Infantile Neurological Cutaneous Articular Syndrome Research Articles

Clinical and Genetic Spectrum of Nine Cases of NLRP3-Associated Autoinflammatory Disease (NLRP3-AID) and Identification of One Novel NLRP3 Mutation by Genetic Variation Analyses.

NLRP3-associated autoinflammatory disease (NLRP3-AID) is characterized by gain-of-function variants in the NLRP3 gene. Since there are little literature focusing on pediatric NLRP3-AID in China, we aimed to elucidate the phenotypic and genotypic profiles of Chinese patients with NLRP3-AID. Patients with NLRP3-AID at three rheumatology centers in China were genotyped through whole exome sequencing or gene panel sequencing. Sanger sequencing was performed on all patients and their parents. Clinical phenotype, treatment, and prognosis were analyzed. Nine patients with NLRP3-AID were enrolled between December 2014 and October 2022 with an average follow-up period exceeding 30 months. The median age of onset was 12 months, and 66.7% were younger than 3 years old. The diagnosis was significantly delayed and the median delay duration was 115 months. The patients most commonly presented with rash (100%), arthritis/arthralgia (88.9%), lymphadenopathy (88.9%), fever (77.8%), and growth retardation (44.4%). During acute attack, white blood cell, C-reactive protein, and/or erythrocyte sedimentation rate all increased in all cases, and inflammatory markers remained elevated beyond 7 days postfever resolution in 57.1% of patients (4/7). Two cases of chronic infantile neurological cutaneous articular syndrome (CINCA) had clubbed fingers, one with interstitial lung disease, a finding rarely reported. Treatment with glucocorticoids (77.8%) and biologic agents (33.3%) yielded 66% complete remission and 33% partial remission. Genetic analysis identified eight pathogenic NLRP3 missense mutations, including one novel mutation. Our study illuminated the distinct clinical and genetic features of Chinese NLRP3-AID patients, emphasizing the significance of early genetic screening. Despite delayed diagnosis, treatment primarily with glucocorticoids and biologic agents, led to favorable outcomes. Genetic heterogeneity, including a novel mutation, highlighted the complexity of NLRP3-AID in this population.

Efficacy and safety of thalidomide in children with monogenic autoinflammatory diseases: a single-center, real-world-evidence study

BackgroundMonogenic autoinflammatory diseases (AIDs) are rare inflammatory diseases caused by genetic variants. The pathogenesis is complex and treatment options are limited. This study aimed to describe the safety and efficacy of thalidomide in the treatment of monogenic AIDs.MethodsThis was a single-center, single-arm, real-world study. From September 2016 to August 2021, patients with monogenic AIDs who met the inclusion and exclusion criteria were given thalidomide for 12 months. There was a 3-month run-in period before dosing. The efficacy and adverse events were evaluated and recorded every 3 months. After 3 and 12 months of thalidomide treatment, clinical manifestations, disease activity score, inflammatory markers, and background medication adjustments were compared with baseline for efficacy analyses.ResultsA total of 16 patients entered this study, including 3 with Aicardi-Goutières syndrome (AGS), 4 Blau syndrome, 2 chronic infantile neurologic cutaneous articular syndrome (CINCA), 2 A20 haploinsufficiency (HA20), 1 adenosine deaminase 2 deficiency(DADA2), 1 familial Mediterranean fever (FMF),1 tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), 1 PLCγ2-associated antibody deficiency and immune dysregulation (PLAID), and 1 stimulator of interferon genes-associated vasculopathy with onset in infancy(SAVI). The efficacy rate in the 16 patients after 3-month and 12-month thalidomide treatment in patients was 56.3%. Twelve patients completed the study, the fever improved in all of them, rash improved in 7 patients, and 5 patients stopped using glucocorticoids or other immunosuppressive agents. C-reactive protein was normal in 8 patients and erythrocyte sedimentation rate was normal in 11 patients. Anorexia and nausea occurred in 2 cases, with no other reported drug-related adverse reactions.ConclusionThe largest cohort of monogenic AIDs with the treatment of thalidomide demonstrated that thalidomide can help reduce disease activity and inflammation, reduce the dosage of glucocorticoids, and improve clinical outcomes. Thalidomide is relatively safe in monogenic AIDs.

Diagnosis and Management of the Cryopyrin-Associated Periodic Syndromes (CAPS): What Do We Know Today?

