| Gene region | First mutation | Second mutation | N° pt | Age at onset (years) | Disease course (n. of patients) | Prevalent clinical manifestations (n. of patients) | Less common manifestations (n. of patients) | Treatment response (n. of patients) | Complications (n. of patients) |
| Exon 2 | S108R | V726A | 1 | 0 | Recurrent | Fever or low fever episodes of 4 days, 12 episodes/year, with exudative and erythematous pharyngitis, arthralgia, myalgia, enlarged bilateral and painful cervical lymphonodes, periorbital pain and conjunctivitis, vomiting, oligoarthritis, chest pain, headache in the morning or anytime, constipation and abdominal pain. | Partial response to steroids. Complete response to colchicine. | ||
| E148V | M694V | 15 | 5 (0-27) | Recurrent | Fever episodes of 2-3 days, 13/year (mean), with regular pattern, chills at fever onset (6) and abdominal pain (12), arthralgia (10) and chest pain (5). | Vomiting, headache (4), diarrhea, erythematous pharyngitis, aphtous stomatitis (3), monoarthritis, erysipelas-like erythema, costipation, myalgia (2), general or cervical bilateral enlarged lymphonodes, oligoarthritis, maculopapular rash, pseudofollicolitis, oral herpetic-like lesions, myositis, fascitis, tenosynovitis,bone pain, aseptis peritonitis, pleurisy, urethritis/cistitis (1). Episodes induced by stress (2), menstruation, fatigue, cold and vaccin (1). | Response to NSAIDs partial (3); response to colchicine partial (5) or complete (9). One patient responds partially to adalimumab. One patient presented complete response to steroids but developed a fulminant hepatitis A and vertebral collapse as side effect. After liver transplantation, he started cyclosporine and micophenolate mofetil with complete response. | Hydrocephalus (1 patient). One patient developed mental retardation post fulminant hepatitis. | |
| V726A | 1 | 2 | Recurrent | - | |||||
| E167D | M694V | 1 | 1 | Recurrent | Fever episodes of 2 days, 18/year, infection induced, with conjunctivitis and abdominal pain. | Complete response to colchicines. | |||
| E225G | M694V | 1 | 1 | Recurrent | Fever episodes of 5 days, 12/year, with arthralgia, myalgia, pseudofolliculitits, erythematous pharyngitis, abdominal and chest pain. | Partial response to steroids during attacks. Complete response to colchicineas mantainance treatment. | |||
| Exon 5 | F479L | V726A | 1 | 4 | Recurrent | Fever episodes of 3 days, 15/year, with abdominal pain, conjunctivitis. | Complete response to colchicine. | ||
| Exon 9 | I591T | V726A | 1 | 5 | Recurrent | Fever episodes of 2 days, 5/year, stress, fatigue and exercise induced, with diarrhea, constipation and abdominal pain. | - | ||
| Exon 10 | M680IGA | M680IGA | 3 | 4 (0-8) | Recurrent | Fever or low fever episodes of 1-2 days, 5/year, with erythematous pharyngitis, myalgia, arthralgia (2) and abdominal pain (3). | Diarrhea, enlarged cervical bilateral lymphonodes (1). | During the attacks, complete response to NSAIDs (1). Complete response to colchicine as maintenance treatment (3). | |
| M694V | 2 | 2 | Recurrent | Fever episodes of 2 days, 6/year, induced by cold and exercise and wit regular pattern (1), with maculo-papular rash, myalgia, abdominal pain, chest pain, costipation (2), exudative or erythematous pharyngitis, urticarial rash, arthralgia, gastrointestinal bleeding, hepatomegaly and splenomegaly, aseptic peritonitis, bone pain, pericarditis, periorbital oedema and conjunctivitis(1). | Tonsillectomy and adenoidectomy failed. Complete responseto colchicine as maintenance therapy(1). | ||||
| V726A | 4 | 5 (1-7) | Recurrent (3). Continuous and recurrent (1). | Fever or low fever episodes of 4 days, 12/year, with abdominal pain (4), vomiting and arthralgia (2). Triggers: cold and stress (2). | Myalgia, mono/oligoarthritis, diarrhea or constipation, enlarged cervical lymphonodes, hepatomegaly, chest pain, aseptic peritonitis and costipation, headache, vertigo. Triggers: infection (1). | Complete (1) or partial response to Colchicine (2). Tonsillectomy, Steroids and NSAIDs failed (1). Partial response to NSAID (1). | Peritoneal adhesions (1). | ||
| R761H | 1 | 0 | Recurrent | Fever or low fever of 1 days, 12/year, vaccin induced, with regular pattern, chills, urticarial rash and abdominal pain. | During the attacks, complete response to NSAIDs or Steroids. Complete response to maintenance with Colchicine. | ||||
| M680IGC | M680IGC | 5 | 3 (1-6) | Recurrent | Fever episodes of 2 days, 18/year, with regular pattern, with exudative pharyngitis with enlarged cervical bilateral and painful lymphonodes, erysipelas-like erythema, splenomegaly, headache (2), myalgia, arthralgia, vomiting and diarrhea, pericarditis (3), aseptis peritonitis and pleurity (4), abdominal and chest pain (5). | Oligoarthritis and tenosynovitis, costipation, gastrointestinal ulcers, hepatomegaly, episode cold-induced, gonal-pain and orchitis (1). | Complete response to colchicine as maintenance therapy (5). | Delayed puberty, peritoneal adhesions, and severe infection (1). | |
| T681I | 1 | 11 | Recurrent | Fever episodes of 3 days, 3/year, with eruthematous pharyngitis, chest pain, pleurisy, arthralgia, myalgia, abdominal pain. | Complete response to colchicine as maintenance therapy. | ||||
| M694V | 27 | 2 (0-30) | Recurrent | Fever or low fever episodes of 3 days, 15/year, regular pattern with arthralgia, abdominal pain (21), myalgia (17), oligoarthritis (16), chest pain (15), pleurisy (12), vomiting (10), aseptic peritonitis (9). | Headache (7), erysipelas-like erythema, diarrhea, chills at fever onset (6), exudative (1) or erythematous pharyngitis, tenosynovits, enlarged bilateral and painful cervical lymphonodes (5), hepatomegaly, pericarditis (4), urticarial rash, bone pain, poliarthritis, GI ulcers (3), pneumonia, persistent cough, monoarthritis (2), hemoptysis, purpuric or maculopapular rash, myositis, periorbital oedema, uveitis anterior, constipation, urethritis/cistictis, enuresis, hypoplasia of left kidney (1). Episodes induced by cold (8), stress (3), exercise, food (2), hunger, trauma, travel, infection (1). | Response to Colchicine complete (15) or partial (11). Response to NSAIDs partial (6) or complete (2). Partial response to steroids, methotrexate (3), sulphasalazine (1). One patient responds completely to allopurinol. |
Flexion contractures, osteoporosis (5), bone alteration, spondilloarthropathy, renalamyloidosis (2), bone deformity, atrophy of the muscles of the lower extremities, cataract, cranial neuropathy, macrophage activation syndrome (1). | ||
| V726A | 4 | 5 (1-12) | Recurrent | Fever episodes of 3 days, 13/year, with myalgia (2), chest pain (3) and abdominal pain (4). | Arthralgia, oligoarthritis, vomiting, constipation, gastrointestinal ulcers, aseptic peritonitis, pleuritis, pneumonia, headache, urethritis/cistitis (1). | Response to colchicine complete (3) or failed (1). Partial response to NSAID (1). Complete response to steroids (1) or anakinra (1). | |||
| R761H | 2 | 17 (4-30) | Recurrent | Fever episodes of 2-3 days, 9/year with chest pain (2), pleurisy, arthralgia, myalgia, abdominal pain (1). | Complete response to colchicine as maintenance therapy. | ||||
| M680L | M680L | 1 | 1.5 | Recurrent | Fever episodes of 6 days, 10/year, with regular pattern and chills at fever onset, associated with arthralgia, oligoarthritis, vomiting and diarrhea, abdominal pain. | Partial response to NSAIDs; complete response to to colchicine as maintenance therapy. Bilateral sacro-iliac joints steroid injection and tonsillectomy. | |||
| E148Q | 1 | 6 | Recurrent | Fever or low fever episodes, 3 per year, with erythematous pharyngitis, arthralgia, abdominal pain and headache. | Complete response to colchicine. | ||||
| T681I | M680IGC | 1 | 11 | Recurrent | Fever episodes of 3 days, 3/year, with eruthematous pharyngitis, chest pain, pleurisy, arthralgia, myalgia, abdominal pain. | Complete response to colchicine as maintenance therapy. | |||
| I692del | M694V | 1 | 2 | Recurrent | Fever or low fever episodes of 2 days, 18/year, with abdominal pain. | Complete response to colchicine as maintenance therapy. | |||
| M694I | M694I | 4 | 3 (1-5) | Recurrent | Fever episodes of 8 days, 9/year, with vomiting and costipations, arthralgia, chest pain (2) and abdominal pain (4). | Erythematous pharyngitis with enlarged cervical bilateral lymphonodes, chills at fever onset, myalgia, monoarthritis or oligoarthritis, conjuntivitis, diarrhea, aseptic peritonitis, pneumonia, headache (1). | Partial response to NSAIDs (1) or colchicine (2). One patient with complete response to colchicine (1). | Peritoneal adhesions, occlusion/sub-occlusion (1). | |
| M694V | 6 | 3 (1-30) | Recurrent | Fever episodes of 2-3 days, 18/year, with abdominal pain, arthralgia (5), chest pain (4), myalgia, headache (3) and vomiting, diarrhea, pleurisy (2). | Urticarial rash, erysipelas-like erythema, psoriasis, eczema, monoarthritis, tenosynovitis, GI ulcers, generalized or cervical bilateral enlargement lymphonodes, hepatomegaly and splenomegaly, pericarditis, pneumonia (1). Episodes induced by food, fatigue and vaccin (1). | Only two patients respond completely to colchicineas maintenance therapy. Response to NSAIDs partial (1) or failed (1). Steroids failed (1). One patient responds completely to anakinra, with urticarial rash at start, disappeared. | Peritoneal adhesions (1). | ||
| M694V | M694V | 93 | 3 (0-17) | Recurrent | Fever episodes of 2 days, 14/year, with abdominal pain (86), arthralgia (79), myalgia (57), chest pain (52), oligoarthritis (34), vomiting (32), chills at fever onset and diarrhea (30). | Pleurisy (27), pericarditis (20), exudative (7) or erythematous (18) pharyngitis, monoarthritis (25), erysipalas-like erythema, aseptic peritonitis (20), splenomegaly (16), hepatomegaly (15), seasonal changes of frequency of fever episodes (13), enlarged bilateral and painful cervical lymphonodes (12), maculo-papular rash and costipation (10), tenosynovitis (9), headache anytime (25) or only in the morning (7), flexion contractures and gastrointestinal ulcers (6), poly/oligoarthritis, conjunctivitis (5), gonadal pain (4), anal/perianal ulcers, aphtous stomatitis and urticarial rash, urethritis/cistitis (3), papulopustular lesions and palpable purpura, bone pain, GI bleeding, pneumonia and persistent cough, vertigo (2), hemoptysis, generalized enlargement, psoriasis and ichthyosiform rash, herpetic-like oral lesions, hemorrhagic rash, erythema nodosum, mesadenitis, optic neuritis, seizures and cranial nerve palsy (1). Episodes inducted by cold (18), stress (8), infect (4), fatigue (3), travael and exercise (2), food and vaccin (1). |
Response to NSAIDs partial (27), complete (8) or failed (4). Response to steroids partial (7), complete (4) or failed (6). Response to colchicine partial (38), complete (38) or failed (3). Response to sulphasalazine complete (1) and partial (2). Response to methotrexate complete (1), partial (4) and failed (1). One patient responds partially to cyclosporine. One patient responds partially and one completely to anakinra but develops skin reaction, pustular lesion on the injection site. One patient responds partially to canakinumab. One patient responds partially to etanercept but develops a worsening of kidney. | Peritoneal adhesions (8), occlusion, osteoporosis non steroids-related, bone deformity (3), gut perforation and bone alteration (2), bone erosions, hyperostosis and cholelithiasis (1). | |
| E148Q | 16 | 5 (0-27) | Recurrent | Fever episodes of 2-3 days, 13 per year, with regular pattern, chills at fever onset (6) and abdominal pain (13), arthralgia (10) and chest pain (6). | Vomiting, headache (4), diarrhea, erythematous pharyngitis, aphtous stomatitis (3), monoarthritis, erysipelas-like erythema, costipation, myalgia (2), general or cervical bilateral enlarged lymphonodes, oligoarthritis, maculopapular rash, pseudofollicolitis, oral herpetic-like lesions, myositis, fascitis, tenosynovitis,bone pain, aseptis peritonitis, pleurisy, urethritis/cistitis (1). Episodes induced by stress (2), menstruation, fatigue, cold and vaccin (1). | Response to NSAIDs partial (3); response to colchicine partial (5) or complete (10). One patient responds partially to adalimumab. One patient presented complete response to steroids but developed a fulminant hepatitis A and vertebral collapse as side effect. After liver transplantation, he started cyclosporine and micophenolate mofetil with complete response. | Hydrocephalus (1). One patient developed mental retardation post fulminant hepatitis. | ||
| E148V | 15 | 5 (0-27) | Recurrent | Fever episodes of 2-3 days, 13/year, with regular pattern, chills at fever onset (6) and abdominal pain (12), arthralgia (10) and chest pain (5). | Vomiting, headache (4), diarrhea, erythematous pharyngitis, aphtous stomatitis (3), monoarthritis, erysipelas-like erythema, costipation, myalgia (2), general or cervical bilateral enlarged lymphonodes, oligoarthritis, maculopapular rash, pseudofollicolitis, oral herpetic-like lesions, myositis, fascitis, tenosynovitis,bone pain, aseptis peritonitis, pleurisy, urethritis/cistitis (1). Episodes induced by stress (2), menstruation, fatigue, cold and vaccin (1). | Response to NSAIDs partial (3); response to colchicine partial (5) or complete (9). One patient responds partially to adalimumab. One patient presented complete response to steroids but developed a fulminant hepatitis A and vertebral collapse as side effect. After liver transplantation, he started cyclosporine and micophenolate mofetil with complete response. | Hydrocephalus (1). One patient developed mental retardation post fulminant hepatitis. | ||
| E167D | 1 | 1 | Recurrent | Fever episodes of 2 days, 18/year, infection induced, with conjunctivitis and abdominal pain. | Complete response to colchicine. | ||||
| R202Q* | 7 | 9 (4-30) | Recurrent | Fever episodes of 2 days, 8 per year, with abdominal pain (6), arthralgia and myalgia (4). | Bilateral cervical enlargement lymphonodes (2), generalized painful lymphonodes, chills at fever onset, urticarial rash, diarrhea (1). | During the attacks, partial (3) or complete (1) response to NSAIDs; partial (1) or complete (1) response to Steroids. Two patients respond completely to maintenance with colchicine. | 7 | ||
