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OBJECTIVE: To examine the synthesis, processing, and secretion of interleukin-1beta (IL-1beta), as well as the clinical and biologic effects of IL-1 blockade, in patients with chronic infantile neurologic, cutaneous, articular (CINCA) syndrome and Muckle-Wells syndrome (MWS), in an effort to understand the molecular mechanisms linking mutations of the CIAS1 gene and IL-1beta hypersecretion, and the underlying response to IL-1 receptor antagonist (IL-1Ra). METHODS: Six patients with CINCA syndrome or MWS were treated with IL-1Ra and followed up longitudinally. Monocytes obtained from the patients and from 24 healthy donors were activated with lipopolysaccharide (LPS) for 3 hours, and intracellular and secreted IL-1beta levels were determined by Western blotting and enzyme-linked immunosorbent assay before and after exposure to exogenous ATP. RESULTS: LPS-induced IL-1beta secretion was markedly increased in monocytes from patients with CIAS1 mutations. However, unlike in healthy subjects, secretion of IL-1beta was not induced by exogenous ATP. Treatment with IL-1Ra resulted in a dramatic clinical improvement, which was paralleled by an early and strong down-regulation of LPS-induced IL-1beta secretion by the patients' cells in vitro. CONCLUSION: Our results showed that the requirements of ATP stimulation for IL-1beta release observed in healthy individuals are bypassed in patients bearing CIAS1 mutations. This indicates that cryopyrin is the direct target of ATP and that the mutations release the protein from the requirement of ATP for activation. In addition, the dramatic amelioration induced by IL-1Ra treatment is at least partly due to the strong decrease in IL-1beta secretion that follows the first injections of the antagonist. These findings may have implications for other chronic inflammatory conditions characterized by increased IL-1beta. [ABSTRACT FROM AUTHOR]

Background: Data from routine clinical practice are needed to further define the efficacy and safety of biologic medications in children with juvenile idiopathic arthritis (JIA). The aim of this analysis was to investigate the disease status, reasons for discontinuation and adverse events in Italian JIA patients treated with etanercept (ETN)., Methods: In 2013, all centers of the Italian Pediatric Rheumatology Study Group were asked to make a census of patients given ETN after January 2000. Patients were classified in three groups: group 1 = patients still taking ETN; group 2 = patients discontinued from ETN for any reasons; group 3 = patients lost to follow-up while receiving ETN. All three groups received a retrospective assessment; patients in group 1 also underwent a cross-sectional assessment., Results: 1038 patients were enrolled by 23 centers: 422 (40.7%) were in group 1, 462 (44.5%) in group 2, and 154 (14.8%) in group 3. Median duration of ETN therapy was 2.5 years. At cross-sectional assessment, 41.8% to 48.6% of patients in group 1 met formal criteria for inactive disease, whereas 52.4% of patients in group 2 and 55.8% of patients in group 3 were judged in clinical remission by their caring physician at last visit. A relatively greater proportion of patients with systemic arthritis were discontinued or lost to follow-up. Parent evaluations at cross-sectional visit in group 1 showed that 52.4% of patients had normal physical function, very few had impairment in quality of life, 51.2% had no pain, 76% had no morning stiffness, and 82.7% of parents were satisfied with their child's illness outcome. Clinically significant adverse events were reported for 27.8% of patients and ETN was discontinued for side effects in 9.5%. The most common adverse events were new onset or recurrent uveitis (10.2%), infections (6.6%), injection site reactions (4.4%), and neuropsychiatric (3.1%), gastrointestinal (2.4%), and hematological disorders (2.1%). Ten patients developed an inflammatory bowel disease and 2 had a malignancy. One patient died of a fulminant streptococcal sepsis., Conclusions: Around half of the patients achieved complete disease quiescence under treatment with ETN. The medication was overall well tolerated, as only one quarter of patients experienced clinically significant adverse events and less than 10% had treatment discontinued for toxicity.

