Tumor necrosis factor receptor associated periodic syndrome R21.x

Most common, monogenic, autoinflammatory disease, characterized by recurrent fever episodes, combined with abdominal complaints, arthralgias, myalgias, conjunctivitis and periorbital oedema as well as a generalized maculo-papular, also urticarial (non-pustular) exanthema (detectable in >80% of cases).

Autosomal-dominantly inherited mutations in the TNFRSF1A gene (gene locus: 12p13.2). The TNFRSF1A gene encodes a member of the TNF receptor superfamily, tumor necrosis factor receptor superfamily member 1A(TNFRSF1A), also known as tumor necrosis factor receptor 1 (TNFR1/CD120a). This is a ubiquitous membrane receptor that binds tumor necrosis factor-alpha (TNFα). The binding of TNF-alpha to its receptor leads to trimerization and activation of the receptor and ultimately to an overproduction of interleukin-1beta with leukocytosis and fever.

There are > 70 known mutations in this gene. The majority of these are missense mutations. They are located in exons 2-4 and 6, which code for the first two extracellular receptor domains and the cleavage site. The TM50 mutations are characterized by earlier onset, more severe and complicative (amyloidosis) progression. Variants such as R92Q and P46L show milder progression.

After binding of the ligand, the extracellular part of the receptor is shed from the cell surface in a negative feedback loop, goes into solution and now captures free TNF-alpha in soluble form. This inhibits TNF-alpha-induced inflammation in a kind of feedback loop (physiologically speaking).

The missense mutations of the receptor protein lead to its misfolding, a loss of function and furthermore to a disruption of receptor shedding. Excess TNF-alpha leads to autoinflammation. The intermittent inflammation leads to increased SAA levels and the risk of amyloidosis.

Clinical symptoms always accompanied by fever attacks, lasting 4-21 days. In 80% of cases, TRAPS is associated with dermatological sympotmatism. There are non-pruritic exanthema consisting of saturated red, flat, but also anular or serpiginous, non-scaly erythema, urticarial papules and plaques of various sizes; erysipelas-like lesions have also been reported. Vasculitic lesions have also been observed. The skin symptoms are often combined with painful conjunctivitis, arthralgia, chest pain and myalgia.

AA amyloidosis is to be expected as a complication in the event of prolonged persistence, with the kidneys and liver being the most frequent points of attack.

The febrile attacks in TRAPS last significantly longer than in other periodic fever syndromes.

Severe dermal edema; superficial and deep lymphocytic and monocytic (CD3+,CD4+,CD8+,CD79a-, CD20-) perivascular accentuated infiltrates.

IgM and C3 at the dermo-epidermal junction zone. Also diffuse interstitial deposits of IgA, IgG and C3. Peri-vascular C3 and C4 deposits are possible.

Familial Mediterranean fever: Predominantly Mediterranean populations; recurrent febrile episodes (in 96% of patients) of irregular periodicity.) of irregular periodicity, usually accompanied by acute peritonitis (91%), frequently also pleuritis (57%), arthritis or sacroiliitis (45%), and a transient, erysipelas-like, macular exanthema 10-15 cm in diameter with pruritus, occurring unilaterally or bilaterally, mainly below the knee (13%). 2% of patients develop amyloidosis. In phenotype 2: amyloidosis as the first manifestation.

Hyper-IgD syndrome: Massive onset of fever attacks without real periodicity. Duration of attacks about 5-7 days. Attacks are usually associated with cervical lymphadenopathy, abdominal and joint pain and maculo-papular exanthema. IgD elevated!

Chronic spontaneous urticaria: recurrent exanthema with pruritus; but not feverish! No systemic involvement such as lymphadenopathy, abdominal and joint pain!

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