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Chapter 5 Familial Mediterranean Fever and Other Autoinflammatory 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), Muckle–Wells 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 email: [email protected] A.S. Teebi (ed.), Genetic Disorders Among Arab Populations, DOI 10.1007/978-3-642-05080-0_5, # Springer-Verlag Berlin Heidelberg 2010 111

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Chapter 5

Familial Mediterranean Fever and Other

Autoinflammatory 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), Muckle–Wells 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

email: [email protected]

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

111

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

1–3 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 15–30% 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

episodes.

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. Henoch–Schonlein purpura (HSP) has been reported in 3–11% 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 1–2 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 human

chromosome 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 (Bernot

et 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 http://fmf.igh.cnrs.fr/

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 in

granulocytes, 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

N99ND102DD103DS108RL110PL110LG111GG112fsP124PE125EN130_13lineG138GS141IR143PE148QE148VR151SE163AA165AE167DP175HT177IS179IP180P

L9LR42WY65YA89T

317Sizes (bp)

5’flanking

633

277/27893

CDS joints

PositionsCodons

910/911304

1260/1261420/421

1356/1357452/453

1587/1588529/530

1610/1611537

1726/1727576

1759/1760587

1792/1793598

350 96 231 23 116 33 33 1667

INFEVERS:May25,2009N Sequence variants:181

1653611861936468166242643771520

11 12 13 14 15 16 17 18 19

–792C>T

910+29C>T

1260+10C>T

1356+44A>G

1587+18C>T

1610+47A>T1610+96C>T

1727-587>C

L559FT577S

*9C>T

P588P

1759+8C>T1760–30A>T1760–28T>A1760–4G>A

I591TG592GA595V

*12T>C*21C>G

1792+39 G>A1792+57C>T1793–14A>GM582L

1587+29G>T1587+33C>G1540+69G>A

1260+18C>G1260+92G>A1261–11T>G1261–28A>G

911-22T>G911-78T>C

–751A>T–740C>T–614C>G–382C>G–330G>A

–12C>G

P180RG196WR202QS208AfsG219GP221PE225DE230KY232HG236V

R314RT309M

A457VG632SI640M Y688X

I692delM694delM694IM694LM694VK695MK695RK695NA701AS702CS703SV704IP705SP706PR708CL709R

I720MF721FV722MD723DV726AF743FF743LA744SS749CQ753QI755VP758SR761H1772VG779GP780T

R717SI641FP646LP646PL649PR652RR653HE656AD66INS675NG678EM680LM680IG>AM680IG>CT68IIS683SY688C

V469LY471XE474EE474KQ476QH478YF479LV487MQ489QR501GR501HR501RI506II506VD510DI513TG514E

R314HE319KV328AR329HS339FR348HC352CR354W

1423VQ440E

P369SQ383KP393PR408QV415V

S363S

S242S

E251K

I259VT267IA268VR278PP283LP283RA289VF299GG304R

N256Dfs

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 detail by clicking on its name for possible edited nomenclature.

1 4 7 8 9 10652 33’flanking

Fig. 5.1 MEFV and its variations

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders 115

microtubules, and it is proposed that it regulates inflammatory responses at the level

of the cytoskeletal organization (Mansfield et al. 2001; Papin et al. 2000). However,

nuclear localization of full-length pyrin in synovial fibroblasts, dendritic cells

and granulocytes has been demonstrated (Diaz et al. 2004). Several alternatively

spliced forms have been described (Diaz et al. 2004; Papin et al. 2000). In addition,

it appears that pyrin acts as an upstream regulator of interleukin (IL)-1b activation

(Chae et al. 2003; Yu et al. 2005), having both inhibitory and potentiating effects on

IL-1b production. There is also evidence that pyrin plays a role in regulating

nuclear factor (NF)-kB activation and apoptosis (Chae et al. 2003; Dowds et al.

2003; Masumoto et al. 2003; Stehlik and Reed 2004; Yu et al. 2005).

Genotype/Phenotype Correlation Patterns

The Tel Hashomer severity score (Pras et al. 1998), has been used to facilitate

comparison of FMF phenotype severity among the different ethnic groups. Several

studies have examined the correlation between certain mutations and phenotype

severity in the different affected ethnic groups. Most studies showed correlation

betweenM694V and severity of the disease or the presence of amyloidosis across all

affected ethnic groups with the exception of the Turkish FMF patients (Brik et al.

1999; Cazeneuve et al. 1999; Dewalle et al. 1998; Livneh et al. 1999; Majeed et al.

2002; Mansour et al. 2001; Shinar et al. 2000; Shohat et al. 1999; Sidi et al. 2000;

Yalcinkaya et al. 2000). The results of selected studies are summarized in Table 5.1.

Upon reviewing the FMF genotype/phenotype correlation literature, we can con-

clude that there is no consistency in the correlation between a specific MEFVmutation and amyloidosis or other phenotypic feature across all populations, with

the exception of M694V and amyloidosis or severity of the FMF symptoms. How-

ever, there is a specific pattern of severity or amyloidosis within the same population,

such as in homozygosity for M694V in the North African Jews and M694V homo-

zygosity in the protracted febrile myalgia syndrome in the Arabs. Overall, the studies

that explored the reasons accounting for the fact that only a subset of FMF patients

develops amyloidosis did not lead to definitive conclusions. These studies tested a

limited number of variables in often small series. In addition the studies had variable

designs which do not allow comparisons or meta-analytic approaches. A web-based

project denoted “metaFMF” emerged with the goal of resolving discrepant published

conclusions related to genotype/phenotype correlation patterns in FMF (Milhavet

et al. 2008; Pugnere et al. 2003; Sarrauste de Menthiere et al. 2003; Touitou et al.

2004, 2007). This project that utilizes a standardized mode of data collection

represents an international effort with significant contribution from the Arabic

FMF investigator teams. The project evolved into an online mutation registry for

autoinflammatory disorders (Milhavet et al. 2008; Sarrauste de Menthiere et al.

2003; Touitou et al. 2004) (available at http://fmf.igh.cnrs.fr/infevers).

