean fever (FMF) - Mendelian Inheritance in Man (MIM) 249100
• Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) - MIM 260920
• Tumor necrosis factor (TNF) receptor–associated periodic syndrome (TRAPS) - MIM 142680
• Muckle-Wells syndrome (MWS) - MIM 191900
• Familial cold autoinflammatory syndrome (FCAS) - MIM 120100
• Chronic infantile neurologic cutaneous articular syndrome (CINCA), also known as neonatal-onset multisystem inflammatory disease (NOMID) -MIM 607115

MWS, FCAS, and CINCA are also known as cryopyrin-associated periodic syndromes (CAPS).

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 Hereditary Periodic Fever Syndromes

Open table in new window

General pathogenesis

Cryopyrin (also called NALP3, PYPAF1, or NACHT, leucine-rich repeat (LRR), and PYD domains-containing protein 3) is the product of the NLRP3 (CIAS1) 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 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.^2,5 NF-kappaB is a proinflammatory transcription factor.

The interaction of NALP3 with ASC and caspase-1 causes a high pro-interleukin (IL)-1 beta processing activity. NLRP3 (CIAS1) mutations are gain-of-function mutations that cause constitutive activation of the inflammasome, a complex with pro-interleukin-1 processing activity,⁶ and macrophage necrosis.⁷ Alternatively, 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.⁸ Mutations in pyrin-marenostrin can lead to autoinflammation by reducing the inhibitory pathway. Furthermore, pyrin interacts with proline-serine-threonine phosphatase-interacting protein (PSTPIP1) also known as CD2-binding protein 1 (CD2BP1), which is a tyrosine-phosphorylated protein involved in cytoskeletal organization and thereby involved in immunologic cellular interactions.⁹ See Media file 1.

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 Fever

Background

Familial Mediterranean fever (FMF), 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. Familial Mediterranean fever 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 (familial Mediterranean fever protein) is the subject of intensive research, and a consensus regarding its function is gradually growing (see Media file 1).

Frequency

Familial Mediterranean fever is the most common disease among the hereditary periodic fever syndromes (HPFSs) and is common among Mediterranean people. Most cases occur in the following ethnic groups: Jews, Arabs, Armenians, 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 familial Mediterranean fever 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 in which dialysis and kidney transplantation are widely available, the outcome of patients who develop end-stage renal disease due to familial Mediterranean fever amyloidosis can be similar to that in the general transplant population.¹¹ Patients with familial Mediterranean fever without amyloidosis are expected to have a normal life span.

Race

Familial Mediterranean fever 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 familial Mediterranean fever 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.¹²

Sex

The male-to-female ratio of cases has consistently been reported to be about 1.5-2:1, 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.¹² 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.^13,14

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

History

The main complication in familial Mediterranean fever 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).¹⁵

Patients with familial Mediterranean fever have recurrent acute febrile painful attacks that last 12 hours to 4 days. The pain usually involves 1-2 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 familial Mediterranean fever is sometimes confused with the acute surgical abdomen caused by appendicitis. The use of elective appendectomy to prevent misdiagnosis and the possible devastating consequences in emergency surgery is still undetermined.¹⁶

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 familial Mediterranean fever.¹⁷

The febrile joint attacks, which occur in 70% of patients with familial Mediterranean fever, manifest as recurrent episodes of nondestructive acute monoarthritis of short duration and most frequently involve the large joints of lower extremities.¹⁸ In about 1% of patients, arthritis is the sole disease manifestation. Myalgia is a frequent finding in patients with familial Mediterranean fever. The febrile myalgia syndrome is a severe, disabling, and painful attack that lasts weeks and responds only to treatment with corticosteroids and not colchicine, which is the basic treatment in familial Mediterranean fever.

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, shallow breathing than patients who are either homozygotes for the V726A mutation or any other combination of mutations.¹⁹

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 is also involved in familial Mediterranean fever, and the typical lesion is erysipelaslike erythema on the lower extremities. Furthermore, vasculitis emerges as an important yet not a widely recognized feature of familial Mediterranean fever 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 familial Mediterranean fever than in the general population.^20,21

Other rare but well-documented manifestations include pericarditis, meningitis, headache during attacks, and infertility in women (due to defective ovulation and peritoneal pelvic adhesions).¹⁵

Until 1997, no specific laboratory test for familial Mediterranean fever was available, and the diagnosis was based on clinical findings, including a favorable response to colchicine. The discovery of the gene for familial Mediterranean fever has since changed the approach, and most cases are currently confirmed with molecular testing. The diagnostic criteria for familial Mediterranean fever are as follows:²²

• Major criteria
  • Recurrent febrile episodes of peritonitis, synovitis, or pleuritis
  • Amyloid-associated protein (AA)–type amyloidosis with no predisposing disease
  • Favorable response to continuous colchicine treatment
• Minor criteria
  • Recurrent febrile episodes
  • Erysipelaslike erythema
  • Familial Mediterranean fever in a first-degree relative

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 reveals 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 erysipelaslike 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.

Causes

Inheritance and genes

The mode of inheritance is autosomal recessive with reduced penetrance for certain mutations.

