Table 5 Genotype-phenotype associations in patients with CAPS

Exon 3

R260L

8 m

Continuous

Presence of persistent urticarial rash, arthralgia, monoarthritis and morning headache. Occasional fever episodes associated with fatigue.

Sometimes presence of abdominal pain.

Colchicina failed. Complete response to anakinra as maintenancetherapy.

Hearing loss.

R260W

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 NSAIDson-demand (2) and NSAIDs (1) or steroids (2) as maintenance therapy. Complete (6) or partial (4) response to anakinra or complete (4) or partial (1) response to canakinumeb as maintenance therapy.

Clubbing (1), amyloidosis (1), hearing loss (2), infertility (1).

Recurrent (16)

Fever episodes of variable length (from 12 h to 5 days), 2 to more than 24/year, characterized by urticarial rash, conjunctivitis (16), arthralgia (14), myalgia (12), headache, fatigue (11), arthritis (8), malaise and 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 NSAIDson-demand and partial (2) or failure (1) as maintenance therapy. Partial response to colchicine (2). Cyclophosphamide and cyclosporine failed (1). Complete (2) or partial (1) response to anakinra. Complete response to canakinumab (11).

Clubbing (4) and amyloidosis (2). Hearing loss (5). Infertility (5). Delay in language acquisition (1), facial nerve palsy (1), 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).

NSAIDs (2),steroids (1) and colchicine (1)failed. Complete (1) or partial (1) response to anakinra. Complete response to canakinumab (3) as maintenance therapy.

Clubbing (3), hearing loss (3), cerebellar syndrome with white matter lesions (1), arterial hypertension (1). Infertility (1).

D303N

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 on-demand. Partial response to methotrexate, etanercept or adalimumab as maintenance therapy, but worsening of the uveitis. Complete response to anakinra.

Severe impaired vision.

Recurrent (3)

Fever episodes of 8 days. Chronic papilledema (1) and sometimes 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 on-demand (1). Complete response to anakinra (2) as maintenance therapy. Complete (1) and partial (1) response to canakinumab.

Bone alterations and frontal bossing (1), development of hydrocephalus (1) and hearing loss (2).

Continuous and recurrent (1)

Recurrent fever episodes of 12–24 h, 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 NSAIDson-demand. Complete response to anakinra as maintenance therapy.

Hearing loss.

G307 V

6 m

Continuous

Persistence of urticarial rash, arthralgia, myalgia, bone pain, arthritis, papilledema, headache, aseptic meningitis.

NSAIDs or steroids failed. Complete response to anakinra or canakinumab.

Patellar overgrowth and hypertrophy of tibia metaphysis.

Recurrent

Fever episodes of variable length, 3/year. Occasional presence of urticarial rash, arthralgia, oligoarthritis, papilledema and headache, with or without fever.

Episodes of palpable purpura with or without fever.

Partial response to NSAIDs on-demand.

Hydrocephalus and ventricular dilatation.

E311K

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 (1)on-demand.Complete (3) or partial(1) response to anakinra and partial response to canakinumab (1) as maintenance therapy.

Hearing loss (3).

Continuous and recurrent (1)

Fever episodes of 2 days. Presence of occasional urticarial rash, aphthous stomatitis, arthralgia, oligo-polyarthritis, conjunctivitis, malaise, fatigue and mood alterations with or without fever.

Occasional abdominal pain.

Partial response to anakinra or canakinumab.

Gut perforation, peritoneal adhesion and gut sub/occlusion.

I334V

At birth

Continuous and recurrent

Fever episodes of 7 days, associated with urticarial rash, arthritis, uveitis anterior, papilledema, vomiting, headache, aseptic meningitis.

On-demandNSAIDs failed. Partial response to steroids, anakinra or canakinumabas maintenance therapy, while methotrexate failed.

Impaired vision, mental retardation, hearing loss.

T348 M

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).

Complete (5) or partial (1) response to anakinraand complete response to canakinumab (10).

Hearing loss (8).

Recurrent (4)

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).