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

FMF in the Arabs

Currently, FMF is established as a common genetic disease among the Arabs and in

the early 1980s it became recognized as a public health concern in some Arabic

countries (Barakat et al. 1984a, b, 1986; Majeed and Barakat 1989). Since then, it

became increasingly notable that FMF has a considerable impact on the health and

welfare of children and adults in the Arabic countries (El-Shanti et al. 2006). FMF

may be complicated by amyloidosis which leads to renal failure and it is associated

with loss of school days or work hours and unnecessary hospitalizations and

surgeries. In addition, the painful and febrile episodes are extremely uncomfortable

for FMF patients. However, similar to other ethnic groups commonly affected by

FMF, the mortality and morbidity associated with FMF are preventable with early

identification of affected individuals followed by appropriate treatment and pro-

phylaxis. Clinical and molecular studies involving a variety of Arabic subpopula-

tions demonstrate the high prevalence of FMF and high MEFV mutation-carrier

Table 5.1 Summary of selected genotype/phenotype correlation studies

Mutation Ethnic group Phenotype assessed Relation

1 M694V/M694V Non-Ashkenazi

Jews

Arthritis & Pleuritis Increased 2X Dewalle

et al. (1998)

Amyloidosis Increased

2 M694V/M694V Armenians Arthritis Increased Cazeneuve

et al. (1999)

Amyloidosis Increased

3 M694V/M694V Non-Ashkenazi

Jews

Severity (no specific

index)

Increased Brik et al.

(1999)

Arabs Amyloidosis Increased

4 M694V/M694V North African

Jews,

Amyloidosis Increased Shohat et al.

(1999)

Others Armenians & Turks Severity No relation

5 M694V/M694V Non-Ashkenazi

Jews

Amyloidosis Increased Livneh et al.

(1999)

6 M694V/M694V Mixed Jewish Tel Hashomer

Severity Score

Increased Shinar et al.

(2000)

7 M694V/M694V Mixed Jewish Protracted febrile

myalgia

Increased Sidi et al.

(2000)

8 M694V/M694V Turks Severity (12

parameters)

No relation

Yalcinkaya et al.

(2000)

M694V/M694V Amyloidosis No relation

M680I/M680I Arthritis Decreased

9 M694V/M694V Arabs Amyloidosis Increased Mansour

et al. (2001)

M694I/M694I Amyloidosis Increased

M694V/M694I Amyloidosis Increased

10 M694V/M694V Arabs Severity (modified

score)

Increased Majeed et al.

(2002)

M694V/V726A Protracted febrile

myalgia

Increased

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders 117

frequency (Al-Alami et al. 2003; Gershoni-Baruch et al. 2001; Rawashdeh and

Majeed 1996). However, the clinical and particularly the molecular aspects FMF

have not been adequately studied in the Arabs when compared to other ethnic

groups commonly affected by FMF.

Clinical Aspects

The studies that elaborate on the clinical features of Arabic patients were carried out

either prior to the identification of theMEFV as the gene responsible for FMF or did

not incorporate molecular data in the analyzes (Barakat et al. 1986; Majeed 2000;

Majeed and Barakat 1989; Majeed and Rawashdeh 1997; Majeed et al. 1990, 1999,

2000a, c; 2002, 2005a; Rawashdeh and Majeed 1996; Said and Hamzeh 1990; Said

et al. 1988, 1989, 1992). The majority of these studies employed the original

diagnostic criteria (short attacks of fever and abdominal pain recurring at varying

intervals in the absence of any causative factor) proposed by Heller and coworkers

(1958). However, more recent studies employed the validated diagnostic criteria of

Livneh and coworkers (1997) as a standard for the diagnosis (Majeed 2000; Majeed

et al. 1999; Majeed et al. 2000a, 2000c, 2002, 2005a). In addition, most of these

studies were done after the establishment of colchicine as an effective treatment and

this may have influenced the reported phenotype. We conclude that different

diagnostic standards and colchicine therapy are the primary confounding factors

that may have contributed to the reported clinical peculiarities of the FMF pheno-

type in the Arabs. In addition, several other confounding factors may have con-

tributed to the difference in phenotype, such as under-reporting of symptoms,

criteria for patient selection, reliance on family history, chance variations, and the

lack of a definitive diagnostic test.

About 80% of Arabic FMF patients present before the age of 10 years and

abdominal pain is the most commonly reported presenting feature (Majeed et al.

1999). This earlier age at onset is probably explained by the skewed patient

selection in the reported case series which is influenced by the clarity of symptoms

and the presence of family history. Unlike the higher prevalence in men in other

ethnic groups commonly affected by FMF, the male to female ratio in Arabs is

almost equal (Majeed et al. 1999; Rawashdeh and Majeed 1996). This is probably

due to the accurate estimation of the number of affected women, also influenced by

patient selection. In addition, this finding does not support the suggestion that FMF

may have incomplete penetrance in females (Shohat et al. 1992b).

Arthritis is less common in the Arabic FMF children and adults (Barakat et al.

1986; Majeed and Barakat 1989; Majeed and Rawashdeh 1997; Majeed et al. 1999),

as compared to that in Jews (Sohar et al. 1967; Zemer et al. 1991); however, it is

similar to arthritis in Turks (Ozdemir and Sokmen 1969; Sayarlioglu et al. 2005)

and Armenians (Cazeneuve et al. 1999; Schwabe and Peters 1974). The decreased

frequency of arthritis in Arabs, Turks, and Armenians may be due to under-reporting

of the symptoms, as well as due to delay in the diagnosis.

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

The pleural attacks (Majeed et al. 1999), peritoneal attacks (Barakat et al. 1986;

Majeed and Barakat 1989; Rawashdeh and Majeed 1996), and myalgia (Majeed

et al. 2000a) are not different from those in other ethnic groups commonly affected

by FMF. About 20% of Jewish and Arab children with functional abdominal pain

were homozygous for an MEFV mutation (Brik et al. 2001). In one early report,

non-specific purpuric rash was reported more commonly than erysipelas-like ery-

thema in Arabic FMF patients (Majeed et al. 1990), while erysipelas-like erythema

is the most common in other ethnic groups commonly affected by FMF. This

unusual finding is probably due to the small number in that series and the

differences were probably not statistically significant. In addition, the erysipe-

las-like erythema was noted to be a common cutaneous manifestation of FMF in

Arabs in a later case series (Majeed et al. 1999).

The acute scrotal swelling reported in Arabic FMF patients sometimes occurred

in the absence of peritonitis (Majeed et al. 1999) and is associated with a high rate

of decreased favorable response to colchicine therapy in Arabic and Jewish FMF

patients (Eshel et al. 1994, 1988; Majeed et al. 1999, 2000c). This therapy failure

rate is alarming due to a report of testicular necrosis following recurrent scrotal

attacks in the latter ethnic group (Livneh et al. 1994).

Recurrent hyperbilirubinemia has been described in the early FMF literature but

very few patients were clinically icteric (Priest and Nixon 1959). This probably

explains why this feature is not mentioned in the large clinical series reported from

all ethnic groups commonly affected by FMF. Recurrent hyperbilirubinemia has

been described in two Arabic patients in 1994 (Neequaye and Jelly 1994) and in

1998 (Majeed et al. 1998). In these two reports, the hyperbilirubinemia was

transient, occurring only during a peritoneal attack and clinical jaundice was mild

with only a minimal rise in serum bilirubin (mainly conjugated) (Majeed et al.