The gene responsible for familial Mediterranean fever (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 Familial Mediterranean Fever Consortium²³ and the French Familial Mediterranean Fever consortium.²⁴ It consists of 10 exons (complementary DNA [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 familial Mediterranean fever chromosomes identified in patients with the disease.^25,26,27 An updated list of mutations for familial Mediterranean fever can be found online at the Infevers Web site, or the Repertory of Familial Mediterranean Fever 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 familial Mediterranean fever and in healthy individuals.²⁶ 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.^25,26

Gene product

The MEFV product, pyrin-marenostrin, is predominantly expressed in granulocytes (the cell most frequently found in familial Mediterranean fever inflammatory exudates) and in cytokine-activated monocytes.²⁸ 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 familial Mediterranean fever 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.²⁹

A potentially important clue to the function of pyrin was the elucidation that the 92 amino acids at the N-terminal compose the pyrin domain (PD) that has been found in several regulators of apoptosis and inflammation. LPS and proinflammatory cytokines induce apoptosis-associated speck-like protein (ASC), which binds procaspase-1 by means of cognate caspase recruitment domain (CARD) interactions and leads to caspase-1 oligomerization and autocatalysis.⁵ LPS and anti-inflammatory cytokines (eg, IL-4) induce pyrin in macrophages and monocytes, the predominant lineage in IL-1-beta secretion. Pyrin binds and sequesters ASC, preventing caspase-1 activation.^10,5

Genotype-phenotype correlation

The severity of familial Mediterranean fever symptoms can be evaluated according to severity-scale scores, as follows:³⁰

• Age of onset
  • Younger than 5 years - 3 points
  • 5-10 years - 2 points
  • 10-20 years - 1 point
  • 20 years or older - 0 points
• Frequency of attacks (number per month)
  • More than 2 - 3 points
  • 1-2 - 2 points
  • Less than 1 - 1 point
• Colchicine dosage to control attacks (tablets per day)
  • More than 4 (no response) - 4 points
  • 4 - 3 points
  • 3 - 2 points
  • 2 - 1 point
• Arthritis
  • Protracted - 3 points
  • Acute - 2 points
• Erysipelaslike erythema present - 2 points
• Amyloidosis
  • Present - 3 points
  • Phenotype II - 4 points

A score of 2-5 points represents mild severity, a score of 6-10 points is moderately severe, and a score of more than 10 is severe.

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.^31,32 Mutation M680I induces a moderate form of disease phenotype.^25,33 Mutations E148Q, K695R, and V726A have reduced penetrance, and many individuals who are either homozygous or compound heterozygous for these mutations remain asymptomatic.^34,26 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 familial Mediterranean fever, 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 familial Mediterranean fever.^13,35,14 Furthermore, the occurrence of arthritis attacks and male sex were significantly and independently associated with renal amyloidosis.^13,36

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.³³

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.¹⁰ This heightened sensitivity to endotoxin suggests that transient bacteremias might provoke exaggerated IL-1 alpha production and, thereby, might provoke 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 familial Mediterranean fever.

Environmental causes

Emotional stress, extreme physical exercise, and menses can trigger the inflammatory attacks of familial Mediterranean fever.

Differential Diagnosis

The differential diagnosis of familial Mediterranean fever includes the following:

• Acute appendicitis
• Gynecologic problems (pelvic inflammatory disease [PID], endometriosis, ovarian cyst)
• Porphyria
• Hereditary angioedema
• Pancreatitis (with hypertriglyceridemia)
• HSP
• PAN
• Pneumonia
• Septic arthritis
• Juvenile rheumatoid arthritis (JRA), systemic onset
• Amyloidosis
• Infectious pleuritis
• Infectious pericarditis
• Other HPFSs, especially hyperimmunoglobulinemia D with periodic fever syndrome (HIDS)
• Cyclic neutropenia
• Acute scrotum - Torsion of the testis, epididymitis, orchitis

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 age 5 years. Throat culture results are negative, but levels of acute-phase reactants are elevated. The attacks spontaneously resolve, but a single dose of prednisone at 2 mg/kg given orally (PO) at the beginning of the attack is abortive.³⁷ The condition completely resolves in most patients. PFAPA is sporadic, and no ethnic predilection has been found.

Workup

Laboratory studies

During attacks, laboratory studies show elevation in the total WBCs (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], serum amyloid A [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 polymorphonuclear infiltration.

Imaging studies

Upright abdominal radiographs may reveal air-fluid levels (peritonitis). Chest radiography may reveal 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 reveals 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 reveal pericardial fluid (pericarditis). Regarding lumbar puncture (LP), few reports describe increased levels of protein and leukocytes in the cerebrospinal fluid (CSF) during attacks.

Treatment

Medical care

Treatment with colchicine reduces the number and severity of the familial Mediterranean fever 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 familial Mediterranean fever (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.³⁸ At low doses, colchicine is a relatively safe medication; GI manifestations are the most common adverse effects.

Treatment with colchicine is started with 1 mg/d 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 may not prevent amyloidosis.¹⁵ When the dosage is more than 1 mg per 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 familial Mediterranean fever (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 mg 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 as much as 3 mg/d, 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 and include nausea, vomiting, diarrhea, and abdominal pain. Cardiovascular adverse events include hypotension, sinus bradycardia, and vasculitis. CNS effects include confusion, delirium, and seizures. Dermatologic effects include rash, alopecia, bullous skin disease, toxic epidermal necrolysis, urticaria, pruritus, axonopathy, licheniform eruptions, and exanthema. Endocrine and metabolic effects include dehydration. Genitourinary effects include azoospermia.

