Table 3.
Genotype-phenotype associations in patients with MKD
| Gene region | First mutation | Second mutation | N° pt | Age of 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) |
|---|---|---|---|---|---|---|---|---|---|
| Exon 2 | c.1_26del | V377I | 1 | 3 | Continous and recurrent | Fever episodes of 7 days, 10/year, with aphthous stomatitis, exudative or erythematous pharyngitis, abdominal pain, arthralgia and myalgia. | Partial response to NSAIDs and complete response to steroids on demand. | ||
| H20N | R215Q | 2 | At birth | Continuous | 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. Partial response to steroids, cyclosporine, biphosphonates and anakinra as maintenance therapy. Colchicine, infliximab, methotrexate, sulphasalazine, azathioprine, statins, tacrolimus and etanercept failed. | Bone alterations and erosions, flexion contractures, osteolytic lesions, osteoporosis, cataract, impaired vision. | ||
| At birth | Recurrent | Fever episodes of 5 days, 12/year, 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 anakinra and partial to steroids, biphosphonates, intravenous immunoglobulin and etanercept as maintenance therapy. Colchicine, sulphasalazine, methotrexate, azathioprine and statins and tonsillectomy failed. | Bone alterations and erosions, flexion contractures, osteolytic lesions, osteoporosis, cataract, peritoneal adhesions, sub−/occlusions, gut perforations and recurrent inguinal hernia. | |||||
| H20P | V377I | 3 | 4 | Recurrent | Fever episodes of 4 days, 8/year, with myalgia, vomiting,maculo-papular rash, abdominal pain, fatigue, malaise, diarrhea (3), exudative or erythematous pharyngitis, arthralgia, lymphadenopathy, mood disorders, headache (2), hepatosplenomegaly (1). Occasional episodes of aphthous stomatitis with or without fever. | Partial response to NSAIDs (1) or anakinra (1) on-demand. Steroids (1) failed. Colchicine (2) or statins (1) failed as maintenance therapy. No response to tonsillectomy (1). | Neuropathy (1). | ||
| V20R | V377I | 1 | 1 | Recurrent | Fever episodes, 10/year, with urticarial rash, lymphadenopathy, arthralgia and occasional vomiting and diarrhea. | Partial response to steroids on-demand. | |||
| Exon 3 | H44Qfs*35 | V377I | 1 | 7 | Recurrent | Fever episodes, 6/year, with maculo-papular rash, arthralgia, myalgia, abdominal pain, vomiting, diarrhea, fatigue, malaise and weith loss. | On-demand Steroids failed. Partial response to etanercept and azithromicine as maintenance therapy. Colchicine and anakinra failed. Complete response to Infliximab. | ||
| W62* | V377I | 1 | At birth | Recurrent | Fever episodes of 6 days, 24/year, 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. | On-demand NSAIDs failed. Partial response to steroids on demand. | |||
| Exon 4 | Y114Ifs*71 | N205D | 1 | 0.1 | Recurrent | Fever episodes of 13 days, 17/year, with occasional abdominal pain and splenomegaly. Occasional episodes of erythema marginatum, arthralgia, myalgia and oligoarthritis with or without fever. | Partial response to steroids and anakinra as maintenance therapy. Colchicine and etanercept failed. | ||
| Y116H | V377I | 1 | 0.2 | Recurrent | Fever episodes of 5 days, 22/year, with aphthous stomatitis, arthralgia, headache, abdominal pain, diarrhea, lymphadenopathy and occasional urticarial rash. | Partial response to colchicine and anakinra as maintenance therapy. Partial response to tonsillectomy. | |||
| I119M | A148T | 1 | 2 | Recurrent | Fever episodes of 7 days, 24/year, with always arthralgia, abdominal pain, vomiting, diarrhea and lymphadenopathy. Presence of headache with or without fever. | Partial response to NSAIDs or steroids on-demand. Partial response to etanercept as maintenance therapy. | |||