Partial response to NSAID on-demand and complete response to steroids (1). Complete response to anakinra (3) or canakinumab (2) as maintenance therapy.

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, livedo reticularis, conjunctivitis, episcleritis, papilledema, abdominale pain and vomiting, aseptic meningitis, hypotonia and vertigo (1).

Colchicine (1) failed. Complete response to anakinra (2). Complete (4) or partial (1) response to canakinumab. Adenotonsillectomy failed (1).

Presence of bone alterations (2), frontal bossing (2), clubbing (1), cataract (1), glaucoma (1) and hearing loss (2).

P350L

1

Continuous

Persistent urticarial rash, arthralgia, fatigue and weight loss (2).

Aphthous stomatitis, erythematous pharyngitis, acne, erythema nodosum, oligoarthritis, conjunctivitis, headache,uveitis, scleritis, papilledema, abdominal and chest pain with diarrhea (1).

NSAIDs or methotrexate failxed (1). Partial response to anakinra (1) as maintenance therapy.

Hearing loss (2), impaired vision (1), delayed puberty and bone age (1).

V351 M

At birth

Continuous and recurrent

Fever episodes of 12–24 h. Persistent urticarial rash, with or without fever, and occasional arthralgia, conjunctivitis, papilledema, vomiting, headache and aseptic meningitis.

Partial response to anakinra as maintenance therapy.

Presence of bone alterations and frontal bossing, hearing loss, hydrocephalus and severe mental delay.

A352V

5 m

Continuous e recurrent

Fever episodes of 2 days, 2/year, with fatigue and malaise. Occasional presence of urticarial rash, conjunctivitis and fatigue, with or without fever.

Complete response to canakinumab as maintenance therapy.

E354D

2 m

Continuous

Persistent presence of urticarial rash, arthralgia, lymphadenopathy and malaise, not associated with recurrent fever episodes.

Complete response to anakinra as maintenance therapy.

H358R

At birth

Continuous and recurrent

Fever episodes of 16–20 days, 8/year. Constant presence of maculo-papular rash, sometimes associated with aphthous stomatitis and aseptic meningitis, with or without fever.

Vomiting and diarrhea with orwithout fever.

Complete response to anakinra or canakinumab as maintenance therapy. Dapsone failed.

Hearing loss and severe mental retardation.

K375E

9 m

Recurrent

Fever episode of 2 days, >24/year, with urticarial rash, aphthous stomatitis, arthro-myalgia, periorbital oedema, conjunctivitis, headache and fatigue.

Partial response to steroids or anakinra on-demand. Complete response to canakinumab as maintenance therapy.

M406I

5 m

Recurrent

Fever episode of 3 days, >24/year. 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 canakinumab as maintenance therapy.

Bone alterations and frontal bossing. Moderate mental retardation. Delayed puberty.

T436A

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

At birth

Continuous and recurrent

Fever episodes of 12–24 h, >24/year, with fatigue, mood alterations, malaise and occasional urticarial rash, conjunctivitis, periorbital pain and morning headache. Occasional aphthous stomatitis, exudative and erythematous pharyngitis, maculo-papular rash, arthralgia, myalgia, papilledema, headache and persistent polyarthritis, with or without fever.

Severe cutaneous involvement with pathergia.

Partial response to NSAIDson-demand and to canakinumab as maintenance therapy.

Flexion contractures, cataract, optic neuritis and optic nerve atrophy, band keratopathy and impaired vision. Hearing loss.

A439V

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). Persistent (1) and episodic (2) conjunctivitis.

Presence of xerophthalmia and xerostomia, diarrhea (1).

Complete response to anakinra (4) or canakinumab (1) as maintenance therapy.

Tinnitus (1), renal 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, episodes of uretritis and frequent episodes of urinarial tract infections (1).

Partial (1) or complete (2) response to anakinra as maintenance therapy. Partial (1) or complete (6) response to canakinumab.

Clubbing (2), bone alterations and frontal bossing (1). Diverticulitis (1).

Continuous and recurrent (1)

Fever episodes of 5 days, 12/year. Occasional presence of urticarial and maculo-papular rash, arthralgia, myalgia, arthritis, conjunctivitis, malaise and fatigue with or without fever.