1999). The etiology of the hyperbilirubinemia is unclear, but seems to be a benign

process as no cases of acute or chronic liver failure have been reported.

It has been noted that amyloidosis and chronic renal disease are less common in

the Arabic FMF patients when compared to the other ethnic groups commonly

affected by FMF (Bakir and Murtadha 1975; Barakat et al. 1986; Majeed and

Barakat 1989; Majeed et al. 1999; Rawashdeh and Majeed 1996). The frequency

of amyloidosis ranged from 0.4% in Jordanian FMF patients (Majeed et al. 1999) to

2% in a mixed Arabic population residing in Kuwait (Majeed and Barakat 1989).

The frequency of amyloidosis in Sephardic Jews ranges from 26 to 42% (Gafni

et al. 1968; Sohar et al. 1967), while in Armenians it is about 24% (Aivazian et al.

1977) and in Turks about 60% (Ozdemir and Sokmen 1969; Saatci et al. 1993). The

low rate of occurrence of FMF-related amyloidosis in the Arabic patients is

probably due to the fact that these figures were obtained after the worldwide

establishment of colchicine as the standard of care for FMF patients (Barakat

et al. 1986; Majeed and Barakat 1989; Majeed et al. 1999; Rawashdeh and Majeed

1996). In two studies from Lebanon, the frequency of amyloidosis was about 10%

(Armenian and Khachadurian 1973; Khachadurian and Armenian 1974). This

higher figure can be explained by the conduction of the two studies prior to the

establishment of colchicine therapy in Lebanon and that some of the Lebanese FMF

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders 119

patients in the studied cohorts were Armenian in origin. The frequency of amyloid-

osis in the Arabic FMF patients and the factors influencing its occurrence have been

studied together with specific MEFV mutations and examination of genotype/

phenotype correlation patterns and is discussed in detail below. Besides amyloid-

osis, kidney involvement in the form of IgM nephropathy, IgA nephropathy, or

rapid progressive glomerulonephritis has been described in Arabic FMF patients

(Said and Hamzeh 1990, Said et al. 1988, 1989, 1992). However, the numbers in

these case series are small to draw firm conclusions but may point to the higher

prevalence of vasculitis or glomerulonephritis in FMF patients.

MEFV Mutations

The mutation analysis studies that include a substantial number of Arabic FMF

patients are limited in number and in methodology (Al-Alami et al. 2003; Ayesh

et al. 2005; Brik et al. 1999; Chaabouni et al. 2007; Dode et al. 2000; Gershoni-

Baruch et al. 2001, 2002a, b; Jarjour 2010; Majeed et al. 2002, 2005a; Mansour

et al. 2001; Mattit et al. 2006; Medlej-Hashim et al. 2000, 2001, 2002, 2004, 2005;

Sabbagh et al. 2008). All of these studies examined for the five common mutations

(E148Q, M680I, M694V, M694I, and V726A) using a combination of restriction

endonuclease-based test, ARMS (Amplification Refractory Mutation System) test,

DGGE (denaturing gradient gel electrophoresis), and selective exonic sequencing.

A few studies examined for additional mutations but also in a selective manner

(Ayesh et al. 2005; Chaabouni et al. 2007; Dode et al. 2000; Jarjour 2010; Medlej-

Hashim et al. 2000, 2005; Sabbagh et al. 2008). A summary of selected MEFVmutation analysis studies that included Arabic FMF patients is provided in

Table 5.2. However, despite their limitations, these studies point to the high

MEFV mutation carrier frequency among the Arabs, which is similar to that

among the other ethnic groups commonly affected by FMF (1 in 3–6 individuals).

The most common MEFV mutation is the M694V (Al-Alami et al. 2003; Ayesh

et al. 2005; Brik et al. 1999; Dode et al. 2000; Gershoni-Baruch et al. 2001,

2002a, b; Jarjour 2010; Majeed et al. 2002, Majeed et al. 2005a; Mansour et al.

2001; Mattit et al. 2006; Medlej-Hashim et al. 2000, 2001, 2002, 2004, 2005;

Sabbagh et al. 2008), although it is less common than in other ethnic groups

commonly affected by FMF (Cazeneuve et al. 1999; Medlej-Hashim et al. 2005;

Padeh et al. 2003; Yalcinkaya et al. 2000). The V726A is the second most common

mutation in Arabs (Al-Alami et al. 2003; Ayesh et al. 2005; Brik et al. 1999; Dode

et al. 2000; Gershoni-Baruch et al. 2001, 2002a, b; Jarjour 2010; Majeed et al. 2002,

2005a; Mansour et al. 2001; Mattit et al. 2006; Medlej-Hashim et al. 2000, 2001,

2002, 2004, 2005; Sabbagh et al. 2008) similar to the findings in Armenians, Turks,

and Jews (Cazeneuve et al. 1999; Padeh et al. 2003; Yalcinkaya et al. 2000). M694I

is the third most common mutation in Arabs (Al-Alami et al. 2003; Ayesh et al.

2005; Brik et al. 1999; Gershoni-Baruch et al. 2002a; Majeed et al. 2002, 2005a;

Mansour et al. 2001; Mattit et al. 2006; Medlej-Hashim et al. 2000, 2005; Sabbagh

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

Table

5.2

Summaryofselected

MEFV

mutational

analysisstudiesthat

included

Arabic

patientswithFMF

Proportion(%

)mutantallelesidentified

(n/N)

Methodofanalysis

Arabs

Jews

Arm

enians

Turks

Briket

al.(1999)

Restrictionendonuclease

digestion

90%

(28/31)a

96%

(47/49)a

ns

ns

Dodeet

al.(2000)

Sequencingofexon10,restrictionendonuclease

digestion&

DGGE

49%

(48/98)

70%

(131/186)

90%

(56/62)

75%

(36/48)

Medlej-Hashim

etal.(2000)

Restrictionendonuclease

digestion&

ARMS

56%

(47/84)

ns

ns

ns

Mansouret

al.(2001)

Sequencingofexon10,restrictionendonuclease

digestion,DGGE&

ARMS

67%

(97/143)

ns

ns

ns

Gershoni-Baruch

etal.(2001)

Restrictionendonuclease

digestion

85%

(121/142)

96%

(144/150)

ns

ns

Majeedet

al.(2002)

Sequencingofexon10,restrictionendonuclease

digestion&

ARMS

32%

(176/556)

ns

ns

ns

Al-Alamiet

al.(2003)

Sequencingofexon10,restrictionendonuclease

digestion&

ARMS

54%

(31/58)

ns

ns

ns

Majeedet

al.(2005a)