Hematologic effects include neutropenia, agranulocytosis, thrombocytopenia, aplastic anemia, methemoglobinemia, and megaloblastic anemia. Hepatic effects include hepatotoxicity. Neuromuscular and skeletal effects include myopathy, peripheral neuritis, paralysis, and rhabdomyolysis. Ocular effects include diplopia. Renal effects include hematuria, and acute tubular necrosis. Respiratory effects include 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 induces CYP2C8/9 (weak), CYP2E1 (weak), and 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.¹⁵ 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-up

Tests

Routine urinalyses are imperative for patients with familial Mediterranean fever 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 familial Mediterranean fever 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 Pitfalls

Continuous daily treatment is urged for the prevention of amyloidosis. Patients with familial Mediterranean fever 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 Syndrome

Background

In 1984, van der Meer et al first described hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), also known as mevalonate kinase (MK) deficiency (MKD), in 6 patients of Dutch ancestry.³⁹ 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 included 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

Hyperimmunoglobulinemia D with periodic fever syndrome is caused by mutations in the MVK gene that result in a depressed enzymatic activity, which has been confirmed in fibroblasts from patients with hyperimmunoglobulinemia D with periodic fever syndrome.^40,41 MK, a homodimeric enzyme, is mainly found 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 Media file 2).

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).⁴⁴

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.⁴⁵

As of May 2003, the hyperimmunoglobulinemia D with periodic fever 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 one study⁴⁶ but about 3:2 in another large series;⁴⁷ 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, although patients have a reduction in intensity and frequency of attacks after adolescence.

Clinical

History

Patients have a long history of episodic attacks of fever that occur every 4-8 weeks and that may last 3-7 days, although individual variability is considerable.

Attacks manifest as high, spiking fever is preceded by chills in 76% of patients.⁴⁷ During the attacks, 72% of patients reported abdominal pain, 56% reported vomiting, 82% reported diarrhea, and 52% reported headache. Joint involvement is common in the hyperimmunoglobulinemia D with periodic fever syndrome, with polyarthralgia reported in 80% and a nondestructive arthritis reported in 68% of patients. About 82% of patients reported skin lesions with some attacks. Serositis has been seen in only a minority of patients. Surprisingly, amyloidosis has not been recorded in any of the patients with this syndrome.

Diagnostic criteria for hyperimmunoglobulinemia D with periodic fever syndrome are as follows:⁴⁷

• Constant: High IgD level (>100 U/mL) measured on 2 occasions at least 1 month apart
• During attacks
  • Elevated erythrocyte sedimentation rate (ESR) and leukocytosis
  • Abrupt onset of fever (temperature at least 38.5°C)
  • Recurrent attacks
  • Elevated immunoglobulin A (IgA) level
  • Cervical lymphadenopathy
  • Abdominal distress (vomiting, diarrhea, pain)
  • Skin manifestations (erythematous macules and papules)
  • Arthralgias and/or arthritis
  • Splenomegaly

Drenth and van der Meer recommended the following diagnostic strategy:⁴⁸

1. Review the clinical and family history.
2. Measure IgD and IgA. IgD should be measured on 2 occasions at least 1 month apart.
3. Measure urinary mevalonic acid. These tests help in detecting only a slight elevation and are generally ineffective.
4. Perform genetic testing to screen for the most common V377I mutation. Sequencing of the gene in highly suspicious cases with negative V377I mutation is a possibility, although the large size of the gene and the nonavailability of this testing in many countries are major obstacles.
5. In rare cases, measure MK activity.

Steichen et al have validated a method for excluding HIDS on the basis of a clinical criterion.⁴⁹ In deriving the method, the researchers confirmed that among 149 patients undergoing genetic testing, 35 of the patients with HIDS had onset of attacks before 5 years of age or the combination of joint pain during attacks and length of attacks less than 14 days. On testing of this criterion in 93 patients, 35 of whom had HIDS, it was found to have a sensitivity of 100% (95% confidence interval [CI], 88-100%) and a specificity of 28% (95% CI, 17-40%). Steichen et al note that had genetic testing been limited to patients fulfilling this criterion, 19% of unnecessary tests would have been avoided.

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.

Causes

Genetic causes

Hyperimmunoglobulinemia D with periodic fever syndrome 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 hyperimmunoglobulinemia D with periodic fever syndrome. Sequence analysis of MVK complementary DNA (cDNA) showed different mutations, of which V377I is most common.^40,41

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.⁵⁰

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-fold to 8-fold when patients with hyperimmunoglobulinemia D with periodic fever syndrome have febrile attacks.

A similar phenomenon occurs in vitro, when hyperimmunoglobulinemia D with periodic fever syndrome 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.⁵¹ 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 hyperimmunoglobulinemia D with periodic fever syndrome and identified 2 groups: 41 patients with MK mutations (classic-type hyperimmunoglobulinemia D with periodic fever syndrome) and 13 patients without mutations (variant-type hyperimmunoglobulinemia D with periodic fever syndrome).⁴⁷ Patients with classic-type hyperimmunoglobulinemia D with periodic fever syndrome 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 Diagnosis

Mevalonic aciduria (MVA) is typically a disease of infantile onset. It is characterized by psychomotor retardation, ataxia, failure to thrive, cataracts, and dysmorphic features.^52,53,54 Patients also have periodic fever attacks that are similar to but more severe than in hyperimmunoglobulinemia D with periodic fever syndrome. In general, they die in early childhood. Patients have dysmorphic features that include microcephaly, triangular face, and hypoplastic alae nasi.⁵⁵ The residual MK activity in patients with hyperimmunoglobulinemia D with periodic fever syndrome is 1-7%, whereas residual MK activity in almost every patient with MVA is undetectable (<0.5%).⁵⁰

In hyperimmunoglobulinemia D with periodic fever syndrome, 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.⁴⁶ The most common MVK mutation, V377I (1129G>A), is identified exclusively in patients with hyperimmunoglobulinemia D with periodic fever syndrome. Other common mutations have been associated with both hyperimmunoglobulinemia D with periodic fever syndrome and MVA.

