Table 6.
Patients with an incomplete or not confirmatory genotype
| Disease | Gene region | First variant | Second variant | N° pt | Age at onset (years; average, range) | 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) |
|---|---|---|---|---|---|---|---|---|---|---|
| FMF | Exon 2 | S141I | – | 1 | 7 | Recurrent | Fever episodes of 1 day, 2/year, with abdominal pain. | Complete response to steroids or NSAIDs. | ||
| E148V | – | 1 | 7 | Recurrent | Fever episodes of 3 days, with myalgia, arthralgia, mono/oligo/poliarthritis with tenosynovitis, abdominal pain. | Partial response to NSAID on demand. Complete response to cochicine. | ||||
| E148Q | 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. | Ppartial response to NSAIDs on demand. Partial response to colchicine, cimetidine or steroids as maintenance therapy. Cotrimoxazole and infusions of immunoglobulins failed. | |||||
| E148Q | – | 7 | 5 (0–11) | Recurrent | Fever episodes of 4 days, 12/year, with abdominal pain (6), arthralgia (5), myalgia, weight loss (4) and 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) | Partial (1) or complete (1) response to NSAIDs or steroids. Complete (1) or partial (1) response to colchicine as maintenance therapy that failed in two patients. Complete response to canakinumab (1). Methotrexate failed (1). | |||
| E148Q | 6 | 2 (1–10) | Recurrent | Fever (3) or low fever (6) episodes of 2–3 days, 16/year, with abdominal pain (5), myalgia, arthralgia (4), vomiting, diarrhea (3), generalized lymphonodes enlargement and chest pain (2). | Aphtous stomatitis, monoarthitis, acne, pseudofolliculitis, enlarged cervical lymphonodes, flexon contractures, osteolytic lesions and sacroileitis, hepatomegaly and splenomegaly, pericarditis, headache, urethritis/cititis, gonal pain, epidydimitis and weight loss (1). | Partial response to NSAIDs (2). Steroids failed as maintenance therapy (1). Complete response to azathioprine or colchicina or sulphalazine and methotrexate (1). | ||||
| R202Qa | 1 | 40 | Recurrent | Low fever episodes of 2 days, 10/year, with aphtous stomatitis, arthralgia, myalgia, generalized lymphonodes enlargement, hepatosplenomegaly and chest pain. | Partial response to NSAIDs on demand. Complete response to colchicine as maintenance therapy. | |||||
| P369S | 3 | 3 (2–10) | Recurrent | Fever or low fever episodes of 4 days, 12/year, with regular pattern and chills at fever onset, abdominal pain, myalgia, arthralgia, vomiting and diarrhea (3). | Poliarthritis or bone pain (1). | Partial response to NSAIDs on demand (2). Partial response to steroids as maintenance therapy (2). Complete response to colchicine (3). | ||||
| P180R | R202Qa | 1 | 3 | Continuos and recurrent | Fever or low fever episodes of 2 days, 20/year, with regular pattern, characterized by maculo-papular or urticarial rash, arthralgia, mono/oligo/polyarthritis and headache. | Partial response to steroids or cochicine as maintenance therapy. Methotrexate failed. | ||||
| R202Q^ | – | 4 | 4 (1–8) | Recurrent | Fever episodes of 4 days, 12/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). | Painful enlarged generalized lymphonodes, myalgia, bone pain and bone age delay (1). | Complete or partial response to NSAIDs or steorids. Partial response to colchicine as maintenance therapy (1), that failed in one patient. Partial response to anakinra (1). | |||
| M694 V | 7 | 9 (4–30) | Recurrent | Fever episodes of 2 days, 8/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). | Partial (3) or complete (1) response to NSAIDs on demand. Partial (1) or complete (1) response to steroids. Complete response to colchicine as maintenance therapy. | ||||
| 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 on demand. | |||
