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Table 4 Genotype-phenotype associations in patients with TRAPS

From: A web-based collection of genotype-phenotype associations in hereditary recurrent fevers from the Eurofever registry

Gene region Mutation N° pt Age at onset (years; average, range) Disease course Prevalent clinical manifestations (n. of patients) Less common manifestations (n. of patients) Treatment response (n. of patients) Complications (n. of patients)
Intron 2 c.193-14G > A 1 11 Recurrent Stress-induced fever for 6 days with erythematous pharyngitis, generalized lymphadenopathy, headache, arthralgia, myalgia and abdominal pain. Photophobia left eye. Complete response to steroids during the attacks. Failure with colchicine as maintenance. Tonsillectomy partially effective.  
Exon 2 D12E 3 31 (12–33) Recurrent Fever or low fever episodes of 5–15 days, 10/year, with arthralgia, myalgia, conjunctivitis and chest pain with pleurisy. One patient with a mutation in the MEFV gene presented pericarditis.   Partial response to NSAIDs on demand (1). Partial response (1) or deterioration (1) with colchicine. Complete response to steroids, except the patient with a MEFV mutation that responded partially. Complete response to etanercept (1).  
H22Q 2 0 Continous and recurrent Fever episodes of 8 days, 10–16/year, with arthralgia, myalgia, periorbital edemaand general malaise. Chronic weight loss.   Partial response to steroids on-demand. Colchicine failed. Complete response to anakinra as maintenance therapy (2).  
H22R 3 6 (1–8) Recurrent Fever episodes of 12 days, 10/year, with urticarial rash, myalgia, and conjunctivitis.   Complete response to steroids on-demand. Complete response to anakinra as maintenance therapy.  
C29F 1 10 Recurrent Fever episodes of 7 days, 3/year, induced by stress and fatigue, with urticarial rash, arthralgia and myalgia.   NSAIDs failed.  
C29Y 1 0 Recurrent Febrile episodes of 10 days, 4/year, with chills at the onset, erythematous pharyngitis and painful bilateral cervical lymphadenopathy.   NSAIDs failed. Partial response to steroids on-demand. Complete response to canakinumab and anakinra.  
C30F 1 36 Recurrent Fever episodes of 8 days, > 24/year, with aphthous stomatitis, myalgia, abdominal pain and mono/oligo/poliarthritis.   Partial response to maintenance with Colchicine.  
C30R 4 1 (0–1) Recurrent Febrile episodes regions of 2–20 days, 1–4/year, sometimes induced by infections, with abdominal pain (4), arthralgia, myalgia, diarrhea and maculo-papular rash(3).   Partial response to steroids (3), colchicine (2) or etanercept (3). Complete response to anakira (1) or steroids (1).  
C30Y 1 2 Continous and recurrent Low grade fever with fatigue, malaise and weight loss. Fever episodes of 10–15 days, 6/year, induced by stress and travel, with chills at the onset, with maculo-papular rash, arthralgia, myalgia, oligoarthritis and abdominal pain.   Partial response to steroids. Failure with colchicine as maintenance therapy.  
C33G 1 1 Recurrent Episodes of arthralgia, myalgia, periorbital edema and pain, abdominal pain, and fever episodes of 16–20 days, 4/year, with regular frequency. A patient with two mutations in the MEFV gene: E148Q and M694 V. Partial response to colchicineand complete response to steroids as maintenance therapy.  
C33Y 12 7 (0–13) Recurrent Fever episodes of 7 days, from 2 to more than 24 episodes/year, with myalgia (9) and abdominal pain (10). In 50–30% were also present urticarial rash (6), chest pain, conjunctivitis and weight loss (4).   Partial response to steroids on-demand (6), failed in one patient. Partial response to thalidomide on-demand (1). Partial responses (2) or failure (2) to NSAIDs. Partial response (4) or complete (1) to etanercept. Complete response to anakinra as maintenance therapy (2). Renal amyloidosis after 40 years of age (3). Fatal sepsis and renal failure at the age of 60 years (1).
Exon 3 T37I 2 6 (1–9) Recurrent Fever episodes of 5 days, 10/year, with maculopapular or urticarial rash, arthralgia, myalgia, abdominal pain, chest pain with pericarditis, pleurisy, pneumonia and persistent cough.   Complete response to steroid (1). Complete response to anakinra (1)with compliance problems. Initial response to Etanercept then failed (2). Partial response with NSAIDs (1) or colchicine (1). Persistence of elevated sierum amyloid type A (2). Renal amyloidosis at the age of 28 years (1).
Y38S 1 0 Continous and recurrent Fever episodes of >20 days, 3/year, with chills at the onset, induced by fatigue, infections, stress and traveling, with maculopapular or migratory rash, arthralgia, myalgia, periorbital edema with conjunctivitis and diarrhea. Chronic low fever with fatigue, malaise and weight loss. Patient with V198 M mutation in the NALP3 gene. Partial response to steroids on-demand. Complete response to Anakinra as maintenance therapy. Renal amyloidosis at the age of 76 years.
