Familial mediterranean fever R50.9

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

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%.

Autosomal recessive inherited 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 (Latin: mare nostrum for Mediterranean), leads to the triggering of a systemic inflammatory reaction. This is caused by the uncontrolled release of interleukin-1beta and interleukin-18.

To date, >100 disease-associated mutations, 89 mutations with unknown effects and 33 mutations without an associated phenotype have been described. A cluster of mutations is found in exons 2 and 10, with the most relevant mutations such as M694V, M6941, M6801 and V726A located in exon 10 of the MEFV gene. It was initially assumed that FMF follows a classic autosomal recessive inheritance pattern. 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 changes in regulatory elements or other gene segments must 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).

This must be distinguished from people who never develop clinical symptoms of FMF but develop amyloidosis due to two mutations in the MEFV gene (type II FMF). The prevalence of this phenotype varies greatly.

Recurrent fever attacks (in 96% of patients) of irregular periodicity, usually accompanied by acute peritonitis (91%), frequently also pleuritis (57%), arthritis or sacroiliitis (45%), as well as a transient, erysipelas-like exanthema consisting of red-livid, occasionally itchy plaques with a maximum diameter of 10-15 cm, occurring unilaterally or bilaterally, mainly below the knee (13%). 2% of patients develop amyloidosis.

Other dermatological phenomena include diffuse palmo-plantar erythema, disseminated purpuric papules on the face, trunk and extremities. Purpura Schönlein-Henoch is often associated (IgA vasculitis), polyarteritis nodosa and Behcet's aphthosis.

• Phenotype 1: Onset with fever attacks.
• Phenotype 2: Amyloidosis as initial manifestation.

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.

The erysipelas-like plaques are characterized by mild to moderate oedema, a rather sparse infiltrate of lymphocytes, neutrophils, histiocytes and nuclear debris. Mild acanthosis with hyperkeratosis may also occur.

Determination of IgM, fibrinogen and C3 in the capillaries of the papillary dermis.

Consequential damage such as kidney failure due to systemic amyloidosis.

Infertility in around 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 frequently, is not certain (Delplanque M et al. 2022):

• Neutrophilic panniculitis
• Sweet syndrome
• Pyoderma gangraenosum

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, patients with severe hidradenitis supp urativa have an increased rate of familial Mediterranean fever and heterozygous mutations in the Mediterranean fever gene (MEFV) compared to 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). Notably, in some patients with hidradenitis suppurativa and pyoderma gangreanosum, dual pathogenic mutations in MEFV without clinical FMF and promoter elongation in PSTPIP1 coexisted (Vural S et al. 2018).

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 effective in 70-90% of patients. In about 10% of children, however, the fever episodes cannot be influenced by colchicine, although a lack of compliance is often the cause. Lifelong use of colchicine leads to a favorable influence on fever attacks and decisively prevents complications.

Interleukin (IL)-1 antagonists are the treatment of choice for refractory cases. Experience with the IL-1 antagonists anakinra and canakinumab is now available for several thousand colchicine-resistant FMF patients (Tufan A et al. 2020).

The use of next-generation sequencing in FMF has uncovered many new gene variants whose clinical significance could be clarified through the development of functional tests and biomarkers. Although FMF is clinically considered an episodic disease characterized by brief attacks, systematic studies have identified several associated chronic inflammatory conditions (Tufan A et al. 2020).

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. Figueras-Nart I et al. (2019) Dermatologic and Dermatopathologic Features of Monogenic Autoinflammatory Diseases. Front Immunol 10:2448.
4. 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.
5. 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.
6. Osler W (1895) On the visceral manifestations of erythema multiforme. Am J Med Sci 110: 629.
7. Panossian A et al. (2003) Plasma nitric oxide level in familial Mediterranean fever and its modulations by Immuno-Guard. Nitric Oxide 9: 103-110.
8. Sayarlioglu M et al. (2003) Colchicine-induced myopathy in a teenager with familial Mediterranean fever. Ann Pharmacother 37: 1821-1824.
9. 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.

10. Tufan A et al. (2020) Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review. Turk J Med Sci 50(SI-2):1591-1610.

11. Vural S et al. (2017) Familial Mediterranean fever patients with hidradenitis suppurativa. Int J Dermatol 56: 660-663.