Familial Mediterranean Fever

Familial Mediterranean Fever (FMF), also known as

an autoinflammatory syndrome, is the most frequent

periodic fever syndrome, affecting not only eastern

Mediterranean people such as non-Ashkenazi Jews,

Armenians, Arabs, and Turks but also reported

throughout the world’s populations.

Genetics/Basic Defects

1. An autosomal recessive disorder caused by mis-

sense mutations in the MEFV gene, located on the

short arm of chromosome 16 (16p13.3). TheMEFVgene is responsible for encoding a protein called

pyrin or marenostrin.

2. Pathogenesis

a. Partially elucidated only after the identification

of pyrin or marenostrin

b. A new macromolecular complex, called

inflammasome, seems to play a major role in the

control of inflammation and it might be involved

in the pathogenesis of FMF.

3. Phenotype expression of the FMF should depend on

the presence of a homozygote or heterozygote

genotype for the MEFV gene mutations.

4. Genotype-phenotype correlation, however, is com-

plex due to influence of genotype and the ethnic and

environmental factors, playing a role in the clinical

outcome with a very wide clinical spectrum

5. Etiology of the periodicity and the self-limited

nature remain largely unexplained

Clinical Features

1. Clinical manifestations (Fonnesu et al. 2009)

a. Onset of the disease: occurs before the age of 30

in almost all patients

b. Recurrent attacks

i. Last 1–4 days on average

ii. Resolve spontaneously with a frequency

varying from once a week to once every

3–4 months or, sometimes, years

iii. Severity and frequency of attacks have an

inter- and intra-individual variations

c. Presence of fever: absent in rare cases

d. Gastrointestinal symptoms

i. Abdominal pain: localized or diffuse

ii. Stypsis/diarrhea

iii. Associated disease

e. Musculoskeletal symptoms

i. Arthralgia: transient or abortive

ii. Arthritis

a) Acute asymmetric nondegenerative mono/

oligoarthritis

b) Protracted arthritis

c) Chronic degenerative arthritis

d) Migrating polyarthritis: usually induced

by exertion

iii. Myalgias

iv. HLA-B27 negative sacroiliitis during the

prodromes or the attack

f. Cardiopulmonary symptoms

i. Pleuritis

ii. Pericarditis

H. Chen, Atlas of Genetic Diagnosis and Counseling, DOI 10.1007/978-1-4614-1037-9_87,# Springer Science+Business Media, LLC 2012

789

g. Cutaneous symptoms: erysipelas-like erythema

h. Vasculitis

i. Henoch–Schoenlein purpura

ii. Polyarteritis nodosa

iii. Behcet disease

i. Other manifestations

i. Acute orchitis

ii. Mollaret’s meningitis

iii. Splenomegaly

iv. Retinopathy

2. Known trigger factors

a. Physical and emotional stress

b. Exposure to cold

c. Fat-rich meals

d. Banal infections

e. Drugs such as cisplatin

f. Menstrual cycle

g. Presence of Helicobacter pylori3. Secondary amyloidosis: the most devastating and

important long-term complication

a. Predominantly renal

b. Genetic risk factors

i. Genetic factors linked to MEFV gene

ii. Genetic factors linked to modifier genes

(Seroamyloid A gene – SAA – and Major

Histocompatibility Complex class 1 chain-

related A gene – MICA)

c. Nongenetic factors

i. Male gender: males four times higher than in

females

ii. Environmental factors: country identified as the

primary risk factor for renal amyloidosis (e.g.,

Armenians residing in Armenia have higher

incidence than those who reside in the USA)

4. Two phenotypes of FMF (Shohat et al. 2009)

a. FMF type I

i. Characterized by recurrent short episodes of

inflammation and serositis including:

a) Fever

b) Peritonitis

c) Synovitis

d) Pleuritis

e) Rarely pericarditis and meningitis

ii. Inter-individual and intra-familial variation

of symptoms

iii. Amyloidosis which can lead to renal failure is

the most severe complication of FMF type I

b. FMF type II: characterized by amyloidosis as the

first clinical manifestation of disease in an

otherwise asymptomatic individual (Pras 1998;

Langevitz et al. 1999; Shohat et al. 1999; Kone

Paut et al. 2000)

