Genetic Disorders Among Arab Populations || Familial Mediterranean Fever and Other Autoinflammatory Disorders

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  • Chapter 5

    Familial Mediterranean Fever and OtherAutoinflammatory Disorders

    Hatem El-Shanti and Hasan Abdel Majeed

    Autoinflammatory diseases are a group of disorders characterized by seemingly

    unprovoked inflammation in the absence of high-titer autoantibodies or antigen-

    specific T-cells (Stojanov and Kastner 2005). The autoinflammatory diseases

    include the hereditary periodic fever syndromes and are thought to be due to

    disturbances in the regulation of the innate immunity (Kastner 2005). Familial

    Mediterranean Fever (FMF) is the archetypal hereditary periodic fever syndrome

    and autoinflammatory disease. Other disorders include tumor necrosis factor receptor-

    associated periodic syndrome (TRAPS); hyperimmunoglobulinemia D with periodic

    fever syndrome (Hyper-IgD); pyogenic arthritis, pyoderma gangrenosum, and acne

    (PAPA) syndrome; the cryopyrinopathies: familial cold autoinflammatory syn-

    drome (FCAS), MuckleWells syndrome (MWS), and neonatal-onset multisystem

    inflammatory disease (NOMID, also called chronic infantile neurologic cutaneous

    and articular syndrome, or CINCA syndrome); and chronic recurrent multifocal

    osteomyelitis (McGonagle and McDermott 2006; Milhavet et al. 2008).

    Familial Mediterranean Fever (FMF, MIM 249100; MEFV,MIM 608107)

    FMF is characterized by recurrent self-limiting episodes of fever and painful

    polyserositis affecting mainly the peritoneum, pleura, and synovium. It was first

    described as a distinct disease entity, under the name of benign paroxysmal

    peritonitis, in 1945 (Siegal 1945). The international medical community adopted

    the name FMF, as suggested by the team led by Heller (Sohar et al. 1961), although

    the disorder had several other names including recurrent polyserositis, recurrent

    H. El-Shanti (*)Director, Shafallah Medical Genetics Center, Doha, Qatar

    Adjunct Associate Professor of Pediatrics, University of Iowa, Iowa City, Iowa, USA


    A.S. Teebi (ed.), Genetic Disorders Among Arab Populations,DOI 10.1007/978-3-642-05080-0_5,# Springer-Verlag Berlin Heidelberg 2010


  • hereditary polyserositis, periodic disease and periodic peritonitis. FMF is an auto-

    somal recessive disorder (Sohar et al. 1961), with considerable prevalence in

    specific ethnic groups, namely, non-Ashkenazi Jews, Armenians, Turks, and

    Arabs. The impact of FMF on patients is determined mainly by the presence or

    absence of its most deleterious complication, amyloidosis (Heller et al. 1961).

    However, the burden of the febrile and painful episodes as manifested in loss of

    school or work days, repetitive suffering, and unnecessary hospitalization, and

    surgery (Kasifoglu et al. 2009) is also substantial.

    Clinical Aspects

    The classic clinical picture consists of recurrent febrile episodes that are usually of

    acute onset, variable frequency, sometimes without a recognized triggering factor

    but often occurring with menstruation, emotional stress, or strenuous physical

    activity (Samuels et al. 1998). These febrile episodes are short-lived, lasting

    13 days but may last 4 days or longer, and usually abort abruptly. The episodes

    are often accompanied by pain due to peritonitis, pleuritis, or acute synovitis of

    large joints. The frequency of the attacks varies from once per week to long periods

    of remission. Over the course of the lifelong illness, an affected individual will

    probably experience several forms of the febrile and painful episodes, but the

    recurrence of one type over many years is common (Sohar et al. 1967). During

    the attack there is neutrophilia and a brisk acute-phase response, and histologically

    there is a massive sterile influx of polymorphonuclear leukocytes (PMNs) into the

    affected site (Sohar et al. 1967). Between attacks, patients feel well, although

    biochemical evidence for inflammation may persist (Kastner 2005). The episodes

    start, most commonly during childhood, with more than 80% of patients presenting

    before the age of 20 years and a very few after the age of 40 years (Barakat et al.

    1986; Padeh 2005; Sohar et al. 1967).

    The painful abdominal (peritoneal) attack is the most frequent association with

    the febrile episode. It is experienced by the majority of patients (Padeh 2005) and is

    reported in about 50% of patients as the first symptom (Sohar et al. 1967). The

    abdominal pain can be diffuse or localized, ranging in intensity from mild bloating

    to real peritonitis with guarding, rigidity, tenderness, and rebound tenderness

    (Padeh 2005; Samuels et al. 1998). The organization of the peritoneal inflammatory

    exudate may result in fibrous adhesions and may give rise to mechanical intestinal

    obstruction (Michaeli et al. 1966). These adhesions are probably the cause of

    sterility in some women affected by FMF (Ehrenfeld et al. 1987; Ismajovich

    et al. 1973; Mijatovic et al. 2003; Rabinovitch et al. 1992).