Restrictionendonuclease

digestion&

ARMS

47%

(387/814)

ns

ns

ns

Ayeshet

al.(2005)

Sequencingofexon10&

ARMS

49%

(504/1022)

ns

ns

ns

Medlej-Hashim

etal.(2005)

Sequencingofexon10,restrictionendonuclease

digestion,SSCP&

resequencingexons1–9

50%

(553/1116)

ns

ns

ns

Chaabouniet

al.(2007)

Restrictionendonuclease

digestion&

ARMS

38%

(105/278)

ns

ns

ns

Sabbaghet

al.(2008)

Strip

assay

38.5%

(205/532)

ns

ns

ns

Jarjour(2010)

Strip

assay

49%

(150/306)

ns

ns

ns

ARMSAmplificationrefractory

mutationsystem

;DGGEDenaturinggradientgel

electrophoresis;ns

populationnotstudied

aProportionofpatientsidentified

tohaveoneortwomutationsandnotproportionofidentified

alleles

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders 121

et al. 2008) and appears to be found mainly in this ethnic group (Aksentijevich et al.

1999; Ben-Chetrit et al. 2002; Booth et al. 1998; French FMF Consortium 1997;

Samuels et al. 1998). The M680I mutation found mostly in Armenians and Turks

(Cazeneuve et al. 1999; Yalcinkaya et al. 2000) is the fourth common mutation in

Arabs (Al-Alami et al. 2003; Ayesh et al. 2005; Brik et al. 1999; Gershoni-Baruch

et al. 2002a; Majeed et al. 2002, 2005a; Mansour et al. 2001; Mattit et al. 2006;

Medlej-Hashim et al. 2000, 2005; Sabbagh et al. 2008). There are few studies that

show that in Arabic patient series M680I is more common than M694I (Gershoni-

Baruch et al. 2002a; Gershoni-Baruch et al. 2001; Jarjour 2010; Medlej-Hashim

et al. 2000) or even the most common mutation among the population studied

(Chaabouni et al. 2007). The E148Q mutation is the least penetrant and might be a

polymorphism (Ben-Chetrit et al. 2000; Chaabouni et al. 2007; Jarjour 2010; Mattit

et al. 2006; Medlej-Hashim et al. 2005; Sabbagh et al. 2008; Touitou 2001). It has

been identified in Arabic FMF patients alone or in a complex allele with other exon

ten mutations (Majeed et al. 2002, 2005a; Mansour et al. 2001; Medlej-Hashim

et al. 2000, 2002), but is more commonly identified in healthy carriers (Al-Alami

et al. 2003; Mattit et al. 2006). Table 5.3 provides a summary of the distribution of

the five common MEFV mutations in the Arabic FMF patients in selected studies

that provided clear mutant allele frequencies.

The distribution of the five common MEFV mutations among healthy Arabic

individuals has been the subject of two studies to date (Al-Alami et al. 2003; Mattit

et al. 2006). In the first study, healthy cohorts from Jordan, Egypt, Syria, Saudi

Arabia, and Iraq were examined for the five common MEFV mutations. The

distribution of each mutation in each Arabic population and the collective distribu-

tion are shown in Table 5.4. This study concludes that E148Q has reduced pene-

trance in the Arabic population and thus, a proportion of the genetically affected

individuals remain asymptomatic. It is of note that utilizing the restriction endonu-

clease digestion test for the detection of the E148Q mutation can lead to misdiag-

nosis in presence of the E148V mutation (Medlej-Hashim et al. 2002), which

may have increased the number of E148Q identified in healthy Arabic cohorts

(Al-Alami et al. 2003). M694I and M680I are more prevalent in affected indivi-

duals when compared to the healthy individuals, which points to their higher

Table 5.3 The distribution of the five common MEFV mutations in the Arabic FMF patients in

selected studies

Mutation

M694V (%) V726A (%) M694I (%) M680I (%) E148Q (%)

Medlej-Hashim et al. (2000) 20.2 14.3 1.2 9.5 7.1

Dode et al. (2000) 36 0 55.4 4.3 4.3

Gershoni-Baruch et al. (2001) 17.4 34.7 9.9 21.5 16.5

Gershoni-Baruch et al. (2002a) 16.7 26.7 13.3 22.5 5.8

Al-Alami et al. (2003) 35.5 29 16 9.7 0

Majeed et al. (2005a) 37.5 26 14 10 12.5

Ayesh et al. (2005) 49 16.7 11.9 4 8.5

The percentage value is the contribution of the mutation to the pool of the identified mutant alleles

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

penetrance. The overall carrier rate for the five commonMEFVmutations from this

study is 1 in 5 which is very similar to the calculated carrier rate. Despite the high

carrier rate, the heterozygote advantage for the MEFV mutations could not be

demonstrated in the study probably because of the relatively small sample size. In

the second study, examination of healthy Syrian controls for the five common

mutations revealed a carrier status of 17.5% (1:5.8) (Mattit et al. 2006).

One of the remarkable conclusions from these studies is that the percentage of

unidentified disease-causingMEFV alleles is highest in the Arabic population when

compared to the other ethnic groups commonly affected by FMF (Al-Alami et al.

2003; Ayesh et al. 2005; Brik et al. 1999; Chaabouni et al. 2007; Dode et al. 2000;

Gershoni-Baruch et al. 2001; Jarjour 2010; Majeed et al. 2002, 2005b; Mansour

et al. 2001; Medlej-Hashim et al. 2000, 2005; Sabbagh et al. 2008). This is clearly

shown in one study that used a combination of methods including direct sequencing

of exon 10, DGGE, and restriction endonuclease digestion in a cohort of well

characterized FMF patients from the four commonly affected ethnic groups

(Dode et al. 2000). While 51% of the alleles in Arabic FMF patients were not

identified in this study, only 30, 25, and 9% of the alleles were not identified in non-

Ashkenazi Jews, Turks, and Armenians, respectively. A recent study that employed

methods that detect 24 previously described mutations (ARMS test followed by

resequencing of exon 10 and exploration of five other mutations in exons 2, 3, 4, 5,

and 6) in Palestinians failed to detect 51% of the alleles, which is quite high

considering the detailed methodology (Ayesh et al. 2005). It is unlikely that the

diagnosis of FMF in these studies is inaccurate, as all published reports follow the

validated diagnostic criteria (Livneh et al. 1997). In a recently published study on

Table 5.4 Distribution of the five common mutations, allele frequencies, and carrier rates among

the healthy adult cohort from five Arabic countries

Nationality and

number

Egyptians

(231)

Syrians

(225)

Jordaniansa

(200)

Iraqies

(176)

Saudies

(107)

Total

(939)

