Chronic Infantile Neurological Cutaneous And Articular Research Articles

Clinical spectrum of Cryopyrin-associated Periodic Syndrome associated with a single nucleotide variant of the NLRP3 gene in a Puerto Rican family

Cryopyrin-associated Periodic Syndromes (CAPS) are a group of autoinflammatory disorders of varying degrees of severity that include familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID, or as Chronic Infantile Neurological, Cutaneous, and Articular (CINCA). There is one case per one million inhabitants in the United States. Cryopyrinopathies arise from mutations in the NOD-like receptor protein 3 (NLRP3) gene, which assembles with the cysteine protease caspase-1 to form the NLP3 and releases several proinflammatory cytokines, including IL-1β. An autosomal dominant GOF mutation of the NLRP3 gene causes the overproduction of IL-1β, inducing excessive inflammation and even permanent organ damage. We describe a Puerto Rican family of three with Cryopyrin-associated Periodic Syndrome and varying degrees of severity that received Canakinumab. A 40-year-old mother and her two sons, ages 26 and 20, presented for an evaluation of cold-induced maculopapular rash, arthralgia, and lower extremity swelling. Their symptoms initially presented at birth and continued into their adulthood. The episodes started briefly after exposure to cool temperatures and lasted hours to days. High fevers and chills often accompany episodes. They all presented with chronic leukocytosis and high inflammatory laboratory values. The oldest son showed the most intense, enduring flares and severe complications. At age 1, he was diagnosed with neuroblastoma of the right adrenal gland and achieved remission with a combination of surgical resection, chemotherapy, and radiotherapy. He subsequently required multiple hospitalizations due to episodes of high fevers as a child. He also developed severe leptomeningeal inflammation at age 12 and underwent an exploratory craniotomy that yielded normal findings. The three family members underwent genetic testing two decades after the children were born, revealing a heterozygous missense mutation. They had a single nucleotide variant of the NPL3 gene c.913G>A (p. Asp305Asn) that has been linked to CAPS. Severe inflammatory neurologic symptoms and familial cold urticaria were the clues for the diagnostic suspicion of CAPS. IL-1β antagonists have been demonstrated to be effective in substantially reducing inflammatory markers and thus decreasing inflammation-related signs and symptoms. Residence in the tropics could have contributed to delayed diagnosis.Table 1General characteristics of the Cryopyrin-associated Periodic SyndromesFCASMWSNOMID/CINCAGenes and pattern of inheritanceNLRP3 gene ADNLRP3 gene ADNLRP3 gene ADEpidemiology Age of onset1:1 million.1Infancy1:1 million1Infancy1:1 million1Neonatal/early infancyCutaneous NeurologicUrticaria-like rash Headaches with fever after cold exposureUrticaria-like rash Headaches with fever during flares. Uncommon to have other CNS symptoms. 3Urticaria-like rash Headaches, fever, chronic aseptic meningitis, and high CNS pressure. Many develop mental or cognitive impairment.AuditoryMild hearing lossSensorineural hearing loss starting in adolescenceSensorineural hearing loss from infancy/childhoodOphthalmicConjunctivitis during flaresConjunctivitis during flaresPapilledema, uveitis, iritis, conjunctivitis, and vision lossLymphaticNot notedMay be notedMay have enlarged lymph nodesJointsArthralgiaArthralgia, stiffness, and swelling during flaresArthralgia, stiffness, and swelling during flaresLaboratory valuesHigh ESR, CRP, SAA, and leukocytosis with flaresHigh ESR, CRP, SAA, and leukocytosis with flaresChronically elevated ESR, CRP, SAA, and leukocytosisFCAS, Familial cold autoinflammatory syndrome; MWS Muckle Wells Syndrome; CINCA/NOMID, chronic infantile neurologic, cutaneous, and articular syndrome/neonatal-onset multisystem inflammatory disease.

Giant pattern VEPs in children.

Our aim is to elaborate the clinical significance of giant amplitude pattern reversal visual evoked potentials (VEPs) in children. 'Giant' amplitude VEPs exceed the upper 97.5th centile, 90% CI for age. We scrutinised 2750 pattern VEPs recorded to international standards between Jan 2015 and 2017 from children aged 16 years and under, attending a specialist children's hospital. Twenty seven children, median age 6yrs, (range 1-16yrs), were identified with giant VEPs (P100 amplitude range 65-163μV). Most, 22/27 (81%), had conditions associated with a risk of raised ICP. Sixteen of these twenty two children had craniosynostosis; six multi-sutural and eight single suture disease. Others had Idiopathic Intracranial Hypertension, arachnoid cyst, NF1 with shunted hydrocephalus, chronic infantile neurological cutaneous and articular (CINCA) syndrome, nephrotic cystinosis and obstructive sleep apnoea. Five children presented with a range of conditions, some associated with seizures some symptomatic, but as yet undiagnosed. Frequent structural associations were optical coherence tomography measures of optic disc maximum anterior axial horizontal retinal thickness projection >160μm and neuro-radiological findings of CSF effacement and copper beaten appearance. Ultrasonography measures of optic nerve sheath diameters varied, but in one child took 2 years to resolve after treatment for raised ICP. Optic disc gradings by fundoscopy were mostly normal, as were visual acuities. Raised ICP was confirmed by gold standard ICP bolt measurements in five of seven children tested. These data suggest that rICP should be considered if a child has sustained giant amplitude VEPs at normal latency.