| R124W | V377I | 1 | 2 | Recurrent | Fever episodes of 4 days, 24/ years, with arthromialgia, myalgia, malaise and occasional abdominal pain, diarrhea, vomiting, erythematous pharyngitis, cervical and painful lymphadenopathy. | Complete response to steroids on demand. No response to tonsillectomy. | |||
| Exon 5 | V132I | V377I | 1 | 0.4 | Recurrent | Fever episodes of 8 days, 13/year, with exudative and erythematous pharyngitis, arthralgia, myalgia, abdominal pain, lymphadenopathy and occasional splenomegaly. | Partial response to NSAIDs or steroids. Partial response to colchicine and etanercept as maintenance therapy. | ||
| A141Rfs*18 | A334T | 1 | At birth | Recurrent | Fever episodes of 4 days, 12/year, with aphthous stomatitis, arthralgia, myalgia, abdominal pain, vomiting, diarrhea, lymphadenopathy, fatigue, malaise and occasional erythematous pharyngitis, maculo-papular rash and mood disorders. Episodes of oligoarthritis and headache with or without fever. | Partial response to NSAIDs. Anakinra failed as maintenance therapy. | Impaired vision, cerebellar syndrome, retinitis pigmentosa, mental retardation. | ||
| A147T | V377I | 1 | 0.05 | Recurrent | Fever episodes of 3 day, with occasional vomiting, diarrhea, aphthous stomatitis, maculo-papular rash and lymphadenopathy. | Partial response to etanercept. No response to tonsillectomy. | |||
| C152Wfs*6 | V377I | 1 | 0.2 | Recurrent | Fever episodes of 2 days, 24/year, 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. On-demand Steroids and etanercept as maintenance therapy failed. | |||
| 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. | Partial response to steroids on-demand and anakinra as maintenance therapy. Etanercept, statins and montelukast failed. No response to adenotonsillectomy. | Peritoneal adhesions, occlusion/sub-occlusion, venous thrombosis, severe infections. | |
| 0.3 | Recurrent | Fever episodes of variable length, 12/year, 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. | On-demand NSAIDs failed. Partial response to steroids and anakinra on-demand. Statins failed as maintenance therapy. | Mental retardation. | |||||
| V377I | 2 | 0.7 | Recurrent | Fever episodes of 4 days, 9/year, with abdominal pain, lymphadenopathy, fatigue, malaise (2), diarrhea, arthralgia, headache, aphthous stomatitis, maculo-papular rash (1). | Partial response to NSAIDs on-demand (2). Partial response to colchicine (1) as maintenance therapy. No response to tonsillectomy. | ||||
| N166I | G336S | 1 | 5 | Recurrent | Fever episodes of 7 days, 12/year, 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 colchicine as maintenance therapy. | |||
| Exon 6 | W188* | V337I | 1 | 0.5 | Recurrent | Fever episodes of 6 days, 24/years, 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 NSAIDs or steroids on demand. Partial response to tonsillectomy. | ||
| Q190fs | V377I | 1 | 11 | Recurrent | Fever episodes, 13/year, with lymphadenopathy, vomiting, abdominal pain, erythematous pharyngitis and occasional aphthous stomatitis and arthralgia. | Partial response to NSAIDs on-demand. Partial response to colchicine as maintenance therapy. | |||
| V203 fs | V377I | 2 | 0.3 | Recurrent | Fever episodes of 3 days, 16/year, with urticarial rash, arthralgia, myalgia, abdominal pain, malaise 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) or failure (1) to NSAIDs and partial to steroids (2) or colchicine (1) on-demand. Cyclosporine and statins (1) failed as maintenance therapy. | Cataract, cerebral nerve palsy and mental retardation (1). | ||
| V203A | I268T | 1 | At birth | Continous and recurrent | Fever episodes of 7 days, 12/year, 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 steroid as maintenance therapy. | Peritoneal adhesions. | ||