The 16p13.3p13.1 region has been reported as a "critical" hotspot region for recurrent microdeletions/duplications, which may contribute to epilepsy, learning difficulties and facial dysmorphisms. Cytogenetic and array-CGH analyses were performed because of the clinical characteristics of the patient. The girl showed de novo 16p13.3p13.13 duplication spanning a region of ∼5.3 Mb. She presented brain anomalies, intellectual disability, epilepsy, facial and vertebral dysmorphisms. To our knowledge, this is the first reported case of 16p13.3p13.13 duplication; only three patients with an overlapping deletion in 16p13.2p13.13 were previously described. The duplicated region contains 21 OMIM genes and, six of them (RBFOX1, TMEM114, ABAT, PMM2, GRIN2A and, LITAF) were found to be associated with known diseases. Although no duplication of these genes has been described in the literature, we discuss here if they had some role in determining phenotype of our patient., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Objective: Measurement of urinary fractionated metanephrines represents a first-line test for the biochemical diagnosis of pheochromocytoma. The high performance liquid chromatography coupled to electrochemical detection (HPLC-EC) assays used in the routine clinical laboratory can be subjected to analytical interferences by the presence of drugs or their metabolites. In this paper we describe the interference on urinary normetanephrine (uNMN) caused by amoxicillin., Design and Methods: Two pediatric patients suspected of pheochromocytoma had very high uNMN levels (2543 and 4227μg/g Cr respectively; upper reference value: 339μg/g Cr). Amoxicillin interference was assessed by comparison for co-elution with uNMN and by LC-MS/MS analysis., Results: After amoxicillin interference was suspected and the therapy was stopped uNMN levels returned to normal (149 and 214μg/g Cr respectively). Chromatograms obtained by HPLC-EC clearly showed that amoxicillin co-elutes with uNMN. Patients' uNMN levels measured by LC-MS/MS were in the normal range., Conclusion: Amoxicillin is responsible for analytical interference on HPLC-EC assay for uNMN. This finding can be of help in distinguishing true-positive from false-positive results in the course of a biochemical diagnosis for pheochromocytoma., (Copyright © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Inverted duplications associated with terminal deletions are complex anomalies described in an increasing of chromosome ends. We report on the cytogenetic characterization of the first de novo inv dup del(4) with partial 4p duplication and 4q deletion in a girl with clinical signs consistent with "recombinant 4 syndrome". This abnormality was suspected by banding, but high-resolution molecular cytogenetic investigations allowed us to define the breakpoints of the rearrangement. The terminal duplicated region extending from 4p15.1 to the telomere was estimated to be 29.27 Mb, while the size of the terminal deletion was 3.114 Mb in the 4q35.1 region. Until now, 10 patients with duplicated 4p14-p15 and deleted 4q35 chromosome 4 have been described. In all cases the abnormal chromosome 4 was derived from a pericentric inversion inherited from one of the parents. In conclusion, we have identified the first case of inv dup del(4) with normal parents suggesting that, often, terminal duplications or terminal deletions mask complex rearrangements., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Summary: CDG-1a is an early-onset neurodegenerative disease with selective hindbrain involvement and highly variable clinical presentation. We retrospectively reviewed the clinical records and MR imaging studies of 5 children (3 boys and 2 girls aged 12 days to 2 years at presentation) with molecularly confirmed CDG-1a. The cerebellum was hypoplastic at presentation in 4 cases, progressive bulk loss involved the cerebellum and the pons in all cases, and the cerebellar cortex and subcortical white matter were hyperintense on T2-weighted and FLAIR images in all. We conclude that CDG-1a likely results from a combination of cerebellar hypoplasia and atrophy. Cerebellar volume loss with diffuse T2/FLAIR hyperintensity seems to be a peculiar association in the field of cerebellar atrophies, and may be useful to address the differential diagnosis.