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 hyperimmunoglobulinemia D with periodic fever syndrome instead of 2 separate phenotypic entities. The identification of adult patients with phenotypic overlap between these syndromes supports this continuum.⁴

Workup

Laboratory studies

The most typical finding is the consistently elevated serum IgD level (>100 U/mL, comparable to 141 mg/L), although patients can have normal IgD levels. The IgD level is not correlated with disease severity, MK enzyme activity, or genotype.⁴⁷ Approximately 82% also have elevated serum IgA levels.⁵⁶

During attacks, an acute-phase response occurs, with high c-reactive protein (CRP) levels, increased ESR, and leukocytosis. Symptomatic episodes are associated with increased concentrations of inflammatory mediators (tumor necrosis factor [TNF]-alpha, interleukin [IL]-6, interferon [IFN]-gamma) and anti-inflammatory compounds (IL-1 receptor antagonist and soluble TNF receptors p55 [sTNFr p55] and sTNFr p75]).⁵⁷ 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.⁴⁷ Approximately 90% of patients are compound heterozygous. About 80% of mutations are missense. In hyperimmunoglobulinemia D with periodic fever syndrome, 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.⁴⁶ 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.

Treatment

Medical care

The treatment of hyperimmunoglobulinemia D with periodic fever syndrome 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.⁴⁸

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 hyperimmunoglobulinemia D with periodic fever syndrome. This effect was tested in 6 patients with hyperimmunoglobulinemia D with periodic fever 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.⁵⁸ 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.

Consultations

Consultations with the following specialists may be helpful: dermatologist, rheumatologist, and infectious disease specialist (to evaluate periodic fever).

Follow-up

Patients with the hyperimmunoglobulinemia D with periodic fever syndrome have febrile attacks throughout their lives, with a slight decrease after adolescence. Amyloidosis has not been reported in with this disease.

Medicolegal Pitfalls

A 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–Associated Periodic Syndrome

Background

Tumor necrosis factor (TNF) receptor–associated periodic syndrome (TRAPS), or familial Hibernian fever, is a disorder that was first reported in 1982 in a large family of Irish-Scottish ancestry.⁵⁹ Tumor necrosis factor receptor–associated periodic syndrome 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 tumor necrosis factor receptor–associated periodic syndrome than in hyper-IgD syndrome or familial Mediterranean fever (FMF).

Pathogenesis

Tumor necrosis factor receptor–associated periodic syndrome is caused by mutations in TNFRSF1A, the gene that encodes the receptor for TNF.⁵⁹ 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.⁶⁰

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 tumor necrosis factor receptor–associated periodic syndrome because some mutations have normal shedding.⁶¹ 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.⁶¹ This high carrier frequency might reflect a combination of underdiagnosis, reduced penetrance, and variable expressivity.

Mortality and morbidity

The prognosis for patients with the tumor necrosis factor receptor–associated periodic syndrome mainly depends on amyloidosis. The medical literature does not provide clear mortality data.

Race

Most patients are of northern European descent. Although tumor necrosis factor receptor–associated periodic syndrome 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.⁶⁰

Sex

A male-to-female ratio of 3:2 is reported.⁶⁰ 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

History

The rate and duration of the inflammatory attacks widely vary. 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 tumor necrosis factor receptor–associated periodic syndrome 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.⁶²

The following clinical characteristics suggestive of tumor necrosis factor receptor–associated periodic syndrome may serve as guidelines or indications for ordering genetic testing:⁶⁰

• Recurrent episodes of inflammatory symptoms spanning a period longer than 6 months
  • Fever
  • Abdominal pains
  • Migratory myalgia
  • Migratory erythematous patches
  • Conjunctivitis, periorbital edema
  • Chest pain
  • Arthralgia or arthritis
• Episodes last longer than 5 days on a average
• Responsive to glucocorticoids but not colchicine
• Affected family members
• Any ethnicity

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).

Causes

Genetics

Tumor necrosis factor receptor–associated periodic syndrome is an autosomal dominant disease caused by mutations in the TNFRSF1A gene. The gene is composed of 10 exons. Thus far, 58 mutations have reported in patients (see the Infevers Database for tumor necrosis factor receptor–associated periodic syndrome 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.⁶¹ 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 also increase the probability of life-threatening amyloidosis (24% vs 2% for noncysteine residue substitutions).⁶¹ 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 Diagnosis

Other hereditary periodic fever syndromes (HPFS), especially FMF should be considered.⁶³ Acute peritonitis is another differential diagnosis. A substantial number of patients undergo explorative laparotomy and appendectomy because of signs of acute abdomen. (Also see the Differential Diagnosis section for FMF.)