| E225G | 1 | 1 | Recurrent | Fever episodes of 5 days, 12/year, with arthralgia, myalgia, pseudofolliculitits, erythematous pharyngitis, abdominal and chest pain. | Partial response to steroids during attacks. Complete response to colchicine as maintenance therapy. | ||||
| M680IGA | 2 | 2 | Recurrent | Fever episodes of 2 days, 6/year, induced by cold and exercise and wit regular pattern (1), with maculo-papular rash, myalgia, abdominal pain, chest pain, costipation (2), exudative or erythematous pharyngitis, urticarial rash, arthralgia, GI bleeding, hepatomegaly and splenomegaly, aseptic peritonitis, bone pain, pericarditis, periorbital oedema and conjunctivitis(1). | Tonsillectomy and adenoidectomy failed. Complete response to colchicine as maintenance therapy (1). | ||||
| M680IGC | 28 | 2 (0-30) | Recurrent | Fever or low fever episodes of 3 days, 15/year, regular pattern with arthralgia, abdominal pain (23), myalgia (18), oligoarthritis (16), chest pain (15), pleurisy (12), vomiting (11), aseptic peritonitis (9). | Headache, diarrhea (7), erysipelas-like erythema, chills at fever onset (6), exudative (1) or erythematous pharyngitis, tenosynovits, enlarged bilateral and painful cervical lymphonodes (6), hepatomegaly (5), pericarditis (4), urticarial rash, bone pain, poliarthritis, GI ulcers (3), pneumonia, persistent cough, monoarthritis (2), hemoptysis, purpuricor maculopapular rash, myositis, periorbital oedema, uveitis anterior, constipation, urethritis/cistictis, enuresis(1). Episodes induced by cold (8), stress (3), exercise, food (2), hunger, trauma, travel, infection (1) | Response to colchicine complete (16) or partial (11). Response to NSAIDs partial (6) or complete (2). Partial response to steroids, methotrexate (3), sulphasalazine (1). One patient responds completely to allopurinol. |
Flexion contractures, osteoporosis (5), bone alteration (3), spondilo-arthropathy, renalamyloidosis (2), atrophy of lower extremities muscles, cataract, cranial neuropathy, peritoneal adhesions, macrophage activation syndrome (1). | ||
| I692del | 1 | 2 | Recurrent | Fever or low fever episodes of 2 days, 18/year, with abdominal pain. | Complete response to colchicine as maintenance therapy. | ||||
| M694del | 1 | 0 | Recurrent | Fever episodes of 1 days, 12 per year, with abdominal pain and arthralgia. | Partial response to Colchicine. | ||||
| M694I | 6 | 3 (1-30) | Recurrent | Fever episodes of 2-3 days, 18/year, with abdominal pain, arthralgia (5), chest pain (4), myalgia, headache (3) and vomiting, diarrhea, pleurisy (2). | Urticarial rash, erysipelas-like erythema, psoriasis and eczema, monoarthritis, tenosynovitis, GI ulcers, generalized or cervical bilateral enlargement lymphonodes, hepatomegaly and splenomegaly, pericarditis, pneumonia (1). Episodes induced by food, fatigue and vaccin (1). | Only two patients respond completely to colchicine as maintenance therapy. Response to NSAIDs partial (1) or failed (1). Steroids failed (1). One patient responds completely to anakinra, with urticarial rash at start, disappeared. | Peritoneal adhesions (1). | ||
| M694L | 1 | 6 | Recurrent | Fever or low fever episodes of 7 days, 12/year, with bone and abdominal pain, constipation. | Complete response to maintenance with colchicine. | ||||
| K695R | 2 | 7 | Recurrent | Fever episodes, 7/year, with arthralgia, constipation and abdominal pain (2). | Partial response to sulphasalazine (1), complete response to colchicine (2). | ||||
| V726A | 27 | 3 (0-45) | Recurrent | Fever or low fever episodes of 2-3 days, 12/year, with abdominal pain (25), arthralgia (20), myalgia, chest pain (16), vomiting (14). | Diarrhea (8), chills at fever onset (7), bilateral and painful cervical enlargement lymphonodes,oligoarthritis (6), pericarditis, pleurisy, exudative pharyngitis (5), aseptic peritonitis, headache (4), constipation, GI ulcers, erythematous pharyngitis, urethritis/cistitis (3), erysipelas-like erythema, hepatomegaly, generalized enlargement lymphonodes, bone pain, monoarthritis (2), splenomegaly, maculo-papular rash, aphtous stomatitis, vaginal hydrocele, periorbital pain and conjunctivitis or uveitis anterior and choreoretinitis, aseptis meningitis, gonadal enlarged, height related ipertension (1). Episodes induced by cold (2), infection or fatigue (1). | Complete (3) or partial (5) response to NSAIDs. Complete (1) or partial (2) response to Steroids. Complete (14) or partial (10) response to Colchicine: two patients developed diarrhea. Partial response to tonsillectomy (4). |
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| R761H | 6 | 5 (1-11) | Recurrent | Fever or low fever episodes of 2 days, 10/year, with abdominal pain (6), vomiting (4), arthralgia, myalgia, constipation, chest pain (3), pericarditis and pleurisy (2). | Erythematous pharyngitis, urticarial rash, aseptic peritonitis, bilateral cervical enlargement lymphonodes, hepatomegaly, persistent cough, hemoptysis, headache and orchitis (1). Episodes induced by cold, stress, food (1). | Complete response to colchicine (4), steroids (1) and NSAIDs (1). | |||
| M694del | M694V | 1 | 0 | Recurrent | Fever episodes of 1 days, 12/year, with abdominal pain and arthralgia. | Partial response to colchicine. | |||
| M694L | M694V | 1 | 6 | Recurrent | Fever or low fever episodes of 7 days, 12/year, with bone and abdominal pain, constipation. | Complete response to colchicine as maintenance therapy. | |||
| K695R | M694V | 2 | 7 | Recurrent | Fever episodes, 7/year, with arthralgia, constipation and abdominal pain (2). | Partial response to sulphasalazine (1), complete response to colchicine (2). | |||
| V726A | V726A | 2 | 0 | Recurrent | Fever episodes of 4-5 days, 11/year, with seasonal changes of frequency, stress or fatigue as triggers, with abdominal pain, arthralgia, myalgia, enlarged bilateral cervical lymphonodes, hepatomegaly, splenomegaly and seizures (1). | One patient responds partially to colchicine and develops alopecia areata. Tonsillectomy and adenoidectomy failed (1). | |||
| S108R | 1 | 0 | Recurrent | Fever or low fever episodes of 4 days, 12/year, with exudative and erythematous pharyngitis, arthralgia, myalgia, enlarged bilateral and painful cervical lymphonodes, periorbital pain and conjunctivitis, vomiting, oligoarthritis, chest pain, headache in the morning or anytime, constipation and abdominal pain. | Partial response to steroids. Complete response to colchicine. | ||||
| E148Q | 4 | 3 (2-7) | Recurrent | Fever (4) or low fever (2) episodes of 2 days, 21 per year, with arthralgia (2), abdominal pain (4). | Chest pain, hepatomegaly and splenomegaly, maculo-papular rash (1). | Partial response to NSAIDs, steroids, colchicine (2) and cimetidine (1). Response complete (1) to colchicine or failed (1). | |||
| E148V | 1 | 2 | Recurrent | - | |||||
| F479L | 1 | 4 | Recurrent | Fever episodes of 3 days, 15/years, with abdominal pain, conjunctivitis. | Complete response to colchicine. | ||||
| I591T | 1 | 5 | Recurrent | Fever episodes of 2 days, 5/year, stress, fatigue and exercise induced, with diarrhea, constipation and abdominal pain. | - | ||||
| M680IGA | 5 | 5 (1-7) | Recurrent. Continuous and recurrent (1). | Fever or low fever episodes of 4 days, 14/year, with abdominal pain (5), vomiting and arthralgia (3). Triggered by cold and stress (2). | Myalgia, mono/oligoarthritis, diarrhea or constipation, enlarged cervical lymphonodes, hepatomegaly, chest pain, pleurisy, aseptic peritonitis and costipation, headache, vertigo, maculo-papular rash, myalgia. Triggered by infection (1). | Complete (2) or partial (2) response to colchicine. Tonsillectomy, steroids and NSAIDs failed in one patient. Partial response to NSAIDs in other patient. | Peritoneal adhesions (1). | ||
| M680IGC | 4 | 5 (1-12) | Recurrent | Fever episodes of 3 days, 13/year, with myalgia (2), chest pain (3) and abdominal pain (4). | Arthralgia, oligoarthritis, vomiting, constipation, gastrointestinal ulcers, aseptic peritonitis, pleuritis, pneumonia, headache, urethritis/cistitis (1). | Response to Colchicine complete (3) or failed (1). Partial response to NSAID (1). Complete response to steroids (1) or anakinra (1). | |||
| M694V | 27 | 3 (0-45) | Recurrent | Fever or low fever episodes of 2-3 days, 12/year, with abdominal pain (25), arthralgia (20), myalgia, chest pain (16), vomiting (14). | Diarrhea (8), chills at fever onset (7), bilateral and painful cervical enlargement lymphonodes,oligoarthritis (6), pericarditis, pleurisy, exudative pharyngitis (5), aseptic peritonitis, headache (4), constipation, GI ulcers, erythematous pharyngitis, urethritis/cistitis (3), erysipelas-like erythema, hepatomegaly, generalized enlargement lymphonodes, bone pain, monoarthritis (2), splenomegaly, maculo-papular rash, aphtous stomatitis, vaginal hydrocele, periorbital pain and conjunctivitis or uveitis anterior and choreoretinitis, aseptis meningitis, gonadal enlarged, height related ipertension (1). Episodes induced by cold (2), infection or fatigue (1). | Complete (3) or partial (5) response to NSAIDs. Complete (1) or partial (2) response to steroids. Complete (14) or partial (10) response to colchicine: two patients developed diarrhea. Partial response to tonsillectomy (4). |
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| A744S | A744S | 1 | 3 | Recurrent | Fever or low fever episodes of 11-15 days, 3/year, with abdominal pain, chest pain, pericarditis, vomiting, diarrhea, erysipelas-like erythema, arthralgia, myalgia, fatigue e malaise. | Partial response to NSAIDs or steroids or colchicine. Complete response to etanercept as maintenance therapy. | |||
| E148Q | 3 | 35 (14-51) | Recurrent | Low fever (2) or fever (1) of 3-4 days, 9 per year with abdominal pain, arthralgia (3), erysipelas-like erythema, myalgia (2), monoarthritis, conjunctivitis and chest pain (1). | During the attacks, partial response to NSAIDs (2) or steroids (1). Complete response to colchicine (2). | ||||
| P369S | 1 | 8 | Recurrent | One more mutation: A408G. Fever episodes of 4 days, 3 per year, stress and travel induced, with exudative pharyngitis and arthralgia. | During the attacks, partial response to NSAIDs. colchicine maintenance. | ||||
| R761H | E148Q | 4 | 5 (1-16) | Recurrent | Low fever of 3 days, 16 per year, exercise-induced (2), with arthralgia (4), chills, myalgia, vomiting, abdominal and chest pain (3), pleurisy and diarrhea (2). | Enlarged cervical lymphonodes, headache in the morning or anytime, polyarthritis, dysmenorrhea (1). | Complete response to colchicine (4). | ||
| M680IGA | 1 | 0 | Recurrent | Fever or low fever of 1 days, 12/year, vaccin induced, with regular pattern, chills, urticarial rash and abdominal pain. | During the attacks, complete response to NSAIDs or Steroids. Complete response to colchicine as maintenance therapy. | ||||
| M680IGC | 2 | 17 (4-30) | Recurrent | Fever episodes of 2-3 days, 9/year with chest pain (2), pleurisy, arthralgia, myalgia, abdominal pain (1). | Complete response to colchicine as maintenance therapy. | ||||
| M694V | 6 | 5 (1-11) | Recurrent | Fever or low fever episodes of 2 days, 10/year, with abdominal pain (6), vomiting (4), arthralgia, myalgia, constipation, chest pain (3), pericarditis and pleurisy (2). | Erythematous pharyngitis, urticarial rash, aseptic peritonitis, bilateral cervical enlargement lymphonodes, hepatomegaly, persistent cough, hemoptysis, headache and orchitis (1). Episodes induced by cold, stress, food (1). | Complete response to colchicine (4), steroids (1) and NSAIDs (1). |
| Gene region | First mutation | Second mutation | N° pt | Age of onset | Disease course (n. of patients) | Prevalent clinical manifestations (n. of patients) | Less common manifestations (n. of patients) | Treatment response (n. of patients) | Complications (n. of patients) |
| (years) | |||||||||
| Exon 2 | delM1-26 | V377I | 1 | 3 | Continous and recurrent | Recurrent fever episodes (10/year, lasting 1 week) with aphthous stomatitis, exudative or erythematous pharyngitis, abdominal pain, arthralgia and myalgia. | Partial response to NSAIDS on-demand. Complete response to steroids on demand. | ||
| H20N | R215Q | 2 | At birth | Continuous | Presence of persistent high-grade fever with polyarthritis, arthralgia, persistent cough and occasional low-grade fever, erysipelas-like erythema, papulopustular lesions, tenosynovitis, lymphadenopathy, chest pain, pericarditis, pneumonia, myalgia, bone pain, fatigue and malaise. | Partial response to NSAIDS on-demand. Failure with Infliximab on-demand. Partial response with the maintenance therapy with steroids, cyclosporine, biphosphonates and anakinra; failure with colchicine, methotrexate, sulphasalazine, azathioprine, statins, tacrolimus and etanercept. |
Bone alterations and erosions, flexion contractures, osteolytic lesions, osteoporosis, cataract, impaired vision. | ||
| At birth | Recurrent | Recurrent fever episodes (12/year, lasting a mean of 5 days) with acne, diarrhea, hepatomegaly, splenomegaly, lymphadenopathy, polyarthritis and occasional abdominal pain, vomiting, aseptic peritonitis, exudative pharyngitis, scleritis, pneumonia, persistent cough, arthralgia, myalgia, fatigue, malaise and bone pain. | Partial response to NSAIDS on-demand. Complete response to the maintenance with anakinra, and partial with steroids, biphosphonates, intravenous immunoglobulin and Etanercept. Failure with colchicine, sulphasalazine, methotrexate, azathioprine and statins. No response to tonsillectomy. | Bone alterations and erosions, flexion contractures, osteolytic lesions, osteoporosis, cataract, peritoneal adhesions, sub-/occlusions, gut perforations, recurrent inguinal hernia. | |||||
| H20P | V377I | 3 | 4 | Recurrent | Recurrent fever episodes (8 episodes/ year, lasting a mean of 4 days) with maculo-papular rash (3), exudative (1) and erythematous (1) pharyngitis, arthralgia (2), myalgia (3), vomiting (3), abdominal pain (3), diarrhea (3), lymphadenopathy (2), fatigue (3), malaise (3), mood disorders (2) and headache (2), hepatosplenomegaly (1). Occasional episodes of aphthous stomatitis with or without fever. | Partial response to NSAIDS (1) or anakinra (1) on-demand, failure with steroids (1).Failure with the maintenance treatment with colchicine (2) or statins (1). No response to tonsillectomy (1). | Neuropathy (1). | ||
