Chronic Infantile Neurological Cutaneous And Articular Syndrome Research Articles

Tumor necrosis factor-alpha blockade ameliorates inflammatory response in two children with chronic infantile neurological, cutaneous and articular syndrome.

Chronic infantile neurological, cutaneous and articular (CINCA) syndrome is a rare autoinflammatory disease caused by monogenic defects in the NLRP3 gene. Pro-inflammatory cytokines such as interleukin (IL)-1β play a crucial role in the pathogenesis, and IL-1 receptor antagonists have been regarded as the mainstay therapy. Endogenous tumor necrosis factor (TNF)-α was found recently to be involved in the onset of the disease. Here, we report two Chinese children with CINCA syndrome who had elevated serum levels of TNF-α, with one carrying a novel mutation of c.1330T/G (p.444Phe/Val) in exon 3 of the NLRP3 gene. Anti-TNF-α (etanercept) therapy successfully alleviated both clinical symptoms and systemic inflammation after 6months. These results suggest the complexity of the mechanisms of the disease and that TNF-α blockade will broaden the therapeutic approach for a subset of patients.

Autoinflammatory retinopathy in chronic infantile neurological cutaneous and articular (CINCA) syndrome

Chronic infantile neurological cutaneous and articular (CINCA) syndrome is a rare autosomal dominant autoinflammatory disease. We report the cases of monozygotic twins with CINCA syndrome whose predominant ocular manifestation was inflammatory rod-cone retinal dystrophy. Atypically, there were significant differences between twins in phenotype severity, suggestive of epigenetic differences and/or involvement of environmental factors.

Early progression of atherosclerosis in children with chronic infantile neurological cutaneous and articular syndrome.

Chronic inflammation plays a key role in the development of atherosclerosis. Early progression of atherosclerosis has been reported in patients with RA. Cryopyrin-associated periodic syndromes (CAPS) are autosomal dominant autoinflammatory disorders caused by heterozygous NLRP3 gene mutations. Chronic infantile neurological cutaneous and articular (CINCA) syndrome is the most severe form of CAPS and patients display early onset of rash, fever, uveitis and joint manifestations. However, there has been no previous report on atherosclerosis in patients with CAPS. The objective of this study is to assess the development of atherosclerosis in patients with CINCA syndrome. Intima-media thickness (IMT) of the carotid arteries, stiffness parameter β, ankle brachial index (ABI) and pressure wave velocity (PWV) were evaluated by ultrasonography in 3 patients with CINCA syndrome [mean age 9.0 years (S.D. 5.3)] and 19 age-matched healthy controls [9.3 years (S.D. 4.3)]. The levels of carotid IMT, stiffness parameter β and PWV in CINCA syndrome patients were significantly higher than those in healthy controls [0.51 mm (S.D. 0.05) vs 0.44 (0.04), P = 0.0021; 6.1 (S.D. 1.7) vs 3.9 (1.0), P = 0.0018; 1203 cm/s (S.D. 328) vs 855 (114), P = 0.017, respectively]. Patients with CINCA syndrome showed signs of atherosclerosis from their early childhood. The results of this study emphasize the importance of chronic inflammation in the development of atherosclerosis. Further analysis on atherosclerosis in young patients with CINCA syndrome may provide more insights into the pathogenesis of cardiovascular disease.