L39F 1 6 Recurrent Febrile episodes, 12/year, with arthralgia, myalgia, polyarthritis, abdominal pain with aseptic peritonitis.   Colchicine failed.  
D42del 4 5 (1–6) Continous and recurrent Fever episodes of 15 days, 10/year, with abdominal pain (5). In 50–30% of patients fevr episodes with chills at the onset, maculo-papular or migratory or urticarial rash, arthralgia, pleuritis with chest pain, headache and periorbital edema, malaise, fatigue and chronic weight loss (2).   Partial response to NSAIDs on-demand (1). Colchicine failed (3). Complete response to Anakinra as maintenance therapy (2). Partial response to steroids, azathioprine or Etanercept (1). Renal amyloidosis after the age of 40 years (3). Fatal renal failure (1).
C43G 1 2 Recurrent Fever episodes of >20 days, 1/year, with chills at the onset, sometimes induced by exercise, with myalgia, myositis, fasciitis, oligoarthritis, periorbital edema, abdominal pain with aseptic peritonitis, painful bilateral cervical lymphadenopathy, scrotal pain and maculo-papular rash. Seizures. Partial response to NSAIDs or steroids on-demand. Methotrexate and colchicine failed. Complete response to Canakinumab. Laparotomy for peritoneal adhesions at the age of 12 years.
C43R 3 1 (0–1) Recurrent Fever episodes of 10 days, 2/year, with chills at the onset, induced by stress, infections, fatigue, exercise, with arthralgia, myalgia, painful periorbital edema and conjunctivitis, abdominal pain, constipation and chest pain. Ptosis, perianal ulcers (1). Chronic disease course withlow grade fever, fatigue, malaise, mood disorders and weight loss (1). Cataract and visual changes at the age of 31. Partial response to NSAIDs or steroids on-demand.Complete response to Anakinra. Renal amyloidosis (1).
C43S 1 1 Recurrent Febrile episodes of 20 days, 4/year, sometimes induced by infections, with urticarial rash, migratory rash, arthralgia, myalgia, abdominal and chest pain.   Partial response to NSAIDs or steroids on-demand. Partial response to cimetidine or etanercept as maintenance therapy, stopped because the patient developed esophagitis. Complete response to Anakinra.  
C43Y 1 4 Recurrent Episodes of maculo-papular or migratory rash, arthralgia, myalgia, abdominal pain with constipation, sometimes fever of 8 days, 3/year.with aseptic peritonitis.   NSAIDs failed. Partial response to steroids and Colchicine on-demand. Partial response to etanercept and anakinra as maintenance therapy. Peritoneal adhesions and intestinal occlusions at the age of 35 years. Renal amyloidosis at the age of 41 years. Renal failure at the age of 52 years.
T50 K 2 2 Continous and recurrent Fever episodes of 10 days, 4 or >24/year, with arthralgia and myalgia. Chronic low grade fever, fatigue and malaise.   Partial response to etanercept or colchicine. Complete response to steroids.  
T50 M 16 6 (0–41) Recurr ent Fever episodes of 10 days, 5/year, with myalgia (12), arthralgia (11), abdominal pain (11). 50–30% of patients presented bilateral cervical lymphadenopathy (7) andchest pain (6). Chronic fatigue and malaise (1). Partial response to steroids or NSAIDs on-demand (5). NSAIDs failed (2). Complete response to steroids (3). Complete response to anakinra (3) or canakinumab (1) as maintenance therapy. Complete (2) or partial (2) response to etanercept. Tonsillectomy failed (2).  
C52Y 5 3 (0–11) Recurrent Fever episodes of 11 days, 7/year, with painful periorbital edema with conjunctivitis (4), arthralgia, myalgia and abdominal pain (3). Two patients presented chills atthe onset and constipation.   NSAIDs fail (1). Partial (2) or complete (1) response to steroids as maintenance therapy. Complete response to anakinra (2) or canakinumab (1)as maintenance therapy.Colchicine (3) and methotrexate (1) failed as maintenance therapy. Partial response (1) or complete (1) to etanercept withskin reactions at the site of injections. Renal amyloidosis with organ failure after 33 years (2). In a patient paroxysmal atrial fibrillation at age 45.
C55Y 4 3 (1–18) Recurrent Low fever or fever episodes of 20 days, 4/year, with arthralgia, myalgia, abdominal pain (3). In 50–30% of patients the episodes were induced by stress or menstruation, and were associated with urticaria rash, diarrhea, generalized lymphadenopathy and bilateral cervical pain (2).   Partial response to NSAIDs (2) and complete (2) or partial (1) response to steroids on-demand. Colchicine failed (2). Complete response to anakinra as maintenance therapy (2). Complete response to infliximab (1). Appendicectomy (1).  