| V20R | V377I | 1 | 1 | Recurrent | Recurrent fever episodes (10/ year) with urticarial rash, lymphadenopathy, arthralgia and occasional vomiting and diarrhea. | Partial response with steroids on-demand. | |||
| Exon 3 | H44fs | V377I | 1 | 7 | Recurrent | Recurrent fever episodes (6/r year) with maculo-papular rash, arthralgia, myalgia, abdominal pain, vomiting, diarrhea, fatigue, malaise and weith loss. | Steroids on-demand failed. Partial response to maintenance treatment with etanercept and azithromicine. Failure with maintenance therapy with colchicine and anakinra. Complete response to Infliximab. | ||
| W62X | V377I | 1 | At birth | Recurrent | Recurrent fever episodes (24/ year, lasting 6 days) with abdominal pain, fatigue and malaise, occasional with urticarial rash, arthralgia, myalgia, vomiting, diarrhea, gastrointestinal bleeding. Persistence of hepato-splenomegaly, mood disorders, generalized enlarged lymphadenopathy. | Failure with NSAID on demand. Partial response to steroids on demand. | |||
| Exon 4 | Y114fs | N205D | 1 | 0.1 | Recurrent | Recurrent fever episodes (17/ year, lasting 13 days) with occasional abdominal pain and splenomegaly. Occasional episodes of erythema marginatum, arthralgia, myalgia and oligoarthritis with or without fever. | Partial response to the maintenance treatment with steroids and anakinra. Failure with the maintenance therapy with colchicine and etanercept. | ||
| Y116H | V377I | 1 | 0.2 | Recurrent | Recurrent fever episodes (22/ year, lasting 5days) with aphthous stomatitis, arthralgia, headache, abdominal pain, diarrhea, lymphadenopathy and occasional urticarial rash. | Partial response to the maintenance treatment with colchicine and anakinra. The patient underwent to tonsillectomy with a partial response. |
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| I119M | A148T | 1 | 2 | Recurrent | Recurrent fever episodes (24/ year, lasting 7 days) with always arthralgia, abdominal pain, vomiting, diarrhea and lymphadenopathy. Presence of headache with or without fever. | Partial response with both on-demand and maintenance treatment with NSAIDS and steroids. Partial response with the maintenance therapy with etanercept. | |||
| R124W | V377I | 1 | 2 | Recurrent | Recurrent fever episodes (24/ years, lasting 4 days) with arthromialgia, myalgia, malaise and occasional abdominal pain, diarrhea, vomiting, erythematous pharyngitis, cervical and painful lymphadenopathy. | Complete response to steroids on demand. No tonsillectomy efficacy. | |||
| Exon 5 | V132I | V377I | 1 | 0.4 | Recurrent | Recurrent fever episodes (13/ year, lasting 8 days) with exudative and erythematous pharyngitis, arthralgia, myalgia, abdominal pain, lymphadenopathy and occasional splenomegaly. | Partial response with both on-demand and maintenance treatment with NSAIDS and steroids. Partial response with the maintenance therapy with colchicine and etanercept. | ||
| A141fs | A334T | 1 | At birth | Recurrent | Recurrent fever episodes (12/r year, lasting 4 days) with aphthous stomatitis, arthralgia, myalgia, abdominal pain, vomiting, diarrhea, lymphadenopathy, fatigue, malaise and occasional erythematous pharyngitis, maculo-papular rash and mood disorders. Moreover, occasional episodes of oligoarthritis and headache with or without fever. | Partial response to the maintenance treatment with NSAIDS and failure with the maintenance therapy with anakinra. | Impaired vision, cerebellar syndrome, retinitis pigmentosa, mental retardation. | ||
| A147T | V377I | 1 | 0.05 | Recurrent | Recurrent fever episodes, lasting on the average 3 day, with occasional vomiting, diarrhea, aphthous stomatitis, maculo-papular rash and lymphadenopathy. | Treated with etanercept with partial response. The patient underwent to tonsillectomy without response. | |||
| A148T | I119M | 1 | 2 | Recurrent | Recurrent fever episodes (24/year, lasting 7 days) with always arthralgia, abdominal pain, vomiting, diarrhea and lymphadenopathy. Presence of headache with or without fever. | Partial response with NSAIDS or steroids on-demand. Partial response to NSAIDS, steroids or etanercept as maintenance therapy. | |||
| C152fs | V377I | 1 | 0.2 | Recurrent | Recurrent fever episodes (24/r year, 2 days) with vomiting, diarrhea, painful and enlarged cervical lymphadenopathy, with occasional gastrointestinal bleeding. Abdominal pain and constipation with or without fever. | Partial response to NSAIDS on-demand. Failure with steroids on-demand and with maintenance therapy with etanercept. | |||
| P165L | I268T | 2 | At birth | Continuous | Persistent maculo-papular rash, vomiting, diarrhea, lymphadenopathy, hepatosplenomegaly, malaise and fatigue with occasional episodes of aphthous stomatitis, exudative pharyngitis, arthralgia, myalgia, oligo-arthritis, abdominal pain, aseptic peritonitis and pneumonia with persistent cough, headache and mood disorders. | Occasional episodes of osteitis. | Treated both with on-demand and maintenance therapy with steroids with partial response. Partial response with the maintenance therapy with anakinra. Failure with etanercept, statins and montelukast. The patient underwent to adenotonsillectomy without response. | Peritoneal adhesions, occlusion/sub-occlusion, venous thrombosis, severe infections. | |
| 0.3 | Recurrent | Recurrent fever episodes (12/ per year, of variable length) with occasional exudative and erythematous pharyngitis, maculo-papular rash, palpable purpura, arthralgia, myalgia, mono-arthritis, vomiting, abdominal pain, diarrhea, constipation, lymphadenopathy, headache, fatigue and malaise. Presence of acne with or without fever. | Failure with NSAIDS on-demand. Partial response with steroids and anakinra on-demand. Failure with the maintenance therapy with statins. | Mental retardation. | |||||
| V377I | 2 | 0.7 | Recurrent | Recurrent fever episodes (9/year, lasting 4 days) with abdominal pain, lymphadenopathy, fatigue and malaise (2), diarrhea, arthralgia, headache, aphthous stomatitis, maculo-papular rash (1). | Partial response to NSAIDS on-demand (2). Partial response to the maintenance therapy with colchicine (1). No response to tonsillectomy. | ||||
| N166I | G336S | 1 | 5 | Recurrent | Recurrent fever episodes (12/year, lasting 7 days) with occasional aphthous stomatitis, exudative and erythematous pharyngitis, arthralgia, myalgia, abdominal pain, diarrhea, aseptic peritonitis, lymphadenopathy, fatigue and malaise. Presence of occasional episodes of pseudo-folliculitis, papulo-pustular lesions, peri-anal lesions and hepatomegaly with or without fever. | Partial response to the maintenance treatment with colchicine. | |||
| Exon 6 | W188X | V337I | 1 | 0.5 | Recurrent | Recurrent fever episodes (24/years, lasting 6 days) with vomiting, abdominal pain, diarrhea, cervical painful lymphadenopathy and occasional maculo-papular rash, erythematous pharyngitis, arthralgia, myalgia. Persistence of fatigue and malaise. Since about 12 years of age just gastrointestinal symptoms during attacks. | Partial response to NSAID or steroids on demand and tonsillectomy. | ||
| Q190fs | V377I | 1 | 11 | Recurrent | Recurrent fever episodes (13/year) with lymphadenopathy, vomiting, abdominal pain, erythematous pharyngitis and occasional aphthous stomatitis and arthralgia. | Partial response with the treatment with NSAID on-demand. Partial response with the maintenance therapy with colchicine. | |||
| V203fs | V377I | 2 | 0.3 | Recurrent | Recurrent fever episodes (16/ year, lasting 3 days) with urticarial rash, arthralgia, myalgia, abdominal pain, malaise (2) and occasional lymphadenopathy (2), diarrhea, aphthous stomatitis, exudative and erythematous pharyngitis, maculo-papular or migratory rash, fatigue, mood disorders, palpable purpura, pleurisy, pneumonia, hepatomegaly, splenomegaly (1). Moreover presence of occasional conjunctivitis, vomiting, diarrhea, persistent cough and headache with or without fever (1). | Partial response (1) of failure (1) with NSAIDS, partial to steroids (2) or colchicine (1) on-demand. Failure with both on-demand and maintenance therapy with cyclosporine and statins (1). | Cataract, cerebral nerve palsy, mental retardation (1). | ||
| V203A | I268T | 1 | At birth | Continous and recurrent | Recurrent fever episodes (12/year, lasting 7 days) with aphthous stomatitis, erythematous rash, erysipelas, arthralgia, diarrhea, generalized and painful lymphadenopathy, hepato-splenomegaly, fatigue, malaise and headache. | Partial response to NSAIDS or steroids on demand. Partial response to maintenance therapy with steroid. | Peritoneal adhesions. | ||
| N205D | Y114fs | 1 | 0.1 | Recurrent | Recurrent fever episodes (17/year, lasting 13 days) with occasional abdominal pain and splenomegaly. Occasional episodes of erythema marginatum, arthralgia, myalgia and oligoarthritis with or without fever. | Partial response to the maintenance treatment with steroids and anakinra. Failure with the maintenance therapy with colchicine and etanercept. | |||
| V312A | 1 | At birth | Recurrent | Recurrent fever episodes (6/year, lasting 5 days) triggered by stress, with erythematous pharyngitis, arthralgia, myalgia, abdominal pain and sometimes aphtous stomatitis, ulcers at genitalia, vomiting and diarrhea, generalized lymphadenopathy, fatigue and malaise. Headache and conjunctivitis with our without fever. | Partial response to NSAIDS on-demand, failure with steroids. | ||||
| Exon 7 | G211E | V337I | 1 | 0.7 | Recurrent | Recurrent fever episodes (14/year, lasting 6 days) with palpable purpura. Occasional presence of maculo-papular or urticarial or vasculitic rash, abdominal pain, vomiting, diarrhea, enlarged and painful lymphadenopathy, aphthous stomatitis, arthralgia, myalgia, fatigue and malaise with or without fever. | Periorbital edema. | Complete response to NSAIDS or steroids on-demand, failure with azathioprine. | |
| R215Q | H20N | 2 | At birth | Continuous | Persistent high-grade fever with polyarthritis, arthralgia, cough and occasional low-grade fever, erysipelas-like erythema, papulopustular lesions, tenosynovitis, lymphadenopathy, chest pain, pericarditis, pneumonia, myalgia, bone pain, fatigue and malaise. | Partial response to NSAIDS on-demand, failure with Infliximab. Partial response to maintenance therapy with steroids, cyclosporine, biphosphonates and Anakinra. Failure with colchicine, methotrexate, sulphasalazine, azathioprine, statins, tacrolimus and etanercept. | Bone alterations, flexion contractures, osteolytic lesions, bone erosions, osteoporosis, cataract, impaired vision. | ||
| At birth | Recurrent | Recurrent fever episodes (12/ year, lasting 5 days) with acne, diarrhea, hepato-splenomegaly, lymphadenopathy, polyarthritis and occasional abdominal pain, vomiting, aseptic peritonitis, exudative pharyngitis, scleritis, pneumonia, persistent cough, arthralgia, myalgia, fatigue, malaise and bone pain. | Partial response to NSAIDS on-demand. Complete response with the maintenance tharapy with anakinra, partial response with steroids, biphosphonates, intravenous immunoglobulin and etanercept. Failure with colchicine, sulphasalazine, methotrexate, azathioprine and statins. The patient underwent to tonsillectomy without response. | Bone alterations and erosions, flexion contractures, osteolytic lesions, osteoporosis, cataract, peritoneal adhesions, sub-/occlusions, gut perforations, recurrent inguinal hernia. | |||||
| V377I | 3 | At birth | Recurrent | Recurrent fever episodes (12/ year, lasting 6 days) with abdominal pain, diarrhea (3) and vomiting (2), maculo-papular rash (1), enlarged lymphadenopathy (3), painful lymphadenopathy (2), splenomegaly (1), pneumonia (1), headache (2), erythematous pharyngitis (2), urticarial rash (1), arthralgia (2), myalgia, fatigue, malaise (1). | Aphthous stomatitis and gastrointestinal ulcers during fever attacks (1). | Partial response to NSAIDS (2) on-demand, complete (1) or partial (1) with steroids. Partial response to maintenance therapy with steroids (1) or rilonacept (1). One patient underwent to tonsillectomy without response. | |||
| IVS7-1G>C | V377I | 1 | 2 | Recurrent | Recurrent fever episodes (14/year, lasting 5 days) with aphthous stomatitis, pseudofolliculitis, ulcers at genitalia, arthralgia, myalgia, anterior uveitis, episcrleritis, vomiting, diarrhea, abdominal pain, cervical and painful lymphadenopathy, splenomegaly, fatigue, malaise, mood disorders. | Failure with NSAIDS or steroids on-demand, partial response to maintenance therapy with anakinra e etanercept. | Macrophage activation syndrome. | ||
| Exon 8 | P228P | V377I | 1 | 2 | Recurrent | Recurrent fever episodes (7/years, lasting 6 days), sometimes with enlarged cervical lymphadenopathy, abdominal pain, diarrhea, urticarial rash, fatigue and headache, | Partial response to the maintenance treatment with etanercept. | Renal failure. | |
| T237S | T237S | 1 | - | Recurrent | Recurrent fever episodes (20/years, lasting 5 days). Moreover, episodes of vomiting, abdominal pain, diarrhea, arthralgia and LC lymphadenopathy with or without fever. | Failure with the maintenance treatment with colchicine. Partial response to the maintenance therapy with anakinra. | |||
| I268T | 1 | At birth | Continous | Fever, malaise, weight loss, maculo-papular rash, vomiting, abdominal pain, diarrhea, gastrointestinal bleeding, aseptic peritonitis, hepato-splenomegaly, pneumonia. | Ascites, cholestasis. | Partial response to maintenance therapy with steroids. | Peritoneal adhesion, sub/occlusion, death due to acute respiratory distress syndrome. | ||
| L246P | V337I | 1 | At birth | Recurrent | Recurrent fever episodes (8/years, lasting 3 days) with exudative and erythematous pharyngitis, generalized and painful enlarged lymphadenopathy, abdominal pain, diarrhea and sometimes vomiting, bone pain, arthromyalgia, fatigue, malase, weight loss. Sometimes acne and aphthous stomatitis with or without fever. | Partial response to NSAIDS or steroids on-demand. | |||