    The articular involvement in FMF episodes is the second-most common associ-

    ation with the fever. The articular inflammation presents as an abrupt onset of acute

    arthritis, accompanied by high fever, redness, warmth, tenderness, and swelling

    (Barakat et al. 1986; Majeed and Rawashdeh 1997; Ozer et al. 1971; Schwabe and

    Peters 1974). It is often monoarticular and commonly affects the large joints of the

    112 H. El-Shanti and H.A. Majeed

  • lower limbs. It usually lasts longer than other FMF manifestations and subsides

    gradually rather than abruptly and leaves no residual damage (Padeh 2005). The

    synovial fluid is sterile but contains large numbers of neutrophils (Heller et al. 1966;

    Sohar et al. 1967). Rarely, FMF patients develop protracted arthritis, synovitis,

    muscle atrophy, erosions, and juxta-articular osteoporosis (Heller et al. 1966;

    Salai et al. 1997; Sneh et al. 1977; Yalcinkaya et al. 1997). Non-steroidal anti-

    inflammatory drugs (NSAIDs) are generally effective in FMF arthritis.

    Pleural attacks occur in 1530% of FMF patients (Saatci et al. 1997). Usually,

    the attacks present as an acute one-sided febrile pleuritis resembling the peritoneal

    attacks in their abrupt onset, unpredictable occurrence, and abrupt and rapid

    resolution (Majeed et al. 1999; Ozer et al. 1971; Sohar et al. 1967). Breathing

    may be painful, there may be diminished breath sounds on auscultation, and there

    may be radiological evidence of pleural effusion or lung collapse.

    The characteristic skin lesion is the erysipelas-like erythema which may some-

    times accompany the arthritis (Azizi and Fisher 1976; Sohar et al. 1967). Histological

    examination of the lesions reveals edema of the dermis, sparse perivascular

    infiltrate without vasculitis and C3 deposits seen by immunofluorescence (Barzilai

    et al. 2000).

    Muscle pain occurs in about 10% of FMF patients and is usually mild and

    confined to the lower extremities (Padeh 2005). It may be precipitated by physical

    exertion or prolonged standing, lasts few hours to 1 day and subsides with rest or

    NSAIDs (Majeed et al. 2000a). Rarely, a syndrome of protracted febrile myalgia

    may develop (Kotevoglu et al. 2004; Langevitz et al. 1994; Majeed et al. 2000a; Sidi

    et al. 2000). It is characterized by severe debilitating myalgia, prolonged fever,

    abdominal pain without peritoneal involvement, a high erythrocyte sedimentation

    rate (ESR), and hyperglobulinemia. If treated with NSAIDs alone, the syndrome

    may last for up to 8 weeks, but it will subside promptly if treated with corticosteroids

    (Kotevoglu et al. 2004; Langevitz et al. 1994; Majeed et al. 2000a; Sidi et al. 2000).

    Acute inflammation of the tunica vaginalis in FMF patients may mimic torsion

    of the testis and will present as a unilateral tender scrotal swelling (Eshel et al. 1988,

    1994; Majeed et al. 2000c). This is not surprising as the tunica vaginalis is

    structurally part of the peritoneum. However, these episodes usually do not occur

    with an acute peritoneal attack and are usually unilateral (Majeed et al. 1999). Fever

    and pain are always present with these self-limiting and short-lived acute scrotum


    Uncommon manifestations include headache (Buskila et al. 1997; Gedalia and

    Zamir 1993), meningeal irritation and increased CSF proteins and cells (Barakat

    et al. 1988; Gedalia and Zamir 1993; Karachaliou et al. 2005; Schwabe and Monroe

    1988; Vilaseca et al. 1982), impaired female fertility (Ehrenfeld et al. 1987;

    Ismajovich et al. 1973; Mijatovic et al. 2003), pericarditis (Kees et al. 1997), and

    transient microscopic hematuria.

    Vasculitides are found in FMF at a higher frequency than in the general popula-

    tion. HenochSchonlein purpura (HSP) has been reported in 311% of FMF

    patients (Flatau et al. 1982; Gershoni-Baruch et al. 2003; Majeed et al. 1990;

    Schlesinger et al. 1985). A study identified more than expected homozygous and

    5 Familial Mediterranean Fever and Other Autoinflammatory Disorders 113

  • heterozygous FMF mutations among children presenting with HSP (Gershoni-

    Baruch et al. 2003). Polyarteritis nodosa also occurs more commonly in patients

    with FMF (Sachs et al. 1987). Various types of glomerulonephritis have been

    reported in FMF (Said et al. 1992), but the data are insufficient to draw conclusions

    about its higher prevalence in FMF patients when compared to the general popula-

    tion even within the same ethnic group.