5. Differential diagnosis (Lidar and Livneh 2007)

a. Abdominal attacks (recurrent peritonitis)

i. Appendicitis

ii. Diverticulitis

iii. Cholecystitis

iv. Pyelonephritis

v. Pelvic inflammatory disease

vi. Pancreatitis

b. Recurrent abdominal attacks (without peritonitis)

i. Peptic disease

ii. Renal colic

iii. Endometriosis

iv. Menstruation pain

v. Irritable bowel syndrome

c. Chest attacks (recurrent pleuritic chest pain)

i. Pulmonary embolism

ii. Pleuritis (idiopathic, infectious, autoimmune)

iii. Pericarditis (idiopathic, infectious,

autoimmune)

d. Joint attacks (recurrent synovitis)

i. Gout

ii. Pseudogout

iii. Spondyloarthropathy

iv. Juvenile idiopathic arthritis

e. Febrile attacks (recurrent)

i. Lymphoma

ii. Infections (malaria, relapsing fever)

iii. PFAPA (periodic fever, aphtous stomatitis,

pharyngitis, adenopathy)

f. Non-FMF inflammatory disorders (Ozen 2003)

i. Inflammatory bowel disease

ii. Hyper IgD syndrome

iii. Tumor necrosis factor receptor–associated

periodic fever syndrome

iv. Acute intermittent porphyria

v. Familial cold urticaria or familial cold auto-

inflammatory syndrome

g. Systemic lupus erythematosus

h. Adult Still disease

i. Muckle–Wells syndrome

j. Chronic infantile neurological cutaneous

arthropathy

k. Neonatal onset multi-system inflammatory dis-

ease syndrome

l. Periodic fever-adenopathy-pharyngitis-aphtosis

syndrome

790 Familial Mediterranean Fever

Diagnostic Investigations

1. Pras diagnostic criteria (Pras 2002)

a. Recurrent short inflammatory attacks

b. A favorable response to colchicine treatment

2. Tel-Hashomer diagnostic criteria (Livneh et al.

1997; Fonnesu et al. 2009)

a. Major criteria

i. Fever and serositis

ii. Amyloidosis AA (without risk factors or

other chronic inflammatory diseases)

iii. Effectiveness of colchicine

b. Minor criteria

i. Recurrent attacks of fever

ii. Erysipela-like erythema

iii. Relatives affected by FMF

c. Definitive diagnosis: two major criteria or one

major criterion and two minor criteria

d. Probable diagnosis: one major criterion and one

minor criterion

3. Tel-Hashomer revised diagnostic criteria (Fonnesu

et al. 2009)

a. Presence of typical attacks

i. Fever

ii. Serositis

b. Positive response to colchicine

4. Criteria for the diagnosis of FMF (Lidar and Livneh

2007)

a. Major criteria: typical attacks (recurrent, febrile,

and short)

i. Peritonitis (generalized)

ii. Pleuritis (unilateral) or pericarditis

iii. Monoarthritis (hip, knee, ankle)

b. Minor criteria

i. Incomplete (painful and recurrent) attacks

involving one or more of the following sites:

a) Abdomen

b) Chest

c) Joint

ii. Exertional leg pain

iii. Favorable response to colchicine

c. Supportive criteria

i. Family history of familial mediterranean fever

ii. Appropriate ethnic origin

iii. Age <20 years at disease onset

iv. Features of attacks

a) Severe, requiring bed rest

b) Spontaneous remission

c) Symptom-free interval

d) Transient inflammatory response with

one or more abnormal test result(s) for

white blood cell count, erythrocyte sedi-

mentation rate, serum amyloid A, and/or

fibrinogen

v. Episodic proteinuria/hematuria

vi. Unproductive laparotomy or removal of

“White” appendix

vii. Consanguinity of parents

d. Requirements for diagnosis of FMF

i. Greater than or equal to one major criteria, or

ii. Greater than or equal to two minor criteria, or

iii. One minor plus >5 supportive criteria

5. Molecular genetic study of the MEFV gene to con-

firm the diagnosis

6. General clinical laboratory findings

a. Leukocytosis

b. Leukopenia associated with colchicine treatment

c. Elevated acute-phase reactant proteins such as

ESR, CRP, fibrinogen, haptoglobin, C3, C4, and

serum amyloid A (SAA) protein

d. Urinalysis for the presence of proteinuria

7. Diagnostic algorithm (Lidar and Livneh 2007)

a. Clinical criteria

b. Results of MEFV mutation analysis

c. Therapeutic trial, monitored by clinical response

and SAA levels

8. Renal biopsy: indicated in all FMF patients who

develop proteinuria or nephrotic syndrome

Genetic Counseling

1. Recurrence risk

a. Both parents carrying at least one MEFV gene

mutation

b. Patient’s sib

i. Twenty-five percent with MFM

ii. Fifty percent with MFM carrier

c. Patient’s offspring

i. All offspring inherit one MEFV gene muta-

tion from the proband

ii. Low recurrence risk unless the spouse is

affected or a carrier of MEFV gene mutation

2. Prenatal diagnosis (Shohat et al. 2009)

a. Possible for pregnancies at increased risk by

analysis of DNA extracted from fetal cells

obtained by amniocentesis or chorionic villus

Familial Mediterranean Fever 791

sampling, giving that both disease-causing

alleles of an affected family member must be

identified or linkage established in the family

before prenatal testing can be performed

b. Prenatal diagnosis of FMF, a treatable condition

associated with a good prognosis with early

treatment, may be controversial if the testing is

being considered for the purpose of pregnancy

termination rather than early diagnosis

3. Management

a. Colchicine

i. Should be introduced as soon as the diagno-

sis is made and continued for life

ii. Reduces the attack frequency, severity, and

duration in most FMF patients

iii. Can prevent, arrest, and even reverse renal

amyloidosis, even if it fails to stop the attacks

(Lidar et al. 2004; Kallinich et al. 2007)

