The First Case Series of Cryopyrin-Associated Periodic Syndrome in Korea

Cryopyrin-associated periodic syndrome (CAPS) is a hereditary autoinflammatory syndrome caused by mutations in NLRP3 (encoding cryopyrin), which presents with fever, fatigue and arthralgia. Thus far, however there have been no reports of CAPS in Korea. Herein, we report 3 cases of CAPS for the first time in Korea. The first case, a 28-year-old man with recurrent urticaria, arthralgia and fever induced by cold, all of which were observed in his father, showed elevated erythrocyte sedimentation rate and C-reactive protein. He exhibited a p.Gly303Asp variant of the NLPR3 gene. The second case, a 2-year-old girl who had recurrent urticaria, arthritis and oral and genital ulcers, was positive for HLA B51 and a p.Glu569Lys mutation in exon 3 of the NLRP3 gene. Administration of anakinra greatly improved her symptoms. The third case, a 4-year-old boy who presented with recurrent urticaria, arthralgia, and fever, exhibited a p.Val72Met mutation in exon 1 of the NLRP3 gene. Administration of tocilizumab improved all of his symptoms. This small case series suggests that clinicians consider CAPS and conduct genetic studies when arthralgia and fever are accompanied by urticaria in Korea.

The First Report on Clinical Manifestation of Cryopyrin-Associated Periodic Syndrome in Korean Children

PURPOSE: The aim of this study was to evaluate the clinical characteristics of children diagnosed as cryopyrin-associated periodic syndrome (CAPS) in Korea. METHODS: Diagnosis was made based on clinical features and confirmed by a mutation in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene. Especially, osteocartilaginous overgrowth in the patella or distal femur was so characteristic that its presence warranted a diagnosis of chronic infantile neurologic cutaneous and articular/NOMID. RESULTS: We observed the clinical features of 9 Korean CAPS patients. All the patients suffered from an urticarial rash with recurrent fever. Among the 9 patients, 6 presented with rash and 4 with fever on the 1st or 2nd days of birth. Eight patients showed myalgia, and 7 patients showed arthralgia in the joints, and 6 patients showed radiologic findings of arthropathy including cupping of the metaphysis, excessive growth of the epiphysis, osteopenia or overgrowth of the cartilage. Four patients showed brain atrophy, enlarged ventricles or leptomeningeal enhancement on magnetic resonance imaging. Intellectual disability was observed in 1 patient. Five patients had eye involvement as conjunctivitis, uveitis, chorioretinitis, avascular area or papillary edema, and 3 patients showed progressive hearing loss. All 9 patients showed increased C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). CONCLUSIONS: All the patients carried a mutation on exon 3 of the CIAS1 gene. After the anakinra (interleukin-1 receptor antagonist) therapy, the fever and rash immediately disappeared, and CRP and ESR were improved.

Doenças autoinflamatórias em adultos: abordagem prática ao diagnóstico baseada em um caso clínico / Autoinflammatory diseases in adults: practical approaches to diagnosis based on a clinical case

As doenças autoinflamatórias são doenças inflamatórias raras cujo cerne imunológico baseia-se na imunidade inata. A maioria das doenças autoinflamatórias tem início na idade pediátrica, mas pouco se sabe sobre as doenças que se iniciam na vida adulta. O diagnóstico é feito por exclusão, e, quando possível, com auxílio de técnicas moleculares. Este artigo tem como objetivo relatar um caso de doença autoinflamatória de início na vida adulta e a partir dele estabelecer fluxograma de auxílio ao diagnóstico.

Autoinflammatory diseases are rare inflammatory conditions whose immunopathology relies essentially on innate immunity. The majority of autoinflammatory diseases have their onset in childhood, but little is known about diseases that initiate in adulthood. Diagnosis is made by exclusion and with the aid of molecular techniques whenever possible. This article describes a case of autoinflammatory disease that started in adulthood, and aims to propose a flowchart to aid in the diagnosis of these conditions.

Skin symptoms as diagnostic clue for autoinflammatory diseases

ABSTRACT Autoinflammatory disorders are immune-mediated diseases with increased production of inflammatory cytokines and absence of detectable autoantibodies. They course with recurrent episodes of systemic inflammation and fever is the most common symptom. Cutaneous manifestations are prevalent and important to diagnosis and early treatment of the syndromes. The purpose of this review is to emphasize to dermatologists the skin symptoms present in these syndromes in order to provide their early diagnosis.