| N205D | V312A | 1 | At birth | Recurrent | Fever episodes of 5 days, 6/year, triggered by stress, with erythematous pharyngitis, arthralgia, myalgia, abdominal pain and sometimes aphtous stomatitis, ulcers at genitalia, vomiting, diarrhea, generalized lymphadenopathy, fatigue and malaise. Headache and conjunctivitis with our without fever. | Partial response to NSAIDs on-demand. Steroids failed. | |||
| Exon 7 | G211E | V337I | 1 | 0.7 | Recurrent | Fever episodes of 6 days, 14/year, with palpable purpura. Occasional 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. Azathioprine failed. | |
| R215Q | V377I | 3 | At birth | Recurrent | Fever episodes of 6 days, 12/year, with abdominal pain, diarrhea, enlarged lymphadenopathy (3), headache, erythematous pharyngitis, painful lymphadenopathy, vomiting, arthralgia (2), maculo-papular rash, splenomegaly, pneumonia, urticarial rash, myalgia, fatigue, malaise (1). | Aphthous stomatitis and gastrointestinal ulcers during fever episodes (1). | Partial response to NSAIDs (2) on-demand. Complete (1) or partial (1) response to steroids. Partial response to rilonacept (1) as maintenance therapy. No response to tonsillectomy (1). | ||
| c.632-1G > C | V377I | 1 | 2 | Recurrent | Fever episodes of 5 days, 14/year, with aphthous stomatitis, pseudofolliculitis, ulcers at genitalia, arthralgia, myalgia, anterior uveitis, episcrleritis, vomiting, diarrhea, abdominal pain, painful cervical lymphadenopathy, splenomegaly, fatigue, malaise and mood disorders. | On-demand NSAIDs or steroids failed. Partial response to anakinra and etanercept as maintenance therapy. | Macrophage activation syndrome. | ||
| Exon 8 | P228P | V377I | 1 | 2 | Recurrent | Fever episodes of 6 days, 7/year, sometimes with enlarged cervical lymphadenopathy, abdominal pain, diarrhea, urticarial rash, fatigue and headache, | Partial response to etanercept as maintenance therapy. | Renal failure. | |
| T237S | T237S | 1 | – | Recurrent | Fever episodes of 5 days, 20/year. Episodes of vomiting, abdominal pain, diarrhea, arthralgia and cervical lymphadenopathy with or without fever. | Colchicine failed as maintenance therapy. Partial response to anakinra. | |||
| I268T | 1 | At birth | Continous | Fever, malaise, weight loss, maculo-papular rash, vomiting, abdominal pain, diarrhea, gastrointestinal bleeding, aseptic peritonitis, hepato-splenomegaly and episodes of pneumonia. | Ascites, cholestasis. | Partial response to steroids as maintenance therapy. | Peritoneal adhesion, sub/occlusion. Death due to acute respiratory distress syndrome. | ||
| L246P | V337I | 1 | At birth | Recurrent | Fever episodes of 3 days, 8/year, with exudative and erythematous pharyngitis, generalized and painful enlarged lymphadenopathy, abdominal pain, diarrhea and, sometimes, vomiting, bone pain, arthromyalgia, fatigue, malase, weight loss. Acne and aphthous stomatitis with or without fever. | Partial response to NSAIDs or steroids on-demand. | |||
| Exon 9 | L264F | V377I | 3 | 0.6 | Recurrent | Fever episodes of 5 days, 13/year, with occasional abdominal pain, maculo-papular rash, aphthous stomatitis, diarrhea, exudative (3) and erythematous pharyngitis, lymphadenopathy, malaise, splenomegaly, fatigue, arthralgia (2), headache hepatomegaly, myalgia (1). | Recurrent pericarditis (1). | Partial response to steroids on-demand (3). Partial response to anakinra as maintenance therapy (1). Partial response (2) or failure (1) to NSAIDS on-demand. | |
| L264Sfs*2 | V377I | 1 | At birth | Recurrent | Fever episodes of 5 days, 24/ year, with aphthous stomatitis, abdominal pain, diarrhea, fatigue, malaise and occasional episodes of exudative and erythematous pharyngitis, urticarial rash, vomiting and mood disorders. Anal/perianal ulcers with or without fever. | – | Seizures. | ||
