Table 2 Genotype-phenotype associations in patients with FMF

Exon 2

S108R

V726A

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.

E148Q

M680 L

6

Recurrent

Fever or low fever episodes, 3/year, with erythematous pharyngitis, arthralgia, abdominal pain and headache.

Complete response to colchicine.

M694 V

5 (0–27)

Recurrent

Fever episodes of 2–3 days, 13/year, with regular pattern, chills at onset (6), associated with 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/cystitis and hydrocephalus (1). Episodes induced by stress (2), menstruation, fatigue, cold and vaccins (1)

Patial response to NSAIDs (3). Partial response (5) or complete (9) to colchicine. One patient responded 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 micophenolatemofetil with complete response.

V726A

3 (2–7)

Recurrent

Fever (4) or low fever (2) episodes of 2 days, 21/year, with abdominal pain (4) and arthralgia (2).

Chest pain, hepatomegaly, splenomegaly and maculo-papular rash (1).

Partial response to NSAIDs, steroids, colchicine (2) and cimetidine (1). Complete response(1) or failure (1) with colchicine.

A744S

35 (14–51)

Recurrent

Low fever (2) or fever (1) of 3–4 days, 9/year, with abdominal pain, arthralgia (3), erysipelas-like erythema, myalgia (2), monoarthritis, conjunctivitis and chest pain (1).

Partial response to NSAIDs (2) or steroids (1)on-demand. Complete response to colchicine (2).

R761H

5 (1–16)

Recurrent

Low fever of 3 days, 16/year, induced by exercise (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 and dysmenorrhea (1).

Complete response to colchicine (4).

E167D

M694 V

1

Recurrent

Fever episodes of 2 days, 18/year, induced by infections, with conjunctivitis and abdominal pain.

Complete response to colchicine.

E225G

M694 V

1

Recurrent

Fever episodes of 5 days, 12/year, with arthralgia, myalgia, pseudofolliculitits, erythematous pharyngitis, abdominal and chest pain.

Partial response to steroids on-demand. Complete response to colchicineasmantainance treatment.

Exon 5

F479 L

V726A

4

Recurrent

Fever episodes of 3 days, 15/year, with abdominal pain and conjunctivitis.

Complete response to colchicine.

Exon 9

I591T

V726A

5

Recurrent

Fever episodes of 2 days, 5/year, induced by stress, fatigue and exercise, with diarrhea, constipation and abdominal pain.

–

Exon 10

M680IGA

M680IGA

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).

Complete response to NSAIDs on-demand (1). Complete response to colchicine as maintenance therapy (3).

M694 V

2

Recurrent

Fever episodes of 2 days, 6/year, induced by cold and exercise, with regular pattern (1), associated with maculo-papular rash, myalgia, abdominal pain, chest pain, costipation (2), exudative or erythematous pharyngitis, urticarial rash, arthralgia, gastrointestinal bleeding, hepatosplenomegaly, aseptic peritonitis, bone pain, pericarditis, periorbital oedema and conjunctivitis(1).

Adenotonsillectomy failed. Complete responsetocolchicine as maintenance therapy(1).

V726A

5 (1–7)

Recurrent (3). Continuous and recurrent (1).

Fever or low fever episodes of 4 days, 12/year, sometimes induced by cold and stress (2), with abdominal pain (4), vomiting and arthralgia (2).

Myalgia, mono/oligoarthritis, diarrhea or constipation, enlarged cervical lymphonodes, hepatomegaly, chest pain, aseptic peritonitis and costipation, headache, vertigo (1).

Complete (1) or partial (2) response to colchicine. Tonsillectomy, steroids and NSAIDs failed (1). Partial response to NSAIDs (1).

Peritoneal adhesions (1).

R761H

0

Recurrent

Fever or low fever of 1 days, 12/year, sometimes induced by vaccination, with regular pattern, chills, urticarial rash and abdominal pain.

Complete response to NSAIDs or steroids on-demand. Complete response to colchicine as maintenance therapy.

M680IGC

M680IGC

3 (1–6)

Recurrent

Fever episodes of 2 days, 18/year, with regular pattern, associated with exudative pharyngitis, enlarged cervical bilateral and painful lymphonodes, erysipelas-like erythema, splenomegaly, headache (2), myalgia, arthralgia, vomiting, diarrhea, pericarditis (3), aseptis peritonitis and pleurity (4), abdominal and chest pain (5).

Oligoarthritis and tenosynovitis, costipation, gastrointestinal ulcers, hepatomegaly, painful orchitis (1).

Complete response to colchicine as maintenance therapy (5).

Delayed puberty, peritoneal adhesions, and severe infections (1).

T681I

11

Recurrent

Fever episodes of 3 days, 3/year, with erythematous pharyngitis, chest pain, pleurisy, arthralgia, myalgia and abdominal pain.

Complete response to colchicine as maintenance therapy.

M694 V

2 (0–30)

Recurrent

Fever or low fever episodes of 3 days, 15/year, with regular pattern, with arthralgia, abdominal pain (21), myalgia (17), oligoarthritis (16), chest pain (15), pleurisy (12), vomiting (10) and 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, gastrointestinal 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).

Complete (15) or partial (11) response to colchicine. Partial (6) or complete (2) response to NSAIDs. Partial response to steroids, methotrexate (3),sulphasalazine (1). One patient responded 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

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).

Complete (3) response to colchicine, that failed in one patient. Partial response to NSAIDs (1). Complete response to steroids (1) or anakinra (1).

R761H

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.

M680 L

M680 L

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 tocolchicine as maintenance therapy. Bilateral sacro-iliac joints steroid injection and tonsillectomy.

I692del

M694 V

2

Recurrent

Fever or low fever episodes of 2 days, 18/year, with abdominal pain.

Complete response to colchicine as maintenance therapy.

M694I

M694I

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).

M694 V

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).

M694 V

M694 V

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).

M694del

0

Recurrent

Fever episodes of 1 days, 12 per year, with abdominal pain and arthralgia.

Partial response to Colchicine.

M694 L

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

7

Recurrent

Fever episodes, 7/year, with arthralgia, constipation and abdominal pain (2).

Partial response to sulphasalazine (1), complete response to colchicine (2).

V726A

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).

R761H

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).

V726A

V726A

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).

A744S

A744S

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 and malaise.

Partial response to NSAIDs or steroids or colchicine. Complete response to etanercept as maintenance therapy.