SomaticNLRP3mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes

: Familial cold autoinflammatory syndrome, Muckle-Wells syndrome (MWS), and chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome are dominantly inherited autoinflammatory diseases associated to gain-of-function NLRP3 mutations and included in the cryopyrin-associated periodic syndromes (CAPS). A variable degree of somatic NLRP3 mosaicism has been detected in ≈35% of patients with CINCA. However, no data are currently available regarding the relevance of this mechanism in other CAPS phenotypes. To evaluate somatic NLRP3 mosaicism as the disease-causing mechanism in patients with clinical CAPS phenotypes other than CINCA and NLRP3 mutation-negative. NLRP3 analyses were performed by Sanger sequencing and by massively parallel sequencing. Apoptosis-associated Speck-like protein containing a CARD (ASC)-dependent nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB) activation and transfection-induced THP-1 cell death assays determined the functional consequences of the detected variants. A variable degree (5.5-34.9%) of somatic NLRP3 mosaicism was detected in 12.5% of enrolled patients, all of them with a MWS phenotype. Six different missense variants, three novel (p.D303A, p.K355T and p.L411F), were identified. Bioinformatics and functional analyses confirmed that they were disease-causing, gain-of-function NLRP3 mutations. All patients treated with anti-interleukin1 drugs showed long-lasting positive responses. We herein show somatic NLRP3 mosaicism underlying MWS, probably representing a shared genetic mechanism in CAPS not restricted to CINCA syndrome. The data here described allowed definitive diagnoses of these patients, which had serious implications for gaining access to anti-interleukin 1 treatments under legal indication and for genetic counselling. The detection of somatic mosaicism is difficult when using conventional methods. Potential candidates should benefit from the use of modern genetic tools.

MRP8 and MRP14, phagocyte-specific danger signals, are sensitive biomarkers of disease activity in cryopyrin-associated periodic syndromes

ObjectivesTo assess the sensitivity of the phagocyte-specific molecules myeloid-related protein (MRP) 8 and MRP14 (calprotectin) for monitoring disease activity during anti-interleukin (IL)-1 therapies in patients with cryopyrin-associated periodic syndromes (CAPS),...

Clinical Manifestations and Longterm Followup of a Patient with CINCA/NOMID Syndrome: Figure 1.

To the Editor: Chronic infantile neurological cutaneous and articular (CINCA) syndrome1 is a rare, genetic autoinflammatory disease that belongs to the spectrum of cryopyrin-associated periodic syndromes (CAPS), along with the familial cold autoinflammatory syndrome and the Muckle-Wells syndrome. CAPS are associated with autosomal-dominant mutations in the NLRP3 gene (formerly CIAS1), which encodes the protein cryopyrin2,3. Within the spectrum of CAPS, the CINCA syndrome, also known as neonatal-onset multisystem inflammatory disease (NOMID), is considered to be the most severe phenotype. A triad of urticarial rashes, neurological manifestations, and arthropathy, accompanied by recurrent fever episodes and systemic inflammation, originally defined CINCA syndrome1,4. Systemic AA-amyloidosis is a serious longterm complication that can lead to renal failure and increased mortality4. We describe a 23-year-old Caucasian woman who had developed urticarial skin lesions, lymphadenopathy, and recurrent febrile episodes within the first week after birth. The persistent nonpruritic and migratory urticaria were most pronounced at the patient’s face, trunk, and lower limbs and would intensify during recurrent attacks of fever (Figure 1D). Acute-phase reactants were constantly elevated [C-reactive protein (CRP) up to 170 mg/l, serum amyloid … Address correspondence to Dr. N. Blank, University of Heidelberg, Internal Medicine 5, Division of Rheumatology, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany. E-mail: norbert.blank{at}med.uni-heidelberg.de

Derivation of Engraftable Myogenic Precursors from Murine ES/iPS cells and Generation of Disease-specific iPS cells from Patients with Duchenne Muscular dystrophy (DMD) and Other Diseases