| Exon 9 | L264F | V377I | 3 | 0.6 | Recurrent | Recurrent fever episodes (13/year, lasting 5 days), with occasional aphthous stomatitis (3), exudative (3) and erythematous (2) pharyngitis, maculo-papular rash (3), arthralgia (2), myalgia (1), abdominal pain (3), diarrhea (3), lymphadenopathy (2), hepatomegaly (1), splenomegaly (2), fatigue (2), headache (1) and malaise (2). | One patient presented recurrent pericarditis. | Patients were treated with on-demand steroids with a partial response (3). Maintenance therapy with anakinra with partial response (1) and NSAIDS on-demand with partial response (2) or failure (1). | |
| c.790delC | V377I | 1 | At birth | Recurrent | Recurrent fever episodes (on the average 24 per year, lasting 5 days) with aphthous stomatitis, abdominal pain, diarrhea, fatigue, malaise and occasional episodes of exudative and erythematous pharyngitis, urticarial rash, vomiting and mood disorders. Moreover, occasional episodes of anal/perianal ulcers with or without fever. | - | Seizures. | ||
| L265R | V377I | 4 | 1 | Recurrent (2) | Recurrent fever episodes (20 /year, lasting 3 days) with aphthous stomatitis (2), erythematous pharyngitis, arthralgia, myalgia (1) and occasional conjunctivitis (2), vomiting (1), abdominal pain (2), diarrhea (2), lymphadenopathy (2) and splenomegaly (1), pneumonia (1), fatigue (1). | Complete response (1) or failure (1) to steroids on-demand. Failure with NSAID or colchicine on demand (1). Partial response with anakinra as maintenance therapy (1). | |||
| 0.2 | Continuous and recurrent (2) | Recurrent fever episodes (20/year, lasting 4 days) with aphthous stomatitis, abdominal pain (2), exudative and erythematous pharyngitis, monoarthritis with tenosynovitis (1) and occasional myalgia, vomiting, diarrhea (2), arthralgia, lymphadenopathy and hepatomegaly (1). Headache and fatigue with or without fever (1). Weight loss (1). | Complete response to steroids on-demand (1). | Flexion contractures (1). | |||||
| I268T | P165L | 2 | At birth | Continuous | Persistent maculo-papular rash, vomiting, diarrhea, lymphadenopathy, hepatomegaly, splenomegaly, malaise and fatigue with occasional episodes of aphthous stomatitis, exudative pharyngitis, arthralgia, myalgia, oligoarthritis, osteitis, abdominal pain, aseptic peritonitis, pneumonia, persistent cough, headache and mood disorders. | Treated both with on-demand and maintenance therapy with steroids with partial response. Partial response with the maintenance therapy with anakinra. Failure with etanercept, statins and montelukast. The patient underwent to adenotonsillectomy without response. | Peritoneal adhesions, occlusion/sub-occlusion, venous thrombosis, severe infections. | ||
| 0.3 | Recurrent | Recurrent fever episodes (12/year, of variable length) with occasional exudative and erythematous pharyngitis, maculo-papular rash, palpable purpura, arthralgia, myalgia, monoarthritis, vomiting, abdominal pain, diarrhea, constipation, lymphadenopathy, headache, fatigue and malaise. Presence of acne with or without fever. | Failure with NSAIDS on-demand. Partial response with steroids and anakinra on-demand. Failure with the maintenance therapy with statins. | Mental retardation. | |||||
| V203A | 1 | At birth | Continous and recurrent | Recurrent fever episodes (12/year, lasting 7 days) with aphthous stomatitis, erythematous rash, erysipelas, arthralgia, diarrhea, generalized and painful lymphadenopathy, hepato-splenomegaly, fatigue, malaise and headache. | Partial response to NSAIDS or steroids on demand. Partial response to maintenance therapy with steroid. | Peritoneal adhesions. | |||
| T237S | 1 | At birth | Continous | Fever, malaise, weight loss, maculo-papular rash, vomiting, abdominal pain, diarrhea, gastrointestinal bleeding, aseptic peritonitis, hepato-splenomegaly, pneumonia. | Ascites, cholestasis. | Partial response to maintenance therapy with steroids. | Peritoneal adhesion, sub/occlusion, death due to acute respiratory distress syndrome. | ||
| V377I | 24 | 0.1 | Continuous (1) | Presence of occasional episodes of vomiting and diarrhea. | No fever. | - | Amyloidosis. | ||
| 1 | Recurrent (22) | Recurrent fever episodes (14/ year, lasting 6 days) with aphthous stomatitis (12), erythematous or exudative pharyngitis (7), arthralgia (8), arthritis (7), vomiting (13), abdominal pain (13), diarrhea (12), lymphadenopathy (18), some times painful (4), headache (7), fatigue (10) and malaise (10). | Occasional episodes of aphthous stomatitis (2), urticarial rash (2), myalgia (6), palpable purpura (1), papulo-pustular lesions (1), maculo-papular rash (5), ulcers at genitalia (2), erythema nodosum (2), conjunctivitis (1), constipation (1), aseptic peritonitis (2), chest pain (2), pericarditis (1), persistent cough (1), arthralgia (5), myalgia (2), lymphadenopathy (2), gastrointestinal bleeding (1), abdominal pain (4) and mood disorders (4) with fever. Presence of aphthous stomatitis (2), acne (1), ulcers at genitalia (1), erythema nodosum (1), polyarthritis (1), vomiting (2), abdominal pain (1), diarrhea (1), constipation (1), hepatomegaly (2), splenomegaly (3), chest pain (1), pneumonia (1), persistent cough (1), headache (3), urethritis/cystitis (1), weight loss (3), fatigue (4), malaise (2) and mood disorders (2) with or without fever. | Complete (2) or partial (6) or failure (2) with NSAID on demand; partial (2) or failure (1) as maintenance therapy. Complete (6) or partial (4) response to steroids on demand. Complete (2), partial response (3) or failure (1) to anakinra. Partial (3) response or failure (1) with etanercept. Partial response to thalidomide (1) and statins (2) that failed in one patient. Six patients underwent to tonsillectomy without a response. Cimetidine failure in two patients. Complete response to canakinumab in one patient. |
Amyloidosis (3), peritoneal adhesions (1), occlusion/sub-occlusion episodes (1), seizures (2), cranial nerve palsy (2), cranial neuropathy (1), mental retardation (1) | ||||
| 2 | Continuous and recurrent (1) | Recurrent fever episodes (24/year, lasting 8 days). Occasional episodes of maculo-papular rash, arthralgia, myalgia, headache, conjunctivitis, lymphadenopathy, vomiting, abdominal pain and diarrhea with or without fever. | Failure with the treatment with the maintenance treatment with steroids, colchicine, methotrexate and anakinra. | Clubbing. | |||||
| S272F | V377I | 4 | 3 | Recurrent (1) | Recurrent fever episodes (13/ year, lasting 13 days) with vomiting, diarrhea, fatigue, malaise and occasional abdominal pain, aphthous stomatitis, arthralgia, myalgia, oligoarthritis, headache and lymphadenopathy. Moreover, presence of persistent splenomegaly. | Partial response to the treatment with NSAIDS and steroids on-demand. Partial response to the maintenance therapy with cyclosporine, tacrolimus and anakinra. | Amyloidosis. | ||
| 1 | Continuous and recurrent (3) | Recurrent fever episodes (10/year, lasting 8 days) with occasional aphthous stomatitis (2), arthralgia (2), myalgia (2), oligoarthritis (2), abdominal pain (1), diarrhea (1), constipation (1), lymphadenopathy (1), pericarditis (1), chest pain (1) and pleurisy (1). Moreover, presence of persistent hepatosplenomegaly (2), fatigue (2), malaise (2) and occasional acne (1), hemoptysis (1) and persistent cough (1) with or without fever. | Partial response with the maintenance therapy with steroids (1). One partial response and one failure with colchicine. | ||||||
| Complete response with anakinra and canakinumab (1), failure with etanercept (2). | |||||||||
| R277C | R277C | 1 | 6 | Recurrent | Recurrent fever episodes (on the average 20 per years), lasting 4 days, with generalized lymphadenopathy. Persistent abdominal pain with recurrent episodes of vomiting, arthralgia, fatigue and malaise with or without fever. | Complete response to the maintenance therapy with etanercept. | Hyperostosis. | ||
| Exon 10 | V310L | V310L | 2 | 3 | Continuous and recurrent | Persistent abdominal pain with diarrhea, fatigue and malaise, gastrointestinal bleeding, arthritis (2), bone pain, uveitis, scleritis and episcleritis (1). | No fever. Recurrent episodes of pyoderma gangrenosum (1) or myalgia, myositis (1). | Partial response with the maintenance therapy with steroids (2), cimetidine (2), sulphasalazine (1), anakinra (1), and Infliximab (1). Failure with the maintenance treatment with NSAIDS, methotrexate (2), sulphasalazine and Infliximab (1). | Flexion contractures (1) |
| V310M | V377I | 2 | 2 | Recurrent | Recurrent fever episodes (11/ year, lasting 4 days) with aphtous stomatitis (1), exudative (1) or erythematous (2) rash, maculo-papular rash (1), urticarial rash (1), erysipelas-like rash (1), pseudo-folliculitis (1), acne (1), arthralgia (2), vomiting, myalgia (1), abdominal pain (2), diarrhea (2), cervical and painful lymphadenopathy (2), malaise (2), fatigue (1), bone pain (1). | Itchy of the hands (1). | Complete (1) or partial (1) response to steroids on-demand. Partial response (1) or failure (1) to tonsillectomy. Failure with colchicine (1). Complete response to maintenance therapy with anakinra (1). | ||
| L315V | V377I | 1 | 0.7 | Recurrent | Recurrent fever episodes (24/year, lasting 3 days) with occasional aphthous stomatitis, abdominal pain and arthralgia. | NSAIDS on-demand fails. Complete response with steroids. The patient underwent to the adenoidectomy without response. |
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| G326R | V377I | 1 | 0.3 | Recurrent | Presence of recurrent fever episodes (12/ year, lasting 5 days). Occasional episodes of aphthous stomatitis, arthralgia, myalgia, abdominal pain, lymphadenopathy, pneumonia, headache and ulcers at genitalia with or without fever. | Sinus pilonidalis. | Partial response to the treatment with NSAIDS. Complete response with steroids on-demand. | ||
| S329R | V337I | 1 | 2 | Recurrent | Recurrent fever episodes (12/year, lasting 4 days) with aphthous stomatitis, arthralgia, myalgia, abdominal pain, vomiting, diarrhea, generalized and painful lymphadenopathy, fatigue, malaise and occasional erythematous pharyngitis, osteitis, pseudofolliculitis. | Occasional episodes of osteitis. | Partial response to NSAID on-demand and with the maintenance therapy with etanercept. | ||
| A334T | A141fs | 1 | At birth | Recurrent | Recurrent fever episodes (12/year, lasting 4 days) with aphthous stomatitis, arthralgia, myalgia, abdominal pain, vomiting, diarrhea, lymphadenopathy, fatigue, malaise and occasional erythematous pharyngitis, maculo-papular rash and mood disorders. Occasional episodes of oligoarthritis and headache with or without fever. | Partial response to the maintenance treatment with NSAID and failure with the maintenance therapy with anakinra. | Impaired vision, cerebellar syndrome, retinitis pigmentosa, mental retardation. | ||
| G335A | V377I | 1 | 1 | Recurrent | Recurrent fever episodes (on the average 18 per year, lasting 5 days) with maculo-papular rash, vomiting, diarrhea, cervical lymphadenopathy and occasional arthralgia, abdominal pain and hepatospenomegaly. | Failure with steroids on demand. Complete response to etanercept as maintenance therapy. | |||
| G336S | N166I | 1 | 4 | Recurrent | Recurrent fever episodes (on the average 12 per year, lasting 7 days) with occasional aphthous stomatitis, exudative and erythematous pharyngitis, arthralgia, myalgia, abdominal pain, diarrhea, aseptic peritonitis, lymphadenopathy, fatigue and malaise. Occasional episodes of pseudo-folliculitis, papulo-pustular lesions, peri-anal lesions and hepatomegaly with or without fever. | Partial response to the maintenance treatment with colchicine. | |||
| V377I | 2 | 1 | Recurrent | Recurrent fever episodes, on the average 12 per year, lasting 4 days with vomiting, abdominal pain, diarrhea and enlarged cervical lymphadenopathy (2). | Episodes of arthralgia or retinal vasculitis with or without fever (1). | Complete response to steroids on-demand and as maintenance therapy (1). | |||
| G338D | V377I | 1 | At birth | Recurrent | Recurrent fever episodes (on the average 24 per year, lasting 6 days), with abdominal pain, macula-papular rash and occasional aphthous stomatitis, arthralgia, diarrhea, lymphadenopathy. Presence of persistent hepatomegaly and splenomegaly with or without fever. | Failure with NSAIDS and steroids on demand and with the maintenance therapy with colchicine, anakinra, etanercept and adalimumab. Partial response with the maintenance treatment with canakinumab. | |||
| Exon 11 | H380R | V377I | 1 | 11 | Continuous and recurrent | Recurrent episodes, on the average 12 per year, lasting 14 days, with or without fever, with erythematous or exudative pharyngitis, arthralgia, myalgia, diarrhea, abdominal pain, constipation, cervical painful lymphadenopathy, aseptic peritonitis, conjunctivitis, oligoarthritis. Persistence of fatigue, malaise, mood disorders, chills. Weight loss. | Recurrence of chest pain, pleurisy. | Partial response to NSAIDS on-demand. Failure with maintenance therapy with steroids, methotrexate, etanercept and statins. | |
| R388X | V377I | 2 | 1 | Recurrent | Recurrent fever episodes, on the average 15 per year, lasting up to 3 days, with aphthous stomatitis and cervical lymphadenopathy (2). Presence of hepatomegaly (1), fatigue, malaise, maculo-papular rash and vomiting (2), abdominal pain, diarrhea, exudative or erythematous pharyngitis (1). | Partial response to NSAIDS on-demand (2). Complete (1) or partial (1) response to steroids on-demand. | |||
| V377I | V377I | 12 | 2 | Recurrent | Presence of recurrent fever episodes (on the average 11 per year, lasting 5 days), with erythematous (4) or exudative (1) pharyngitis, maculo-papular rash (4), arthralgia (7), myalgia (8), vomiting (10), diarrhea (9), abdominal pain (10), lymphadenopathy (11) headache (7), fatigue (8), malaise (9) and mood disorders (3), aphthous stomatitis (6 only during fever episodes, 4 with or without fever). | Complete (2) or partial (3) or failure (1) to NSAIDS during attacks and complete (1) or partial (3) as maintenance therapy. Complete (2) or partial (2) response to steroids on-demand. Partial response to anakinra (2). Adenotonsillectomy failure (3). | Seizures (2). | ||