Number of

chromosomes

462 450 400 352 214 1,878

M694V 2 6 13 0 0 21

V726A 8 5 14 9 1 37

M694I 4 0 2 0 0 6

M680I 0 1 1 0 0 2

E148Q 29 30 23 29 12 123

Total 43 42 53 38 13 189

Wild-type allele

frequency “p”

0.907 0.907 0.8675 0.892 0.939 0.899

Mutant allele

frequency “q”

0.093 0.093 0.1325 0.108 0.061 0.101

Calculated carriers

(rate)

39(16.87%) 38(16.92%) 46(23%) 34(19.26%) 12(11.4%) 170

Observed number

of carriers

43 42 37 38 13 173

aThe calculations of the carrier rate and allele frequency are done under the assumption that there

are no complex alleles

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders 123

83 FMF patients from Syria, 76% of mutant alleles were identified by testing for the

five common mutations followed by resequencing of exon 10 in patients with one or

no mutation (Mattit et al. 2006). This is the highest reported percentage of identifi-

able mutation in an Arabic cohort. However, an independent study on 153 patients

from Syria who were screened for a similar number of mutations albeit utilizing a

different technical approach identified only 49% of mutant alleles and 51% of the

alleles remained undetermined (Jarjour 2010). The summary of selected studies

shown in Table 5.2 indicates the high percentage of unidentifiable alleles in Arabic

FMF patients, which suggests the presence of other mutations not identified by the

applied methods.

Genotype/Phenotype Correlation Patterns

There are a few genotype/phenotype correlation pattern studies involving Arabic

FMF patients (Brik et al. 1999; Gershoni-Baruch et al. 2002a; Jarjour 2010;

Majeed et al. 2002; Mansour et al. 2001; Medlej-Hashim et al. 2004). One

study that included mixed Arabic and Jewish FMF patients denoted that in Arabic

patients FMF tends to run a milder course and carries a better prognosis (Brik

et al. 1999). This was attributed to the fact that M694V is less common among the

Arabic FMF patient cohort. Another study concluded that Arabic FMF patients

with the genotypes M694V/M694V or M694V/V726A tend to have a severe

clinical course (Majeed et al. 2002). The genotype M694I/M694I is common in

Arabic FMF patients and seems to be associated with milder disease. However,

this study used a severity score modified from the Tel Hashomer severity score

and both have not been statistically validated. Homozygosity of M694V or the

complex allele V726A/E148Q was associated with most severe course and high-

est risk for amyloidosis in mixed Arabic, Ashkenazi, and Non-Ashkenazi Jewish

FMF patients (Gershoni-Baruch et al. 2002a). In Lebanese patients, M694V and

M694I were associated with higher risk of amyloidosis (Mansour et al. 2001;

Medlej-Hashim et al. 2004). It appears that the phenotype associated with the

M694I mutation is not consistent in the limited number of studies. The genotype/

phenotype correlation pattern studies performed in Arabic FMF patients are

mentioned in Table 5.1.

A new and simple severity score has recently been developed and has been

statistically validated (Mor et al. 2005). It was utilized on one cohort from Syria to

outline a genotype/phenotype correlation pattern (Jarjour 2010). There was a

statistically significant higher severity score in patients homozygous for the

M694V mutations, although the numbers are still small. It would be of interest to

apply this severity score to large cohorts of Arabic FMF patients to outline the

specific genotype/phenotype correlation patterns. As this severity score reflects on

the actual burden of FMF, it will also be of interest to measure the burden of FMF

on Arabic communities utilizing this tool.

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

Needs and Goals for the Future

As a considerable proportion of the disease-causing MEFV alleles in the Arabic

FMF patients remain unidentified, the need arises to perform extensive studies

that take a comprehensive approach to the identification of MEFV mutations.

These studies should explore regulatory sequences and conserved intronic

sequences for disease-causing mutations. The exploration of other non-traditional

mutation mechanisms should also be examined, such as analysis for large dele-

tions or duplication. Furthermore, the exploration of the role of already described

and potential modifier genes and polymorphisms within these genes should be

carried out in conjunction with the appropriate genotype/phenotype relationship

studies.

It is of paramount importance to identify if there is a distinctive pattern of the

relationship between MEFV and modifier gene genotypes on one hand and the

phenotype in the Arabic FMF patient population on the other hand. It is of equal

importance to identify if there is a correlation between the severity of the disease, its

burden, and its common complications with any of the mutations in Arabic FMF

patients. The severity of the disease should be a practical and actual measure of the

disease burden and should not be affected by colchicine therapy, which is the

standard of care for diagnosed patients. The achievement of these goals will lead

to the establishment of adequate population screening protocols for early and

presymptomatic identification of patients and the provision of prophylactic colchi-

cine therapy. There is a paucity of the studies that measure and evaluate FMF as a

public health consideration in the Arabic countries, and the need for such cross-

sectional studies cannot be overstated. There is a need to establish collaborative and

standardized study protocols across the Arabic countries with substantial numbers

of FMF patients to facilitate comparisons and allow the aggregation of data for

robust statistical analysis. These protocols will also provide the guidelines for

the appropriate screening approaches and the instatement of public policies that

provide adequate preventive measures.

The establishment of educational resources parallels the establishment of diag-

nostic laboratory testing and increases the awareness of physicians and medical

personnel to FMF and its complications. As diagnostic laboratory testing is not

specific and the molecular diagnosis is still limited, the clarity of the clinical

diagnostic criteria is the hallmark for making an accurate and precise diagnosis.

The development of these diagnostic skills among physicians requires the appro-

priate and continued medical educational resources to be available to health care

providers.

There is a need for the utilization of clinically well-characterized FMF patients

in research endeavors that aim at exploring the pathogenesis of the disorder. The

understanding of the pathogenesis of the disorder will serve all ethnic groups

commonly affected by FMF and will promote the understanding of inflammation

and the molecular correlates to the innate immunity.

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders 125

TNF Receptor Associated Periodic Syndrome (TRAPS)

(FPF, MIM 142680)

TRAPS is a newly recognized autoinflammatory disease that actually subsumes

several older diagnoses that were consolidated with the recent recognition that all

are caused by mutations in the extracellular domain of the 55 kDa TNF receptor

(TNFRSF1A) (McDermott et al. 1999), Figure 5.2 (Milhavet et al. 2008; Sarrauste

de Menthiere et al. 2003; Touitou et al. 2004). Before the discovery of TNFRSF1Amutations, the dominant periodic fevers included a poorly understood, ethnically

diverse group of illnesses, most of which had been described in case reports of

single families. The most thoroughly characterized was a large pedigree of Irish and

Scottish ancestry ascertained in Nottingham, England, whose illness was denoted

familial Hibernian fever (McDermott et al. 1997; Williamson et al. 1982). A second

large Australian family of Scottish ancestry with similar clinical findings was

denoted as benign autosomal dominant familial periodic fever because of uncer-

tainty over whether this family had the same condition as the first (Mulley et al.