The cryopyrin-associated periodic syndromes (CAPS) are usually caused by heterozygous NLRP3 gene variants, resulting in excessive inflammasome activation with subsequent overproduction of interleukin (IL)-1β. The CAPS spectrum includes mild, moderate, and severe phenotypes. The mild phenotype is called familial cold autoinflammatory syndrome (FCAS), the moderate phenotype is also known as Muckle–Wells syndrome (MWS), and the neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic cutaneous articular syndrome (CINCA) describes the severe phenotype. The CAPS phenotypes display unspecific and unique clinical signs. Dermatologic, musculoskeletal, ocular, otologic, and neurologic disease symptoms combined with chronic systemic inflammation are characteristic. Nevertheless, making the CAPS diagnosis is challenging as several patients show a heterogeneous multi-system clinical presentation and the spectrum of genetic variants is growing. Somatic mosaicisms and low-penetrance variants lead to atypical clinical symptoms and disease courses. To avoid morbidity and to reduce mortality, early diagnosis is crucial, and a targeted anti-IL-1 therapy should be started as soon as possible. Furthermore, continuous and precise monitoring of disease activity, organ damage, and health-related quality of life is important. This review summarizes the current evidence in diagnosis and management of patients with CAPS.

Cryopyrin-Associated Periodic Syndromes and Treatment Options

Cryopyrin-associated periodic syndromes (CAPSs) are a growing family of autoinflammatory diseases, also known as periodic fever syndromes. There are three forms of CAPS: (1) Familial Cold autoinflammatory syndrome or familial cold urticaria, (2) Muckle-wells syndrome, and (3) neonatal-onset multisystem inflammatory disease or chronic infantile neurological cutaneous articular syndrome. Genetic mutations in the NLRP3 gene were found to be present in most patients. The foremost common findings between all the CAPS disorders are rash, fever which is sometimes present at birth or in early childhood, joint problems, and conjunctivitis. More extreme forms of CAPS include more persistent inflammation that can cause hearing loss and meningitis and can lead to mental and developmental delays. Drugs for CAPS target the source of inflammation – which is the over-production of interleukin 1ß by modified cryopyrin inflammasomes. Three drugs are used to treat CAPS: Rilonacept, canakinumab, and anakirna. With these drugs, the prognosis is greatly improved, with most patients having less frequent episodes, decreased buildup of amyloid in the body, and extended life of severe cases up to adulthood.

Overview of the rarest causes of fever in newborns: handy hints for the neonatologist

Neonatal causes of fever are a major source of concern for clinicians. If fever is combined with organ-specific sterile inflammatory manifestations the suspicion of autoinflammatory disorders should be considered, and the list of such conditions starting in the neonatal period includes chronic infantile neurological cutaneous articular syndrome, mevalonate kinase deficiency, deficiency of the interleukin-1 receptor antagonist, otulipenia, STING-associated vasculopathy with onset in infancy and Blau syndrome. Other causes of noninfectious fever that can rarely occur in newborns are Kawasaki disease, Behçet's disease, and hemophagocytic lymphohistiocytosis. Diagnosis of these exceptionally rare disorders is challenging for neonatologists. An early recognition of these complex diseases might lead to use more specific or rational drugs preventing permanent consequences. This review focuses on the rarest causes of fever occurring in the neonatal age with the aim of portraying many protean clinical pictures associated with fever and reviewing the potential available treatments.

Aseptic Μeningitis in Hereditary Autoinflammatory Diseases

Autoinflammatory diseases (ADs) refer to a group of disorders of the innate immune system, mainly monogenic, marked by episodes of systemic inflammation. Aseptic meningitis is a rare neurological manifestation of ADs characterized by meningeal inflammation, negative routine cultures in the cerebrospinal fluid and identical signs and symptoms of bacterial meningitis. Herein, the aim of this review article is to describe the association between aseptic meningitis and ADs, especially in patients with familial Mediterranean fever (FMF) and chronic infantile neurological cutaneous articular (CINCA) syndrome. We will discuss the emerging role of proinflammatory cytokines, such as interleukin 1 (IL-1), interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α), in the pathogenesis of aseptic meningitis in ADs, and will explore recent treatment developments, such as the use of biological agents.