| L265R | V377I | 4 | 1 | Recurrent (2) | Fever episodes of 3 days, 20 /year, with aphthous stomatitis (2), erythematous pharyngitis, arthralgia, myalgia (1) and occasional abdominal pain, diarrhea, lymphadenopathy, conjunctivitis (2), vomiting, splenomegaly, pneumonia and fatigue (1). | Complete response (1) or failure (1) to steroids on-demand. NSAIDs or colchicine on demand failed (1). Partial response to anakinra as maintenance therapy (1). | |||
| 0.2 | Continuous and recurrent (2) | Fever episodes of 4 days, 20/year, 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 | V377I | 24 | 0.1 | Continuous (1) | Occasional vomiting and diarrhea. | No fever. | – | Amyloidosis. | |
| 1 | Recurrent (22) | Fever episodes of 6 days, 14/ year, with lymphadenopathy (18), vomiting, abdominal pain (13), diarrhea, aphthous stomatitis (12), fatigue, malaise (10), arthralgia (8), erythematous or exudative pharyngitis, arthritis, headache (7) | Occasional myalgia (6), maculo-papular rash, arthralgia (5), abdominal pain, mood disorders (4), myalgia, lymphadenopathy, aphthous stomatitis, urticarial rash, ulcers at genitalia, erythema nodosum, aseptic peritonitis, chest pain (2), palpable purpura, papulo-pustular lesions, conjunctivitis, constipation, pericarditis, persistent cough, gastrointestinal bleeding (1) with fever. Presence of fatigue (4), weight loss, headache, splenomegaly (3), vomiting, hepatomegaly, aphthous stomatitis, malaise, mood disorders (2), acne, ulcers at genitalia, erythema nodosum, polyarthritis, abdominal pain, diarrhea, constipation, chest pain, pneumonia, persistent cough, urethritis/cystitis (1) with or without fever. | Complete (2) or partial response (6) or failure (2) to NSAIDs on demand. Partial response (2) or failure (1) to NSAIDs as maintenance therapy. Complete (6) or partial (4) response to steroids on demand. Complete (2) or partial response (3) or failure (1) to anakinra. Partial response (3) or failure (1) to etanercept. Partial response to thalidomide (1) and statins (2) that failed in one patient. Complete response to canakinumab (1). Cimetidine failed (2). No response to tonsillectomy (6). | Amyloidosis (3), cranial nerve palsy, seizures (2), peritoneal adhesions, occlusion/sub-occlusion episodes, cranial neuropathy, mental retardation (1) | ||||
| 2 | Continuous and recurrent (1) | Fever episodes of 8 days, 24/year. Occasional maculo-papular rash, arthralgia, myalgia, headache, conjunctivitis, lymphadenopathy, vomiting, abdominal pain and diarrhea with or without fever. | Steroids, colchicine, methotrexate and anakinra failed as mainenance therapy. | Clubbing. | |||||
| S272F | V377I | 4 | 3 | Recurrent (1) | Fever episodes of 13 days, 13/year, with vomiting, diarrhea, fatigue, malaise and occasional abdominal pain, aphthous stomatitis, arthralgia, myalgia, oligoarthritis, headache and lymphadenopathy. Persistent splenomegaly. | Partial response to NSAIDs and steroids on-demand. Partial response to cyclosporine, tacrolimus and anakinra as mainenance therapy. | Amyloidosis. | ||
| 1 | Continuous and recurrent (3) | Fever episodes of 8 days, 10/year, with occasional aphthous stomatitis, arthralgia, myalgia, oligoarthritis (2), abdominal pain, diarrhea, constipation, lymphadenopathy, pericarditis, chest pain and pleurisy (1). Persistent hepatosplenomegaly, fatigue, malaise (2) and occasional acne, hemoptysis and persistent cough (1) with or without fever. | Partial response to steroids as mainenance therapy (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 | Fever episodes of 4 days, 20/year, 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 | V310 L | V310 L | 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, myalgia or myositis (1). | Partial response to steroids, cimetidine (2) and anakinra (1) as maintenance therapy. NSAIDs and methotrexate (2) failed. Partial response or failure with sulphasalazine or infliximab (1). | Flexion contractures. |