Cryopyrin-associated periodic syndrome:one case report / 临床儿科杂志

Objective To investigate the clinical features and genetic basis of cryopyrin-associated periodic syndrome (CAPS). Methods The clinical manifestations, laboratory tests, and genetic tests of one case of CAPS were retrospectively analyzed. The related literatures were reviewed. Results A 7 year and eight month old male patient had recurrent fever for 7 years and his whole body was covered with patchy red rash which was itchy and faded with pressure. The limbs and joints were normal. The levels of high-sensitivity C-reactive protein, erythrocyte sedimentation rate, rheumatoid factors were increased. The patient had fundus arteriosclerosis, double conjunctival lesions and nerve deafness on both sides. There was no mutation found in NLRP3 gene coding region, but a heterozygous mutation (-2667G>T) had been found in 5 ' untranslated region. Compared with normal control, the mRNA level of NLRP3 increased 4.2 times and the expressions of IL-1βand IL-18 gene increased 2.2 (P=0.002) and 1.2 times (P>0.05). Conclusions The clinical features of CAPS can be recurrent fever, rash, and joint involved. The oph-thalmologic abnormalities and varying degrees of deafness may occur during the progression. The test of NLRP3 gene may help diagnosis.

Autoinflammatory Diseases

Autoinflammatory diseases (AIDs) refer to a broad range of genetically mediated conditions characterized by recurrent attacks of systemic inflammation with typical manifestations of fever, rash, serositis, lymphadenopathy, and musculoskeletal symptoms. The discovery of genetic basis for these conditions have led to the understanding of novel intracellular receptors for infectious and noninfectious danger signals in innate immunity. Innate immunity has a key role in the development of AIDs, in contrast with autoimmune disease, which arise from problems in adaptive immunity. Advances in understanding the molecular mechanisms of intracellular inflammatory cascades have led to renewed interest in its role in the pathogenesis of more common non-genetic autoinflammatory rheumatic conditions, such as Behcet's disease, gouty arthritis, Adult onset Still's diseases, and systemic onset juvenile arthritis. The characterization of cryopyrin (inflammasome) and its significant role in the activation of proinflammatory cytokines, such as IL-1beta and TNF-alpha in the development of AIDs, has provided rational targets of anti-cytokine biologic treatment for some of these conditions.

Enfermedades Autoinflamatorias / Autoinflammatory Diseases

Presentamos un artículo de revisión sobre las enfermedades autoinflamatorias, narrando su origen histórico y describiendo la estructura proteica y molecular del Inflamosoma, la clasificación actual de los trastornos autoinflamatorios y una descripción de las características inmunogenéticas y clínicas más sobresalientes de cada enfermedad.

We present a review article on the autoinflammatory diseases, narrating its historical origin and describing the protein and molecular structure of the Inflammasome, the current classification of the autoinflammatory diseases and a description of the immunogenetics and clinical characteristics more important of every disease.

Effect of LPS on human CIAS1 gene expression and sequence analysis of its mutation region-NACHT domain / 中国病理生理杂志

AIM: To observe the effect of LPS on CIAS1 gene expression and to analyze the function-structure relationship of its mutation region, the NACHT domain of cryopyrin. METHODS: RT-PCR was used to detect the expression of CIAS1 gene in human leucocytes in the presence of LPS. The methods of molecular modeling and bioinformatics were used to observe the relationship of the structure-function of NACHT domain in human CIAS1 gene. RESULTS: LPS increased CIAS1 mRNA expression in a dose-dependent manner. However, the stimulation with LPS at a concentration of 100 mg/L at different time points showed the pattern of early down-regulation and later up-regulation of CIAS1 mRNA expression. The sequence analysis suggested that the motifs Walker A and Walker B, to which the ATP and Mg~ 2+ can bind, were found in the NACHT domaim of CIAS1 gene encoded product cryopyrin. The main points of the disease-associated mutation showed the close relation in sequence and structure to these motifs. The binding sites of Ca~ 2+ and polysaccharide were observed in the leucine rich repeats region of cryopyrin. CONCLUSION: Cryopyrin may act as an important regulator in inflammation. LPS induces human leukocytes to express the CIAS1 gene product.