Cryopyrin-Associated Periodic Syndrome (CAPS) Caused by c.943A>G Variant of NLRP3 Gene: Clinical Case

Background. Cryopyrin-associated periodic syndromes is a g roup of rare congenital autoinflammatory diseases such as familial cold autoinflammatory syndrome, Muckle-Wells syndrome and chronic infantile neurological cutaneous articular syndrome. These syndromes are considered as clinical variants of one disease with different intensity of clinical features and severity of pathologic process. The onset of these syndromes is usually on the first year of life, and they start with fever, urticarial rash, various variants of joint diseases (from arthralgia to residual and persistent arthritis) and nervous system disturbances. There are only single case reports of cryopyrin-associated periodic syndromes in Russia. Clinical Case Description. The disease onset was at the age of 1 year 8 months with fever and rash as well as generalized joint syndrome. Autoinflammatory syndrome was suspected due to to results of blood tests, MRI, molecular genetic testing. Exons 2, 3 and 4 of TNFRSF1A gene and exon 4 of NLRP3 gene with nearby introns were studied with the method of direct automated sequencing. The c.943A>G variant in heterozygous state in NLRP3 gene was revealed. The child was treated with IL-1 beta inhibitor (canakinumab) with positive effect. Conclusion. Diagnostics of cryopyrin-associated periodic syndrome in children is the serious challenge. Timely decision with help of molecular genetic methods is crucial for successful target therapy.

High Efficiency of Kanakinumabum for a Patient with a Late Diagnosed Chronic Infantile Neurological Cutaneous Articular Syndrome (CINCA)

The article presents the monitoring of a severe course of CINCA/NOMID syndrome diagnosed at late stages. The use of monoclonal antibodies to IL 1 — kanakinumabum — in a patient with chronic neurological cutaneous and articular syndrome was successful: fever, cutaneous and pain syndromes were completely stopped, joint contractures decreased after one week of therapy. Laboratory parameters of the child’s disease activity (ESR and CRP) became normal after 8 weeks of treatment. Movements in the affected joints recovered completely after 24 weeks; the audiologist noted an improvement in hearing. The above clinical example demonstrates the high efficiency of kanakinumabum for a patient with chronic neurological cutaneous and articular syndrome, and shows the perspective of therapeutic application of IL 1 blocker for patients with CINCA syndrome including advanced stages of the disease. No adverse effects were noted during kanakinumabum therapy.

Successful kidney transplantation during anakinra treatment without complications

Although the incidence of end stage renal failure in patients with autoinflammatory diseases has decreased since the introduction of the interleukin-1 (IL-1)-receptor antagonist anakinra, it is still relatively common. Cessation of anti-IL-1 therapy during and after kidney transplantation will not be possible in most patients because of the risk of recurrence of inflammation. The effect of continued anti-IL-1 therapy on transplantation-related complications is currently unknown. Recently, we have performed kidney transplantation in two patients while on anakinra therapy. The first patient is a 70 year old male, who suffered from febrile episodes since 2004 and was diagnosed with adult onset Still's disease in 2010. He had been using anakinra ever since. Chronic renal insufficiency due to thrombotic microangiopathy had been present since 2005. In September 2014 he received a kidney transplant of a living related donor, under standard immunosuppression (tacrolimus, prednisone and mycophenolate mofetil (MMF)), while anakinra was continued. Kidney function improved rapidly and he could be discharged from the hospital 7 days post transplantation. Until March 2015, he has been readmitted two times: once for a single day because of drainage of a wound abscess, and for 5 days 1 year post-transplantation because of sepsis with unknown cause. He now has adequate and stable transplant function. The other patient is a 20 year old woman with mutation-negative Chronic Infantile Neurologic Cutaneous Articular (CINCA) syndrome. She had been using anakinra since 2004, which was switched to canakinumab in 2012. She was known with chronic renal insufficiency with proteinuria, probably due to recurrent urinary tract infections, vesico-urethral reflux and chronic use of NSAIDs since 2009. Kidney biopsy was contra-indicated. Because of rapidly progressive renal function loss, she received a pre-emptive kidney transplant of a healthy related donor in September 2014, under standard immunosuppression. Canakinumab was switched to anakinra just before transplantation, because of shorter half-life, making it easier to cease in case of complications. Kidney function increased rapidly and she could be discharged 6 days post-transplantation. She had been readmitted a single time for two days because of a primo-EBV and influenza infection in December 2014. She now has normal kidney function. In these two cases we did not find an increase of transplantation-related complications or post-transplantation infectious complications, when kidney transplantation with a standard immunosuppresive regimen was performed during anakinra therapy. It is important to adapt the dosing of anakinra to the kidney function before and after transplantation. Written informated consent for publication of their clinical details was obtained from the patient/parent/guardian/relative of the patient.