1998). Although amyloidosis was observed in only 1 of 21 affected members of the

first family and in none of the eight affected members of the second family,

TNFRSFIA NM 001065.2 (12p13.2)

DNA: 13231bp, mRNA: 2096bp, Protein: 455aa

G36ET371Y38CL39FD42delC43RC43YC43S N65I C88R

C88YH66YP46LG47G

D12EY20HY20DH22YH22RH22QS27SC29FC29YC30RC30SC30YC30FC33GC33Y

36 A>G

5’flanking 3’flanking

Sizes (bp)229

39/40

13/14Codons(- Leader Seq.) (+ Leader Seq.)

This graph shows the variant usual name (i.e. as first published).Please refer to the variant detail by clicking on its name for possible edited nomenclature.

CDS joints

Positions36 79 129 155 180 218 227/228 324

353

INFEVERS: April19,2009N Sequencevariants: 91

256/25724720918415810865

193/194 322/323 472/473 551/552 625/626 739/740 768/769 1057/1058

154 129 150 79 74 114 29 289 849

7531

11 12 13 14 15 16 17 18 19

225 220 219 2142 141 302 200 155

–609G/T–580A/G–383A/C 39+1899(GT) (GA)

194–29G>A

194–15C>T194–14G>A

194–18 -17del

T50M R92PR92QC70RT50K

C52RC52FC52Y C70Y C96Y

C98Y 472+1G>A

625+10G>A

740–97>CSI97S

552–89A>T323–32A>G

K157K

ll70N

Y331X

V173D

L167 G175del472+6C>T472+64C>T473–72G>A473–33C>T473–16G>A

R104QH105PE109AF112IN116S

C73RC73WS74CC55S

C55RE54E

C70G V95MC70S T94T

L67PH69fs

R92W

T6IN S86PT6II

F60SF60L(C>A)

F60VF60L(I>C)C55Y

1 2 3 4 5 6 7 9 108

Fig. 5.2 TNFRSF1A and its variations

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

amyloidosis was a prominent feature in several other reported families of various

ethnic backgrounds (Gertz et al. 1987).

As is generally the case in the hereditary periodic fevers, patients experience

febrile episodes accompanied by peritoneal or pleural inflammation, arthralgia or

arthritis, and skin rash. However, in TRAPS, the attacks tend to be longer than in

FMF. Many attacks last more than 1 week and some TRAPS patients have episodes

lasting more than 1 month or experience nearly continuous inflammation. Conjunc-

tival involvement and/or periorbital edema, as well as localized myalgia, are also

much more frequent in TRAPS than in FMF. Another distinguishing feature in

TRAPS, although it is not observed in all patients, is a rash that progresses

centrifugally on the limbs. Finally, most patients with TRAPS respond poorly to

colchicine, which is quite effective in FMF, but show significant improvement on

corticosteroids, which are usually ineffective in FMF. Patients with traps TRAPS

respond quite well to etanercept (TNF-alpha blocker) (Arostegui et al. 2005; Jesus

et al. 2008; Morbach et al. 2009).

TRAPS has not been reported in Arabs, probably because of lack of the diag-

nostic tools and for the decreased suspicion as it is an autosomal dominant disease.

In addition, several instances in which autosomal dominant periodic fever syn-

drome was suspected in an Arabic family turned out to be FMF exhibiting pseudo-

dominant transmission because of the high consanguinity rate and the high of

frequency of mutation carriers. One report was of an Israeli Arab who had a denovomutation in TNFRSF1A (Aganna et al. 2002). Mutations in TNFRSF1A should

be always sought in Arab patients with atypical FMF or without identifiable

mutations within MEFV.

Chronic Recurrent Multifocal Osteomyelitis

(CRMO, MIM 259680; 609628)

CRMO is a relatively rare childhood disease that presents with bone pain with or

without associated fever (Giedion et al. 1972; Schultz et al. 1999). The disease

course often lasts several years and is characterized by remissions and exacerba-

tions. The inflammatory bone lesions are typically located at the metaphyses of

tubular long bones, but they can occur at other sites including the mandible,

sternum, clavicle, and vertebrae (Bjorksten and Boquist 1980; El-Shanti and Fer-

guson 2007; Ferguson and El-Shanti 2007; Girschick et al. 2005; Huber et al. 2002;

Jansson et al. 2007; Jurik 2004; Schultz et al. 1999). Plain films reveal lytic bone

lesions surrounded by sclerosis (Bjorksten and Boquist 1980; Jurik 2004). Bone

histology reveals neutrophils early in the disease course, accompanied by multinu-

cleated giant cells, scattered granulomatous foci, and osteoclastic bone resorption.

Later, new bone formation, fibrosis, and lymphocytes predominate (Bjorksten and

Boquist 1980). Cultures and stains for pathogens are negative, and treatment with

antibiotics is rarely associated with clinical improvement (Bjorksten and Boquist

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders 127

1980; Girschick et al. 1999; Schultz et al. 1999). Not long after the initial descrip-

tion of CRMO, its association with other chronic inflammatory disorders began to

be reported. Disease associations included palmar–plantar pustulosis, psoriasis

vulgaris, and inflammatory bowel disease, which suggested that an inflammatory

pathway common to skin, bone, and gut is dysregulated in these disorders (Berg-

dahl et al. 1979; Bjorksten et al. 1978; Bognar et al. 1998; Laxer et al. 1988; Schultz

et al. 1999).

There is evidence that the etiology of sporadic CRMO has a genetic component,

including several reports of affected siblings, affected parent and child, concordant

monozygotic twins, and a report of a susceptibility locus on chromosome

18q21.3–18q22 (Ben Becher et al. 1991; Festen et al. 1985; Golla et al. 2002;

Jansson et al. 2007). In addition, as many as half the patients have a first-degree or

second-degree family member who is affected by a chronic inflammatory disorder,

most often psoriasis (Jansson et al. 2007). In our cohort of 45 CRMO patients,

47% of first-degree relatives have a chronic inflammatory disorder (family history

of psoriasis in 18%, inflammatory bowel disease in 13%, inflammatory arthritis in

11%, and severe acne in 7%; unpublished data).

A syndromic form of CRMO was first described by Dr. Hasan Abdel Majeed

and his colleagues in 1989 (Majeed et al. 1989) and was subsequently named after

him as Majeed syndrome. Affected individuals present with periodic fevers,

early-onset CRMO (age range 3 weeks to 19 months), a microcytic congenital

dyserythropoietic anemia, and often a transiently occurring inflammatory derma-

tosis (Al-Mosawi et al. 2007; Majeed et al. 1989, 2000b, 2001). The congenital

dyserythropoietic anemia presents during the first year of life and the resultant

anemia varies in severity from mild to transfusion-dependent (Al-Mosawi et al.