Duchenne muscular dystrophy (DMD), caused by mutations in the X-linked dystrophin gene, is a progressive, lethal muscle disorder with no effective cure despite extensive research efforts in the field. In recent years, many different myogenic cells originating from adult tissues have been reported. However, the establishment of a reliable cell source is required for clinical application. Embryonic stem (ES) cells and the recently established induced pluripotent stem (iPS) cells are totipotent stem cells that are infinitely expandable and capable of differentiating into all types of somatic cells. In this study, we established a novel protocol to derive myogenic precursors from murine ES iPS cells with a monoclonal antibody SM C-2.6 that recognizes quiescent satellite cells. SM C-2.6-positive cells are highly myogenic and efficiently differentiate into myofibers both in vitro and in vivo. Furthermore, the transplanted cells demonstrated extensive muscle regeneration activity in a second injury model without cell transplantation as well as long-term engraftment up to 24 weeks. Both these results indicated that the transplanted cells act as muscle stem cells as well as myogenic precursors. Our data suggest that iPS cells are a new attractive cell source for cell-based therapies. Recently, we succeeded the generation of disease-specific iPS cells from skin fibroblasts of a DMD patient and his parents by the reprogramming with Oct3 4, Sox2, Klf4 and cMyc. Generation of patient-specific iPS cells indicates possible strategy of regenerative medicine for DMD with normal or patient iPS cells. Finally, I will talk about other diseasespecific iPS cells from the patients with CINCA (Chronic Infantile Neurological Cutaneous and Articular) syndrome with somatic mosaicism

12.3 Long-term follow up of patients with CINCA syndrome: efficacy and tolerability of Anakinra treatment

Oral presentation We report the long-term follow up of 15 Italian patients affected by Chronic Infantile Neurological Cutaneous and Articular (CINCA) syndrome (7 males and 8 females, mean age 13, 5 years). We report the updating of the survey following the introduction of the IL-1 receptor antagonist therapy (Anakinra). 11 patients were treated with subcutaneous injections, at a daily dosage of 1 mg/Kg in children and up to 100 mg in adults, 2 refused the therapy, and the others did not require the treatment due to a mild presentation of the disease so far. In treated patients fever, rash, articular involvement, conjunctivitis, uveitis disappeared or improved. Laboratory data normalized in most of the cases within the first month. The neurologic symptoms ameliorated, papilledema disappeared in four out of eleven treated patients while dysmorphisms (typical facies) and bone alterations constantly persist. No further Cinca related signs and symptoms appeared after Anakinra was introduced. The medication showed very good tolerability: we observed local erythema at the site of injection in 2 out of 11 subjects, and oral aphtosys in another. The untreated subjects kept presenting all their symptoms of CINCA syndrome and the disease went on with its poor manifestation. We found no differences in the response to Anakinra therapy between CIAS1-mutated and not mutated patients. In summary, our study demonstrates that a long lasting treatment with Anakinra appears to be safe and highly effective in patients affected by CINCA syndrome.

Anakinra therapy for CINCA syndrome with a novel mutation in exon 4 of the CIAS1 gene

AbstractWe report on a patient with chronic infantile neurological cutaneous and articular (CINCA) syndrome. Sequence analysis revealed a novel missense mutation in exon 4 of the CIAS1 gene. The patient was unresponsive to several treatments including prednisolone, immunosuppressants (azathioprine and cyclosporin), disease‐modifying antirheumatic drugs (DMARDs: penicillamine, salazopyrin and methotrexate) and the tumour necrosis factor‐alpha (TNF‐α)‐blocker infliximab. At 32 mo of age, administration of the recombinant human interleukin‐1 receptor antagonist anakinra commenced, which caused an immediate and marked improvement in the clinical symptoms and laboratory test results. Continuous inhibition of the inflammation required a dose of 1.0 mg/kg every 12 h. Conclusion: Following the diagnosis of CINCA syndrome, anakinra treatment should be commenced as the first line of therapy.

Anakinra therapy for CINCA syndrome with a novel mutation in exon 4 of the CIAS1 gene

We report on a patient with chronic infantile neurological cutaneous and articular (CINCA) syndrome. Sequence analysis revealed a novel missense mutation in exon 4 of the CIAS1 gene. The patient was unresponsive to several treatments including prednisolone, immunosuppressants (azathioprine and cyclosporin), disease-modifying antirheumatic drugs (DMARDs: penicillamine, salazopyrin and methotrexate) and the tumour necrosis factor-alpha (TNF-a)-blocker infliximab. At 32 mo of age, administration of the recombinant human interleukin-1 receptor antagonist anakinra commenced, which caused an immediate and marked improvement in the clinical symptoms and laboratory test results. Continuous inhibition of the inflammation required a dose of 1.0 mg/kg every 12 h. Following the diagnosis of CINCA syndrome, anakinra treatment should be commenced as the first line of therapy.