| R408Q | 2 | 46 (25–67) | Recurrent | Fever episodes of 2–3 days, 8/year, with chills, athralgia, myalgia (2), chest pain, pericarditis, pleurisy, erythematous pharyngitis, erysipelas-like erythema, conjuntivitis, vomiting, abdominal pain and diarrhea (1). | Partial response to NSAIDs on demand. Steroids failed. Complete or partial response to colchicine. | |||||
| A744S | 1 | 8 | Recurrent | Fever episodes of 4 days, 3/year, stress and travel induced, with exudative pharyngitis and arthralgia. | Partial response to NSAIDs on demand. Partial response to colchicine as maintenance therapy. | |||||
| Exon 5 | D510D | – | 2 | 4 (3–5) | Recurrent | Fever episodes of 2 days, 4–24/year, induced by cold and fatigue (1), with chills at fever onset, athralgia and abdominal pain (2), headache, constipation, arthralgia, myalgia, exudative pharyngitis, maculo-papular rash, fatigue (1). | Complete response to steroids on demand (1) or canakinumab as maintenance therapy (1). | Neurosensorial hearing loss (1). | ||
| Exon 9 | I591T | – | 1 | 13 | Recurrent | Fever episodes of 4 days, 15/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). | Partial response to NSAIDs on demand (1). Complete response to colchicine (2). | |||
| M680IGC | – | 5 | 3 (0–8) | Recurrent | Fever episodes of 3 days, 14/year with abdominal pain (4), arthralgia, myalgia, (3) and vomiting (2). | Exudative pharyngitis, chills, constipation, diarrhea, chest and bone pain and myositis (1). Fever episodes were induced by stress or menstrations (1). | Complete (1) or partial (2) response to NSAIDs on demand that failed in one patient. Non response to tonsillectomy (1). Complete (3) or partial (1) response to colchicine. | |||
| M680 L | – | 2 | 2 | Recurrent | Fever episodes of 1–2 days, >24/year, with regular pattern, associated with abdominal pain (2) and diarrhea (1). | Complete response to colchicine as maintenance therapy (1) or on demand (1). | ||||
| M694I | – | 1 | 0 | Recurrent | Fever episodes of 2 days, >24/year, with chills at onset, associated with aphtous stomatitis, exudative pharyngitis with bilateral cervical or generalized enlarged lymphonodes, maculopapular rash, arthralgia, monoarthritis, chest pain, headache, costipation and abdominal pain. | Complete response to colchicine as maintenance therapy. | ||||
| M694 V | – | 48 | 3 (0–36) | Recurrent | Fever episodes of 3 days, 11/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), gastrointestinal bleeding, oligoarthritis, poyarthritis, migratory or urticarial rash, psoriasis, pneumonia, conjunctivitis, oligoarthritis, periorbital pain and seizures (1). | Partial (11) or complete (6) response to NSAIDs. Partial (4) or complete (7) response to steroids. Partial (17) or complete (22) responseo to colchicine. Complete (2) or partial (2) response to anakinra. Complete response to canakinumab (1). Tonsillectomy failed (1) | Occlusion, peripheral neuropathy, cerebellar syndrome, megalocephaly (1). | ||
| K695R | – | 4 | 7 (3–12) | Recurrent | Fever episodes of 9 days, 12/year, with abdominal pain, mono/oligoarthritis, myalgia, generalized enlargement of lymphonodes (3), arthralgia, vomiting, headache, chest pain, fatigue and malaise(2). | Exudative pharyngitis, erysipelas-like and perioral erythema, herpetiform dermatitis, bone pain, hepatosplenomegaly, aseptic peritonitis diarrhea and gonadal pain (1). Fever episodes were induced by stress or fatigue (1). | Partial response to NSAIDs (1) or steroids (2) on demand. Steroids failed (1). Complete response to methotrexate (1). Complete response to colchicine (2) or anakinra (1) as maintenance therapy. | |||
