Chapter 61. Hereditary Periodic Fever Syndromes

Hereditary periodic fever syndromes are defined by the presence of recurrent incapacitating episodes or fluctuating degrees of fever and inflammation in the absence of infection. Unlike autoimmune diseases, hereditary periodic fever syndromes are marked by the absence of significant levels of autoantibodies and autoreactive T-cells. As a consequence, the name autoinflammatory syndromes has been advocated as a common descriptive denominator for this group of rare disorders.1,2 Since 1997, ten of the major syndromes have been linked to mutations in seven specific genes, facilitating the specific diagnosis of these conditions rather than relegating them to diagnoses of exclusion3 (Table 61–1). The nomenclature of the various autoinflammatory syndromes is complicated, comprising a mix of syndromes described by various typical manifestations and syndromes characterized by identification of specific genetic defects. Most terms originated from the period preceding the discovery of the implicated genetic defects. To confound matters even more, most autoinflammatory syndromes are known by more than one name based on personal and geographical preferences. For the purpose of this chapter we use the most accepted terms as retained in the literature.

Epidemiology

The incidence and prevalence of autoinflammatory syndromes vary by ethnicity and geographic location. For instance, FMF, the most common autoinflammatory syndrome, has a high prevalence among Sephardic Jews (100–400 patients per 100,000 persons) and among residents of Turkey (93 patients per 100,000 inhabitants) but a much lower prevalence among Western Europeans (2.5 patients per 100,000 inhabitants).4,5 The prevalence of the other syndromes, while not specifically known, is estimated to be much lower than FMF. The syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenopathy (PFAPA) is the most common of the remaining syndromes with more than 400 cases reported in English literature since 1989.6 Pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) and Majeed syndrome are probably the least common with five and three affected families reported, respectively.7–9 The prevalence of other autoinflammatory syndromes is unclear, but each probably affects no more than several hundreds of patients.

Mendelian Inheritance

Most autoinflammatory syndromes show a clear Mendelian inheritance pattern. The following six display an autosomal dominant inheritance pattern: Familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome, neonatal onset multisystem inflammatory diseases (NOMID), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), PAPA, and Blau syndrome. There are four autosomal recessive syndromes: FMF, Majeed syndrome, and the mevalonate kinase deficiencies, which include both hyper-IgD with periodic fever syndrome (HIDS) and mevalonic aciduria. PFAPA syndrome is acquired and important to pediatricians because of its relative frequent presentation at an early age.10,11

Stimuli

It is thought that trivial stimuli cause a generalized inflammatory response in children with autoinflammatory syndromes with the immune system being either too sensitive to a stimulus or unable to stop the inflammatory response. In most cases, no obvious trigger can be identified as a cause of an attack. Immunological stimuli (vaccinations, upper respiratory tract infections), mechanical stimuli (insect bites, skin trauma, surgery, exercise), physical stimuli (cold exposure) and emotional stress have been reported to elicit an attack.

Genes and Proteins

In the last decade, the genetic defects of several autoinflammatory syndromes have been discovered. FMF was the first autoinflammatory syndrome that was elucidated at the molecular level; mutations in MEFV which encodes pyrin underlie FMF. TRAPS was termed as such following the discovery of TNFRSF1A, the type 1 TNF-receptor, as the susceptibility gene. FCAS, NOMID, and Muckle-Wells syndrome, syndrome were first seen as three different disorders but genetic research showed that they were allelic and that CIAS1 mutations encoding cryopyrin are responsible for all three syndromes. Therefore, they are collectively termed the cryopyrin-associated periodic syndromes (CAPS). CARD15 gene mutations are responsible for Blau syndrome but are also found in sporadic cases of Crohn's disease. HIDS and mevalonic aciduria are caused by deficiency of mevalonate kinase as a result from MVK mutations. In mevalonic aciduria there is a (near) complete deficiency of mevalonate kinase activity (<1%) while there is some residual activity in HIDS (5–10%). PAPA syndrome is caused by missense mutations in the PSTPIP1 gene. Majeed syndrome is caused by mutations in LPIN2. The discovery of the mutated proteins for all these syndromes has led to an appreciation that most of the proteins involved, including pyrin (in FMF), cryopyrin (in CAPS), TNF receptor type 1 (in TRAPS) and PSTPIP1 (in PAPA) are members of the death domain fold superfamily and are implicated in regulation of apoptosis, NFκB activation and proinflammatory cytokine production. They are molecules intimately involved in innate immunity and play a key role in the hyperinflammatory response found in autoinflammatory syndromes (Table 61–1).3

The common denominator of the autoinflammatory syndromes is lifelong recurrent episodes of fever and other inflammatory symptoms. The acquired PFAPA syndrome is the exception to this rule because it is usually self-limiting and in most cases attacks disappear after childhood.12 Attacks in patients with autoinflammatory syndromes generally occur at irregular intervals without obvious periodicity. Therefore the term recurrent is favorable over periodic.13 In individual patients symptomatology during different attacks is usually similar and the course predictable when it comes to duration and the order in which the symptoms occur.14 The recurrent nature of these diseases in children often leads to frequent absence at school and sometimes inability to finish education despite the presence of normal intellectual capacities.