PReS13-SPK-1588: Recurrent fevers

Fevers are common in childhood, usually due to infections. Some children however experience recurrent episodes of seemingly unprovoked fevers. These so-called periodic fever syndromes are rare diseases. Clinically they are characterized by generalized inflammation and different combinations of localized tissue inflammation. Skin and joints are often affected in these patients and the long-standing inflammation can lead to irreversible organ damage due to tissue deposition of inflammatory amyloid proteins. Especially the kidney is vulnerable tot his so-called AA-amyloidosis. The spontaneous sterile inflammation in the absence of autoantibodies places the periodic fever syndromes in the same category as systemic juvenile idiopathic arthritis: the group of autoinflammatory diseases. Often these are genetically determined. Over the past 15 years genetic defects have been identified underlying more than twenty such genetic autoinflammatory diseases. These are disorders like Familial Mediterranean Fever, caused by mutations in the MEFV gene, TNF-receptor associated periodic syndrome (TRAPS), caused by mutations in the TNFRSF1A gene and the Chronic Infantile Neurological Cutaneous Articular (CINCA) syndrome, caused by mutations in the NLRP3 gene. Identification of the responsible genes has led to understanding of the pathophysiology and hence to effective targeted therapy. Interleukin-1 has proved to be the central mediator in many of these disorders. This finding in the congenital autoinflammatory diseases has led to novel therapies in more common disorders like interleukin-1 blockade in systemic Juvenile Idiopathic Arthritis. The rarity of the periodic fever syndromes hampers evidence based therapy. International collaboration in the EUROFEVER network has enabled us to better define the clinical picture of these disorders and to select targets for therapeutic research. However, many children currently defy genetic diagnosis. Next generation genetic sequencing efforts will hopefully identify the cause of inflammation in this group of patients. The functional consequences of autoinflammatory diseases are primarily related to the unpredictable fever episodes. However irreversible sequelae, such as hypertrophic arthropathy, chronic renal failure, impaired vision or hearing do occur. Since these are largely preventable by adequate control of inflammation, effective therapy is essential.

PW02-033 - Cytokine profile in CSF in CAPS patients

CAPS is a rare autoinflammatory syndrome caused by autosomal dominant mutations in the NLRP3/CIAS 1 gene on chromosome 1q44 encoding for the cryopyrin protein, an important component of the inflammasome, leading to excessive production of interleukin-1beta (IL-1s). CAPS encompasses three different entities of variable clinical severity: familial cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and chronic infantile neurological cutaneous articular syndrome (CINCA)/ neonatal – onset multisystem inflammatory disease (NOMID). They are all characterised by recurrent episodes of systemic inflammation involving particularly skin, joints, central nervous system and eyes.

The schedule of administration of canakinumab in cryopyrin associated periodic syndrome is driven by the phenotype severity rather than the age

IntroductionInterleukin-1 (IL-1) blockade is the treatment of choice of cryopyrin associated periodic syndromes (CAPS). Anti-IL-1 monoclonal antibody (canakinumab) was recently registered. However no clear data are available on the optimal schedule of administration of this drug. The aim of the present study was to analyse the impact of canakinumab on CAPS patients in daily clinical practice and to identify the best schedule of administration according to age and phenotype.Methods13 CAPS patients (10 children and 3 young adults) treated with canakinumab were followed for 12 months. Clinical and laboratory parameters were collected at each visit. Health-related quality of life (HRQoL) was recorded at month 12. Complete response was defined as absence of clinical manifestations and normal examinations. Clinical and laboratory variables at last follow-up were compared with those registered at the moment of anakinra discontinuation.Resultsseven patients with chronic infantile neurological cutaneous articular (CINCA) syndrome, four patients with Muckle-Wells syndrome (MWS) and two patients with an overlapping MWS/CINCA phenotype were analysed. CINCA patients experienced a higher number of modifications of the treatment (increased dosage or decreased dosing interval) in respect to MWS patients. At the end of the follow-up CINCA patients displayed a higher frequency of administration with a median dose of 3.7 mg/kg (2.1 mg/kg for MWS patients). Canakinumab was withdrawn in a patient with CINCA for incomplete response and poor compliance. The effect of canakinumab on HRQoL was similar to that observed during treatment with anakinra, with the exception of an improvement of the psychosocial concepts after the introduction of canakinumab.ConclusionsThe use of canakinumab in daily practice is associated with persistent satisfactory control of disease activity but needs progressive dose adjustments in more severe patients. The clinical phenotype, rather than the age, represents the main variable able to determine the need of more frequent administrations of the drug at higher dosage.