2007; Majeed et al. 1989, 2000b, 2001). The dermatosis is most often Sweet

syndrome. Hepatomegaly, neutropenia, and transient cholestatic jaundice may

occur during the neonatal period (Al-Mosawi et al. 2007). The bone marrow

exhibits increased erythropoiesis associated with evidence of dyserythropoiesis,

including binucleated normoblasts (Majeed et al. 2001). The CRMO in Majeed

syndrome is persistent with a few short remissions, frequent exacerbations, and

prolonged duration. Like sporadic CRMO, there is a predilection for the meta-

physes of the long bones, and radiographs demonstrate extensive lytic lesions

with areas of sclerosis (Majeed et al. 2001). Cultures of the bone lesions are

negative and prolonged antibiotic administration provides no benefit (Al-Mosawi

et al. 2007; Majeed et al. 2001). Permanent joint deformities and growth distur-

bance may occur after years of continued inflammation (Majeed et al. 2001).

Uniformly, there is marked clinical improvement with corticosteroids (Al-

Mosawi et al. 2007; Majeed et al. 1989). Nonsteroidal anti-inflammatory drugs

provide a moderate degree of improvement (Al-Mosawi et al. 2007; Majeed et al.

2001). Majeed syndrome is an autosomal-recessive disorder caused by mutations

in LPIN2 (Ferguson et al. 2005). The gene responsible for Majeed syndrome was

localized to the short arm of chromosome 18 using homozygosity mapping,

because the first two described families were inbred. To date, three different

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

homozygous mutations in LPIN2 have been found in each of the reported families

with Majeed syndrome, all of whom are Arabic (Al-Mosawi et al. 2007; Ferguson

et al. 2005) (available at http://fmf.igh.cnrs.fr/infevers) (Figure 5.3) (Milhavet

et al. 2008).

There are two murine models of CRMO. The first model to be described is a

spontaneous mutant mouse named the cmo (chronic multifocal osteomyelitis)

mouse (Byrd et al. 1991; Ferguson et al. 2006; Hentunen et al. 2000). The cmomouse develops tail kinks and hind foot deformities, which are the results of a

robust mixed inflammatory infiltrate in the bone composed of PMNs, macrophages,

lymphocytes, plasma cells, and osteoclasts (Ferguson et al. 2006; Hentunen et al.

2000). Later, there is presence of osteosclerosis as the inflammatory infiltrate is

replaced by new bone and fibrosis (Ferguson et al. 2006; Hentunen et al. 2000).

Subsequently, the mouse develops inflammation of the ears involving the dermis,

epidermis, and cartilage (Ferguson et al. 2006). A second autosomal-recessive

mouse model of CRMO was produced by chemical (N-ethyl-N-nitrosourea) muta-

genesis; it was noted to have a similar but somewhat more severe phenotype than

the cmo mouse and was named the Lupo mouse (Grosse et al. 2006). The gene

defect was identified in both cmo and Lupo mice utilizing similar genetic

approaches as two different missense mutations in pstpip2/Mayp (Ferguson et al.

2006; Grosse et al. 2006).

288/289

T180fs

A331SP348LK387E L504F E601K S734L R776S

230 201

115’flanking

Sizes (bp)

3’flanking

50868 6049 3147 10342 1001 1442 3241 2907 2097 404 779 916 1354 677 536 1575 399 651 340

12 13 14 15 16 17 18 19 110 111 112 113 114 115 116 117 118 119

96 302 108 124 346 100 188 94 70 90 83 145 149 87 153 115 104 3443

CDS joints

Positions

Codons

192/193-10/-9

96/9764/65 197

233 390 486423 517

540/541570/571

598 696646/647

INFEVERS: April19, 2009N Sequence variants:8

725776 849

814/815274/275

590/591698/699

822/8231168/1169

1268/12691456/1457 1620/1621 1793/1794 2087/2088

1938/1939 2174/2175 2442/24432546/25472327/2328

1550/1551 1710/1711

LPIN2 NM 014646.2(18p11.31)DNA: 94953 bp, mRNA: 6228 bp, protein: 896 aa

This graph shows the variant usual name (i.e as first published).Please refer to the variant detail by clicking on its name for possible edited nomenclature.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Fig. 5.3 LPIN2 and its variations

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders 129

Hyperimmunoglobulinemia D with Periodic Fever Syndrome

(Hyper-IgD) HIDS, MIM 260920)

The hyper-IgD syndrome was recognized as a separate clinical entity in 1984 (van

der Meer et al. 1984). Patients with the hyper-IgD syndrome have recurrent attacks

of fever that usually start before the end of the first year of life (Drenth et al. 1994b).

An attack is heralded by chills, followed by a sharp rise in body temperature, and

lasts for 4–6 days, with gradual defervescence. It can be provoked by vaccination,

minor trauma, surgery, or stress. Cervical lymphadenopathy and abdominal pain

with vomiting, diarrhea, or both almost always accompany the attack. Symptoms

that are common include hepatosplenomegaly, headache, arthralgias, arthritis of

large joints, erythematous macules and papules, and even petechia and purpura

(Drenth et al. 1994a). After an attack, patients are free of symptoms, although skin

and joint symptoms disappear slowly. The attacks generally recur every 4–6 weeks,

but the interval between them can vary substantially in an individual patient and

from one patient to another.

The hyper-IgD syndrome is inherited as an autosomal recessive trait (Drenth

et al. 1994c). Most patients with the hyper-IgD syndrome are white and are from

western European countries; some 60% are either Dutch or French. Although

hyper-IgD syndrome is autosomal recessive, there has been no report from Arabic

countries thus far. The hyper-IgD syndrome is diagnosed on the basis of character-

istic clinical findings and continuously high IgD values (more than 100 IU per mL).

During an attack, there is a brisk acute-phase response, with leukocytosis, high

levels of serum C-reactive protein and serum amyloid A, and activation of the

cytokine network (Drenth et al. 1995).

A genome-wide search established the linkage of the susceptibility gene for the

hyper-IgD syndrome to the long arm of chromosome 12 (Drenth et al. 1999; Houten

et al. 1999a). This information, along with the fortuitous detection of mevalonic

acid in a urine sample obtained during a febrile attack in a patient with the hyper-

IgD syndrome, led to the identification of mutations in the gene for mevalonate

kinase as the cause of the syndrome (Drenth et al. 1999; Houten et al. 1999a).