Necrotizing Funisitis as an Intrauterine manifestation of Cryopyrin-Associated Periodic Syndrome: a case report and review of the literature

BackgroundCryopyrin-associated periodic syndrome (CAPS) is a life-long, autoinflammatory disease associated with a gain-of-function mutation in the nucleotide-binding domain, leucine-rich repeat family, pyrin domain containing 3 (NLRP3) gene, which result in uncontrolled production of IL-1β and chronic inflammation. Chronic infantile neurologic cutaneous and articular (CINCA) syndrome/neonatal-Onset multisystem inflammatory disease (NOMID) is the most severe form of CAPS. Although the first symptoms may be presented at birth, there are few reports on the involvement of the placenta and umbilical cord in the disease. Therefore, we present herein a preterm case of CINCA/NOMID syndrome and confirms intrauterine-onset inflammation with conclusive evidence by using fetal and placental histopathological examination.Case presentationThe female patient was born at 33weeks of gestation by emergency caesarean section and weighted at 1,514 g. The most common manifestations of CINCA/NOMID syndrome including recurrent fever, urticarial rash, and ventriculomegaly due to aseptic meningitis were presented. She also exhibited atypical symptoms such as severe hepatosplenomegaly with cholestasis. The genetic analysis of NLRP3 revealed a heterozygous c.1698 C > G (p.Phe566Leu) mutation, and she was diagnosed with CINCA/NOMID syndrome. Further, a histopathological examination revealed necrotizing funisitis, mainly inflammation of the umbilical artery, along with focal neutrophilic and lymphocytic villitis.ConclusionsThe necrotizing funisitis, which only involved the artery, was an unusual observation for chorioamnionitis. These evidences suggest that foetal inflammation, probably due to overproduction of IL-1β, caused tissue damage in utero, and the first symptom of a newborn with CINCA/NOMID.

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.

Recognising and understanding cryopyrin-associated periodic syndrome in adults.

Cryopyrin-associated periodic syndrome (CAPS) is a group of rare hereditary autoinflammatory diseases characterised by recurrent flares of mild to severe systemic inflammation and fever. CAPS is the umbrella term for a spectrum of individual conditions, namely familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic, cutaneous and articular (CINCA) syndrome. The flare symptoms include fever, fatigue, rashes, headaches, arthralgia and myalgia that can last for a few hours or for several days. These symptoms are debilitating, contributing to poor quality of life for patients if left untreated. Serious life-changing complications such as hearing loss, blindness and AA amyloidosis resulting in kidney failure can occur. Until recently, treatment of the disease was symptomatic using non-steroidal anti-inflammatory and immunosuppressant drugs with limited success. In contrast, biological treatments targeting interleukin 1 (IL-1) have proved remarkably effective, often associated with complete and sustained disease remission, vastly improved quality of life and avoidance of serious long-term complications.

Chronic Infantile Neurological Cutaneous and Articular (CINCA) syndrome: a review.

IntroductionThe Chronic Infantile Neurological Cutaneous and Articular (CINCA, or Neonatal-onset multisystem inflammatory disease NOMID) is a rare autoinflammatory disease identified in 1987 by Prieur et al., typically characterized by the triad of skin rash, arthropathy and central nervous system manifestations. It represents the most severe phenotype of the cryopyrin-associated periodic syndrome (CAPS).Clinical description and etiologyThe syndrome is due to autosomal dominant gain of function mutations in NLRP3, which encodes a key component of the innate immunity that regulates the activation and secretion of interleukin (IL)-1β. From the first days of life, patients display an urticarial rash in association with chronic inflammation with a typical facies featured by frontal bossing and saddle back nose. The CNS manifestations include chronic aseptic meningitis leading to brain atrophy, mental delay and sensorineural hearing loss. Chronic polyarthritis and alteration of the growth cartilage also may be present. CINCA/NOMID diagnosis is made clinically, based on the presence of characteristic features. The detection of NLRP3 mutations is diagnostic in 65–70% of cases. Indeed, up to 40% of affected patients are negative for germline NLRP3 mutations and several subjects are carriers of somatic mosaicism. Due to the pivotal role of Cryopyrin in the control of Caspase-1 activation and the massive secretion of active IL-1β observed in cryopyrin-mutated individuals, anti-IL1 treatment represents the standard therapy.ConclusionPrognosis of CINCA/NOMID syndrome has been changed by the availability of anti-IL1 drugs. Nowadays, the use of anti-IL-1 drugs has sensibly reduced the risk of developing main complications such as severe intellectual disability, hearing-loss and amyloidosis, if treatment is started early on.