Abdominal pain without fever.

Partial response to steroids on-demand. Partial response to anakinra as maintenance therapy.

Cataract, glaucoma, hearing loss and peripheric polyneuropathy.

N477 K

2

Recurrent

Fever episodes ofless then 12 h, >24/year. Occasional urticarial rash, arthralgia, papilledema, generalized lymphadenopathy, hepatomegaly, headache, failure, malaise and mood alterations with or without fever. Constant presence of splenomegaly.

Occasional thoracic pain without fever.

Complete response to anakinra as maintenance therapy.

Clubbing and frontal bossing, impaired vision, severe mental retardation and hearing loss. Cardiomyopathy. Delayed puberty.

Y572F

At birth

Recurrent

Fever episodes, >24/year, with urticarial rash, mood disorders and weight loss.

Partial response to NSAIDson-demand. Complete response to anakinra as maintenance therapy.

Flexion contractures, hydrocephalus.

F523C

1

Continuous and recurrent

Fever episodes of 12–24 h, >24/year,with conjunctivitis, headache, fatigue and malaise. Occasional urticarial rash, arthralgia and myalgia.

Partial response to NSAIDson-demand. Complete response to canakinumab as maintenance therapy.

Frontal bossing and clubbing.

G569R

1 m

Recurrent

Fever episodes of less then <12 h, >24/year, with malaise and fatigue. Occasional migratory urticarial and maculo-papular rash, arthralgia, conjunctivitis, lymphadenopathy and aseptic meningitis.

Occasional anterior and posterior uveitis.

On-demand NSAIDs failed. Complete response to anakinra as maintenance therapy.

Hydrocephalus and hearing loss.

Y570F

1 m

Continuous

Persistent migratory maculo-papular rash, arthralgia, fatigue, malaise, oligoarthritis, conjunctivitis, papilledema, hepatomegaly and splenomegaly.

Occasional episodes of vomiting.

Partial response to NSAIDson-demand. Partial response to steroids, methotrexate, biphosphonates, cimetidine, rhGH, acetazolamide, anakinra and canakinumab as maintenance therapy.

Optic nerve atrophy and impaired vision. Hearing loss and delayed neuromotor development.

I572F

At birth

Continuous and recurrent

Fever episodes of > 20 days. Occasional urticarial rash, arthralgia, oligoarthritis, papilledema, hepatomegaly, splenomegaly and headache.

Occasional seizures with or without fever.

Complete response to anakinra or canakinumab as maintenance therapy.

Bone alterations with frontal bossing, optic nerve atrophy with severe vision impairment, hydrocephalus and hearing loss. Severe mental retardation. Delayed puberty and bone age.

E627G

3 m

Recurrent

Occasional urticarial rash, arthralgia, myalgia, abdominal pain, constipation with and without fever.

Complete response to anakinra as maintenance therapy.

M662 T

6 m

Continuous and recurrent

Fever episodes of 5 days, >24 per year, with urticarial rash, aseptic meningitis and generalized lymphadenopathy (2). Persistent papilledema (2) and headache (1).

Uveitis anterior, chest pain, pericarditis, erythema nodosum.

Partial response to NSAIDs or steroids on-demand (1). Partial response to colchicine (1), anakinra (2) or canakinumab (1) as maintenance therapy. Methotrexate or etanercept (1) failed.

Bone alterations and frontal bossing, hearing loss (2), moderate optic nerve atrophy, hydrocephalus (1).

S710C

2

Recurrent

Fever episodes of 7 days, 2/year, sometimes associated with urticarial and maculo-papular rash, fatigue, malaise, conjunctivitis and cervical bilateral lymphadenopathy. Occasional arthralgia, myalgia, monoarthritis and splenomegaly.

Partial response to NSAIDs and steroids on-demand. Partial response to methotrexate and complete response to anakinra or canakinumab as maintenance therapy.

Exon 9

L1016F

3 m

Continuous

Persistence of fever, urticarial rash, fatigue and weight loss.

Hearing loss.