| Presence of ulcers at genitalia (1), arthritis (2), vertigo (3) and conjunctivitis (2) during the fever episodes. Presence of hepatomegaly (1) and urticarial rash (1) with or without fever. | |||||||||
| I268T | 75 | 0.1 | Continuous | Presence of frequent episodes of vomiting and diarrhea without fever. | No fever. | - | Amyloidosis. | ||
| V20R H20P (3) H44fs W62X Y116H R124W V132I A147T C152fc P165L (2) W188R V203fs (2) G211E R215Q (3) P228P L264F (3) L265R (4) I268T (22) S272F (2) V310M (2) L315V G326R S329R G335A G336S (2) G338D R388X (2) delG571 c.790delC gene del (2) IVS7-1G>C |
1 | Recurrent (68) | Presence of recurrent fever episodes (on the average 12, lasting 5 days), with pharyngitis, (31) aphthous stomatitis (34), arthralgia (37), myalgia (32), vomiting (35), abdominal pain (50), diarrhea (47), lymphadenopathy (45), fatigue (31) and malaise (34), maculo-papular rash (20). | During the fever episodes also reported occasional presence of arthritis (14), headache (14), aphthous stomatitis (3), erysipelas-like rash (1), palpable purpura (5), urticarial rash (9), splenomegaly (9), hepatomegaly (5), pneumonia, erythema nodosum, aseptic peritonitis, constipation, maculo-papular rash (4), arthralgia (6), lymphadenopathy (4), myalgia (5), arthritis (6), ulcers at genitalia (3), conjunctivitis (3), chest pain (2), migratory or vasculitic rash, pleurisy, persistent cough (1), papulo-pustular lesions (1), bone pain (1), anterior uveitis (1), episcleritis (1), pseudo-folliculitis (2), gastrointestinal bleeding (3) and mood disorders (10). Some patients also presented with or without fever episodes of aphthous stomatitis (1), headache (7), vomiting (5), perianal ulcers (4), fatigue (6), abdominal pain (5), diarrhea (4), arthralgia (3), splenomegaly (6), hepatomegaly (5), painful and enlarged lymphoadenopathy (4), malaise (4) and mood disorders (3), panniculitis (2) persistent cough (2), maculo-papular rash (1), acne (1), ulcers at genitalia (1), erythema nodosum (1), myalgia (1), polyarthritis (1), pneumonia (1), conjunctivitis (1), constipation (1), chest pain (1), urethritis/cystitis (1).Recurrent pericarditis (3). Periorbital edema (1) and gastrointestinal ulcers (1) during fever attacks. Occasional episodes of osteitis (1) or itchy rash (1). |
Complete response to steroids (9), NSAID (3) or colchicine (1) on-demand. Partial response (20) or failure (6) to NSAID on-demand. Partial response (12) or failure (6) to steroids on-demand and partial response (3) or failure (2) as maintenance therapy. Partial responses (3) or failure (6) to colchicine as maintenance therapy. Partial responses (3) or failure (2) to NSAID as maintenance therapy. Partial (3) or complete (1) response to anakinra on-demand: complete (4), partial (5) response or failure (2) as maintenance therapy. Complete response to infliximab (1) or canankinumab (1). Complete (1) or partial responses (9) or failure (3) with maintenance therapy with etanercept. Partial response also to canakinumab (1), rilonacept (1), azithromicine (1) and adalimumab (1) as maintenance therapy. Partial response (2) or failure (2) to statins. Failure with cyclosporine (1) or thalidomide (1) or azathioprine (1), cimetidine (2). Partial response (8) or failure (6) to tonsillectomy. | Retinal vasculitis (1), cataract (1), peritoneal adhesion (2), intestinal occlusion (1), seizures (3), cranial nerve palsy (3), neuro-sensorial hearing loss (1), mental retardation (2), amyloidosis (4), renal failure (1), perianal fistula (1), macrophage activation syndrome (1). | |||
| delM1-26 L265R I268T S272F (2) H380R |
3 | Continuous and recurrent -6 | Recurrent fever episodes (16/year, lasting 7 days), with aphthous stomatitis (4), erythematous (3) and exudative (3) pharyngitis, arthralgia (5), myalgia (6), arthritis (3), abdominal pain (5), diarrhea (4), vomiting (3), constipation (2), lymphadenopathy (4), hepato-splenomegaly (1), fatigue (4) and malaise (4). During the fever episodes, sometimes presence of maculo-papular rash (2) and conjunctivitis (2), and headache (1). Presence of persistent acne (1), hepato-splenomegaly (2), mood disorders (1), chills (1) out of the fever episodes. | Persistent cough with episodes of hemoptysis (1).Recurrent chest pain, pleurisy (2) and pericarditis (1). | Complete response to steroids on demand (2). Maintenance therapy with steroids with partial response (1) or failure (1). Partial response (2) or failure (1) with colchicine. 1 patient was treated with a maintenance therapy with anakinra with a complete response, subsequently converted to canakinumab always with a complete response. Failure with methotrexate (1) or anakinra (1) or etanercept (2). | Clubbing (1), seizures (1). |
| Gene region | Mutation | N° pz | Age of onset (years) | Disease course (n. patients) |
Prevalent clinical manifestations (n. of patients) | Less common manifestations (n. of patients | Treatment response (n. of patients) | Complications (n. of patients) |
| Ex 3 | V198M | 18 | 10 (0-45) |
Continuous (5) | Presence of urticarial (4) and maculo-papular (1) rash, arthralgia (5) and myalgia (4). In one patient presence of persistent fever >38°C, in the other three ones occasional episodes of hyperpyrexia. | Occasional episodes of palmo-plantar erythema, vomiting, lymphadenopathy e pericarditis (1 pt). Presence of polyarthritis, tenosynovitis, fatigue and conjunctivitis (1). | Partial response to the treatment with NSAIDS during attacks (1 pt) and to the maintenance therapy with steroids (1). One patient has presented a partial response to the maintenance therapy with methotrexate, cyclosporine, Infliximab, etanercept and adalimumab, sirolimus and mycophenolate mofetil; he has presented a complete response to the maintenance treatment with tocilizumab and biphosphonates. Partial (1) and complete (3) response to the maintenance therapy with anakinra, which failed in one patient. | Development of bone alterations, osteoporosis, osteolytic lesions, bone erosions, hyperostosis and bone deformity (1 pt). Development of cataract (1), amyloidosis (1), arterial hypertension (1). Hearing loss (2). Delayed puberty (1). |
| Recurrent (10) | Recurrent episodes (on the average 12 per year), sometimes associated with fever, characterized by arthralgia (9), urticarial and maculo-papular rash (8), oligo or monoarthritis (7), conjunctivitis (7), headache (6), malaise (6), fatigue (6), weight loss (5) myalgia (5), lachrymal gland involvement (3), periorbital pain (2), lymphadenopathy (3), and triggered by cold in 3 patients. | Occasional episodes of bone pain, abdominal pain or polyarthritis (1). | Failure (1) or partial (3) response to NSAIDS or partial response to steroids (3) during attacks. Failure (1) or partial (1) response to the maintenance treatment with colchicine, failure to the maintenance treatment with methotrexate (2) or cyclosporine (1). Complete (2) or partial (1) response to the maintenance treatment with anakinra and partial response with canakinumab (2). Etanercept fail in 1 patient. |
Hearing loss (1). Impaired vision (1). |
||||
| Continuous and recurrent (3) | Occasional fever episodes (3) and urticarial rash (3), arthralgia, myalgia (2), conjunctivitis (2), periorbital pain (1), papilledema (1), headache (1), fatigue (1) and malaise (1). | Partial response to the treatment with NSAIDS and steroids during attacks (2). Complete response to the maintenance treatment with anakinra (1). | Development of bone alterations and frontal bossing (1). Hearing loss (1). | |||||
| R260L | 1 | 8 m | Continuous | Presence of persistent urticarial rash, arthralgia, monoarthritis and morning headache. Occasional fever episodes associated with fatigue. | Sometimes presence of abdominal pain. | Failure to the maintenance treatment with colchicine. Complete response to the maintenance treatment with anakinra. | Hearing loss. | |
| R260W | 32 | 2 (0-24) |
Continuous -12 |
Presence of persistent urticarial rash (12), associated with arthralgia (7), myalgia (5), conjunctivitis (7), malaise and fatigue (4) and headache (4). Sometimes presence of fever (4). | Occasional episodes of maculo-papular rash, arthritis, (2), aphthous stomatitis, scleritis, papilledema and abdominal pain, conjunctivitis, pleurisy (1). | Partial response to NSAIDS during attacks (2) and to the maintenance treatment with NSAID (1) or steroids (2). Complete (6) or partial (4) response to the maintenance treatment with anakinra. Complete (4) or partial (1) response to the maintenance treatment with canakinumab. | Development of clubbing (1) and amyloidosis (1). Hearing loss (2). Infertility (1). | |
| Recurrent (16) | Episodes (variable number from 2 to more than 24 per year) characterized by fever (14, with variable length from 12 hours to 5 days), associated with urticarial rash and conjunctivitis (16), arthralgia (14), myalgia (12), headache and fatigue (11), arthritis (8), malaise or livedo reticularis (5). | Occasional papilledema (2), aphthous stomatitis, feet oedema, acanthosis nigricans, bone pain, periorbital oedema, lymphadenopathy, seizures and cystitis/urethritis (1). | Complete (2) or partial (1) response to NSAIDS during attacks and partial (2) or failure (1) as maintenance. Partial response to colchicine (2). One patient has been treated with cyclophosphamide and cyclosporine without benefit. Complete (2) or partial (1) response to anakinra. Complete response to canakinumab (11). | Development of clubbing (4) and amyloidosis (2). Hearing loss (5). Infertility (5). Delay in language acquisition (1), facial nerve palsy (1) and stammering (1). Delayed puberty (1). | ||||
| Continuous and recurrent (4) | Presence of persistent urticarial rash, associated with episodes of fever with arthralgia (4), livedo reticularis, myalgia, conjunctivitis and headache (3). | Xerophthalmia (2), papilledema, aseptic meningitis (1). Telangectasia (1). | Treatment failure with NSAIDS during attacks (2). Failure of maintenance with steroids (1) or colchicine (1). Complete (1) or partial (1) response to the maintenance treatment with anakinra. Complete response to canakinumab (3). | Development of clubbing (3), hearing loss (3), cerebellar syndrome with white matter lesions (1), arterial hypertension (1). Infertility (1). | ||||
| D303N | 5 | 1 (0-2) |
Continuous (1) | Presence of constant fever associated with fatigue, urticarial rash, monoarthritis, tenosynovitis and sometimes presence of hyperpyrexia, malaise, mood alterations, aphthous stomatitis, arthralgia, oligoarthritis, conjunctivitis and papilledema. | Occasional episodes of anterior uveitis with or without fever. | Partial response to NSAIDS and steroids during attacks. Partial response to the maintenance with methotrexate, etanercept and adalimumab, but worsening of the uveitis. Complete response to anakinra. | Severe impaired vision. | |
| Recurrent (3) | Recurrent fever episodes lasting on the average 8 days. Moreover, with and without fever, constant presence of papilledema (1) and sometimes of urticarial (3) and maculo-papular (2) rash, arthralgia (3), oligoarthritis (2), generalized lymphadenopathy (2), headache (2) and aseptic meningitis (2). | Occasional episodes of pseudofolliculitis, bone pain, vaginitis, abdominal pain and diarrhea (1) with or without fever. | Partial response to NSAIDS and steroids during attacks (1). Complete response to anakinra (2). Complete (1) and partial (1) response to the maintenance treatment with canakinumab. | Presence of bone alterations and frontal bossing (1), development of hydrocephalus (1) and hearing loss (2). | ||||
| Continuous and recurrent (1) | Recurrent fever episodes lasting 12-24 hours, associated with occasional arthralgia. Moreover, constant presence of urticarial rash and sometimes of fatigue, erythematous pharyngitis, oligoarthritis, conjunctivitis, keratitis, headache, aseptic meningitis and papilledema with or without fever. | Partial response to NSAIDS during attacks. Complete response to the maintenance therapy with anakinra. | Hearing loss. | |||||
| G307V | 2 | 6 m | Continuous | Persistence of urticarial rash, arthralgia, myalgia, bone pain, arthritis, papilledema, headache, aseptic meningitis. | Treatment failure with NSAIDS or steroids. Complete response to anakinra or canakinumab. | Patellar overgrowth and hypertrophy of tibia metaphysis. | ||
| Recurrent | Recurrent fever episodes (3 per year) of variable length. Moreover sometimes with or without fever, presence of urticarial rash, arthralgia, oligoarthritis, papilledema and headache. | Episodes of palpable purpura with or without fever. | Partial response to the treatment with NSAIDS during attacks. | Development of hydrocephalus and ventricular dilatation. | ||||
| E311K | 9 | 3 (0-5) |
Continuous (4) | Occasional presence of urticarial rash (4), aphthous stomatitis (3), arthralgia (4), myalgia (1), bone pain (1), monoarthritis (2), oligoarthritis (1), conjunctivitis (4), headache (3) and fatigue (2). | Occasional abdominal pain (1). | Partial response to anakinra (3). Partial (2) or complete (2) response to canakinumab (2). | Hearing loss (2). | |
| Recurrent (4) | No fever episodes. Presence of persistent arthralgia (4) and occasional urticarial rash (2), headache (2) and vertigo (1). Persistent (2) and occasional (2) conjunctivitis. | Occasional episodes of thoracic pain and pericarditis (1). | Complete response to steroids during attacks (1). Complete response to anakinra (3). Partial response to the maintenance therapy with Anakinra or Canakinumab (1). | Hearing loss (3). | ||||
| Continuous and recurrent (1) | Recurrent fever episodes lasting 2 days. Moreover, with or without fever, presence of occasional urticarial rash, aphthous stomatitis, arthralgia, oligo-polyarthritis, conjunctivitis, malaise, fatigue and mood alterations. | Occasional abdominal pain. | Partial response to the maintenance treatment with Anakinra and Canakinumab. | Gut perforation, peritoneal adhesion and gut sub-/occlusion. | ||||
| I334V | 1 | At birth | Continuous and recurrent | Recurrent fever episodes lasting 7 days, associated with urticarial rash, arthritis, uveitis anterior, papilledema, vomiting, headache, aseptic meningitis. | NSAID during fever attacks failed. Partial response to maintenance with steroids, anakinra or canakinumab, while methotrexate failed. | Impaired vision, mental retardation, hearing loss. | ||