We report on a case of Netherton syndrome showing a new SPINK5 mutation (c.957_960dupTGGT duplication in exon 11), associated with partial defect of biotinidase., (© 2011 Wiley Periodicals, Inc.)

Objectives: To validate the previously proposed classification criteria for Henoch-Schönlein purpura (HSP), childhood polyarteritis nodosa (c-PAN), c-Wegener granulomatosis (c-WG) and c-Takayasu arteritis (c-TA)., Methods: Step 1: retrospective/prospective web-data collection for children with HSP, c-PAN, c-WG and c-TA with age at diagnosis

Objective: To investigate the long-term outcome and prognostic factors of juvenile dermatomyositis (DM) through a multinational, multicenter study., Methods: Patients consisted of inception cohorts seen between 1980 and 2004 in 27 centers in Europe and Latin America. Predictor variables were sex, continent, ethnicity, onset year, onset age, onset type, onset manifestations, course type, disease duration, and active disease duration. Outcomes were muscle strength/endurance, continued disease activity, cumulative damage, muscle damage, cutaneous damage, calcinosis, lipodystrophy, physical function, and health-related quality of life (HRQOL)., Results: A total of 490 patients with a mean disease duration of 7.7 years were included. At the cross-sectional visit, 41.2-52.8% of patients, depending on the instrument used, had reduced muscle strength/endurance, but less than 10% had severe impairment. Persistently active disease was recorded in 41.2-60.5% of the patients, depending on the activity measure used. Sixty-nine percent of the patients had cumulative damage. The frequency of calcinosis and lipodystrophy was 23.6% and 9.7%, respectively. A total of 40.7% of the patients had decreased functional ability, but only 6.5% had major impairment. Only a small fraction had decreased HRQOL. A chronic course, either polycyclic or continuous, consistently predicted a poorer outcome. Mortality rate was 3.1%., Conclusion: This study confirms the marked improvement in functional outcome of juvenile DM when compared with earlier literature. However, many patients had continued disease activity and cumulative damage at followup. A chronic course was the strongest predictor of poor prognosis. These findings highlight the need for treatment strategies that enable a better control of disease activity over time and the reduction of nonreversible damage.

Objective: To investigate the rate of radiographic progression, as measured with the carpo-metacarpal ratio (Poznanski score), during etanercept (ETN) therapy in children with polyarticular juvenile idiopathic arthritis (JIA)., Methods: Patients included in the Italian ETN registry who had a standard radiograph of both hands and wrists in the posteroanterior view made at start of treatment and after 1 year were included in the study. The clinical response was assessed by means of the ACR Pediatric definition of improvement. Radiographic progression was determined by calculating the change in the Poznanski score between the baseline and the 1-year radiographs., Results: A total of 40 patients were studied. The frequency of ACR pediatric 30, 50, and 70 response at 1 year was 77%, 72%, and 50%, respectively. The median change in the Poznanski score between baseline and 1 year was + 0.3 units, meaning that, on average, patients experienced improvement in radiographic progression., Conclusion: Our pilot study provides evidence that ETN is potentially capable of reducing the progression of radiographic joint damage in JIA. This finding deserves confirmation in a controlled trial.

Thalidomide was recently reintroduced to treat several immune-mediated pathologies. Peripheral neuropathy is a significant side effect limiting its clinical use. Our aims include: (1) describing and identifying the incidence of clinical or electrophysiologic peripheral neuropathy in children, (2) determining whether peripheral neuropathy correlates with cumulative dose of thalidomide and with age, and (3) defining its reversibility rate. We studied 13 children manifesting immune-mediated pathologies treated with thalidomide at doses ranging from 25-100 mg/day. Clinical and neurophysiologic evaluation was performed before and after starting treatment. Seven children (53.8%) showed neurophysiologic signs of sensory peripheral axonal polyneuropathy. Five presented associated clinical symptoms, while the other two only presented subclinical, neurophysiologic signs of peripheral neuropathy. We found a significant correlation between the incidence of peripheral neuropathy and thalidomide cumulative dose (P = 0.02). We observed a lower incidence of peripheral neuropathy at a cumulative dose <20 gm, and a correlation with age (P < 0.01). The clinical and electrophysiologic recovery rate was 40%, and clinical improvement alone was observed in another 40%. Thalidomide induces dose-dependent and age-dependent peripheral neuropathy at a significant frequency in childhood (53.8%). In our experience a cumulative dosage at >20 gm and long-term administration for >10 months seem to increase the risk of peripheral neuropathy. We propose clinical and neurophysiologic follow-up every 3 months to identify and monitor possible side effects.