Workup

Laboratory studies

As in other HPFS, levels of acute-phase reactants (serum amyloid A [SAA], C-reactive protein [CRP], fibrinogen, haptoglobin, ferritin) are high, and erythrocyte sedimentation rate (ESR) is elevated during attacks and even between attacks in many patients. The CBC count may reveal anemia of chronic disease, leukocytosis, and thrombocytosis. The immunoglobulin D (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).⁶⁴  

Treatment

Medical care

Conventional treatment includes nonsteroidal anti-inflammatory drugs (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.⁶⁰ One study showed that etanercept does not abort inflammatory attacks but improves disease activity allowing for a reduction of corticosteroids.⁶⁵ The authors concluded that etanercept may be clinically useful in replacing or reducing steroid requirements in the treatment of tumor necrosis factor receptor–associated periodic syndrome.

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.⁶⁶ Failure and lack of efficacy of etanercept and infliximab in patients with tumor necrosis factor receptor–associated periodic syndrome has also been reported.⁶⁷   

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 tumor necrosis factor receptor–associated periodic syndrome 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 include 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 congestive heart failure, 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 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, or 50 mg.

The adult dosage is 5-60 mg/d orally (PO) in divided doses given 1-4 times/d. The pediatric dosage is 0.05-2 mg/kg/d PO divided 1-4 times daily. 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, congestive heart failure, 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-up

Complications

Amyloidosis is the most serious long-term complication of tumor necrosis factor receptor–associated periodic syndrome. About 14% of patients with tumor necrosis factor receptor–associated periodic syndrome develop amyloidosis, which has a strong predilection for those with mutations that result in cysteine substitutions. Approximately 24% patients with tumor necrosis factor receptor–associated periodic syndrome and cysteine mutations (substitutions) develop amyloidosis versus 2% of patients with noncysteine mutations.⁶¹

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 Pitfalls

A 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 Syndrome

Background

Muckle-Wells syndrome (MWS), a  cryopyrin-associated periodic syndrome, was first described as a rare hereditary disorder with an autosomal dominant mode of inheritance.⁶⁸ Since then, most published studies have focused on kindreds from northern Europe. Patients with autosomal dominant Muckle-Wells syndrome 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 NLRP3 (CIAS1) gene are associated with the autoinflammatory diseases Muckle-Wells syndrome, familial cold autoinflammatory syndrome (FCAS), and cutaneous articular syndrome (CINCA)/neonatal-onset multisystem inflammatory disease (NOMID) syndrome, collectively called cryopyrin associated periodic syndromes (see Media file 1).

Frequency

Muckle-Wells syndrome 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 Muckle-Wells syndrome. 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

Muckle-Wells syndrome manifests at birth or in early infancy.

Clinical

History

The disease is characterized by acute febrile inflammatory attacks that last 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 Muckle-Wells syndrome from other inflammatory disorders. After several years, amyloidosis of the AA type develops.

Physical examination

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. 

Causes

Genetics

Muckle-Wells syndrome is caused by mutations in a gene called NLRP3 (CIAS1) , which encodes a protein known as cryopyrin, NALP3, cryopyrin, or PYPAF1. This protein is a member of the pyrin superfamily of DD-fold proteins.^69,70 The NLRP3 (CIAS1) gene is expressed in polymorphonuclear neutrophils (PMNs), monocytes, and chondrocytes. It contains a nucleotide-binding site (NACHT), a C-terminal domain containing 7 leucine-rich repeats (LRRs), and an N-terminal PD (PyD).⁷¹ The pyrin domain (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 NLRP3 (CIAS1) mutations.^72,8,73

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 Media file 1).

NLRP3 (CIAS1) mutations were initially identified in patients with Muckle-Wells syndrome and FCAS disorders.⁶⁹ Since then, 111 mutations in this gene have been found, as listed in the Infevers Database of cryopyrin-associated periodic syndromes (CAPS) mutations. Some mutations in this gene are associated with different phenotypes in different families. The clinical features of the various syndromes associated with mutations in the NLRP3 (CIAS1) gene may overlap more than previously recognized.⁷³ The correlation of phenotype and NLRP3 (CIAS1) genotype is broad in terms of disease characteristics, penetrance, and severity. All phenotypes caused by NLRP3 (CIAS1) gene mutation are collectively known as CAPS. NLRP3 (CIAS1) mosaicism plays an important role in mutation-negative CAPS.⁷⁴

Aggravating factors

Cold, dampness, and stress trigger cutaneous symptoms.

Differential Diagnosis

Muckle-Wells syndrome 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.^75,73 In fact, cold-induced skin lesions in Muckle-Wells syndrome represent typical generalized inflammatory reactions to cold air or win, as is also observed in familial cold urticaria (FCU).⁷⁵

The differential diagnosis also includes other hereditary periodic fever syndromes (HPFSs), Alport syndrome (which has the common features of renal, ear, and ocular involvement), amyloidosis, conjunctivitis, and arthritis.

Workup

Laboratory studies

Laboratory testing may reveal 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, more than 90% of mutations in CAPS have been identified in exon 3 of the NLRP3 (CIAS1) 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 NLRP3 (CIAS1) gene. For an update on the laboratories that perform the test, visit the GeneTests Web site funded by the National Institutes of Health (NIH).

Histology

Microscopic features are similar to those observed in other types of urticaria. A 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).⁷⁵

Treatment

Medical care

Until recently, no treatment has been proved to be beneficial for Muckle-Wells syndrome, although data suggest that colchicine and high-dose corticosteroids exert a favorable effect on the intensity and recurrence of attacks. The rarity of Muckle-Wells syndrome 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 Muckle-Wells syndrome complicated by amyloidosis.⁷⁶ 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. This remarkable response suggests that IL-1 has a role in the pathogenesis of inflammation associated with NLRP3 (CIAS1) mutations.