| T348M | 21 | At birth (0-2) |
Continuous (12) | Presence of urticarial rash (11), conjunctivitis (10) and headache (6). Sometimes presence of fever (7). | Occasional presence of aphthous stomatitis (1), maculo-papular rash (3), arthralgia (3), myalgia (2), bone pain (1), arthritis (4), anterior uveitis (1), papilledema (3), abdominal pain and gastrointestinal bleeding (1), lymphadenopathy (1), splenomegaly (1), hepatomegaly (1), aseptic meningitis (3). | 6 patients were treated with anakinra, with 5 complete responses and 1 failure. 10 patients were treated with canakinumab, with complete response to the treatment. | Hearing loss (8). | |
| Recurrent (4) | Recurrent episodes with fever (3), urticarial rash (4), aphthous stomatitis (3), maculo-papular rash (2), arthralgia (4), myalgia (1), arthritis (3), conjunctivitis (2), papilledema (3), lymphadenopathy (1), splenomegaly (1), hepatomegaly (1), headache (3), aseptic meningitis (2), fatigue (2), mood alterations (1) and malaise (1). | Presence of occasional livedo reticularis (1). | During attacks, partial response to NSAID and complete response to steroids (1). Complete response to the maintenance therapy with anakinra (3) or canakinumab (2). | Development of bone alterations and frontal bossing (2). Hearing loss (2). | ||||
| Continuous and recurrent (5) | Presence of urticarial rash (5), arthralgia (3), myalgia (4) and headache (3). Some patients present fever (3). | Occasional presence of maculo-papular rash (1), livedo reticularis (1), conjunctivitis (1), episcleritis (1), papilledema (1), abdominale pain and vomiting (1), aseptic meningitis (1), hypotonia (1) e vertigo (1). | Failure with colchicine (1). Complete response to anakinra (2). 5 patients were treated with canakinumab with 4 complete response and 1 partial response. Adenotonsillectomy in 1 patient. | Presence of bone alterations (2), frontal bossing (2), clubbing (1), cataract (1), glaucoma (1). Hearing loss (2). | ||||
| P350L | 2 | 1 | Continuous | Persistent urticarial rash, arthralgia, fatigue and weight loss (2). | Aphthous stomatitis, erythematous pharyngitis, acne, erythema nodosum, oligoarthritis, conjunctivitis, uveitis, scleritis, papilledema (1). Abdominal and chest pain with diarrhea (1). Headache | Failure with NSAID or methotrexate (1). Partial response to the maintenance treatment with anakinra (1). | Hearing loss (2). Impaired vision (1). Delayed of puberty with bone age delay of 2 years (1). | |
| V351M | 1 | At birth | Continuous and recurrent | Recurrent fever episodes lasting 12-24 hours. Persistent urticarial rash, with or without fever, and occasional arthralgia, conjunctivitis, papilledema, vomiting, headache and aseptic meningitis. | Partial response to the maintenance treatment with anakinra. | Presence of bone alterations and frontal bossing, hearing loss, hydrocephalus and severe mental delay. | ||
| A352V | 1 | 5 m | Continuous e recurrent | Recurrent fever episodes (2 per year) lasting 2 days characterized by the presence of fatigue and malaise. Moreover, with or without fever, occasional presence of urticarial rash, conjunctivitis and fatigue. | Complete response to the maintenance treatment with canakinumab. | |||
| E354D | 1 | 2 m | Continuous | Persistent presence of urticarial rash, arthralgia, lymphadenopathy and malaise, not associated with recurrent fever episodes. | Complete response to the maintenance treatment with anakinra. | |||
| H358R | 1 | At birth | Continuous and recurrent | Recurrent fever episodes (8 per year) lasting 16-20 days. Moreover, with or without fever, constant presence of maculo-papular rash, sometimes associated with aphthous stomatitis and aseptic meningitis. | Vomiting and diarrhea also out the fever episodes. | Complete response to the maintenance treatment with anakinra and canakinumab. Moreover, maintenance treatment with dapsone discontinued. | Hearing loss and presence of severe mental retardation. | |
| K375E | 1 | 9 m | Recurrent | Recurrent fever episode (>24 per year) lasting 2 days, with urticarial rash, aphthous stomatitis, arthro-myalgia, periorbital oedema, conjunctivitis, headache, fatigue. | Partial response to steroids or anakinra during attacks. Complete response to canakinumab as maintenance therapy. | |||
| M406I | 1 | 5 m | Recurrent | Recurrent fever episode (>24 per year) lasting 3 days. With or without fever, Occasional presence of urticarial and maculo-papular rash, erythematous pharyngitis, aphthous stomatitis, arthro-myalgia, papilledema, generalized lymphadenopathy, fatigue, malaise, mood alterations and headache. | Complete response to the maintenance treatment with canakinumab. | Presence of bone alterations and frontal bossing. Moderate mental retardation. Delayed of puberty. | ||
| T436A | 1 | At birth | Continuous | Persistent presence of urticarial rash, arthralgia, headache and optic neuritis. Sometimes conjunctivitis. | Partial response to steroids. Complete response to anakinra. | Hearing loss, infertility and bone age delayed. | ||
| T436I | 1 | At birth | Continuous and recurrent | Recurrent fever episodes (>24 per year) lasting 12-24 hours, associated with fatigue, mood alterations, malaise and occasional urticarial rash, conjunctivitis, periorbital pain and morning headache. Moreover, with or without fever, presence of occasional aphthous stomatitis, exudative and erythematous pharyngitis, maculo-papular rash, arthralgia, myalgia, papilledema, headache and persistent polyarthritis. | Severe cutaneous involvement with pathergia. | Partial response to the treatment with NSAID during attacks and to the maintenance treatment with canakinumab. | Presence of flexion contractures, cataract, optic neuritis and optic nerve atrophy, band keratopathy and impaired vision. Hearing loss. | |
| A439V | 14 | 5 (0-20) |
Continuous -5 |
Persistent presence of urticarial rash (4), arthralgia (3), myalgia (1), oligoarthritis (1). Sometimes presence of aphthous stomatitis (3), headache (2) and fever (1). Moreover presence of persistent (1) and episodic (2) conjunctivitis. | Presence of xerophthalmia and xerostomia (1). Diarrhea (1). | Complete response to the maintenance treatment with anakinra (4) one of them converted to canakinumab with a complete response. | Presence of tinnitus (1). Development of amyloidosis (1). | |
| Recurrent -8 | Two patients present persistent fever. Presence of urticarial rash (8), in some patients only with fever, arthralgia (7), myalgia (3), arthritis (3), conjunctivitis (6), fatigue and malaise (3) and headache (5). | Presence of anterior uveitis and periorbital pain (1). Episodes of uretritis and frequent episodes of UTI (1). | Partial (1) and complete (2) response to the maintenance treatment with anakinra (3). Partial (1) and complete (6) response to the maintenance treatment with canakinumab. One of them discontinued the therapy for diverticulitis. | Development of clubbing (2), bone alterations and frontal bossing (1). | ||||
| Continuous and recurrent (1) | Recurrent fever episodes (12 per year) lasting 5 days. With or without fever, occasional presence of urticarial and maculo-papular rash, arthralgia, myalgia, arthritis, conjunctivitis, malaise and fatigue. | Abdominal pain regardless fever episodes. | Partial response to the treatment with steroids during attacks. Partial response to the maintenance therapy with anakinra. | Development of cataract, glaucoma, hearing loss and peripheric polyneuropathy. | ||||
| N477K | 1 | 2 | Recurrent | Recurrent fever episodes (>24 per year) lasting some hours (<12). With or without fever, occasional presence of urticarial rash, arthralgia, papilledema, generalized lymphadenopathy, hepatomegaly, headache, failure, malaise and mood alterations. Constant presence of splenomegaly. | Occasional thoracic pain without fever. | Complete response to the maintenance treatment with anakinra. | Clubbing and frontal bossing, impaired vision, severe mental retardation and hearing loss. Cardiomyopathy. Delay of puberty. | |
| Y572F | 1 | At birth | Recurrent | Recurrent fever episodes (>24 per year) with urticarial rash, mood disorders and weight loss. | Partial response to NSAIDS during attacks. Complete response to the maintenance treatment with anakinra. | Flexion contractures, hydrocephalus. | ||
| F523C | 1 | 1 | Continuous and recurrent | Recurrent fever episodes (>24 per year) lasting 12-24 hours characterized by the presence of conjunctivitis, headache, fatigue and malaise. Moreover, with or without fever, presence of occasional urticarial rash, arthralgia and myalgia. | Partial response to NSAIDS during attacks. Complete response to the maintenance treatment with canakinumab. | Presence of frontal bossing and clubbing. | ||
| G569R | 1 | 1 m | Recurrent | Recurrent fever episodes (>24 per year) of short length (<12 hours) associated with malaise and fatigue. Moreover, with or without fever, occasional presence of migratory urticarial and maculo-papular rash, arthralgia, conjunctivitis, lymphadenopathy and aseptic meningitis. | Presence of anterior and posterior uveitis, with or without fever. | Failure with NSAIDS during attacks and with the maintenance treatment with steroids. Complete response to the maintenance therapy with anakinra. | Development of hydrocephalus and hearing loss. | |
| Y570F | 1 | 1 m | Continuous | Persistent presence of migratory maculo-papular rash, arthralgia, fatigue, malaise, oligoarthritis, conjunctivitis, papilledema, hepatomegaly and splenomegaly. | Occasional episodes of vomiting. | Partial response to NSAIDS during attacks and to the maintenance therapy with steroids and methotrexate, biphosphonates, cimetidine, rhGH and acetazolamide. Partial response to the maintenance treatment with anakinra, and then with canakinumab. | Optic nerve atrophy and impaired vision. Hearing loss and delayed neuromotor development. | |
| I572F | 1 | At birth | Continuous and recurrent | Recurrent fever episodes lasting 20 days or more. With or without fever, presence of occasional urticarial rash, arthralgia, oligoarthritis, papilledema, hepatomegaly, splenomegaly and headache. | Presence of occasional seizures with or without fever. | Complete response to the maintenance therapy with anakinra and canakinumab. | Bone alterations with frontal bossing, optic nerve atrophy with severe vision impairment, hydrocephalus and hearing loss. Severe mental retardation. Delayed puberty and bone maturation. | |
| E627G | 1 | 3 m | Recurrent | Recurrent episodes, with or without fever, presence of occasional urticarial rash, arthralgia, myalgia, abdominal pain, constipation. | Complete response to the maintenance therapy with anakinra. | |||
| M662T | 2 | 6 m | Continuous and recurrent | Recurrent fever episodes (>24 per year), lasting 5 days, with or without fever, presence of urticarial rash, aseptic meningitis and generalized lymphadenopathy (2). Persistent papilledema (2) and headache (1). | Uveitis anterior, chest pain, pericarditis, erythema nodosum. | Partial response to NSAID or steroids during attacks (1). Partial response to the maintenance treatment with colchicine (1), anakinra (2) or canakinumab (1). Failure with methotrexate or Etanercept (1). | Bone alterations and frontal bossing (2). Hearing loss (2), Moderate optic nerve atrophy, and hydrocephalus (1). | |
| S710C | 1 | 2 | Recurrent | Recurrent fever episodes (2 per year) lasting 7 days, sometimes associated with urticarial and maculo-papular rash, fatigue, malaise, conjunctivitis and LC lymphadenopathy. With or without fever, presence of occasional arthralgia, myalgia, monoarthritis and splenomegaly. | Partial response to the treatment with NSAIDS and steroids during attacks. Partial response to the maintenance treatment with methotrexate and complete response with the maintenance therapy with anakinra and then with canakinumab. | |||
| Ex 9 | L1016F | 1 | 3 m | Continuous | Persistence of fever, urticarial rash, fatigue and weight loss. | Hearing loss. |
| Gene region | Mutation | N° pt | Age at onset (years) | Disease course | Prevalent clinical manifestations (n. of patients) | Less common manifestations (n. of patients) | Treatment response (n. of patients) | Complications (n. of patients) |
| Exon 2 | D12E | 3 | 31 (12-33) | Recurrent | Episodes of fever or low fever of 5-15 days, 10 per year, with arthralgia and myalgia, conjunctivitis and chest pain with pleurisy; the patient with a mutation in the gene MEFV has pericarditis. | Partial response to NSAIDs during the attacks (1 patient). Partial response (1) or deterioration (1) with Colchicine in both. Complete response to maintenance with steroids (except patient with MEFV mutation that responds partially) and with Etanercept (1). | ||
| H22Q | 2 | 0 | Continous and recurrent | Episodes of arthralgia, myalgia, fever of 8 days, 10-16 per year, with periorbital edema, in the context of general malaise and weight loss chronic. | Partial response to Steroids during the attacks. Failure with Colchicine. Complete response to maintenance with Anakinra in both. | |||
| H22R | 3 | 6 (1-8) | Recurrent | Febrile episodes of 12 days, 10 per year, with urticarial rash, myalgia, and conjunctivitis. | Complete response to Steroids during the attacks. Complete response to maintenance with Anakinra. | |||
| C29F | 1 | 10 | Recurrent | Febrile episodes of a week, 3 per year, induced by stress and fatigue with urticarial rash, arthralgia, myalgia. | NSAIDs fail. | |||
| C29Y | 1 | 0 | Recurrent | Febrile episodes of 10 days, 4 per year, with chills at onset, erythematous pharyngitis and painful bilateral cervical lymphadenopathy. | NSAIDs fail. Partial response to Steroids during attacks. Complete response to Canakinumab and Anakinra. | |||
| C30F | 1 | 36 | Recurrent | Febrile episodes of 8 days, very frequent (> 24 year) with aphthous stomatitis, myalgia, abdominal pain, mono/oligo/poliarthritis. | Partial response to maintenance with Colchicine. | |||