A novel CIAS1mutation in a Japanese patient with chronic infantile neurological cutaneous and articular syndrome

We report here a Japanese patient with chronic infantile neurological cutaneous and articular (CINCA) syndrome with a novel mutation in the CIAS1gene. An 18-month-old girl was referred to our hospital for the evaluation of skin manifestations. She was born at 36 weeks of gestation with a birth weight of 1584 g. Shortly after birth, she had generalised maculopapular erythema, an increased WBC count, and an increased serum C-reactive protein level. On admission, her weight, height, and head circumstance were 8150 g (-1.6 SD), 72 cm (-2.6 SD), and 49.5 cm (+2.3 SD), respectively. The physical examination revealed maculopapular erythema on her trunk (Fig. 1A) and extremities, a wide fontanelle (4·5 cm), frontal bossing, and a saddle nose. Her joints were normal. Haematological investigations revealed the following: a WBC count of 22.01·10/l (48.5% neutrophils, 42.5% lymphocytes, 0.5% monocytes, 7.5% eosinophils and 1.0% atypical lymphocytes), a haemoglobin of 8.0 g/dl, and a platelet count of 590·10/l. The ESR was 91 mm/h. Serum IL-1b and IL-6 concentrations were 7.51 pg/ml (less than 5.0 pg/ml in normal controls) and less than 5.0 pg/ml (less than 5.0 pg/ml in normal controls), respectively. The CSF examination showed a pleocytosis (156 cells/ll, 59.4% neutrophils, and 40.6% mononuclear cells), a protein concentration of 110 mg/ dl, and a glucose concentration of 27 mg/dl. IL-1b and IL-6 concentrations were less than 5.0 pg/ml (less than 5.0 pg/ml in normal controls) and 312 pg/ml (less than 5.0 pg/ml in normal controls), respectively. The ophthalmological examination revealed bilateral papilloedema. A skin biopsy was performed and an infiltration of inflammatory cells, predominantly polymorphonuclear cells, was observed in the upper dermis and perivascular area (Fig. 1B). As shown in Fig. 1C, a heterozygous mutation (c.1431C>A, N477K) was observed within the NACHT (NAIP, CIITA, HET-E, and TP-1) domain in exon 3 of the CIAS1gene, which has not been previously reported. The mutation was not observed in both parents (Fig. 1C). Moreover, this mutation was not observed among 100 healthy Japanese donors by using allelespecific PCR (data not shown). Mutations in the CIAS1gene were recently found to be associated with a spectrum of auto-inflammatory disorders that include CINCA syndrome, Muckle-Wells syndrome, and familial cold urticaria [1,3]. The CIAS1gene product, cryopyrin, has been implicated in the regulation of inflammation [5]. Previous reports indicated that 6 among 13 CINCA patients had CIAS1mutations [1], and almost all the CIAS1mutations were identified in exon 3 that encodes the NACHT domain [2,6]. The mutation found in this patient was within the NACHT domain but not in the hotspots [6]. Since the NACHT domain plays a crucial role in protein oligomerisation, the mutant cryopyrin may have an increased propensity to oligomerize spontaneously, which leads to the binding to the apoptosis-associated specklike protein containing a card, inflammasome formation, activation of caspase-1, and over-secretion of IL-1b [5]. The effectiveness of IL-1 receptor antagonist in patients with CINCA syndrome strongly suggests the central role of IL-1b in this disorder [4]. IL-1 receptor antagonist will be given to this patient. H. Takada (&) AE K. Kusuhara AE A. Nomura AE S. Ohga AE T. Hara Department of Paediatrics, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582 Fukuoka, Japan E-mail: takadah@pediatr.med.kyushu-u.ac.jp Tel.: +81-92-6425421 Fax: +81-92-6425435