Common Features

Most of these syndromes are invariably marked by episodes of high spiking fever (often >40°C) accompanied by chills and sweating. For example, in Blau syndrome and PAPA syndrome, fever is not a major symptom. One of the hallmarks, common to all autoinflammatory syndromes, is the accompanying acute phase response with elevated C-reactive protein (CRP) (often 10–30 mg/dL), erythrocyte sedimentation rate, serum amyloid A and leukocytosis (often 15–30 × 109/L) usually caused by neutrophilia. Parents and patients often describe a short but recognizable prodromal phase with aspecific symptoms like fatigue, irritability, headache, and malaise before the onset of fever. Recurrent inflammation can cause general symptoms such as normocytic anemia, fatigue, weight loss, or growth retardation. With the exception of PFAPA syndrome, all other syndromes are associated with a positive family history for comparable symptoms. A negative family history does not exclude an autoinflammatory syndrome since sporadic cases have been described in all hereditary autoinflammatory syndromes except PAPA and Majeed syndrome. Symptoms resolve spontaneously, and in between inflammatory attacks patients are asymptomatic although also in asymptomatic periods an acute phase response can be present. In the more severe syndromes (mevalonic aciduria, NOMID, Muckle-Wells syndrome), there is usually a fluctuating degree of inflammation without complete resolution between episodes.2

Distinguishing Features

Skin rash, if present, is an important clue for the diagnosis (Figure 61–1, 61–2 and 61–3). The urticarial-like rash in CAPS patients (Figure 61–3) can be distinguished from classical urticaria as histopathology demonstrates neutrophils and lymphocytes instead of mast cells. Both the migratory erythematous rash and erysipeloid erythema in TRAPS (Figure 61–2) and FMF, respectively, are very painful and mimic skin infections caused by Staphylococcus aureus and streptococci. The erysipeloid erythema is usually localized on the distal lower extremities (ankle, calf) and expands. The migratory rash is usually localized on the trunk, abdomen and proximal extremities slowly migrating from one location to the next. The maculopapular rash in Blau syndrome and mevalonate kinase deficiencies mimics varicella and other viral infections. In Blau syndrome histopathology shows noncaseating granulomas while cultures for mycobacteria remain negative.

Peritonitis in FMF, TRAPS, and occasionally HIDS can lead to intra-abdominal adhesion formation and unnecessary abdominal surgery with removal of an uninflamed appendix (appendix sana). Painful scrotal swelling in FMF and TRAPS is caused by involvement of the tunica vaginalis testis and has to be distinguished from other conditions such as testicular torsion and epididymitis. Pleuritis causes chest pain and dyspnoea. Pericardial involvement (pericarditis) is rare, but can be seen in FMF.

The lymphadenopathy in HIDS can be prominent and is tender at palpation. In PFAPA syndrome only cervical nodes are involved. Another feature both PFAPA and HIDS have in common is the painful aphthous stomatitis. Dysmorphic features, mental retardation and neurological symptoms are seen in NOMID, Muckle-Wells syndrome, and mevalonic aciduria. Perceptive deafness is an important feature of Muckle-Wells syndrome, and usually develops before adolescence. Uveitis is one of the characterizing symptoms of Blau syndrome but is also seen in mevalonic aciduria and NOMID.

An overview of distinguishing symptoms and characteristics for each syndrome can be found in Tables 61–2 to 61–3. It is important to realize that FCAS, Muckle-Wells syndrome, and NOMID are three syndromes representing a continuous phenotypic spectrum (cryopyrin-associated periodic syndromes or CAPS) and symptoms may overlap. HIDS and mevalonic aciduria also represent two ends of the same phenotypic spectrum (mevalonate kinase deficiencies).15,16

Complications

Reactive amyloidosis (type AA) is a serious complication sometimes leading to renal failure. The first sign usually is proteinuria and regular checks for its presence are necessary in all patients with autoinflammatory syndromes. The risk of amyloidosis is the highest for FMF and Muckle-Wells syndrome, and low in HIDS.17,18 Reduction of the acute phase response with serum amyloid A levels <10 mg/L decreases the risk of amyloidosis and can halt its progression. Therefore early diagnosis and treatment of autoinflammatory syndromes is necessary. Several forms of vasculitis sometimes leading to renal impairment have occasionally been reported in TRAPS, FMF, Blau syndrome and mevalonate kinase deficiency patients (Table 61–2 to 61–3).