Although the long-term effect of this treatment is unknown, anakinra has the potential to be lifesaving in patients with Muckle-Wells syndrome 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.⁷³

In February 2008, the IL-1 antagonist rilonacept (Arcalyst) was approved by the US Food and Drug Administration (FDA). Rilonacept was shown to improve symptoms associated with CAPSs, including FACS and Muckle-Wells syndrome. Studies report improvement in symptoms such as joint pain, rash, fever or chills, eye irritation and pain, and fatigue.

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 Muckle-Wells syndrome is a selective recombinant IL-1 receptor antagonist.

• Loading dose - 320 mg as 2 subcutaneous (SC) injections of 160 mg each on day 1 at 2 different injection sites
• Maintenance - 160 mg SC every week

The pediatric dose for rilonacept is as follows:

• Patients younger than 12 years - Not established
• Patients aged 12-17 years
  • Loading dose - 4.4 mg/kg, not to exceed 320 mg, as 1 SC injection or divided into 2 SC injections on day 1; not to exceed 2 mL (160 mg) for single injection volume
  • Maintenance - 2.2 mg/kg/dose SC every wk; not to exceed 160 mg/dose

Anakinra (Kineret) is given in an adult dose 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 include 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 tumor necrosis factor (TNF), including infliximab and thalidomide. Anakinra is pregnancy class B; 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 are available, even then it should be used only with extreme caution.

Impact on the development and course of malignancies is not fully defined. Use caution in patients with a history of significant hematologic abnormalities. Use has been associated with uncommon but significant decreases in hematologic parameters (particularly neutrophil counts). Patients must be advised to seek medical attention if they develop signs and symptoms suggestive of blood dyscrasias. Discontinue if clinically significant hematologic abnormalities are confirmed.

A second IL-1 receptor antagonist was recently approved by the FDA. Canakinumab (Ilaris) is a highly selective IL-1 beta-receptor antagonist.⁷⁷ In June 2009, canakinumab was approved by the FDA as an orphan drug for inflammation associated with CAPS. The adult dose is 150 mg SC every 8 weeks. For children older than 4 years, the dose is 2 mg/kg SC every 8 weeks if the patient weighs less than 40 kg. For children who weigh 40 kg or more, administer as in adults. Common adverse effects include nasopharyngitis, diarrhea, influenza, headache, and nausea. Similar to other monoclonal antibodies, injection site reactions may occur and an increased risk for infection may be noted.

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-up

Complications

Approximately 26% of patients have renal amyloidosis. AA amyloidosis is not required for the diagnosis of Muckle-Wells syndrome, does not occur in every patient, can be delayed in the course of the disease, or 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 Syndrome

Background

Familial cold autoinflammatory syndrome (FCAS) is also known as familial cold urticaria (FCU), familial polymorphous cold eruption, and cold hypersensitivity. FCAS 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 hereditary periodic fever syndromes (HPFSs) in that cold is a consistent trigger, the age of onset is usually younger than 6 months, and the episodes usually last less than 24 hours.⁷⁸

Pathogenesis

Mutations in the NLRP3 (CIAS1) gene are associated with the cryopyrin-associated periodic syndromes (Muckle-Wells syndrome [MWS], familial cold autoinflammatory syndrome, and chronic infantile neurologic cutaneous articular syndrome [CINCA]/neonatal-onset multisystem inflammatory disease [NOMID] syndrome). The gene product, cryopyrin, interacts with apoptosis-associated speck-like protein (ASC), leading to the activation of caspase 1 and the subsequent release of interleukin (IL)-1. In addition, activation of nuclear factor (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 serum amyloid A (SAA) by hepatocytes during the acute-phase response; SAA accumulates in different organs, causing amyloidosis.

Frequency

Familial cold autoinflammatory syndrome 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 cases and within the first few days of life in 60% of cases.⁷⁸ 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

History

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.⁷⁸ 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 familial cold autoinflammatory syndrome that Hoffman et al proposed are listed below.⁷⁸ When these criteria were applied in one study, 41% of affected subjects met all 6 criteria for familial cold autoinflammatory syndrome, 90% met 5 criteria, and 100% met 4 criteria. None of the unaffected subjects met more than 2 criteria.⁷⁹

Proposed diagnostic criteria for familial cold autoinflammatory syndrome are as follows:⁷⁸

• Recurrent, intermittent episodes of fever and rash that primarily follow natural, experimental, or both types of generalized cold exposures
• Autosomal dominant pattern of disease inheritance
• Age of onset younger than 6 months
• Duration of most attacks less than 24 hours
• Conjunctivitis associated with the attacks
• Absence of deafness, periorbital edema, lymphadenopathy, and serositis

Physical examination

Patients may have fever, profuse sweating, conjunctivitis, and urticaria (mostly on the extremities and face).