Objectives: To examine the change in health-related quality of life (HRQOL) and its determinants in children with juvenile idiopathic arthritis (JIA) treated with methotrexate (MTX)., Methods: Patients were extracted from the PRINTO clinical trial which aimed to evaluate the efficacy and safety profile of MTX administered in standard, intermediate or higher doses (10, 15 and 30 mg/m(2)/week respectively). Children with polyarticular-course JIA, who were less than 18 years and had a complete HRQOL assessment were included., Results: A total of 521 children were included. At baseline, patients with JIA showed poorer HRQOL (p<0.01) than healthy children. In 207/412 (50%) and 63 (15%) children, HRQOL values were 2 standard deviations below the mean of healthy controls in the physical and psychosocial summary scale, respectively. After 6 months of treatment with standard dose MTX, there was a statistically significant improvement in all HRQOL health concepts, particularly the physical ones. Similar improvements were observed in those who did not respond to a standard dose of MTX and were subsequently randomised to a higher dose. The presence of marked disability at baseline was associated with a fivefold increased risk of retaining poor physical health after 6 months of active treatment with standard dose MTX. Other less important determinants of retaining poor physical well-being were the baseline level of systemic inflammation, pain intensity and an antinuclear-antibody-negative status., Conclusions: MTX treatment produces a significant improvement across a wide range of HRQOL components, particularly in the physical domains, in patients with JIA.

Background: Most of the available documentation in the literature on ocular involvement in localised scleroderma (LS) are descriptions of single cases in adult patients. This article reports the frequency and specific features of ocular involvement in a large cohort of children with juvenile LS (JLS)., Methods: Data from a large, multi-centre, multinational study of children with LS were used to collect and analyse specific information on ocular involvement., Results: 24 out of 750 patients (3.2%) revealed a significant ocular involvement. 16 were female and 8 male. 16 patients (66.7%) had scleroderma "en coup de sabre" (ECDS) of the face, 5 (20.8%) had the linear subtype, 2 (8.3%) had generalised morphea (GM) and one (4.2%) had plaque morphea (PM). Of the 24 patients with eye involvement, 10 patients (41.7%) reported adnexa (eyelids and eyelashes) abnormalities, 7 (29.2%) anterior segment inflammation (5 anterior uveitis, 2 episcleritis) and 3 central nervous system-related abnormalities. 4 patients presented single findings such as paralytic strabismus (1), pseudopapilloedema (1) and refractive errors (2). Other extracutaneous manifestations were detected in a significantly higher number of patients with ocular involvement and were mostly neurological., Conclusion: Ocular abnormalities are not unusual in patients with JLS, especially in the ECDS subtype. They are frequently associated with other internal organ involvement, particularly the central nervous system (CNS). Careful ophthalmic monitoring is recommended for every patient with JLS, but is mandatory in those with skin lesions on the face and/or concomitant CNS involvement.