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.

Somatic NLRP3 mosaicism in Muckle-Wells syndrome

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. All these diseases are currently considered as different phenotypes of the cryopyrin-associated periodic syndromes (CAPS). A variable degree of somatic NLRP3 mosaicism has been recently detected in ≈35% of patients with CINCA. However, no data are currently available regarding the relevance of this genetic mechanism in other CAPS phenotypes.

Safe and effective canakinumab-treatment of neonatal onset multisystem inflammatory disease (NOMID)/ chronic infantile neurologic cutaneous and articular (CINCA)

NOMID/CINCA is the most severe phenotype of cryopyrin-associated periodic syndrome (CAPS), characterized by persistence of inflammation-mediated symptoms and overproduction of interleukin (IL)-1β, associated with significant morbidity, if untreated. In CAPS-patients early initiation of anti-IL1β-treatment appears to prevent severe disease sequelae. However, canakinumab as a 1st-line treatment in young infants suffering from NOMID has been scarcely reported.

Detection of low frequency variants of the NLRP3 gene in “mutation- negative” CAPS patients using massive parallel sequencing

Recent studies showed a notable frequency of somatic mosaicism of the NLRP3 gene in chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome (35%) and Muckle-Wells syndrome (MWS)(12.5%) patients that were not detectable by common Sanger sequencing.

CAPS--pathogenesis, presentation and treatment of an autoinflammatory disease.

The cryopyrin-associated periodic syndrome (CAPS) is a severity spectrum of rare diseases. CAPS comprises the three conditions previously described as familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disorder (NOMID), also known as chronic infantile neurologic, cutaneous, and articular (CINCA) syndrome. The clinical phenotype of CAPS is characterized by systemic inflammation. General symptoms are fatigue and fever. Local manifestations affect multiple tissues such as skin, joints, muscles, eyes, and the central nervous system. Distinct clinical features are characteristic for each subphenotype. In FCAS, these are cold-induced urticaria and fever, in MWS systemic amyloidosis and hearing loss and in NOMID/CINCA central nervous system inflammation and bone deformities. CAPS is caused by single heterozygous germline or somatic gain of function mutations in the NLRP3 gene encoding the protein cryopyrin. Cryopyrin nucleates an NLRP3 inflammasome, which regulates the activation and cleavage of caspase-1 that cleaves the pro-inflammatory cytokines, IL-1β and IL-18. IL-1β plays the key role in the induction of inflammation in CAPS. This has been confirmed by the application of IL-1 blocking agents, which lead not only to a rapid and sustained reversal of daily symptoms but also to some extent of long-term disease sequelae. To prevent CAPS-induced organ damage, early diagnosis and swift initiation of effective treatment are mandatory.

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.

Canakinumab in patients with cryopyrin-associated periodic syndrome: an update for clinicians

The cryopyrin-associated periodic syndrome (CAPS) is a very rare disease. It is estimated that there are 1-2 cases for every 1 million people in the US and 1 in every 360,000 in France. However, many patients are diagnosed very late or not at all, meaning the real prevalence is likely to be higher. CAPS encompasses the three entities of familial cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous and articular (CINCA) syndrome. They have in common a causative mutation in the NLRP3 gene. The altered gene product cryopyrin leads to activation of the inflammasome which in turn is responsible for excessive production of interleukin (IL)-1β. IL-1β causes the inflammatory manifestations in CAPS. These appear as systemic inflammation including fever, headache or fatigue, rash, eye disease, progressive sensorineural hearing loss, musculoskeletal manifestations and central nervous system (CNS) symptoms (NOMID/CINCA only). With the advent of IL-1 Inhibitors, safe and effective therapeutic options became available for this devastating disease. To prevent severe and possible life-threatening disease sequelae, early and correct diagnosis and immediate initiation of therapy are mandatory in most patients. Canakinumab is a fully human monoclonal IgG1 anti-IL-1β antibody. It provides selective and prolonged IL-1β blockade and has demonstrated a rapid (within hours), complete and sustained response in most CAPS patients without any consistent pattern of side effects. Long-term follow-up trials have demonstrated sustained efficacy, safety and tolerability. Canakinumab is approved by the US Food and Drug Administration for FCAS and MWS and by European Medicines Agency for treatment of all three phenotypes of CAPS.