Chronic infantile neurological cutaneous and articular syndrome: a new case with pseudotumor cerebri

Objectives To report the case of a seven-year-old girl who had a bilateral papilledema with chronic cutaneous and articular manifestations. Chronic infantile neurological cutaneous and articular (CINCA) syndrome is a rare pediatric multisystem inflammatory condition. Optic disc abnormalities are the most common ocular manifestation of this syndrome and consist of optic-disc swelling, pseudopapilledema, and optic atrophy. Results: We report the case of a seven-year-old girl who had cutaneous manifestations from the age of three months, articular manifestations from the age of three years, and recurrent fever. Papilledema was the sign that led us to suspect the diagnosis of the CINCA syndrome, which was confirmed by our finding of the D303N de-novo mutation of the CIAS1 gene. The pathophysiology of papilledema remains unknown, but some reports suggest that the chronic meningoencephalitis associated with the CINCA syndrome may explain it. In our patient, the cause of papilledema was pseudotumor cerebri. She had increased intracranial pressure with normal composition of the cerebrospinal fluid, normal neuroimaging studies (computed tomography and magnetic resonance imaging), and absence of localizing findings on neurologic examination. The papilledema did not resolve either with repeated lumbar punctures or acetazolamide and eventually a ventriculoperitoneal shunt had to be performed. Conclusion: The CINCA syndrome is rare and its diagnosis requires the joint workup of different specialists.

Chronic Infantile Neurological Cutaneous and Articular Syndrome Is Caused by Mutations in CIAS1, a Gene Highly Expressed in Polymorphonuclear Cells and Chondrocytes

Chronic infantile neurological cutaneous and articular (CINCA) syndrome is a severe chronic inflammatory disease of early onset, characterized by cutaneous symptoms, central-nervous-system involvement, and arthropathy. In the present study, we report, in seven unrelated patients with CINCA syndrome, distinct missense mutations within the nucleotide-binding site of CIAS1, a gene encoding cryopyrin and previously shown to cause Muckle-Wells syndrome and familial cold urticaria. Because of the severe cartilage overgrowth observed in some patients with CINCA syndrome and the implications of polymorphonuclear cell infiltration in the cutaneous and neurological manifestations of this syndrome, the tissue-specific expression of CIAS1 was evaluated. A high level of expression of CIAS1 was found to be restricted to polymorphonuclear cells and chondrocytes. These findings demonstrate that CIAS1 missense mutations can result in distinct phenotypes with only a few overlapping symptoms and suggest that this gene may function as a potential inducer of apoptosis.

Pseudomaladie périodique avec hyperimmunoglobulinémie D: une histoire sans fin de début anténatal probable

Diagnosis of inflammatory non-infectious diseases with a neonatal onset is often retrospective. It may lead to aggressive and iatrogenic procedures. A 6-year-old boy was suffering, since birth, from recurrent febrile attacks including rashes, gastrointestinal manifestations and inflammatory joint involvement. This syndrome, partially improved with steroids, could have been of antenatal onset. Since the age of 4 years, the patient is considered as having hyper-IgD syndrome (HIDS). HIDS must be distinguished from familial Mediterranean fever. Patients suffer from recurrent fever concomitant to inflammatory joint involvement, abdominal distress, skin lesions, swollen lymph nodes and hepatosplenomegaly (especially seen in children). All patients have high serum IgD (> 100 UI/mL) and IgA levels. Nevertheless, a high IgD level is not specific. Our case could also be part of the CINCA (chronic, infantile, neurological, cutaneous and articular) syndrome, which includes similar early manifestations associated with a constant neurological and frequent ophthalmological involvement and epiphyseal changes; to date, these last three manifestations are not present in our patient. HIDS and CINCA syndrome are not known to be modified by any effective therapeutic agent. When presenting at birth, these inflammatory diseases must be considered as entities with a rarely described potential severity.