Inflammation and fever caused by autoinflammatory syndromes must be distinguished from other and more frequent causes of chronic and recurrent fever. Patients with prolonged recurrent fever present a diagnostic challenge for physicians especially since the chance of reaching a diagnosis is significantly smaller than in patients with continuous fever.19 In young children, it is important to differentiate between the multiple self-limiting viral infections and other more pathological conditions. It has been estimated that the viral infections can occur up to ten times a year in the first three years of life.14 The differential diagnosis of recurrent fever is extensive and includes among others vasculitis, rheumatological conditions, metabolic diseases, infections, and malignancies as listed in Table 61–4.4,13,20,21 In approximately one-third of FMF patients fulfilling clinical criteria (Table 61–5)22 a positive genetic diagnosis can be made. Furthermore, only in a minority of the patients (<30%) fitting the clinical phenotype of an autoinflammatory syndrome a genetic diagnosis can be made.2,3,23 These things suggest that there are more, as yet unknown genetic defects that can lead to periodic fever and that the list of autoinflammatory disorders is probably incomplete at this moment.

When a patient presents with a history of recurrent episodes of fever, meticulous evaluation is necessary to exclude the presence of infection and the other conditions mentioned earlier (Table 61–4).14,24 In patients with a long history of recurrent fever episodes in the absence of symptom progression or additional complaints, malignant and infectious causes become less likely. Patients with autoinflammatory syndromes often go undiagnosed for many years after the onset of their first symptoms. The presence of an autoinflammatory syndrome is suggested by recurrent inflammatory attacks with predictable course and set of symptoms especially when family members are affected as well.

The clinician should elicit a detailed medical history with special attention for features of autoinflammatory syndromes (Tables 61–2 to 61–3), family history and previous febrile episodes (including reactions after vaccination and hospital admissions). Parents should be asked to take photographs of potentially important clues such as transient skin lesions and to keep a temperature and symptom diary. Since medical history, physical examination, and laboratory tests to evaluate the acute phase response (serum amyloid A levels, CRP, erythrocyte sedimentation rate, peripheral leukocyte count and differential) are usually unremarkable during asymptomatic periods, these tests should be repeated during a febrile episode. Hospital admission during an attack for clinical observation, cultures, and laboratory and radiological examination may be warranted. The evaluation of a child suspected of having an autoinflammatory syndrome largely depends on the presence of potential diagnostic clues, however, suggestions for initial evaluation are provided in Table 61–6.14,20,21

Apart from high plasma IgD and IgA (which can be normal in young children) and high urinary mevalonate during attacks in mevalonate kinase deficiency patients, there are no specific nongenetic laboratory tests to distinguish one autoinflammatory syndrome from another. Genetic confirmation is warranted if an autoinflammatory syndrome remains in the differential diagnosis after initial evaluation. Specialized clinical genetic laboratories perform these tests. The specimen can be placed in 2 × 10 mL EDTA tubes kept and shipped at room temperature. Studies have shown that the DNA quality from buccal swabs is comparable to that of isolated blood leukocytes. The yield from EDTA blood is considerably higher, reason that we prefer this as the source for DNA preparation. It is important to bear in mind that genetic testing is expensive and not covered by all insurance companies. The yield of genetic testing is low in patients without clinical features suggestive of a specific autoinflammatory syndrome. In two studies, more extensive genetic testing was performed in patients suffering recurrent fever episodes in whom no genetic diagnosis was established after 1 or 2 specific tests for the most likely syndromes based on clinical findings. This additional testing revealed the presence of a hereditary autoinflammatory syndrome in only 5% and 6.8% of patients, respectively.23,25 Because of this low yield of random genetic analysis, it is important to focus the differential diagnosis based on several characteristics: Inheritance pattern, age of onset, duration of attacks, attack frequency, geographical region of origin, symptoms, and complications.25