Cryopyrin-Associated Periodic Syndromes

Cryopyrin-associated periodic syndromes (CAPS) are a group of rare autoinflammatory disorders; many cases of CAPS are caused by mutations in the NLRP3 gene. In these conditions, interleukin (IL)-1 is overproduced, and this overproduction plays a major role in disease onset and progression. CAPS include three variants, ranging in order of increasing severity from familial cold autoinflammatory syndrome, previously termed familial cold urticaria, through Muckle-Wells syndrome, to chronic infantile neurologic cutaneous articular syndrome, also known as neonatal onset multisystemic inflammatory disease. Diagnosis of CAPS is initially based on clinical manifestations and medical history, and later confirmed genetically. CAPS should be suspected when characteristic skin lesions, typical periodic fever episodes, bone/joint manifestations, and CNS involvement are recognized. CAPS are life-long diseases, and early diagnosis and early treatment with IL-1-targeted therapies may improve prognosis.

Bridging the Gap between the Clinician and the Patient with Cryopyrin-Associated Periodic Syndromes

Cryopyrin-associated periodic syndromes are categorized as a spectrum of three autoinflammatory diseases, namely familial cold auto-inflammatory syndrome, Muckle-Wells syndrome and chronic infantile neurological cutaneous articular syndrome. All are caused by mutations in the NLRP3 gene coding for cryopyrin and result in active interleukin-1 release: their rarity and shared clinical indicators involving skin, joints, central nervous system and eyes often mean that correct diagnosis is delayed. Onset occurs early in childhood, and life-long therapy with interleukin-1 blocking agents usually leads to tangible clinical remission and inflammatory marker normalization in a large number of patients, justifying the need to facilitate early diagnosis and thus avoid irreversible negative consequences for tissues and organs.

Biomarkers of inflammatory and auto-immune central nervous system disorders

Inflammatory and auto-immune disorders of the central nervous system are a heterogeneous group of disorders. Many of these disorders are potentially treatable with immune therapies that can reduce disability or prevent death. We review the clinical value of biomarkers which can aid in the diagnosis of paediatric inflammatory and auto-immune central nervous system (CNS) disorders. This review will first describe the clinical usefulness of nonspecific biomarkers of CNS inflammation such as cerebrospinal fluid neopterin and oligoclonal bands. Neopterin is produced by immune and neuronal cells after stimulation by interferon species and is increased in a broad range of inflammatory and auto-immune CNS disorders. Oligoclonal bands represent clonal production of immunoglobulin G in the CNS and are present in demyelinating, auto-immune, and infectious CNS disorders. In addition, we will review new advances in the immunogenetic investigation of familial auto-inflammatory disorders such as Aicardi-Goutières syndrome and Chronic Infantile Neurologic Cutaneous Articular syndrome. Finally, we will review the clinical utility of auto-antibodies in CNS disorders, with specific focus on auto-antibodies that bind to cell surface proteins such as N-methyl-D-asparate receptor, voltage-gated potassium channels, myelin oligodendrocyte glycoprotein, and aquaporin-4. These biomarkers are increasingly important in the recognition and treatment of inflammatory and auto-immune CNS disorders. Like many biomarkers in paediatric practice, it is essential to interpret the findings in the context of the patient history and examination.

Autoinflammatory syndromes: report on three cases

Autoinflammatory syndromes are diseases manifested by recurrent episodes of fever and inflammation in multiple organs. There is no production of autoantibodies, but interleukins play an important role and acute-phase reactants show abnormalities. Our aim was to report on three cases of autoinflammatory syndromes that are considered to be rare entities. The authors describe the clinical features of three patients whose diagnosis were the following: tumor necrosis factor receptor-associated periodic syndrome (TRAPS), chronic infantile neurological cutaneous articular (CINCA) syndrome and familial Mediterranean fever (FMF). All of the patients presented fever, joint or bone involvement and increased acute phase reactants. The genetic analysis confirmed the diagnoses of two patients. The great diversity of manifestations and the difficulties in genetic analyses make the diagnosing of these diseases a challenge.

