Review Article

Monogenic Autoinflammatory Syndromes: State of the Art on Genetic, Clinical, and Therapeutic Issues

Table 2

Clinical, laboratory, genetic, and therapeutic aspects of the monogenic autoinflammatory syndromes.

Onset ageCriteria and main suggestive clinical featuresLaboratory findings Therapy

FMFFirst two decades of life and more rarely adulthoodTel-Hashomer diagnostic criteria.
(A) Major: (1) recurrent febrile episodes with serositis (peritonitis, pleurisy, and pericarditis) or synovitis; (2) AA amyloidosis in the absence of another predisposing disease; (3) good clinical response to daily administration of colchicine.
(B) Minor: (1) recurrent febrile episodes; (2) erysipelas-like rash; (3) positive FMF family history in a first-degree relative.
FMF diagnosis can be formulated on the basis of the presence of two major criteria or one major criterion and two minor ones; presence of one major and one minor criterion can point towards a probable FMF diagnosis.
Secondary amyloidosis is not a rare event in patients not adequately treated or noncompliant patients.
Increased inflammatory markers (ESR, CRP, SAA, aptoglobin, and fibrinogen)
Neutrophilic leukocytosis, anemia, thrombocythemia, and increased serum IgA and IgD levels; renal function tests and proteinuria/24 hours are needed (abnormal results can point towards secondary amyloidosis)
MEFV analysis
Colchicine
Anti-IL-1β agents
Anti-TNF-α agents

TRAPSChildhood and adolescence; adulthoodRecurrent inflammatory attacks (mean duration: 1–3 weeks) characterized by the following:
fever, arthralgia; more rarely monooligoarthritis and/or tenosynovitis; periorbital edema, often associated with painful conjunctivitis, serpiginous erythematosus skin rash (migratory erythematous macules and/or painful plaques); polyserositis; abdominal pain, vomiting, diarrhoea, and constipation; chronic monocytic fasciitis with cramps and migratory myalgia; lymphadenopathy; headache, and fatigue, generalized malaise.
Secondary amyloidosis is not rare.
Neutrophilic leukocytosis and thrombocythemia; renal function tests and proteinuria/24 hours are needed (abnormal results can point towards secondary amyloidosis)
TNFRSF1A analysis
Corticosteroids
Anti-IL-1β agents
Anti-TNF-α agents

CAPSFirst 6 months of life; in rare cases in adulthoodFever, urticaria-like rash, conjunctivitis, and arthralgia.Neutrophilic leukocytosis and thrombocythemia; increased inflammatory markers (ESR, CRP, SAA, aptoglobin, and fibrinogen); renal function tests and proteinuria/24 hours are needed (abnormal results can point towards secondary amyloidosis)
NLRP3 and NLP12 analysis
Anti-IL-1β agents
First months of lifeFever, urticaria-like rash, conjunctivitis, episcleritis, arthralgia, sensorineural hearing loss, and AA amyloidosis.
Perinatal onsetFever, urticaria-like rash, anterior chronic uveitis, papillitis, optic nerve atrophy, arthralgia, chronic aseptic meningitis, sensorineural hearing loss, and AA amyloidosis.

Mevalonate kinase deficiencyEarly childhoodInflammatory recurrent attacks (mean duration of 3–7 days) characterized by the following:
fever; gastrointestinal involvement (abdominal pain, vomiting, and/or diarrhoea); polymorphic skin rash; painful lymphadenopathy, mainly laterocervical; splenomegaly; arthralgia and/or arthritis; headache, fatigue, and generalized malaise. Secondary amyloidosis is a rare but possible event.
Leukocytosis; increased inflammatory markers (ESR, CRP, SAA, aptoglobin, and fibrinogen); possible increase of serum IgD level (>100 IU/mL) in any phase of the disease; increased urinary levels of mevalonic acid during febrile attacks
MVK analysis
NSAIDs and corticosteroids (with partial remission of acute symptoms)
Anti-IL-1β agents
Anti-TNF-α agents

Granulomatous disordersChildhoodBS: triad of granulomatous arthritis, dermatitis, uveitis.
EOS: polyarthritis with ocular, cutaneous, and lymph node involvement.
Histologic findings are suggestive of noncaseating granulomatous inflammation.
Increased inflammatory markers (ESR and CRP)
NOD2/CARD15 analysis
Corticosteroids
Anti-IL-1β agents
Anti-TNF-α agents

Autoinflammatory pyogenic disordersEarly childhoodPAPAs: recurrent self-limited sterile pyogenic arthritis, pyoderma gangrenosum, and nodulocystic acne.
MS: multifocal sterile osteomyelitis, dyserythropoietic anemia, and chronic neutrophilic dermatosis.
DIRA: multifocal sterile osteomyelitis, periostitis, pustulosis with ichthyosis-like features, nail alterations, and risk of multiorgan failure.
Increased inflammatory markers (ESR and CRP)
PSTPIP1, LPIN2, and IL1RN analysis
Corticosteroids
Anti-IL-1β agents (DIRA)
Anti-TNF-α agents (PAPAs)

AD: autosomal dominant; AR: autosomal recessive; BS: Blau syndrome; CAPS: cryopyrin-associated periodic syndromes; CARD: caspase recruitment domains; CD2BP1: CD2-binding protein-1; CIAS1: cold-induced autoinflammatory syndrome-1; CINCAs: chronic infantile neurological cutaneous articular syndrome; CRP: C-reactive protein; DIRA: deficiency of the interleukin-1 receptor antagonist; EOS: early-onset sarcoidosis; ESR: erythrosedimentation rate; FCAS: familial cold autoinflammatory syndrome; FMF: familial Mediterranean fever; IL1RN: interleukin-1 receptor antagonist; LPIN2: lipin-2; MEFV: MEditerranean FeVer; MVK: mevalonate kinase gene; MKD: mevalonate kinase deficiency; MS: Majeed syndrome; MWS: Muckle-Wells syndrome; NLRP3: nucleotide-binding domain, leucine-rich repeat, and pyrin domain containing protein-3; NLRP12: nucleotide-binding domain, leucine-rich repeat, and pyrin domain containing protein-12; NOD: nucleotide-binding oligomerization domain; PAPAs: pyogenic arthritis with pyoderma gangrenosum and cystic acne syndrome; PSTPIP1: proline serine threonine phosphatase-interacting protein-1; SAA: serum amyloid-A; TNFRSF1A: TNF-receptor superfamily 1A; TRAPS: tumor necrosis factor receptor-associated periodic syndrome.