    The most significant complication of FMF is amyloidosis, which mainly affects

    the kidneys causing proteinuria and leading to renal failure (Heller et al. 1961).

    Chemically, it is the same type of reactive amyloidosis, with amyloid A deposits,

    which takes place with chronic infectious and non-infectious inflammatory condi-

    tions, such as tuberculosis, bronchiectasis, and rheumatoid arthritis (Pras et al.

    1982). Family history of amyloidosis and consanguinity are factors causing a higher

    risk of development of amyloidosis in FMF patients (Saatci et al. 1993, 1997).

    Colchicine treatment greatly influenced the occurrence of amyloidosis as a compli-

    cation of FMF. In a group of patients, clinically designated as phenotype II FMF

    patients, renal amyloidosis develops without being preceded by typical attacks of

    the disease (Balci et al. 2002; Konstantopoulos et al. 2001; Melikoglu et al. 2000;

    Tunca et al. 2005).

    A daily regimen of 12 mg of oral colchicine remains the recommended

    treatment since its introduction in 1972 (Ben-Chetrit and Levy 1998; Goldfinger

    1972; Ozkan et al. 1972). Adherence to a daily dose of colchicine produces

    significant decrease in the frequency and severity of the attacks or even cessation

    of the attacks all together in about 95% of FMF patients (Zemer et al. 1974).

    Continuous prophylactic treatment with colchicine in FMF patients inhibits the

    development of amyloidosis (Cabili et al. 1985), even in the patients who do not

    experience a decrease in the frequency or severity of the attacks (Ben-Chetrit and

    Levy 1991).

    The diagnosis of FMF remains a clinical bedside diagnosis with well-outlined

    validated diagnostic criteria (Livneh et al. 1997); however, a positive response to

    colchicine is supportive of the diagnosis. An attempt at the revision of the diagnos-

    tic criteria, especially as it applies to children, produced a newer set of clinical

    diagnostic criteria although this set awaits independent validation (Yalcinkaya et al.

    2009). There is slight predominance of males affected with FMF, because of either

    reduced penetrance in females (Shohat et al. 1992b) or more probably because of

    underestimation of the disease in females (Medlej-Hashim et al. 2005).

    The Genetics

    The gene responsible for FMF, MEFV, is located on the short arm of humanchromosome 16 (Gruberg et al. 1992; Pras et al. 1992, 1994; Shohat et al. 1992a),

    and was independently identified by two positional cloning consortia (French FMF

    Consortium 1997; International FMF Consortium 1997). With the cloning of the

    gene, four missense mutations in exon 10, namely M694V, V726A, M694I,

    114 H. El-Shanti and H.A. Majeed

  • and M680I, were identified (French FMF Consortium 1997; International FMF

    Consortium 1997). These four mutations and E148Q in exon 2 are the most

    common MEFV mutations among the putative mutations identified to date (Bernotet al. 1998; Booth et al. 1998; Touitou 2001). Exon 10 remains the major site of

    mutations, with a smaller cluster in exon 2 (available at

    infevers) (Fig. 5.1) (Milhavet et al. 2008; Sarrauste de Menthiere et al. 2003;

    Touitou et al. 2004). The FMF carrier rate can be as high as 1 in 3 in the commonly

    affected ethnic groups, raising the possibility of selective heterozygote advantage

    (Al-Alami et al. 2003; Gershoni-Baruch et al. 2001; Kogan et al. 2001; Stoffman

    et al. 2000; Touitou 2001; Yilmaz et al. 2001). Although FMF is an autosomal

    recessive disease, pseudodominance is frequently observed, because of the high

    mutation frequency and also because of consanguinity, which is practiced fre-

    quently in the ethnic groups commonly affected by FMF (Aksentijevich et al.

    1999; Yuval et al. 1995).

    Consistent with the biology of FMF, MEFV is expressed predominantly ingranulocytes, monocytes, dendritic cells, and in fibroblasts derived from skin,

    peritoneum, and synovium (Centola et al. 2000; Diaz et al. 2004; Matzner et al.

    2000). MEFV encodes a full-length 781 amino acid protein named pyrin (Inter-national FMF Consortium 1997) or marenostrin (French FMF Consortium 1997).

    Native pyrin protein is localized in different subcellular compartments in different

    cell types (Diaz et al. 2004). Wild-type pyrin is cytoplasmic, co-localizes with



    317Sizes (bp)




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    INFEVERS:May25,2009N Sequence variants:181


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    S242R C>GS242R C>A

    MEFV NM 000243.1(16p13.3)DNA: 14600bp, mRNA: 3499bp, Protein: 781aa

    This graph shows the variant usual name (i.e. as first published).Please refer to the variant d...


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