| V310 M | V377I | 2 | 2 | Recurrent | Fever episodes of 4 days, 11/year, with abdominal pain, diarrhea, cervical and painful lymphadenopathy, arthralgia, malaise, erythematous rash (2), aphtous stomatitis, maculo-papular or urticarial or erysipelas-like rash, pseudo-folliculitis, acne, vomiting, myalgia, fatigue, 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. Colchicine failed (1). Complete response to anakinra (1) as maintenance therapy. | ||
| L315 V | V377I | 1 | 0.7 | Recurrent | Fever episodes of 3 days, 24/year, with aphthous stomatitis, abdominal pain and arthralgia. | On-demand NSAIDs failed. Complete response to steroids. No response to tonsillectomy. | |||
| G326R | V377I | 1 | 0.3 | Recurrent | Fever episodes of 5 days, 12/year. 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 NSAIDs and complete response to steroids on-demand. | ||
| S329R | V337I | 1 | 2 | Recurrent | Fever episodes of 4 days, 12/year, 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 NSAIDs on-demand and to etanercept as maintenance therapy. | ||
| G335A | V377I | 1 | 1 | Recurrent | Fever episodes of 5 days, 18/year, with maculo-papular rash, vomiting, diarrhea, cervical lymphadenopathy, occasional arthralgia, abdominal pain and hepatospenomegaly. | On demand Steroids failed. Complete response to etanercept as maintenance therapy. | |||
| G336S | V377I | 2 | 1 | Recurrent | Fever episodes of 4 days, 12/year, 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 | Fever episodes of 6 days, 24/year, with abdominal pain, macula-papular rash, occasional aphthous stomatitis, arthralgia, diarrhea, lymphadenopathy. Persistent hepatomegaly and splenomegaly with or without fever. | NSAIDs and steroids on-demand and colchicine, anakinra, etanercept or adalimumab failed. Partial response to canakinumab as maintenance therapy. | |||
| Exon 11 | H380R | V377I | 1 | 11 | Continuous and recurrent | Episodes of 14 days, 12/year, 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 and weight loss. | Recurrent chest pain with pleurisy. | Partial response to NSAIDs on-demand. Steroids, methotrexate, etanercept and statins failed as as maintenance therapy. | |
| R388* | V377I | 2 | 1 | Recurrent | Fever episodes of 3 days, 15/year, with aphthous stomatitis, cervical lymphadenopathy, fatigue, malaise, maculo-papular rash and vomiting (2), abdominal pain, diarrhea, hepatomegaly and exudative or erythematous pharyngitis (1). | Partial response to NSAIDs (2) and complete (1) or partial (1) response to steroids on-demand. | |||
| V377I | V377I | 12 | 2 | Recurrent | Fever episodes of 5 days, 11/year, with lymphadenopathy (11), vomiting, abdominal pain (10), aphthous stomatitis (6 only during fever episodes, 4 with or without fever), diarrhea, malaise (9),myalgia, fatigue (8), headache,arthralgia (7), erythematous (4) or exudative (1) pharyngitis, maculo-papular rash (4), mood disorders, vertigo (3),), arthritis, conjunctivitis (2) and ulcers at genitalia (1). Presence of hepatomegaly or urticarial rash (1) with or without fever. | Complete (2) or partial response (3) to NSAIDs on demand that failed in one patient. Complete (1) or partial response (3) to NSAIDs as maintenance therapy. Complete (2) or partial (2) response to steroids on-demand. Partial response to anakinra (2). Non response to adenotonsillectomy (3). | Seizures (2). |
*Designate a translation termination codon according to Human Genome Variation Society nomenclature