iv. Also recommended for treatment of

amyloidosis

v. Higher colchicines dosage, up to 2 mg/day,

may be needed in high-risk patients such as

after kidney transplantation or patients with

amyloidosis

b. No effective mean to treat acute attacks of FMF

i. Methylprednisolone may relieve abdominal

pain and tenderness (Erken et al. 2008),

although steroids in general play no role

ii. Interferon (IFN)-a injection at the earliest

signs of an attack may provide some benefit

(Tunca et al. 2004; Tweezer-Zaks et al. 2008)

c. Controversy in treating asymptomatic individ-

uals with mutations in the MEFV gene who

may or may not develop FMF in the future

References

Borman, P., Gokoglu, F., Tasbas, O., et al. (2009). Familial

Mediterranean fever-related spondyloarthropathy. SingaporeMedical Journal, 50, e116.

Erken, E., Ozer, H. T., Bozkurt, B., et al. (2008). Early suppres-

sion of familial Mediterranean fever attacks by single

medium dose methyl-prednisolone infusion. Joint, Bone,Spine, 75, 370–372.

Fonnesu, C., Cerquaglia, C., Giovinale, M., et al. (2009). Famil-

ial Mediterranean fever: A review for clinical management

[review]. Joint, Bone, Spine, 76, 227–233.Guz, G., Kanbay, M., & Ozturk, M. A. (2009). Current perspec-

tives on familial Mediterranean fever. Current Opinion inInfectious Diseases, 22, 309–315.

Kallinich, T., Haffner, D., Niehues, T., et al. (2007). Colchicine

use in children and adolescents with familial Mediterranean

fever: Literature review and consensus statement. Pediatrics,119, e474–e483.

Kone Paut, I., Dubuc, M., Sportouch, J., et al. (2000).

Phenotype-genotype correlation in 91 patients with familial

Mediterranean fever reveals a high frequency of

cutaneomucous features. Rheumatology (Oxford, England),39, 1275–1279.

Langevitz, P., Livneh, A., Padeh, S., et al. (1999). Familial

Mediterranean fever: New aspects and prospects at the end

of the millennium. The Israel Medical Association Journal,1, 31–36.

Lidar, M., & Livneh, A. (2007). Familial Mediterranean fever:

Clinical, molecular and management advancements

[review]. Journal of Medicine, 65, 318–324.Lidar, M., Scherrmann, J. M., Shinar, Y., et al. (2004). Colchi-

cine nonresponsiveness in familial Mediterranean fever:

Clinical, genetic, pharmacokinetic, and socioeconomic

characterization. Seminars in Arthritis and Rheumatism,33, 273–282.

Livneh, A., & Langevitz, P. (2000). Diagnostic and treatment

concerns in familial Mediterranean fever. Bailliere’s BestPractice & Research. Clinical Rheumatology, 14,4774–4798.

Livneh, A., Langevitz, P., Zemer, D., et al. (1997). Criteria for

the diagnosis of familial Mediterranean fever. Arthritis andRheumatism, 40, 1879–1885.

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and laboratory findings in 105 patients. Digestive and LiverDisease, 32, 504–509.

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ancient disease [review]. European Journal of Pediatrics,162, 449–454.

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analysis study. Annals of Human Genetics, 72, 752–761.Pras, M. (1998). Familial Mediterranean fever: From the clinical

syndrome to the cloning of the pyrin gene. ScandinavianJournal of Rheumatology, 27, 92–97.

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Available at: http://www.ncbi.nlm.nih.gov/books/NBK1227/Tunca, M., Akar, S., Soyturk, M., et al. (2004). The effect of

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792 Familial Mediterranean Fever

Fig. 1 A 40-year-old female

was diagnosed to have familial

Mediterranean fever. She has

a history of low grade fever,

abdominal pain, joint pain, and

peritonitis. She responded well

to colchicine treatment. She is

a compound heterozygote for

two different mutations:

MM680I and V726A, in exon

10 of the MEFV gene which

confirms the clinical

diagnosis. Her brother and

sister are similarly affected.

Her 5-year-old daughter was

found to be heterozygous for

the V726A FMF mutation.

The parents are from Egypt

Familial Mediterranean Fever 793