| V726A | – | 2 | 21 (12–30) | Recurrent | Fever episodes of 1–2 days, 14/year, with arthralgia and abdominal pain (2). | Aphtous stomatitis, exudative pharyngitis, urticarial rash, erythematous pharyngitis, 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/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 on demand (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/year, with arthralgia, myalgia (3), generalized painful enlargement of lymphonodes, headache (2), constipation, mono/oligoarthritis, abdominal pain, chest pain, seizure, fatigue, malaise and weight loss(1). | Partial response to NSAIDs (2) or steroids (2) on demand. Complete response to colchicine (1) or steroids (1). Partial response to methotrexate (1). NO response to tonsillectomy (1). | – | |||
| MKD | Exon 2 | H20Q | – | 1 | 2 m | Continous and recurrent | Fever episodes of 4 days, 12/year, with lymphadenopathy, fatigue, malaise and mood disorders. Occasional 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. On-demand NSAIDs failed. Partial response to etanercept as maintenance therapy. Methotrexate and cyclosporine failed. | Bone alterations and deformity, flexion contractures and osteoporosis. |
| Exon 5 | P165L | – | 1 | 6 | Recurrent | Fever episodes of 5 days. Occasional palpable purpura, arthralgia, myalgia, vomiting, abdominal pain, diarrhea and lymphadenopathy with or without fever. | Occasional urethritis/cystitis with or without fever. | Partial response to NSAIDs on-demand. | ||
| Exon 7 | R215* | – | 1 | 2 | Recurrent | Fever episodes of 20 days, 5/year, with lymphadenopathy and persistent arthralgia, myalgia and polyarthritis. | Partial response to NSAIDs as maintenance therapy. | |||
| Exon 11 | V377I | – | 11 | 3 | Recurrent | Fever episodes of 5 days, 9/year, with abdominal pain, diarrhea, lymphadenopathy (10), vomiting (9), fatigue, myalgia, malaise (7), arthralgia (6), arthritis (4), exudative (1) or erythematous pharyngitis, maculo-papular rash, headache, aphthous stomatitis, and mood disorder (1). Occasional episodes of palpable purpura (2), erythema nodosum, aseptic peritonitis, pericarditis (1) during the fever episodes. Splenomegaly (2), hepatomegaly, panniculitis, persistent cough and perianal ulcers (1) with or without fever. | Episodes of erythematous and itchy rash during fever episodes (1) or without fever (2). Recurrent pericarditis (1). | 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). colchicine failed (2). Partial response to etanercept (1) or anakinra (1). | Peritoneal adhesions (1). | |
| TRAPS | Intron 2 | c.194-15C > T | – | 1 | 4 | Recurrent | Fever or low fever episodes of 9 days, 2/year, with aphthous stomatitis, myalgia, abdominal pain, fatigue and cervical unilateral lymphadenopathy. | Partial response to steroids as maintenance therapy. | Renal failure at the age of 15 years. | |
| Intron 4 | c.472 + 6C > T | – | 2 | 43 e 6 | Recurrent | Fever episodes of 10–20 days or more, 6–10/year, with arthralgia, myalgia, abdominal and chest pain. | NSAIDs and colchicine failed (1). Partial response to etanercept (2). | |||
| Intron 6 | c.626-32G > T | – | 1 | 2 | Recurrent | Fever episodes of 5 days, 10/year, with chills at the onset, and maculo-papular rash, arthralgia, myalgia, abdominal pain, aseptic peritonitis, vomiting, diarrhea, chest pain, testicular pain and pericarditis. | Partial response to NSAIDs and steroids. Colchicine failed. | Appendectomy at the age of 32 years. | ||
| Exon 3 | P46L | – | 5 | 6 (2–63) | Recurrent | Fever episodes of >7 days, 7/year, with urticarial rash and myalgia. 50–30% of patients had erythematous pharyngitis, maculopapular rash, arthralgia, abdominal pain, headache. | Swelling of the scalp, cranial nerve palsy, mental retardation, urethritis/cystitis (1). Persistent fever, fatigue, malaise and weight loss (1). | Complete (1) or partial (1) response to steroids on demand. Etanercept failed (1). Partial response to NSAIDs (1). | Renal amyloidosis at the age of 20 years (1). | |