In patients with the hyper-IgD syndrome, the activity of mevalonate kinase is

reduced to 5–15% of normal; as a result, serum cholesterol levels are slightly

reduced, and during attacks, urinary excretion of mevalonic acid is slightly ele-

vated. Less than 1% of patients have a complete deficiency of mevalonate kinase,

which is associated with mevalonic aciduria, a rare inherited disorder characterized

by developmental delay, failure to thrive, hypotonia, ataxia, myopathy, and catar-

acts. In mevalonic aciduria, the disease-associated mutations are mainly clustered

within a specific region of the protein (Houten et al. 1999b).

No uniformly successful treatment of the hyper-IgD syndrome is available.

Patients with the hyper-IgD syndrome have febrile attacks throughout their lives,

although the frequency of attacks is highest in childhood and adolescence. Patients

may be free of attacks for months or even years. Amyloidosis has not been reported

in association with the hyper-IgD syndrome.

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

Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne

Syndrome (PAPA, MIM 604416)

This syndrome, first described in 1997, is a rare autoinflammatory disease mainly

involving the joints and the skin (Lindor et al. 1997). It is inherited in an autosomal

dominant pattern and the disease gene was mapped to chromosome 15 (Yeon et al.

2000). Subsequently, the CD2-binding protein 1, CD2BP1, also called the proline/

serine/thronine phosphatase interacting protein 1, PSTPIP1, was reported as the

PAPA syndrome susceptibility gene (Wise et al. 2002). The CD2BP1 protein

appears to interact with pyrin where PAPA-associated mutations lead to increased

binding to pyrin (Shoham et al. 2003). As a result, CD2BP1 may sequester pyrin

and therefore reduce pyrin’s inhibitory role in regulation of the IL-1b pathway and

the innate immune response.

Individuals with PAPA syndrome typically develop cystic acne, sterile

abscesses, and cutaneous ulcers, including pyoderma gangrenosum-like lesions.

They may also develop sterile abscesses at injection sites (Lindor et al. 1997).

Histologic examination of skin shows a superficial and deep perivascular, intersti-

tial, periadnexal infiltrate predominantly consisting of lymphocytic and neutro-

philic leukocytes. At a young age, patients with PAPA syndrome develop a

severe sterile, pyogenic, destructive arthritis that affects the non-axial skeleton

(Lindor et al. 1997).

Corticosteroids can provide relief for patients with PAPA syndrome but their

adverse effects often limit their use. Biologic therapies provide a possible new

avenue for treatment, such as the TNF-a inhibitor etanercept (Cortis et al. 2004).

The Cryopyrinopathies

Familial cold autoinflammatory syndrome (FCAS, MIM 120100), Muckle–Wells

syndrome (MWS, MIM 191900), and neonatal-onset multisystem inflammatory

disease (NOMID, MIM 607115), also called chronic infantile neurologic cutane-

ous and articular syndrome, or CINCA syndrome, represent unique disease

entities, which are also known as the cryopyrinopathies. The cryopyrinopathies

share a number of similar phenotypic features and appear to represent a continuum

of disease, with FCAS at the mild end and NOMID/CINCA syndrome representing

the severe end of the spectrum. Genetic studies using linkage analysis of large

families with FCAS and MWS identified the susceptibility loci for these two

disorders at chromosome 1q44.4 (Hoffman et al. 2000). In 2001, it was shown that

both FCAS and MWS were associated with mutations in the same gene, CIAS1(Dode et al. 2002; Hoffman et al. 2001a). CIAS1 encodes for cryopyrin (also

called PYPAF1, NALP3, and CATERPILLER 1.1). Subsequently, it was shown

that mutations in CIAS1 are also associated with NOMID/CINCA syndrome

5 Familial Mediterranean Fever and Other Autoinflammatory Disorders 131

(Aksentijevich et al. 2002; Feldmann et al. 2002). To date, more than 50mutations in

CIAS1 have been identified. Almost all of these mutations, except three, are mis-

sense mutations that are localized to exon 3 of CIAS1, which encodes for the

NACHT domain. These findings suggest that the mutated cryopyrin may have a

dominant negative or gain-of-function effect over the wild-type product (Neven

et al. 2004).

FCAS, also known as familial cold urticaria and MWS are rare autosomal

dominant disorders that are characterized by fever, urticarial-like eruption, and

limb pain (Hawkins et al. 2004; Muckle and Wellsm 1962). Erythematous and

edematous papules and plaques are the most common dermatologic manifestations

of FCAS and MCS. They are present in almost all patients in the first 6 months of

life (Hoffman et al. 2001b). In addition to skin findings during attacks, patients with

FCAS also have fever, headache, nausea, sweating, drowsiness, extreme thirst,

conjunctivitis, blurred vision, ocular pain, and polyarthralgia. Progressive sensori-

neural hearing impairment, nephropathy, and amyloidosis are reported in MWS

(Muckle 1979; Muckle and Wellsm 1962).

In the past, aside from avoidance of cold exposure, there was no effective

treatment for patients with FCAS or MWS. Nonsteroidal anti-inflammatory drugs

are often used for relief of arthralgias. Therapy with high dose corticosteroids is

effective, but adverse effects usually limit long term use. Anakinra, an IL-1 receptor

antagonist, has been shown not only to prevent a recurrence of episodes but also to

decrease a chronic inflammatory response that can lead to systemic amyloidosis

(Hawkins et al. 2003, 2004; Hoffman et al. 2004).

NOMID/CINCA syndrome is a rare inflammatory disease that is characterized

by the triad of disabling arthropathy, skin eruption, and central nervous system

inflammation. Patients have progressively worsening visual, auditory, and nervous

system manifestations. Only a few cases of NOMID/CINCA syndrome have been

reported with autosomal dominant transmission, but most cases seem sporadic

(Aksentijevich et al. 2002; Feldmann et al. 2002). Nonpruritic, migratory eruption

of edematous papules and plaques, which fluctuates in intensity, arises in a large

percentage of patients with NOMID/CINCA syndrome (Prieur 2001) About two-

thirds of affected newborns have the “urticaria-like eruption” at birth, and most

develop it in the first 6 months of life. Patients with NOMID/CINCA syndrome

commonly have short episodes of recurrent fevers. They also develop an assortment

of neurologic abnormalities, including headaches, macrocephaly, cerebral atrophy,

chronic aseptic meningitis, high-frequency hearing loss, and developmental delay

(Mallouh et al. 1987). Arthropathy, varying greatly in severity between patients,

may develop (Mallouh et al. 1987).

High-dose steroids have been effective in attenuating pain and inflammation, but

in general do not alleviate the other manifestations of disease. Recently, there have

been several reports of patients with NOMID who had a dramatic response to

treatment with the IL-1 receptor antagonist, anakinra (Goldbach-Mansky et al.

2006, 2008).

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

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