Objective: To investigate the clinical use patterns, clinical effect and safety of cyclosporine A (CSA) in juvenile idiopathic arthritis (JIA) in the setting of routine clinical care., Methods: An open-ended, phase IV post marketing surveillance study was conducted among members of the Pediatric Rheumatology Collaborative Study Group (PRCSG) and of the Paediatric Rheumatology International Trials Organisation (PRINTO) to identify patients with polyarticular course JIA who had received CSA during the course of their disease., Results: A total of 329 patients, half of whom had systemic JIA, were collected in 21 countries. Data were collected during 1240 routine clinic visits. CSA was started at a mean of 5.8 years after disease onset and was given at a mean dose of 3.4 mg/kg/day. The drug was administered in combination with MTX in 61% and along with prednisone in 65% of the patients who were still receiving CSA. Among patients who were still receiving CSA therapy at the last reported visit, remission was documented in 9% of the patients, whereas in 61% of the patients the disease activity was rated as moderate or severe. The most frequent reason for discontinuation of CSA was insufficient therapeutic effect (61% of the patients); only 10% of the patients stopped CSA because of remission. In 17% of the patients, side effects of therapy was given as the primary reason for discontinuation., Conclusion: This survey suggests that CSA may have a less favourable efficacy profile than MTX and etanercept, whereas the frequency of side effects may be similar. The exact place of CSA in the treatment of JIA can only be established via controlled clinical trial.

Objective: Adrenal hypoplasia congenita (AHC) is a hereditary disorder that leads to adrenal insufficiency and hypogonadotropic hypogonadism (HHG) in childhood. The gene responsible for the X-linked form, DAX-1 (dosage-sensitive sex-reversal, AHC, on the X-chromosome, gene 1)/NR0B1, encodes for an unusual member of the nuclear receptor superfamily. Deletions and point mutations in the DAX-1 gene have been described in more than 70 AHC families. Inter- and intra-familial variability in the clinical presentation of AHC has been observed. Here we present the clinical and genetic data of two brothers affected by AHC., Subjects and Methods: Clinical heterogeneity was observed in the two brothers: the first presented with adrenal insufficiency in early infancy, while the second required no substitution therapy until 4 yr of age. Interestingly, mineralcorticoid hormone deficiency preceded cortisol deficiency in both brothers. HHG was observed at pubertal age in both patients and required substitution therapy with gonadal steroids., Results: Sequence analysis revealed a novel mutation in the DAX-1 gene in the two brothers and in their carrier mother. The mutation, a three nucleotide deletion, results in the loss of leucine 278 (del278L). A missense mutation affecting the same leucine (L278P) was previously shown to cause marked reduction of repressor function with respect to the wild type protein in transcription assays., Conclusions: Missense mutations or amino acid loss in the DAX-1 gene are very rare. Their identification and genotype-phenotype correlation are important for the characterization of protein function and for patient management.

Objective: The aim of our study was to investigate the coexistence of autoimmune diseases (autoimmune thyroid disease and type 1 diabetes mellitus, T1DM) in patients affected by Juvenile Chronic Arthritis (JCA)., Methods: We studied 66 patients affected by JCA, 42 females and 24 males: 42/66 patients had a pauciarticular form of JCA, 13/66 had a polyarticular form and 11/66 had a systemic form. All the patients underwent autoimmune thyroid screening through determination of anti-thyroglobulin (TgA) and anti-peroxidase (TPOA) autoantibodies. Patients with TgA and/ or TPOA, underwent thyroid sonography. T1DM screening included determination of anti-glutamic acid decarboxylase (GADA), anti-insulin (IAA), anti-tyrosine phosphatase-like protein (IA-2A) and anti-islet cell (ICA) autoantibodies. Oral glucose tolerance test (OGTT) was performed only in patients with autoantibody positive values. HLA typing for risk of T1DM was performed in 43 patients., Results: Nine female patients (14%) showed anti-thyroid autoantibodies, in particular: TgA in 3 cases, TPOA in 5, TgA and TPOA in only 1. In 3 of these patients, ultrasound examinations showed thyroid abnormal pattern, suggesting Hashimoto's thyroiditis. As regards T1DM, only 2 patients showed positive levels of GADA. As regards HLA typing, one or more T1DM susceptibility heterodimers were detected in 20 patients (46%) (13 with 1 heterodimer, 7 with 2 heterodimers)., Conclusion: Our study showed that anti-thyroid autoantibody frequency (9/66, 14%) was higher in JCA than in the general population, while T1DM markers (islet autoantibodies and genetic markers) were not frequent. These results suggest to investigate specific markers of thyroid autoimmunity in patients with JCA, in particular in females with JCA pauciarticular form.