S59P 1 49 Recurrent Fever episodes of 6 days, 3/year, associated with maculo-papular and migratory rash, arthralgias and myalgias, splenomegaly, pericarditis, chest pain, pleurisy, pneumonia and persistent cough.   Partial response to steroids as maintenance therapy. Osteoporosis atthe age of 62 years.
F60 L 2 1 e 6 Recurrent Fever episodes of >20 days, 3/year, with chills at the onset, urticarial rash, arthralgia and abdominal pain. A patient presented delayed puberty and bone growth. Complete response to NSAIDs or steroids on-demand. Complete response to anakinra as maintenance therapy.  
T61 N 2 0 Recurrent Fever episodes associated with chills at onset, maculopapular rash, arthralgia, myalgia and abdominal pain.   Complete response to NSAIDs or steroids on-demand.  
N65I 2 0 Recurrent Fever episodes associated with myalgia, migratory rash, conjunctivitis, abdominal pain and painful generalized lymphadenopathy. Swelling and erythema with socks-like distribution.   
H66L 1 0 Recurrent Febrile episodes of 3 days, 21/years with bilateral lymphadenopathy.   Steroids failed.  
L67P 1 0 Recurrent Febrile episodes of >20 days, 3/year, associated with chills at the onset, induced by stress and vaccinations, associated with pseudofolliculitis, migratory urticarial or maculopapular rash, erythematous pharyngitis, arthralgia, oligoarthritis, abdominal and chest pain, vomiting, headache and conjunctivitis.   Partial response to NSAIDs or steroids on-demand.  
H69fs 1 1 Recurrent Fever episodes of 12–24 h, 12/years, with urticarial rash, arthralgia, myalgia, conjunctivitis, periorbital and abdominal pain.   Complete response to NSAIDs on-demand. Steroids failed. Partial response to sulfasalazine as maintenance therapy.  
C73R 1 0 Recurrent Fever episodes of 10 days, 14/year, with arthralgia, myalgia, and abdominal pain with constipation.   Partial response to NSAIDs and complete response to steroids on-demand.  
C73W 2 3 (2–4) Continous Myalgia and abdominal pain.   Complete response to NSAIDs on-demand. Complete response to colchicine as maintenance therapy.  
Exon 4 C88Y 1 7 Recurrent Feverepisodes, 2/year, with chills at the onset and abdominal pain.   Complete response to steroids on-demand.  
R92P 1 19 Recurrent Fever episodes of >20 days with arthralgia, myalgia, abdominal pain with constipation, and chest pain with pleurisy. Abscessesin the groin, armpits, vulva and back after the age of 50 years. Partial response to steroids and complete response to anakinra as maintenance therapy.Azathioprine failed. Renal amyloidosis.
V95 M 2 31 (30–32) Recurrent Fever episodes of 11 days, 6/year. A patient presented aphthous stomatitis, maculo-papular rash, arthralgia, myalgia, fasciitis, conjunctivitis and abdominal pain.A patient presented chest pain, pericarditis, pleurisy.   Partial response to NSAIDs and steroids on-demand(2).Complete response to Anakinra as maintenance therapy (1).  
C96Y 1 30 Recurrent Episodes of conjunctivitis, fever, oligoarthritis and pleurisy.   Partial response to colchicine as maintenance therapy.  
Y103_R104del 1 25 Recurrent Fever episodes of of 7 days, 4/year, with chest pain and pericarditis.   Partial response to NSAIDs, steroids or colchicine.Complete response to etanercept.  
E109A 2 42 e 1 Recurrent The patient with the pediatric onset presentedfever episodes of 3 days, 17/year, with erythematous pharyngitis, cervical lymphadenopathy and periorbital edema. The patient with the adult onset presented headache and myalgia associated with fever episodes induced by stress.   The patient with pediatric onset presented partial response to colchicineas maintenance therapy.  
C114W 1 38 Recurrent Fever episodes of 8 days, 4/year, induced by menstruation, with erythematous or exudative pharyngitis, vomiting, abdominal pain and constipation. The patient presented the E148Q and P369S mutations in the MEFV gene.   
N116S 1 21 Recurrent Fever episodes of 5 days, 3/year, induced by stress, arthralgia, myalgia, abdominal pain and diarrhea.   Partial response to NSAIDs on-demand.  
Exon 6 L167_G175del 1 6 Recurrent Fever episodes of 5 days, 2/year, with chills at the onset, induced by fatigue, associated with erythematous pharyngitis, arthralgia, myalgia, painful periorbital edema, conjunctivitis, nausea, abdominal pain andpainful bilateral cervical lymphadenopathy.   Complete response to steroids on-demand. Partial response to anakinra as maintenance therapy. Renal amyloidosis at the age of 18 years. Renal transplantation at the age of 24 years with an increased number of the fever episodes.