Mediterranean fever, familial R50.9

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 26.02.2022

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Synonym(s)

Familial Mediterranean fever; FMF

History
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Osler, 1895; Janeway and Mosenthal, 1908

Definition
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Hereditary fever syndrome with periodic fever, seizure-like serositis (abdominal cavity, pleura), arthritis, orchitis and possibly volatile, erysipelas-like exanthema.

Occurrence/Epidemiology
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More than 10,000 patients are affected worldwide. The disease occurs mainly in the Mediterranean region (e.g. Armenian, Turkish, Arab and Jewish populations). However, due to immigration, this clinical picture is also of differential diagnostic importance in Western countries.

Depending on the study and the collective, the frequency of heterozygous gene carriers is 1:26 to 1:52. The disease manifests when there is a homozygous (both alleles carry the same mutation) or compound heterozygous (both alleles carry different mutations) status. For heterozygous parents, this means that the risk of producing a homozygous or compound heterozygous (diseased) child is 25%.

Etiopathogenesis
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Autosomal recessive mutations of the MEFV gene (Mediterranean fever gene; gene locus: 16p13.3). The resulting functional impairment of the protein encoded by this gene, the pyrin (cryopyrin) or also called marenostrin (lat.: mare nostrum for Mediterranean), leads to the triggering of a systemic inflammatory reaction.

To date, 100 disease-associated mutations, 89 mutations with unknown effect, and 33 mutations without an associated phenotype have been described. A cluster of mutations is found in exons 2 and 10. FMF was initially thought to follow a classical autosomal recessive mode of inheritance. On the one hand, however, it quickly became apparent that up to 20% of all patients with a clinically clearly defined FMF have only one or no mutation in the MEFV gene, so that further genetic alterations in regulatory elements or other gene segments have to be postulated.

On the other hand, it was shown early on that many people with two mutations in MEFV never develop the disease (type III FMF).

To be distinguished from this are people who never develop clinical symptoms of FMF but do develop amyloidosis due to two mutations in the MEFV gene (type II FMF). Data on the prevalence of this phenotype vary widely.

Manifestation
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In most cases occurring in childhood and adolescence; in about 90% of patients before the age of 20 LJ.

Clinical features
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Recurrent febrile attacks (in 96% of patients) of irregular periodicity, usually accompanied by acute peritonitis (91%), often also pleuritis (57%), arthritis or sacroiliitis (45%), as well as a volatile, erysipelas-like, 10-15 cm in diameter, macular exanthema with pruritus occurring on one or both sides, especially below the knee (13%). 2% of patients develop amyloidosis.
  • Phenotype 1: Beginning with fever attacks.
  • Phenotype 2: Amyloidosis as the first manifestation.

Laboratory
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ESR elevated, rarely leukocytosis. Elevated serum amyloid A is only observed in manifest amyloidosis, which is a complication of FMF and does not serve as the primary diagnosis. Regular (collection!) urine testsshould therefore be an integral part of patient care.

Diagnosis
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Clinical (main criteria: peritonitis, pleuritis, monarthritis, fever, skin symptoms) is diagnostic; signs of inflammation are pronounced in relapses. Diagnosis is confirmed by molecular genetic analysis of the MEFV gene located on the short arm of chromosome 16.

Differential diagnosis
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Complication(s)
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Consequential damage such as kidney failure due to systemic amyloidosis.

Infertility in about 30% of women with the disease. 20-30% of pregnancies in patients end in premature abortion.

An association of familial Mediterranean fever with the following diseases, which have been reported in clusters, is not certain (Delplanque M et al. 2022):

neutrophilic panniculitis

Sweet syndrome

pyoderma gangrenosum

Hidradenitis suppurativa: MEFV mutations are more common in hidradnitis suppurativa than in the normal population. They are associated with the severity of the disease but are also of prognostic significance in many other inflammatory diseases. For example, an increased rate of familial Mediterranean fever and heterozygous mutations in the Mediterranean fever gene (MEFV) is found in patients with severe hidradenitis supp urativa compared with the normal population. In patients with familial Mediterranean fever (FMF), hidradenitis suppurativa may have a severe phenotype and overlapping PAPASH-like features (Vural S et al 2017). Of note, in some patients with hidradenitis suppurativa and pyoderma gangreanosum, double pathogenic mutations in MEFV coexisted without clinical FMF and promoter extension in PSTPIP1 (Vural S et al. 2018).

Therapy
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Colchicine (e.g. Colchicum-Dispert) 0.03 ± 0.02 mg/kg bw/day in 2 ED p.o. or in children under 5 years 0.07 mg/kg bw/day in 2 ED p.o. is well effective in 70-90% of patients. In about 10% of the children, however, colchicine does not have any effect on fever spikes, although a lack of compliance is often the cause. Lifelong colchicine intake leads to a positive influence on fever spikes and prevents complications.

Literature
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  1. Aldea A et al (2004) A severe autosomal-dominant periodic inflammatory disorder with renal AA amyloidosis and colchicine resistance associated to the MEFV H478Y variant in a Spanish kindred: An unusual familial Mediterranean fever phenotype or another MEFV-associated periodic inflammatory disorder? Am J Med Genet 124A: 67-73
  2. Delplanque M et al (2022) Is neutrophilic dermatosis a manifestation of familial Mediterranean fever? Scand J Rheumatol 51:42-49.
  3. Gershoni-Baruch R et al (2003) Prevalence and significance of mutations in the familial Mediterranean fever gene in Henoch-Schonlein purpura. J Pediatr 143: 658-661.
  4. Janeway TC, Mosenthal HO (1908) An unusual paroxysmal syndrome, probably allied to recurrent vomiting, with a study of the nitrogen metabolism. Trans Ass Am Phys 23: 504-518.
  5. Osler W (1895) On the visceral manifestations of erythema multiforme. Am J Med Sci 110: 629.
  6. Panossian A et al (2003) Plasma nitric oxide level in familial Mediterranean fever and its modulations by Immuno-Guard. Nitric Oxide 9: 103-110.
  7. Sayarlioglu M et al (2003) Colchicine-induced myopathy in a teenager with familial Mediterranean fever. Ann Pharmacother 37: 1821-1824.
  8. Timmann C et al (2003) Familial Mediterranean fever with amyloidosis associated with novel exon 2 mutation (S1791) of the MEFV gene. Blood Cells Mol Dis 31: 320-323.
  9. Vural S et al (2017) Familial Mediterranean fever patients with hidradenitis suppurativa. Int J Dermatol 56: 660-663.

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Last updated on: 26.02.2022