Causes

Familial cold autoinflammatory syndrome is caused by heterozygous mutations in NLRP3 (CIAS1) gene.^69,70 For more details, see the Causes section for MWS.) The L353P mutation in the NLRP3 (CIAS1) gene is present in more than 90% of North American patients.^80,81

Cold is a consistent trigger of the attacks. The temperature that is required to induce symptoms widely varies, 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 Diagnosis

Acquired cold urticaria (ACU) is one of the most common forms of physical urticaria. The pathophysiology of ACU involves mast-cell degranulation and histamine effects. Unlike familial cold autoinflammatory syndrome, ACU typically occurs in adulthood and spontaneously resolves. The clinical presentations of the 2 entities also differ; ACU develops within minutes of direct contact with cold, resolves within hours, and 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 familial cold autoinflammatory syndrome. The musculoskeletal system is involved differently in these 3 diseases. The main rheumatologic problems are arthralgia in familial cold autoinflammatory syndrome, synovitis in MWS, and premature patellar and epiphyseal long-bone ossification and bone overgrowth in CINCA syndrome. Currently, these 3 diseases are considered to reflect a spectrum of illnesses, with familial cold autoinflammatory syndrome at the mild end and CINCA syndrome at the severe end.

Few NLRP3 (CIAS1) mutations are found in more than one disorder in which genetic and environmental modifiers play a role in determining the disease phenotype.

Other differential diagnoses include cryoglobulinemia and urticaria.

Workup

Laboratory studies

Laboratory studies may reveal elevated levels of acute-phase reactants, an elevated erythrocyte sedimentation rate (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 findings from samples obtained during attacks reveal 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.⁸²

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 familial cold autoinflammatory syndrome have been identified in exon 3 of the NLRP3 (CIAS1) 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 NLRP3 (CIAS1) gene . For an update on the laboratories that perform the test, visit the GeneTests Web site funded by the National Institutes of Health (NIH).

Treatment

Medical 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.⁸³

Rilonacept administration (100 mg) to 5 patients with familial cold autoinflammatory syndrome improved rash, fever, and joint pain/swelling within days and the markers of inflammation (ESR, C-reactive protein [CRP], and SAA) showed significant reductions. Doses of 160 mg and 320 mg resulted in subjectively better control of the rash and joint pain and in the acute phase reactants were lower. No study drug-related serious adverse events were seen⁸⁴ .

Medications

The drugs of choice for medical therapy are selective recombinant IL-1 receptor antagonists (eg, rilonacept, anakinra, canakinumab), see MWS.

Consultations

Consultations with the following specialists may be helpful: dermatologist, rheumatologist, and nephrologist.

Follow-up

Prevention

Patients should avoid exposure to cold.

Complications

Systemic amyloidosis is a complication, and amyloid nephropathy is a frequent cause of death.

Prognosis

Unlike ACU, familial cold autoinflammatory syndrome occurs early in life, and no cases of spontaneous remission have been reported.

Medicolegal Pitfalls

Failure to give proper genetic counseling and advice about the mode of inheritance is a pitfall.

Chronic Infantile Neurologic Cutaneous Articular Syndrome

Background

Chronic infantile neurologic cutaneous articular syndrome, or neonatal-onset multisystem inflammatory disease (NOMID), is a rare congenital inflammatory disorder characterized by a neonatal onset, recurrent fever and inflammation, cutaneous symptoms, joint manifestations (chronic arthropathy due to epiphyseal overgrowth), facial dysmorphism, and CNS involvement. CNS involvement manifests as chronic meningitis, bilateral papilledema, sensorineural deafness, mental retardation, and cerebral atrophy.⁸⁶

Pathogenesis

Mutations in the NLRP3 (CIAS1) that encode cryopyrin is the cause of this condition.^87,88 Cryopyrin interacts with apoptosis-associated speck-like protein (ASC), leading to the activation of caspase 1 and the subsequent release of interleukin (IL)-1, as well as the activation of nuclear factor (NF)-kappaB, which results in the release of many proinflammatory cytokines. IL-1 is a key proinflammatory cytokine that contributes to increased synthesis of serum amyloid A (SAA) protein by hepatocytes during the acute-phase response; SAA finally accumulates in different organs, causing amyloidosis (see Media file 1).

Frequency

Neonatal-onset multisystem inflammatory disease/chronic infantile neurologic cutaneous articular syndrome is a rare disease, and the exact frequency is unknown.

Mortality and morbidity

Approximately 20% of patients die before reaching young adulthood.

Race

Any ethnicity can be affected.

Sex

Males and females are equally affected.

Age

The first symptoms are generally present at birth or appear in early infancy.

Clinical

History

This dominantly inherited disease is characterized by the onset in the neonatal period and the triad of skin rash, chronic aseptic meningitis, and arthropathy.⁸⁹ The typical features include a persistent and migratory urticarial rash (which is often present from birth), fever, adenopathy, hepatosplenomegaly, and a severe and deforming arthropathy (which predominantly affects the large joints). Short episodes of recurrent fevers frequently occur. The arthropathy starts early in life and has distinctive radiographic findings of premature patellar and epiphyseal long-bone ossification and resultant osseous overgrowth that leads to severe joint contractures and disability.⁹⁰

Progressive neurologic impairment results from chronic aseptic meningitis caused by polymorphonuclear neutrophil (PMN) infiltration. Neurologic manifestations include progressive visual defect and high-frequency hearing loss (which frequently occurs with age), cerebral ventricular dilatation, cerebral atrophy, and mental retardation.

Physical examination

Physical findings may include fever, urticarialike skin rash, splenomegaly and lymphadenopathy, dysmorphic features (saddle-back nose, frontal bossing, protruding eyes), short stature with short and thick extremities, macrocephaly, finger clubbing, and joint contractures (especially in the knees) without evidence of synovial thickening on palpation.

Funduscopic examination may reveal papilledema and uveitis.