| C30R | 4 | 1 (0-1) | Recurrent | Febrile episodes regions of 2-20 days, 1-4 per year, sometimes induced by infection, with abdominal pain (4 patients), arthralgia (3), myalgia (3), diarrhea (3), maculo-papular rash(3) . | Partial response to Steroids (3 patients), Colchicine (2) and Etanercept (3). One patient treated with Anakinra continuously responds completely; one patient responds completely to steroids. | |||
| C30Y | 1 | 2 | Continous and recurrent | Low grade fever with fatigue, malaise and weight loss persisted. Febrile episodes of 10-15 days, 6 per year, stress and travel-induced, onset with chills, maculo-papular rash, arthralgia, myalgia, oligoarthritis, abdominal pain. | Partial response to steroids. Failure with Colchicine as maintenance. | |||
| C33G | 1 | 1 | Recurrent | Episodes of arthralgia, myalgia, periorbital edema and pain, abdominal pain, and fever of 16-20 days, 4 per year, with regular frequency. | A patient with mutations in the MEFV gene: E148Q and M694V. | Partial response to maintenance with Colchicine. Complete response to maintenance with Steroids. | ||
| C33Y | 12 | 7 (0-13) | Recurrent | Febrile episodes of 7 days with varying frequency (from 2 to more than 24 episodes per year) with myalgia (9 patients) and abdominal pain (10). In 50-30% are also present urticarial rash (6), chest pain, conjunctivitis and weight loss (4). | Good response to steroids during the attacks (6 patients) with only one failure. In one patient, partial response to Thalidomide during the attacks. Partial responses (2) or failure (2) to therapy with NSAIDs; with Etanercept more partial responses (4) that complete (1). Complete response to maintaining continued with Anakinra (2). | Three patients developed renal amyloidosis after 40 years. One patient died at age 60 due to sepsis and renal failure. | ||
| Exon 3 | T37I | 2 | 6 (1-9) | Recurrent | Febrile episodes in 5 days, 10 per year, with a maculopapular or urticarial rash, arthralgia, myalgia, abdominal pain, chest pain with pericarditis, pleurisy, pneumonia, persistent cough. | Complete response to maintenance steroid in a patient; in the other, complete response to Anakinra but compliance problems. Initial response to Etanercept and maintenance following failure in both. Partial response with NSAIDs (1) or Colchicine (1). | Persistence of elevated SAA in both. Renal amyloidosis in a patient at age 28. | |
| Y38S | 1 | 0 | Continous and recurrent | Episodes of fever of > 20 days, 3 per year with chills at onset, induced by fatigue, infections, stress, traveling with maculopapular rash and migratory rash, arthralgia, myalgia, periorbital edema with conjunctivitis and diarrhea. Fever or low fever with chronic fatigue and malaise and weight loss. | Patient with mutation V198M in the NALP3 gene. | Partial response to steroids during the attacks. Complete response to Anakinra maintenance. | Renal amyloidosis and nephrotic syndrome at age 76. | |
| L39F | 1 | 6 | Recurrent | Febrile episodes, 12 per year, with arthralgia, myalgia, polyarthritis, abdominal pain with aseptic peritonitis. | Failure with Colchicine. | |||
| D42del | 4 | 5 (1-6) | Continous and recurrent | Febrile episodes of 15 days, 10 per year, with abdominal pain (all patients). In 50-30% of patients: chills at onset, maculo-papular or migratory or urticarial rash, arthralgia, pleuritis with chest pain, headache and periorbital edema, malaise, fatigue and weight loss persistent (2 patients). | Partial response to NSAIDs during the attacks (1 patient). Failure with Colchicine (3). Complete response to Anakinra maintenance (2). Partial response to ongoing maintenance with steroids, Azathioprine or Etanercept (1). | Renal amyloidosis after 40 years (3). One patient died of ESRF in 1982. | ||
| C43G | 1 | 2 | Recurrent | Episodes of fever of > 20 days, 1 per year, with chills at onset (induced by exercise), with myalgia, myositis, fasciitis, oligoarthritis, periorbital edema, abdominal pain with aseptic peritonitis, bilateral cervical lymphadenopathy with pain, scrotal pain, maculo-papular rash. | Seizures. | Partial response to NSAIDs and steroids during the attacks. Failure with Methotrexate and Colchicine. Complete response to Canakinumab. | Laparotomy for peritoneal adhesions at age 12. | |
| C43R | 3 | 1 (0-1) | Recurrent | Febrile episodes of 10 days, 2 per year, with chills at onset (induced by stress, infections, fatigue, exercise), with arthralgia, myalgia, painful periorbital edema and conjunctivitis, abdominal pain, constipation and chest pain. | Ptosis, perianal ulcers. The patient with chronic course presented mild fever, fatigue, malaise, mood disorders and weight loss, and he developed cataract and visual changes at the age of 31. |
Partial response to NSAIDs or steroids during the attacks. Complete response to Anakinra. |
Renal amyloidosis in one patient. | |
| C43S | 1 | 1 | Recurrent | Febrile episodes of 20 days, 4 per year, induced by infection, with urticarial rash, migratory rash, arthralgia, myalgia, abdominal and chest pain. | Partial response to NSAIDs and steroids during the attacks. Partial response to the maintenance with Cimetidine or Etanercept. Complete response to Anakinra. Pain at the site of the injection and gastro-oesophageal reflux esophagitis during the treatement with Etanercept. | |||
| C43Y | 1 | 4 | Recurrent | Episodes of maculo-papular or migratory rash, arthralgia, myalgia, abdominal pain with constipation, fever and aseptic peritonitis of 8 days, 3 per year. | NSAIDs failed. Partial response to steroids and Colchicine during the attacks. Partial response to the maintenance with Etanercept and Anakinra. | Peritoneal adhesions and occlusions over 35 years. Renal amyloidosis at age 41. Renal failure at age 52. | ||
| T50K | 2 | 2 | Continous and recurrent | Febrile episodes of 10 days, 4 or > 24 per year, with arthralgia and myalgia. Fever, fatigue and malaise were chronic. | Partial response to Etanercept or Colchicine, complete response to steroids. | |||
| T50M | 16 | 6 (0-41) | Recurrent | Febrile episodes of 10 days, 5 per year, with myalgia (12), arthralgia (11), abdominal pain (11). 50-30% of patients presented bilateral cervical lymphadenopathy (7) or chest pain (6). | A patient with chronic fatigue and malaise. | Partial response to steroids or NSAIDs during the attacks (5). NSAIDs treatement failed in 2 patients. 3 patients responded completely to steroids, 2 partially. Complete response with the maintenance with Anakinra (3) or Canakinumab (1). 2 patients presented a complete response to Etanercept, 2 partial. Tonsillectomy failed (2). |
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| C52Y | 5 | 3 (0-11) | Recurrent | Febrile episodes of 11 days, 7 per year, with painful periorbital edema with conjunctivitis (4), arthralgia, myalgia and abdominal pain (3). Two patients presented chills at the onset or constipation. | NSAIDs fail (1 patient). Response to maintenance with steroids is partial (2) or complete (1). One patient responds completely to steroids. Fail Colchicine (3) or Methotrexate (1) as maintenance. Partial response (1) or complete (1) to Etanercept but with skin reactions in injection site. Complete response to the maintenance with Anakinra (2) and Canakinumab (1). | Amyloidosis with renal failure after 33 years (2 patients). In a patient paroxysmal atrial fibrillation at age 45. | ||
| C55Y | 4 | 3 (1-18) | Recurrent | Episodes of fever or low fever of 20 days, 4 per year, with arthralgia, myalgia, abdominal pain (3 patients). In 50-30% of patients the febrile 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 patients) and complete (2) or partial (1) to steroids during the attacks. Colchicine fail. Complete response to maintenance with Anakinra (2). A patient with complete response to maintenance ith Infliximab and appendectomy. | |||
| S59P | 1 | 49 | Recurrent | Febrile episodes of 6 days, 3 per year, associated with maculo-papular and migratory rash, arthralgias and myalgias, splenomegaly, pericarditis, chest pain, pleurisy, pneumonia, persistent cough. | Partial response to maintenance with steroid. | Osteoporosis at age 62. | ||
| F60L | 2 | 1 e 6 | Recurrent | Febrile episodes of > 20 days, 3 per year, with chills at onset, urticarial rash, arthralgia, abdominal pain. | A patient presented delayed puberty and bone growth. | Complete response to NSAIDs or steroids during the attacks. Complete response to the maintenance with Anakinra. |
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| T61N | 2 | 0 | Recurrent | Febrile episodes associated with chills at onset, maculopapular rash, arthralgia, myalgia and abdominal pain. | Response to NSAIDs and steroids during the attacks. | |||
| N65I | 2 | 0 | Recurrent | Febrile episodes associated with myalgia, migratory rash, conjunctivitis, abdominal pain and painful generalized lymphadenopathy. | Swelling and erythema with socks distribution. | |||
| H66L | 1 | 0 | Recurrent | Febrile episodes of 3 days, 21 per years with bilateral lymphadenopathy. | Steroids were ineffective. | |||
| L67P | 1 | 0 | Recurrent | Febrile episodes of > 20 days, 3 per year, associated with chills at onset (induced by stress and vaccinations), pseudofolliculitis, migratory, urticarial or maculopapular rash, erythematous pharyngitis, arthralgia, oligoarthritis, abdominal pain with vomiting, chest pain, headache, conjunctivitis. | Partial response to NSAIDs or steroids during the attacks. | |||
| H69fs | 1 | 1 | Recurrent | Febrile episodes of of 12-24 hours, 12 per years, associated with urticarial rash, arthralgia, myalgia, conjunctivitis, periorbital and abdominal pain. | Complete response to NSAIDs during the attacks and failure with steroids. Partial response to maintenance with Sulfasalazine. | |||
| C73R | 1 | 0 | Recurrent | Febrile episodes of 10 days, 14 per year, with arthralgia, myalgia, abdominal pain with constipation. | Partial response to NSAIDs and complete to steroids during the attacks. | |||
| C73W | 2 | 3 (2-4) | Continous | Myalgia and abdominal pain. | Complete response to NSAIDs during the attacks. Maintenance therapy with colchicine. |
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| Exon 4 | C88Y | 1 | 7 | Recurrent | Febrile episodes, 2 per year, with chills at onset and abdominal pain. | Complete response to maintenance with steroid. | ||
| R92P | 1 | 19 | Recurrent | Episodes of fever > 20 days with arthralgia, myalgia, abdominal pain with constipation, chest pain with pleurisy. | Abscesses in the groin, armpits, vulva and back after 50 years. | Partial response to steroids as maintenance. Failure with Azathioprine. Complete response to Anakinra as maintenance. |
Renal amyloidosis. | |
| V95M | 2 | 31 (30-32) | Recurrent | Febrile episodes of 11 days, 6 per 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 (2). Complete response to Anakinra (1). |
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| C96Y | 1 | 30 | Recurrent | Episodes of conjunctivitis, fever and oligoarthritis with pleurisy. | Partial response to maintenance with Colchicine. | |||
| Y103_R104del | 1 | 25 | Recurrent | Episodes of fever or fever of 7 days, 4 per year, associated with chest pain and pericarditis. | Partial response to NSAIDs, steroids and Colchicine. Complete response to Etanercept. | |||
| E109A | 2 | 42 e 1 | Recurrent | In patients with child onset, febrile episodes of 3 days, 17 per year with erythematous pharyngitis, cervical lymphadenopathy and periorbital edema. The patient with adult onset presented headache and myalgia assocated with febrile episodes induced by stress. | Patients with child onset presented a partial response to the maintenance with Colchicine. | |||
| C114W | 1 | 38 | Recurrent | Episodes of fever of 8 days, 4 per year, induced by menstruation, with erythematous or exudative pharyngitis, vomiting, abdominal pain and constipation. | Patients with mutations in the gene MEFV: E148Q and P369S. | |||
| N116S | 1 | 21 | Recurrent | Febrile episodes of 5 days, 3 per year, induced by stress, arthralgia, myalgia, abdominal pain and diarrhea. | Partial response to NSAIDs during the attacks. | |||
| Exon 6 | L167_G175del | 1 | 6 | Recurrent | Febrile episodes of 5 days, 2 per year, with chills at onset, induced by fatigue, associated with erythematous pharyngitis, arthralgia, myalgia, periorbital edema with pain, conjunctivitis, nausea and abdominal pain with alternating alvus, bilateral cervical painful lymphadenopathy. | Complete response to maintenance with steroids. Partial response to maintenance with Anakinra. | At age 18 renal amyloidosis. At 24 renal transplant with increased episodes. |
| Disease | Gene region | First variant | Second variant | N° pt | Age at onset (years) | Disease course | Prevalent clinical manifestations (n. of patients) | Less commonmanifestations (n. of patients) | Treatment response (n. of patients) | Complications (n. of patients) |
| FMF | Exon 2 | S141I | - | 1 | 7 | Recurrent | Fever episodes of 1 days, 2 per year, with abdominal pain. | Complete response to Steroids or NSAID. | ||
| E148V | - | 1 | 7 | Recurrent | Fever episodes of 3 days, with myalgia, arthralgia, mono/oligo/poliarthritis with tenosynovitis, abdominal pain. | Partial response to NSAID during attacks. Complete response to cochicine. | ||||
| E148Q | E148Q | 1 | 6 | Recurrent | Fever episodes of 2 days, more than 24 fir year, with abdominal and chast pain, vomiting, diarrhea, gastrointestinal bleeding, fatigue, malaise and weight loss. | Complete response to steroids during attacks. | ||||
| - | 7 | 5 (0-11) | Recurrent | Fever episodes of 4 days, monthly, with abdominal pain (6), arthralgia (5), myalgia, weight loss (4), vomiting (3). | Enlarged cervical lymphonodes, exudative pharyngitis, urticarial rash, oligoarthritis, orchitis/gonadal pain (2), aphtous stomatitis, palpable purpura, diarrhea, chest pain, persistent cough, headache, seizures, vulvovaginitis, monoarthritis, conjunctivitis (1) | Response to NSAIDs partial (1) or complete (1), as steroids (respectively 1 and 2). Colchicine failed in 2 patients as maintenance therapy: complete and partial response in other 2 patients. Complete response to canakinumab in one patient. Methotrexate failed in one patient. | ||||
