genetic disorders among arab populations || familial mediterranean fever and other autoinflammatory...
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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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