Causes

Chronic infantile neurologic cutaneous articular syndrome is caused by heterozygous mutations in the NLRP3 (CIAS1) gene. For more details, see the Causes section for Muckle-Wells syndrome (MWS). Most cases are caused by de novo mutations, although familial recurrence is described.⁸⁸ Mutations in NLRP3 (CIAS1) are found in only about 50% of patients clinically identified as having neonatal-onset multisystem inflammatory disease/chronic infantile neurologic cutaneous articular syndrome. This observation raises the possibilities of locus heterogeneity and mutations in the regulatory elements or phenocopies (ie, acquired forms that mimic the genetic version of the disease).⁸⁷

Differential Diagnosis

The differential diagnosis includes Still disease and other hereditary periodic fever syndromes (HPFSs), especially MWS and familial cold autoinflammatory syndrome (FCAS). FCAS, MWS, and neonatal-onset multisystem inflammatory disease/chronic infantile neurologic cutaneous articular syndrome appear to represent a spectrum of disease; FCAS is the most mild and neonatal-onset multisystem inflammatory disease/chronic infantile neurologic cutaneous articular syndrome is the most severe.

Workup

Laboratory studies

Laboratory studies may reveal anemia and persistent leukocytosis; and elevated ESR; high levels of eosinophils in the blood, cerebrospinal fluid (CSF), and tissues;⁸⁶ and hyperglobulinemia.

Histology

Evaluation of skin samples may reveal mild perivascular leukocytic and eosinophilic infiltrates.

Imaging studies

Radiography or MRI of knees (or other joints) may be performed. Most patients have epiphyseal radiographic findings that are virtually pathognomonic. These findings are bone overgrowth and deformities of the joints, most commonly the knees.⁹⁰ Brain CT scanning and/or MRI may reveal ventriculomegaly and cerebral atrophy.

Other tests

All mutations except one in chronic infantile neurologic cutaneous articular syndrome have been identified in exon 3 of the NLRP3 (CIAS1) 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 National Institutes of Health (NIH).

Treatment

Medical care

Nonsteroidal anti-inflammatory drugs (NSAIDs) are only partially effective.

In one patient with chronic infantile neurologic cutaneous articular syndrome/neonatal-onset multisystem inflammatory disease syndrome, treatment with etanercept, an agent that blocks tumor necrosis factor (TNF), improved arthropathy.⁹¹

Frenkel et al (2004) reported an impressive clinical response to anakinra in 3 patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic cutaneous articular syndrome, which provides hope for severely affected children and their families.⁹² Hoffman and Patel (2004) suggest that anakinra might be equally effective in all diseases associated with mutations in the NLRP3 (CIAS1) gene.⁸³ In fact, anakinra has been shown to be effective in all 3 of these diseases, which are thought to represent a continuum of 1 disease characterized by IL-1–mediated inflammation. Although the responses to anakinra reported in all 3 autoinflammatory disorders have been dramatic, formal clinical trials are needed before clear treatment recommendations can be made.

Daily injections of anakinra markedly improved clinical and laboratory manifestations in patients with chronic infantile neurologic cutaneous articular syndrome with or without CIAS1 mutations. A rapid disappearance of the rash, improvement in the biochemical markers, and improvement in cochlear and leptomeningeal lesions on MRI was observed; however, withdrawal of anakinra uniformly resulted in relapse within days.⁹³

Medications

The drugs of choice for medical therapy are selective recombinant IL-1 receptor antagonists (eg, anakinra, canakinumab). For more details, see the Medications section for MWS.

Consultations

Consultations with the following specialists may be helpful: rheumatologist, ophthalmologist, otolaryngologist, nephrologist, and neurologist.

Follow-up

Complications

Complications include progressive neurologic impairment, as well as a progressive visual defect and perceptive deafness.

Prognosis

The long-term prognosis is poor, with progressive deafness and visual impairment and worsening of the CNS manifestations. Some deaths are due to infection, vasculitis, or amyloidosis. Most patients have cerebral atrophy and a low intelligence quotient (IQ).

Medicolegal Pitfalls

Negative results on genetic testing do not rule out the diagnosis because mutations in NLRP3 (CIAS1) are found in only about 50% of patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic cutaneous articular syndrome.⁹⁰

Summary

Table 2 provides an overall summary of the genetic and clinical characteristics of the hereditary periodic fever syndromes (HPFSs).

Table 2. Overall Summary of Hereditary Periodic Fever Syndromes

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Multimedia

(Enlarge Image)

Media file 1: Cryopyrin interacts with apoptosis-associated speck-like protein (ASC), leading to activation of caspase 1 and subsequent release of interleukin (IL)-1 and to the activation of nuclear factor kappa B (NF-kappaB). This results in the release of many proinflammatory cytokines. Pyrin interacts and inhibits apoptosis and NF-kappaB activation by disrupting the cryopyrin-ASC interaction. IL-1 is a key proinflammatory cytokine that contributes to increased synthesis of serum amyloid A protein in hepatocytes during the acute-phase response.

(Enlarge Image)

Media file 2: Mevalonate kinase (MK) catalyzes the phosphorylation of mevalonic acid. This pathway is used to synthesize cholesterol and other sterol compounds as well as nonsterol isoprene metabolites; all are involved in many cellular functions.

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, renal failure, renal amyloidosis, nephrotic syndrome, peritonitis, nondestructive acute monoarthritis, pleuritis, vasculitis, Henoch-Schönlein purpura, HSP, polyarteritis nodosa, PAN, splenomegaly, aphthous ulcers

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