| E148V | 1 | 0 | Continuos and recurrent | Fever episodes of 3 days with aphtous stomatitis, ulcers at genitalia, arthralgia associated with monoarthitis and abdominal pain with vomiting, diarrhea or costipation. Chronic fever and weight loss. | During the attacks, partial response to NSAIDs. Partial response to maintenance with colchicine, cimetidine or steroids. Cotrimoxazole and immunoglobulin infusions failed. | |||||
| R202Q* | 1 | 12 | Recurrent | Fever episodes of 11-15 days, 12 per year, withvomiting, chest pain, headache, arthralgia, mylagia, fatigue and malaise. | Complete response to colchicine. | |||||
| P369S | 1 | 4 | Recurrent | Fever episodes of 2 days, mone then 24 per year, with abdominal pain, arthralgia and maculo-papular rash. | Complete response to steroids during attacks. | |||||
| R202Q* | R202Q* | 2 | 10 (8-11) | Recurrent | Fever or low fever episodes of 7 days, monthly, with exudative pharyngitis (2), palmo-plantar erythema, myalgia, abdominal pain with diarrhea, vomiting, chills at fever onset, fatigue, malaise(1). | During the attacks, complete response to NSAIDs or steroids (1). Partial response to colchicine as maintenance therapy (1). | ||||
| - | 4 | 4 (1-8) | Recurrent | Fever episodes of 4 days, 12 per year, with abdominal pain (4) with vomiting or diarrhea, fatigue, chills at fever onset with mood disorders (3), aphtous stomatitis, exudative pharyngitis, malaise, arthalgia, enlarged cervical lymphonodes (2). | Enlarged generalized and painful lymphonodes, myalgia, bone pain and bone age delay (1). | During the attacks, complete or partial response to NSAIDs or steorids. Partial response to colchicine as maintenance therapy (1), failed in one patient.Partial response to anakinra (1). | ||||
| P180R | 1 | 3 | Continuos and recurrent | Fever or low fever episodes of 2 days, 20 per year, with regular pattern, maculo-papular or urticarial rash, arthralgia, mono/oligo/polyarthritis and headache. | Partial response to maintenance with steroids or cochicine. Methotrexate failed. | |||||
| Exon 3 | P369S | - | 1 | At birth | Recurrent | Fever episodes without a specific pattern of recurrency, with abdominal pain, diarrhea, aphtous stomatitis, erythematous pharyngitis, arthralgia, myalgia, monoarthritis, conjunctivitis | Complete response to NSAIDs during attacks. | |||
| R408Q | 1 | 8 | Recurrent | Long fever episodes of more then 20 days, with urticarial and migratory rash, arthralgia, myalgia, oligo/poliarthritis, tenosynovitis, | NSAIDs failed during attacks. Complete response to steroids on-demand and anakinra as maintenance therapy. | |||||
| Exon 5 | D510D | - | 2 | 4 (3-5) | Recurrent | Fever episodes of 2 days, 4-24 per year, with chills at fever onset, athralgia and abdominal pain (2), headache, constipation, arthralgia, myalgia, exudative pharyngitis, maculo-papular rash, fatigue (1). Triggers: cold or fatigue(1). | Complete response to steroidsduring attack (1) or canakinumab as maintenance therapy (1). | Neurosensorial hearing loss (1). | ||
| Exon 9 | I591T | - | 1 | 13 | Recurrent | Fever episodes of 4 days, 15 per year, with abdominal and chest pain, urticarial rash, oligoarthritis, headache, arthralgia, myalgia, fatigue and malaise. | Partial response to colchicine as maintenance therapy. | |||
| Exon 10 | I641F | - | 2 | 3 (0-5) | Recurrent | Fever episodes of 2-3 days characterized by constipation, enlarged cervical lymphonodes, abdominal pain (2), chest pain, pleurisy, hepatosplenomegaly, vomiting, chills, monoarthritis, arthralgia and headache (1). Triggers: muscolar exercise (1). | During the attacks, partial response to NSAIDs (1). Complete response to colchicine (2). | |||
| M680IGC | - | 5 | 3 (0-8) | Recurrent | Fever episodes of 3 days, 14 per year with abdominal pain (4), arthralgia, myalgia, (3) and vomiting (2). | Exudative pharyngitis, chills, constipation, diarrhea, chest and bone pain, myositis (1). Stress and menstration are triggers of episodes. | Response to NSAID complete (1), partial (2) or fail (1). Tonsillectomy fail (1). Complete (3) or partial (1) response to colchicine. | |||
| M680L | - | 2 | 2 | Recurrent | Fever episodes of 1-2 days, >24 per year, with regular pattern associated with diarrhea (1) and abdominal pain (2). | Complete response with colchicine maintenance (1) or during attacks (1). | ||||
| M694I | - | 1 | 0 | Recurrent | Fever episodes of 2 days, >24 per year, with chills at onset, associated with aphtous stomatitis, exudative pharyngitis with enlarged cervical bilateral and generalized lymphonodes, maculopapular rash, arthralgia, monoarthritis, chest pain, headache, costipation and abdominal pain. | Complete response to maintenance with colchicine. | ||||
| M694V | - | 48 | 3 (0-36) | Recurrent | Fever episodes of 3 days, 11 per year, with abdominal pain (42), arthralgia (27), myalgia (23), chest pain (16) and diarrhea (15). | Vomiting (12), costipation (10), monoarthritis (7), erysipelas like erythema, headache (6), enlargement generalized and/or cervical painful lymphonodes, exudative pharyngitis (4), gastrointestinal ulcers, aseptic peritonitis, persistent cough, aphtous stomatitis, headache in the morning (3), palpable porpora, bone pain, pericarditis, pleuritis, maculopapular rash (2), GI bleeding, oligoarthritis, poyarthritis, migratory or urticarial rash, psoriasis, pneumonia, conjunctivitis, oligoarthritis, periorbital pain and seizures (1). | Response to NSAIDs partial (11) or complete (6). Response to Steroids partial (4) or complete (7). Response to colchicine partial (17), complete (22). Response to anakinra complete (2) or partial (2). Response to canakinumab complete (1). Tonsillectomy failed (1) | Occlusion, peripheral neuropathy, cerebellar syndrome, megalocephaly (1) | ||
| K695R | - | 4 | 7 (3-12) | Recurrent | Fever episodes of 9 days, 12 per year, with abdominal pain, mono/oligoarthritis, myalgia, generalized enlargement of lymphonodes(3), arthralgia, vomiting, headache, chest pain, fatigue, malaise(2). | Exudative pharyngitis, erysipelas-like and perioral erythema, herpetiform dermatitis, bone pain, hepatosplenomegaly, aseptic peritonitis diarrhea, gonadal pain (1). Triggered by stress or fatigue (1). | Partial response to NSAIDs(1) or steroids (2) during attacks. Steroids failed in one patient. Complete response to methotrexate (1).Complete response to colchicine as maintenance therapy (2) or anakinra (1). | |||
| V726A | - | 2 | 21 (12-30) | Recurrent | Fever episodes of 1-2 days, 14 per year, with arthralgia and abdominal pain (2). | Aphtous stomatitis, exudative pharyngitis, erythematous pharyngitis, urticarial rash, myalgia, bone pain, diarrhea, painful enlarged cervical lymphonodes, urethritis/cistitis, headache and vertigo (1). | Complete response to colchicine (2). | |||
| A744S | - | 2 | 2 (1-3) | Recurrent | Fever episodes of 3 days, 4-5 per year, with abdominal pain, wight loss (2),arthralgia, myalgia, diarrhea, vomiting, exudative pharyngitis, aphtous stomatitis, enlarged cervical lymphadenopathy, seizures, fatigue and malaise (1). | Partial response to NSAIDs or steroids during attacks (1). Complete (1) or partial (1) response to colchicine as maintenance therapy. | ||||
| R761H | - | 3 | 7 (1-13) | Recurrent | Fever or low fever episodes of 3 days, 11 per year, with arthralgia, myalgia (3), generalized painful enlargement of lymphonodes, headache (2), constipation, mono/oligoarthritis, abdominal pain, chest pain, seizure, fatigue, malaise and wight loss(1). | Partial response to NSAID (2) or steroids (2) during attacks. Partial response to methotrexate (1). Complete response to colchicine (1) or steroids (1). Tonsillectomy failed (1). | - | |||
| MKD | Exon 2 | H20Q | - | 1 | 2 m | Continous and recurrent | Recurrent fever episodes (12 per year, lasting 4 days) with lymphadenopathy, fatigue, malaise and mood disorders. Occasional episodes of vomiting, abdominal pain, diarrhea, gastrointestinal bleeding, perianal ulcers, maculo-papular and migratory rash, myalgia with or without fever. | Persistent constipation, polyarthritis and occasional myositis and tenosynovitis with or without fever. | Partial response to steroids, biphosphonates and anakinra on-demand. Failure with NSAIDS on-demand. Partial response to maintenance therapy with etanercept. Failure with methotrexate and cyclosporine | Bone alterations and deformity, flexion contractures and osteoporosis. |
| Exon 5 | P165L | - | 1 | 6 | Recurrent | Recurrent fever episodes, lasting on the average 5 days. Occasional episodes of palpable purpura, arthralgia, myalgia, vomiting, abdominal pain, diarrhea and lymphadenopathy with or without fever. | Occasional episodes of urethritis/cystitis with or without fever. | Partial response to NSAIDS on-demand. | ||
| Exon 7 | R215X | - | 1 | 2 | Recurrent | Recurrent fever episodes (on the average 5 per year, lasting more than 20 days) with lymphadenopathy and persistent arthralgia, myalgia and polyarthritis. | Partial response to the maintenance treatment with NSAIDS. | |||
| Exon 11 | V377I | - | 11 | 3 | Recurrent | Presence of recurrent fever episodes (on the average 9 per year, lasting 5 days), with exudative (1) or erythematous pharyngitis (4), maculo-papular rash (4), aphthous stomatitis (1), arthralgia (6), myalgia (7), arthritis (4), vomiting (9), abdominal pain (10), diarrhea (10), lymphadenopathy (10), headache (4), fatigue, malaise (7) and mood disorder (1). Occasional episodes of palpable purpura (2), erythema nodosum (1), aseptic peritonitis (1), pericarditis during the fever episodes. Hepatomegaly (1), splenomegaly (2), panniculitis (1), persistent cough (1) and perianal ulcers (1) were reported with or without fever. | 3 patients presented episodes of erythematous and itchy rash, during fever episodes (1) or not (2). One patient presented recurrent pericarditis. | Partial response to NSAID (8). Partial (1) or complete (4) response to stereoids and partial (4) or complete (1) response to anakinra on-demand. Failure or partial response to statins (1). Failure with the maintenance therapy with colchicine (2), partial response with etanercept (1) or anakinra (1). | Peritoneal adhesions (1). | |
| TRAPS | 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. | |
| c.194-15C>T | - | 1 | 4 | Recurrent | Episodes of aphthous stomatitis, myalgia, abdominal pain, fatigue, fever or low fever with cervical unilateral lymphadenopathy for 9 days, 2 per year. | Maintenance with steroids with partial effect and with increased weight. | Renal failure at age 15. | |||
| Intron 4 | c.472+6C>T | - | 2 | 43 e 6 | Recurrent | Febrile episodes of 10-20 days or more, 10-6 per year, with arthralgia, myalgia, abdominal and chest pain. | NSAIDs and Colchicine fail (1 patient). Partial response to Etanercept in both. | |||
| Intron 6 | c.626-32G>T | - | 1 | 2 | Recurrent | Febrile episodes of 5 days, 10 per year, with chills at onset, maculo-papular rash, arthralgia, myalgia, abdominal pain, aseptic peritonitis, vomiting, diarrhea, chest pain, testicular pain and pericarditis. | Appendectomy at age 32. Partial response to NSAIDs and Steroids. Failure with colchicine. | |||
| Exon 3 | P46L | - | 5 | 6 (2-63) | Recurrent | Episodes of fever > 7 days, 7 per year, with urticarial rash and myalgia. 50-30% of patients had erythematous pharyngitis, maculopapular rash, arthralgia, abdominal pain, headache. | Individual patients had swelling of the scalp, cranial nerve palsy, mental retardation, urethritis/cystitis. A patient with continuous course with fever, fatigue, malaise and weight loss persistent. |
A patient with partial response to steroids during the attacks, a patient with complete response to steroid but insomnia. One patient failed therapy with Etanercept, after initial improvement, with epistaxis and headache. The patient with continuous course presents a partial response to treatment with NSAIDs. |
A patient presented renal amyloidosis at the age of 20. | |
| Exon 4 | R92Q | - | 53 | 8 (0-53) | Recurrent | Febrile episodes of 10 days, 7-8 per year, without seasonal changes without regular frequency, arthralgia (37), myalgia (35), abdominal pain (34). 50-30% patients presented chills and headache at the onset (20, 3 in the morning only). |
Papable purpura, chronic rhinitis, visual changes, occlusion, arterial/venous thrombosis and left arm paresthesia, cardiomyopathy (1). 5 patients (10%) had chronic course with fever, fatigue, malaise and weight loss. |
During the attacks, 9 patients treated with steroids responded fully, 11 partially, one fail; 10 partially respond to NSAIDs, 2 fail. One patient presented a complete response during attacks to infliximab, another patient presented partial response to colchicine. Complete response to the maintenance with anakinra (3) or etanercept (6) or steroids (3); partial response to anakinra (1), azathioprine (1), aspirin with Tigecycline (1), etanercept (6), steroids (2) and NSAIDs (5). Partial (2) or complete (1) response to tonsillectomy. Three patients presented osteoporosis during the chronic treatment with steroids. One patient presented a sepsis due to Streptococcus pneumoniae during the treatment with Etanercept. |
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| CAPS | Exon 3 | Q703K* | - | 9 | 16 (0-57) |
Continuous (3) | Presence of urticarial rash, arthralgia, fever, conjunctivitis (2) and malaise or mood alterations (1). | Maculo-papular or eczmatous rash (1), myalgia (1), aphtous stomatitis (1) and headache (1). | Partial response to NSAID during attacks (1). Complete response to the maintenance treatment with anakinra or canakinumab. | Cranial neuropathy (1). |
| Recurrent (6) | Febrile episodes (4, on the average 9 per year, lasting 4 days), with maculo-papular or urticarial rash (4), palpable purpura (2), arthro-myalgia (4), weight loss (3), erythematous pharyngitis, sometimes exudative, aphthous stomatitis, headache, periorbital oedema and conjunctivitis (2). Recurrent episodes without fever (2). | Abdominal pain, diarrhea, urethritis/cystitis (1). Chest pain (1). | Partial response to NSAID (5) during attacks. Failure with the maintenance therapy with colchicine. Failure with the adenotonsillectomy. One patient has been treated with steroids as maintenance with complete response. |