Cochlear implantation in children with syndromic deafness

ObjectiveTo examine the outcome of cochlear implantation in children with syndromic deafness, who are increasingly being considered for cochlear implants and who represent a unique challenge to the cochlear implant team. MethodIn this retrospective case series in a tertiary referral cochlear implant centre, we describe a series of 38 children with a clinical syndrome causing deafness who have undergone cochlear implantation. The outcome measures are Bench–Kowal–Bamford (BKB) speech reception score (range 0–100%) and speech perception ability using the Geers and Moog Speech Reception Score (SRS) (range from 0; no speech perception, to 6; open set recognition of words). ResultsThe syndromes identified were Waardenburg syndrome (n=10), Usher syndrome (n=9), Pendred syndrome (n=7), Jervell and Lange–Nielsen syndrome (n=5), CHARGE syndrome (n=2), and 1 each of Stickler, CINCA (Chronic Infantile Neurological Cutaneous and Articular), Bartter, Down, and Donnai–Barrow syndromes. After a minimum of 19 months following implantation, BKB was measurable in 20 of 38 patients, and ranged from 46 to 100% in quiet (median 87%, mean 81%). Eighteen children (55%) achieved a SRS at level six, and a further 8 (24%) achieved level five. There was significant variation of outcome between and within syndrome groups. ConclusionsAdditional disabilities are frequently encountered when considering children for cochlear implantation, and may be part of a recognised syndrome. Outcome is often excellent but can be variable even within the same syndrome group, and such children are therefore assessed on an individual basis to ensure a realistic expectation.

OP0260 The pathophysiology of S100A8/A9 in familial mediterranean fever (FMF)

BackgroundFamilial Mediterranean Fever (FMF) is an auto-inflammatory syndrome caused by mutations within the MEFV gene encoding pyrin protein. The FMF syndromeis associated with activation of phagocytic cells and secretion of...

Indications et modalités d’utilisation des antagonistes de l’interleukine (IL)-1 dans les dermatoses inflammatoires

IL-1 antagonists are used in the treatment of patients with rheumatoid arthritis and cryopyrinopathies. As yet anecdotal observations suggest that they may allow effective treatment of patients with different types of inflammatory skin disease. This review focuses on our current knowledge of the use of IL-1 antagonists in dermatology. A Medline search was performed combining the keywords: "anakinra; canakinumab; rilonacept" AND "skin; neutrophilic dermatoses; Sweet syndrome; pyoderma gangrenosum; hidradenitis suppurativa; Schnitzler syndrome; Still disease". The precise dermatological phenotype of patients with IL-1 antagonist-responsive auto-inflammatory disorders was analysed in order to compare it to related complex disorders. Double-blind randomized controlled trials have demonstrated the efficacy of these treatments in cryopyrinopathies with dermatological involvement including chronic infantile neurological cutaneous and articular (CINCA) syndrome, Muckle-Wells syndrome and familial cold urticaria. Anakinra is the only treatment for Schnitzler syndrome that is almost constantly efficacious, even in refractory disease, as attested by numerous case reports. It is also efficacious in the treatment of patients with adult-onset Still disease and systemic juvenile arthritis. Neutrophilic dermatoses constitute the cutaneous hallmark of IL-1-responsive auto-inflammatory disorders, and neutrophilic dermatoses could thus form an indication for this treatment. However, to date, only 9 reports have been published showing efficiency in patients with Sweet syndrome, in one case of neutrophilic panniculitis, and in two cases of pustular psoriasis. Anakinra appears less efficacious in patients with pyoderma gangrenosum. IL-1 antagonists are a first-line treatment in patients with Schnitzler syndrome and cryopyrinopathies. They could become important alternatives in patients with acute and febrile neutrophilic dermatoses either unresponsive to or with contraindications to conventional treatments, but this requires confirmation by further clinical trials.

Cryopyrin-assoziiertes periodisches Syndrom

The cryopyrin-associated periodic syndrome is a very rare disease. It is estimated that there are 1-2 cases out of 1 million inhabitants in the USA and 1/360,000 in France. However, many patients are diagnosed very late or not at all. Therefore the real prevalence is likely to be higher. CAPS encompasses the three entities familial cold autoinflammatory syndrome (FCAS), the Muckle-Wells syndrome and the neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic cutaneous and articular (CINCA) syndrome. They have in common a causative mutation in the NLRP3-gene. The altered gene product cryopyrin leads to activation of the inflammasome which in turn is responsible for excessive production of IL-1β. IL-1β causes the inflammatory manifestations in CAPS. These appear as systemic inflammation including fever, headache or fatigue, rash, eye disease, progressive sensorineural hearing loss, musculoskeletal manifestations and CNS symptoms (NOMID/CINCA only). With the advent of the IL-1 inhibitors anakinra, rilonacept and canakinumab for the first time safe and effective therapeutic options are available for this devastating disease. To prevent severe and possible life-threatening disease sequelae, early and correct diagnosis and immediate initiation of therapy are mandatory.

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