Although the mainstay of the diagnosis is clinical evaluation by an experienced clinician, we propose an algorithm that can guide the performance of specific diagnostic testing. It is important to consider that clinical presentation can vary highly in terms of symptom constellation, attack duration and frequency within one disease entity. Especially in young children the full-blown phenotype might not have fully developed (e.g., deafness and neurological symptoms in Muckle-Wells syndrome, and CINCA or uveitis in Blau syndrome). Furthermore, a small group of patients fulfilling clinical criteria for a specific diagnosis will be mutation negative. If the phenotype is typical for a specific disease a clinical diagnosis will be made although clinicians should be aware that in the future the diagnosis might have to be reconsidered. If a clinical diagnosis cannot be confirmed by genetic testing, the terms variant HIDS, variant NOMID, and clinical FMF are used.26,27

A continuously updated list of mutations responsible for autoinflammatory syndromes and the associated phenotypes can be found at the INFEVERS Web site: http://fmf.igh.cnrs.fr/infevers/ There are associations between certain genotypes and phenotype. In mevalonate kinase deficiencies the V377I mutation is associated with higher residual mevalonate kinase enzyme activity and a less severe phenotype, therefore most HIDS patients carry at least one copy. In CAPS the association between genotype and phenotype seems less strict and the same mutations can be found in for instance FCAS, Muckle-Wells syndrome, and NOMID patients. There are also low penetrance mutations with a high prevalence in the normal population found in patients with less severe phenotypes. Examples are R92Q and P46L in TNFRSF1A and E148Q in MEFV. These mutations are no longer considered disease defining but rather disease modifying polymorphisms.28

FMF

Continuous treatment with colchicine prevents attacks and development of amyloidosis in FMF. It can safely be used during conception, pregnancy and lactation. Failure to this therapy is usually as a result of poor compliance but in 5% of FMF patients there is a genuine lack of efficacy in terms of preventing attacks. However, these patients should still use continuous colchicine therapy to reduce the risk of amyloidosis. Small series and single case reports demonstrate beneficial responses to treatment with interferon-α, anakinra, etanercept, and infliximab combined with colchicine. However, the actual benefit is unclear as larger observational studies and randomized trials never have been performed.29–31 Systemic corticosteroids are only warranted in FMF patients with prolonged febrile myalgia or vasculitis.32,33

HIDS

The first placebo-controlled crossover trial in HIDS showed that thalidomide was not effective, and toxicity remains the limiting factor.34 A crossover trial demonstrated some benefits of simvastatin in terms of reduction of the number of days of illness in HIDS.35 Some cautions are warranted when simvastatin treatment is started in mevalonic aciduria since two patients developed severe inflammatory attacks during simvastatin treatment.36 Anakinra treatment seems to be more effective than etanercept treatment37 and some patients benefit from systemic corticosteroids during attacks.

TRAPS

TRAPS patients generally respond well to NSAIDs and on-demand corticosteroid treatment during attacks but often escalating doses are necessary and treatment becomes chronic leading to toxicity. Some, but not all, TRAPS patients respond well to etanercept and there were reports that etanercept is effective in treating amyloidosis. There is a single report that one TRAPS patient developed amyloidosis despite effective etanercept treatment. Infliximab results in exacerbation of symptoms in TRAPS but anakinra was effective in one patient.38,39

PFAPA

Continuous cimetidine treatment was effective in some patients with PFAPA syndrome, but later results have not substantiated the early successes.6 Systemic corticosteroid treatment reduced attack duration, but sometimes leads to a shorter asymptomatic period. One steroid-resistant PFAPA patient responded well to thalidomide. The role of tonsillectomy in these patients is still under discussion.6,40

CAPS

CAPS patients generally respond well to on demand corticosteroid treatment during attacks but often escalating doses are necessary and treatment becomes chronic leading to toxicity. Anakinra has shown to be remarkably effective in CAPS patients and leads to stabilization or even improvement of neurological symptoms and amyloidosis.41–45

Other Autoinflammatory Syndromes

PAPA patients generally respond well to on-demand corticosteroid treatment, but if limited by toxicity it was shown that anakinra (on demand) and etanercept (continuous) was also effective in PAPA syndrome. Leflunomide and sulphasalazine were able to induce remission in a PAPA patient primarily suffering from arthritis. Isolated arthritis also responds to intra-articular steroids.7,8 There are few reports on effective treatment for Majeed and Blau syndrome, but systemic corticosteroid treatment is effective and in Blau syndrome infliximab was used effectively as steroid sparing treatment.46–48

In general, NSAIDs are effective for pain control but do not influence attack duration except in some TRAPS patients with a mild phenotype. Figure 61–4 shows an algorithm for treatment options and Table 61–7 gives an indication of dose regimens used. If asymptomatic periods are long, on-demand treatment is to be preferred over continuous treatment. Treatment with colchicine, simvastatin, and cimetidine are the exceptions to this rule. Table 61–8 lists the indications for referral to other subspecialists.