Chapter 157 Hereditary Periodic Fever Syndromes

Hereditary periodic fever syndromes are a group of autoinflammatory diseases caused by an inborn error in the innate immune system. They are characterized by recurrent short episodes of fever that are self-limited and occur in the absence of infection or autoimmune reaction, such as high titer autoantibodies or autoreactive T cells. The innate immune system provides the first immunologic line of defense against many microbes and uses pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) to recognize a limited number of widely expressed viral and bacterial molecular structures known as pathogen-associated molecular patterns (PAMPs). These pattern recognition receptors stimulate inflammation by activating intracellular proteins (also known as intracellular sensors), which mediate the regulation of nuclear factor-κB (NF-κB), cell apoptosis, and interleukin-1β (IL-1β) through cross-regulated and common signaling pathways. Mutations in these intracellular proteins lead to increased production and secretion of IL-1β, resulting in clinical signs and symptoms.

The most common hereditary periodic fever disorders are familial Mediterranean fever (FMF), tumor necrosis factor (TNF) receptor–associated periodic syndrome (TRAPS), and hyperimmunoglobulinemia D syndrome (HIDS) (Table 157-1). The cryopyrin-associated periodic syndromes (CAPS) include Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS) (also known as familial cold urticaria [FCU]), and chronic infantile neurologic cutaneous and articular (CINCA) disease (also known as neonatal-onset multisystem inflammatory disease [NOMID]). A syndrome called pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) and Blau syndrome (known also as familial juvenile systemic granulomatosis) have now been added to this group. Secondary amyloidosis (AA amyloidosis) is a complication in all of these periodic fever disorders, although it is less commonly reported with HIDS. FMF and HIDS are autosomal recessive diseases, whereas TRAPS, PAPA, and Blau syndrome are autosomal dominant conditions. The diagnosis of each of these entities depends on the clinical features and the genetic confirmation (see Table 157-1). Another periodic fever syndrome is periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA), but it is not clear yet whether PFAPA is an autoinflammatory syndrome (see Table 157-1). Among the conditions that are not in the category of periodic fever and that have been classified as autoinflammatory diseases are Crohn disease, Behçet diseases, early-onset childhood sarcoidosis, systemic juvenile idiopathic arthritis (JIA), and chronic recurrent multifocal osteomyelitis (known also as Majeed syndrome) (Table 157-2).

Table 157-1 SUMMARY OF CLINICAL FINDINGS ASSOCIATED WITH HEREDITARY PERIODIC FEVERS

Familial Mediterranean Fever

FMF is an autosomal recessive disorder characterized by brief, acute, self-limited episodes of fever and polyserositis that recur at irregular intervals and are associated with development of AA amyloidosis (Chapter 158).

Etiology

The gene responsible for FMF is mapped to a small interval on the short arm of chromosome 16p13.3. It is designated MEFV (ME for Mediterranean and FV for fever) and is a member of the RoRet gene family. It has 10 exons that express a 15-kb transcript encoding a 781–amino acid protein known as pyrin (from pyrus, the Greek word for “fever”), or marenostrin (Latin word for “our sea”), which is expressed in myeloid cells. Exon 10 and exon 2 carry most FMF-associated mutations. To date, more than 70 mutations have been discovered, mostly missense mutations. It is unclear whether all are truly disease-related mutations. The 5 most common mutations (M694V, V726A, M694I, M680I, E148Q) are found in more than two thirds of Mediterranean patients with FMF. Haplotypes and mutational analyses show ancestral relationships among carrier chromosomes that have been separated for centuries.

Approximately 70% of patients with clinical manifestations of FMF are heterozygous and have one of the two mutations that are identifiable by genetic analysis. The most common missense mutation is M694V (substitution of methionine with valine at codon 694), which occurs in 20-67% of cases and is associated with full penetrance. Homozygosity for M694V is associated with a greater disease severity and a higher incidence of amyloidosis. It is also associated with increased risk for onset at an early age. The V726A mutation occurs in 7-35% of cases and is associated with milder disease and a lower incidence of amyloidosis. The E148Q mutation is associated with low penetrance and very mild phenotype. These findings suggest that phenotypic differences may reflect different mutations. As with other recessive diseases, it is likely that some heterozygous patients may show attenuated clinical symptoms, with or without increased levels of acute phase reactants.

Epidemiology

FMF occurs primarily among ethnic groups of Mediterranean origin, mainly Sephardic Jews, Turks, Armenians, and individuals of Arab descent. In these populations, the carrier frequency is estimated to be as high as 1 in 5 persons, suggesting a carrier advantage for heterozygotes. Greeks, Hispanics, and Italians are less commonly affected. In addition, cases of FMF are found among non-Mediterranean persons. It is seen rarely among Ashkenazi Jews, Germans, and Anglo-Saxons.

Pathogenesis

The exact pathogenesis of the acute episodes of FMF is unknown. Between episodes, patients with FMF have increased serum levels of interferon-γ and enhanced production of other proinflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IL-8, in circulating leukocytes. Pyrin/marenostrin is a member of the death domain superfamily and consists of 4 different functional domains that interact with other proteins. Of particular interest is the domain known as the pyrin domain (PYD), a 92–amino acid N-terminal domain shared by several proteins that are involved in the regulation of the inflammatory response and apoptosis. Pyrin acts as an anti-inflammatory factor by inhibiting processing of pro–IL-1β cytokine to the active form. This inhibition normally takes place through interactions with a caspase recruitment domain (ASC) and NF-κB. It has been suggested that normally pyrin inhibits the binding of ASC to caspase-1 in a competitive manner. The C-terminal domain of the pyrin molecule interacts with caspase-1, leading to inhibition of IL-1β production. It is speculated that the defective (or mutated) pyrin found in patients with FMF is functionally inactive, allowing binding of ASC to caspase-1 to take place. As a consequence, stimulation of IL-1β processing and secretion occur, resulting in increased IL-1β levels that are responsible for the uncontrolled inflammation (Fig. 157-1). Another possibility that was previously more popular is based on the finding of C5a inhibitor (inactivating enzyme) deficiency in peritoneal and synovial fluids of patients with FMF. C5a is a fragment of complement, an anaphylatoxin, and a potent chemotactic agent (Chapter 127). Normally, C5a inhibitor neutralizes the small amounts of C5a released into serosal cavities before they precipitate overt inflammation. The hypothesis is that a deficiency of C5a inhibitor, which is a consequence of pyrin/marenostrin dysfunction in patients with FMF, allows further accumulation of C5a, leading to the acute attack. Further understanding of pyrin/marenostrin functions will shed light on aspects of FMF pathogenesis that are not yet fully understood.

Figure 157-1 Proteins containing pyrin domain (PYD) regulate inflammation through their interaction with apoptotic speck protein (ASC). The assembly of cryopyrin and ASC induces interleukin-1 (IL-1) processing through caspase-1, whereas pyrin may act as an inhibitor. Loss of function by mutations in the pyrin could potentially lead to autoinflammation by reducing the pyrin inhibitory role. Alternatively, gain-of-function mutations in cryopyrin, as found in patients with Muckle-Wells syndrome/familial cold urticaria/neonatal-onset multisystem inflammatory disease, could activate this pathway. ASC participates in apoptosis and activation of nuclear factor–κB (NF-κB), a transcription factor involved in both initiation and resolution of the inflammatory response. LRR, leucine-rich repeat(s); TNF, tumor necrosis factor.

(From Padeh S: Periodic fever syndromes, Pediatr Clin North Am 52:577–609, 2005.)

Clinical Manifestations

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