Síndrome CINCA: presentación de un caso con exacerbación febril de sus lesiones cutáneas

Chronic infantile neurologic cutaneous articular (CINCA) syndrome is a serious chronic systemic inflammatory disease that presents at a young age and that is characterized by skin, joint, and central nervous system disease. Skin symptoms are the first to appear, in the form of a longstanding nonpruritic urticarial rash, with exacerbations coinciding with episodes of fever, arthritis, and enlarged lymph nodes. The findings of biopsy of skin lesions are extremely variable but characterized by perivascular neutrophilic infiltrate.With the discovery of mutations in the CIAS1 gene, which encodes a protein known as cryopyrin, this entity has been classified as one of the cryopyrin-associated autoinflammatory diseases, along with familial cold urticaria and Muckle-Wells syndrome. This discovery has also made available new therapeutic options. We present the case of a boy diagnosed with CINCA syndrome who presented with an outbreak of painful skin lesions and fever. These lesions were thought to be an exacerbation of underlying lesions during an episode of fever.

Cryopyrinopathies: update on pathogenesis and treatment

Cryopyrinopathies are a group of rare autoinflammatory diseases that includes familial cold autoinflammatory syndrome, Muckle-Wells syndrome and chronic infantile neurologic cutaneous articular syndrome (also termed neonatal-onset multisystemic inflammatory disease). These syndromes were initially considered to be distinct disease entities despite some clinical similarities; however, mutations of the same gene have since been found in all three cryopyrinopathies. These diseases, therefore, are not separate but represent a continuum of subphenotypes. The gene in question, CIAS1 (now renamed NLRP3) encodes NALP3 (also known as cryopyrin). NALP3 is an important mediator of inflammation and interleukin 1beta processing. New therapies based on biologic agents that specifically target interleukin 1beta are currently being developed. These new agents have provided very encouraging results for patients with these long-lasting inflammatory conditions--which used to be considered refractory to treatment. The development of therapeutic options for these cryopyrinopathies illustrates effective translation of basic science to clinical practice and the convergence of human genetics and targeted therapies.

Exacerbation of Skin Lesions During Fever in a Patient With Chronic Infantile Neurologic Cutaneous Articular Syndrome

Chronic infantile neurologic cutaneous articular (CINCA) syndrome is a serious chronic systemic inflammatory disease that presents at a young age and that is characterized by skin, joint, and central nervous system disease. Skin symptoms are the first to appear, in the form of a longstanding nonpruritic urticarial rash, with exacerbations coinciding with episodes of fever, arthritis, and enlarged lymph nodes. The findings of biopsy of skin lesions are extremely variable but characterized by perivascular neutrophilic infiltrate. With the discovery of mutations in the CIAS1 gene, which encodes a protein known as cryopyrin, this entity has been classified as one of the cryopyrin-associated autoinflammatory diseases, along with familial cold urticaria and Muckle-Wells syndrome. This discovery has also made available new therapeutic options. We present the case of a boy diagnosed with CINCA syndrome who presented with an outbreak of painful skin lesions and fever. These lesions were thought to be an exacerbation of underlying lesions during an episode of fever.

Autoinflammatory syndromes with a dermatological perspective

The term autoinflammatory syndromes describes a distinct group of systemic inflammatory diseases apparently different from infectious, autoimmune, allergic and immunodeficient ones. Originally, it was almost synonymous with clinically defined hereditary periodic fever syndromes, including familial Mediterranean fever, hyper immunoglobulin D syndrome with periodic fever and tumor necrosis factor receptor-associated periodic syndrome. Similar but distinct periodic fever syndromes accompanied by urticarial rash, familial cold autoinflammatory syndrome, Muckle-Wells syndrome and chronic infantile neurological cutaneous articular syndrome, have all been reportedly associated with CIAS1 mutations and are collectively called cryopyrin-associated periodic syndromes. Consequently, the concept of autoinflammatory syndromes has been spread to contain other systemic inflammatory diseases: rare hereditary diseases with or without periodic fevers, such as pyogenic sterile arthritis, pyoderma gangrenosum and acne syndrome, Blau syndrome and chronic recurrent multifocal osteomyelitis, and the more common collagen disease-like diseases, such as Behcet's disease, Crohn's disease, sarcoidosis and psoriatic arthritis. These diseases are all caused by or associated with mutations of genes regulating innate immunity and have common clinical features accompanied with activation of neutrophils and/or monocytes/macrophages. In this review, major autoinflammatory syndromes are summarized and the pathophysiology of related skin disorders is discussed in association with dysregulated innate immune signaling.