| Exon 4 | R92Q | – | 53 | 8 (0–53) | Recurrent | Fever episodes of 10 days, 7–8/year, without seasonal changes or regular frequency, with arthralgia (37), myalgia (35), abdominal pain (34). 50–30% patients presented chills and headache at the onset (20), three patients only during the morning. | Papable purpura, chronic rhinitis, visual changes, occlusion, arterial/venous thrombosis and left arm paresthesia, cardiomyopathy (1). Five patients (10%) had chronic course with fever, fatigue, malaise and weight loss. | Complete (9) or patial (11) response to steroids on demand, that failed in one patient. Partial response to NSAIDs (10), that failed in 2 patients. Complete response to infliximab (1) or partial response to colchicine (1) on demand. Complete response to anakinra (3) or etanercept (6) or steroids (3) as maintenance therapy. Partial response to etanercept (6), NSAIDs (5), steroids (2), anakinra or azathioprine or aspirin with tigecycline (1). Partial (2) or complete (1) response to tonsillectomy. | Osteoporosis (3). Sepsis due to Streptococcus pneumoniae during the treatment with etanercept (1). | |
| CAPS | Exon 3 | V198 M | – | 18 | 10 (0–45) | Continuous (5) | Presence of arthralgia (5), urticarial rash and myalgia (4). | Occasional episodes of fever (3), maculo-papular rash, palmo-plantar erythema, vomiting, lymphadenopathy and pericarditis (1). Presence of polyarthritis, tenosynovitis, fatigue and conjunctivitis (1). Persistent fever (1). | Partial response to NSAIDs on-demand (1). Partial response to steroids as maintenance therapy (1). Partial response to methotrexate, cyclosporine, infliximab, etanercept, adalimumab, sirolimus and mycophenolate mofetil (1). Complete response to tocilizumab and bisphosphonates as maintenance therapy (1). Partial (1) or complete (3) response to anakinra, which failed in one patient. | Hearing loss (2). Osteoporosis, osteolytic lesions, bone erosions, hyperostosis and bone deformity, cataract, amyloidosis, arterial hypertension, delayed puberty (1). |
| Recurrent (10) | Episodes, 12/year, induced by cold (3), sometimes with fever, characterized by arthralgia (9), urticarial or maculo-papular rash (8), oligo/monoarthritis, conjunctivitis (7), headache, malaise, fatigue (6), weight loss, myalgia (5), lachrymal gland involvement, periorbital pain and lymphadenopathy (3). | Occasional bone pain, abdominal pain or polyarthritis (1). | Failure (1) or partial (3) response to NSAIDs on demand. Partial response to steroids (3) on-demand. Methotrexate (2), etanercept or cyclosporine (1) failed as maintenance therapy. Failure (1) or partial (1) response to colchicine. Complete (2) or partial (1) response to anakinra. Partial response to canakinumab (2). | Hearing loss, impaired vision (1). | ||||||
| Continuous and recurrent (3) | Episode characterized by fever, urticarial rash (3), arthralgia, myalgia, conjunctivitis (2), periorbital pain, papilledema, headache, fatigue and malaise (1). | Partial response to NSAIDs or steroids on-demand (2). Complete response to anakinra as maintenance therapy (1). | Bone alterations, frontal bossing, hearing loss (1). | |||||||
| 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, myalgia, aphtous stomatitis and headache (1). | Partial response to NSAIDs on demand (1). Complete response to anakinra or canakinumab as maintenance therapy. | Cranial neuropathy (1). | ||
| Recurrent (6) | Fever episodes of 4 days, 9/year, with arthro-myalgia, maculo-papular or urticarial rash (4), weight loss (3), palpable purpura, erythematous pharyngitis, sometimes exudative, aphthous stomatitis, headache, periorbital oedema and conjunctivitis (2). Recurrent episodes without fever (2). | Abdominal pain, diarrhea, urethritis/cystitis, chest pain (1). | Partial response to NSAIDs on demand (5). Colchicine and adenotonsillectomy failed (1). Complete response to steroids (1). |
a p.R202Q of the MEFV gene is considered a common and neutral polymorphism that should not be even reported