Background: Evidence is accumulating about the efficacy of pulse intravenous (iv) cyclophosphamide (pCy) treatment for lupus nephritis (LN), but concern still exists on the use of this drug in children, on account of its oncogenic potential and gonadal toxicity. Medical records of 33 LN children were retrospectively analysed in order to assess the effect of treatment with pCy and corticosteroids (Cs) on renal survival and child growth., Patients and Methods: From 1974 to 1999, 33 pediatric patients with LN were admitted to our hospital. Clinical and hematological data were recorded for a mean period of eight years (range 1.5-18.9). Two groups of children who received different treatment protocols were compared: 19 were treated with Cs alone or combined with azathioprine (Aza) and 14 received Cs and pCy (0.5 g/m2 monthly); the mean number of Cy infusions was 13 (range 6-27)., Results: In the pCy treated group, survival was better, protection of renal function lasted longer, and there were no evident short- and long-term side effects. pCy treated children showed better growth than the other group. Many important factors could have contributed to these positive effects, such as the time of onset of the disease, its duration before referral to the pediatric nephrology unit, year at first admission (mean 1985 Cs +/- AZA group vs 1988 pCy group), renal failure at onset, degree of renal lesion (renal histology not evaluated in 36% of cases)., Conclusion: pCy treatment in pediatric LN may improve patient and renal survival and seems safe, causing less growth impairment.

We report herein the results of the cross-cultural adaptation and validation into the Italian language of the parent's version of two health related quality of life instruments. The Childhood Health Assessment Questionnaire (CHAQ) is a disease specific health instrument that measures functional ability in daily living activities in children with juvenile idiopathic arthritis (JIA). The Child Health Questionnaire (CHQ) is a generic health instrument designed to capture the physical and psychosocial well-being of children independently from the underlying disease. The Italian CHAQ was already published in the literature and was therefore revalidated while the Italian CHQ was fully cross culturally adapted with 3 forward and 3 backward translations, and than validated. A total of 1,192 subjects were enrolled: 404 patients with JIA (16% systemic onset, 31% polyarticular onset, 21% extended oligoarticular subtype, and 32% persistent oligoarticular subtype) and 788 healthy children. The CHAQ clinically discriminated between healthy subjects and JIA patients, with the systemic, polyarticular and extended oligoarticular subtypes having a higher degree of disability, pain, and a lower overall well-being when compared to their healthy peers. Also the CHQ clinically discriminated between healthy subjects and JIA patients, with the systemic onset, polyarticular onset and extended oligoarticular subtypes having a lower physical and psychosocial well-being when compared to their healthy peers. In conclusion the Italian version of the CHAQ-CHQ are reliable, and valid tools for the functional, physical and psychosocial assessment of children with JIA.

The arthropathy of inflammatory bowel disease (IBD) is a noninfectious arthritis occurring before or during the course of either regional enteritis or ulcerative colitis. Two patterns of joint disease are described: a chronic asymmetric oligoarthritis affecting peripheral joints, and a spondylo-sacroiliitis similar to the idiopathic type. Different criteria for diagnosis and classification (ACR and EULAR) of arthropathies associated with IBD are used and this is not helpful in order to a correct nosography. An unusual case of ulcerative colitis with thrombocytopenia and oligoarticular arthritis at onset, 4 and 2 years before the assessment of IBD, is reported. Moreover the arthritis had characteristics much more similar to a juvenile chronic arthritis (JCA) with pauciarticular onset of type I (FR-; ANA+) than to an enteropathic arthropathy.