Proceedings of the 23rd Paediatric Rheumatology European Society Congress: part two
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Methods: The Agilent SureDesign tool was used to design an NGSpanel targeting 113 genes, grouped into 9 broad clinical pheno-types: autoinflammatory disease; monogenic vasculitis/vasculopa-thy; complement defects; monogenic lupus; HLH; early-onsetinflammatory bowel disease; autoimmune lymphoproliferativesyndromes; monogenic stroke; and hereditary amyloidosis. Thetargeted region includes coding exons, conserved non-codingexons, upstream promoter regions, and splice sites. Captured andindexed libraries (QXT Target Enrichment System) were se-quenced as a multiplex of 16 samples on an Illumina MiSeqsequencer in paired-end mode. Read alignment, variant calling,and annotation were performed using Agilent SureCall v3.0 soft-ware. Validation of the VIP gene panel is described in a separateabstract.Results: The results showed a mutation in the PTEN gene,c.650 T > A, p.V217D, which encodes for Phosphatase and tensinhomolog protein, mutation of which is associated with CowdenSyndrome (CS), and related entities. CS, also known as "Multiplehamartoma syndrome" is a rare autosomal dominant inherited dis-order characterized by hamartomas in the skin, mucous mem-branes, thyroid gland, and breast tissue. Patients with CS are atincreased risk of cancer including breast, thyroid, endometrial, andrenal cancers. Mutations in PTEN, a tumour suppressor gene, leadto hyperactivity of the mTOR pathway. Clinical clues for possiblediagnosis are macrocephaly, and at least one of autism, dermato-logic features, vascular features and gastrointestinal polyposis. Theassociation between CS and immune dysregulation has been de-scribed in a few cases, and was the reason we included this genein our VIP gene panel. PTEN is an important regulator of T-cellmaturation, and we speculate that lymphocytic vasculitis could belinked to this genetic mutation, although the exact mechanismremains uncertainConclusion: We conclude that our targeted VIP panel revealed adiagnosis that we hitherto had not considered, and provides a fur-ther evidence of the diagnostic utility of this approach.Disclosure of InterestNone Declared. P307DOWN'S ARTHROPATHY CLINICAL AND RADIOLOGICAL FEATURESOF ARTHRITIS IN CHILDREN WITH TRISOMY 21Charlene Foley, Orla Killeen, Emma MacDermott, Douglas VealeNational Centre for Paediatric Rheumatology, Our Lady's Children'sHospital Crumlin; Rheumatology, St Vincent's University Hospital, Dublin, IrelandPresenting author: Charlene FoleyPediatric Rheumatology 2017, 15(Suppl 1):P307 Introduction: Down's Arthropathy (DA) was first reported in theliterature in 1984. Crude estimates suggest higher incidence andprevalence rates of DA compared with Juvenile Idiopathic Arthritis(JIA), (JIA prevalence 1/1000, estimated DA prevalence 8.7/1000). Despite this fact, there remains a paucity of data on this condition.DA is rarely recognised at onset, & remains under-diagnosed. As adirect consequence children with DA are presenting with significant joint damage and disability at diagnosis.Objectives: · Perform a musculoskeletal examination on children withTrisomy 21 (T21) aged 0-20 yearsMethods: Children with T21 were invited to attend a screening clinic.Screening involved completion of a health questionnaire & a com-prehensive musculoskeletal examination. DA cases detected were investigated & managed as per normal clinical practice. Data on aconvenience sample of 33 newly diagnosed children with JIA wascollected to create a comparison group.Results: 503 children with T21 have been screened for DA, 22 newcases have been diagnosed. All of these children had poor languageskills or were non-verbal. Only 11% of the parents suspected thattheir child may have arthritis prior to attending our screening clinics, Pediatric Rheumatology 2017, 15(Suppl 1):44Page 167 of 259 and this was only after reading our recruitment literature. In total, wenow have 33 children attending our centre with DA (combiningcases attending pre-dating the start date of the study). This suggeststhe prevalence of DA in Ireland is 18-21/1000. The majority of chil-dren presented with a polyarticular pattern of disease. No cases ofuveitis have been observed to date. 88% of the DA cohort had smalljoint involvement of the hands, significantly higher than that ob-served in the JIA comparison group. Erosive changes were reportedon X-Ray in 29.2% of the DA cohort (9.5% in the JIA Cohort).Methotrexate-associated nausea was a significant barrier to treat-ment with this DMARD in DA. There was a significant delay in diag-nosis of DA, 1.7 years v 0.7 years in the JIA cohort.Conclusion: Children with T21 are at increased risk of developingarthritis. There is a lack of awareness of this risk among health careprofessionals & the general public at large. This almost certainly con-tributes to poor recognition of the disease and a delay in diagnosis.The predominant pattern of disease is polyarticular small jointarthritis. Treatment with standard protocols used in JIA is compli-cated by drug-associated side effects in children with T21. However,a good response to treatment with steroid intra-articular joint injec-tions has been observed. Our study has raised a number of ques-tions. Future research to accurately define this disease & identify bestpractice with regards to treatment would be invaluable. We advocatethat all children with T21 should have annual musculoskeletal exami-nation as part of their health surveillance programme.Disclosure of InterestNone Declared. P308Musculoskeletal anomalies in a cohort of children with trisomy 21Charlene Foley, Orla Killeen, Emma MacDermott, Douglas VealeNational Centre for Paediatric Rheumatology, Our Lady's Children'sHospital Crumlin, Dublin, Ireland; Rheumatology, St Vincent's University Hospital, Dublin, IrelandPresenting author: Charlene FoleyPediatric Rheumatology 2017, 15(Suppl 1):P308 Introduction: Musculoskeletal complications of Trisomy 21 (T21) arecommon. Almost all children with T21 have muscle hypotonia andjoint laxity. The combination of this ligamentous laxity and lowmuscle tone contribute to an increased risk of a number of musculo-skeletal disorders, a delay in acquisition of motor milestones andlower levels of physical activity. Inappropriately low expectations ofphysical activity and motor function from family, health care workersand self, and over-attributing motor difficulties to low tone and hy-permobility may lead to missed pathology and misdiagnoses.Objectives: 1. To describe the musculoskeletal anomalies observed in a national cohort of children with T212. To calculate the average age children with T21 walked unaided in our cohort.Methods: Over an 18-month period, children with T21 were invited toattend for a musculoskeletal assessment by a paediatric doctor. Relevant musculoskeletal history and clinical findings were documented.Results: 503 children with T21 were examined (56% male). Medianage 8.1 years (0.6-19.2 years).Musculoskeletal Anomalies and Trisomy 21. Pes Planus was the most com-mon musculoskeletal anomaly detected, occurring in 91.1% of the childrenwith T21 examined. Just under a quarter of these children did not avail oforthoses (23.6%). A range of other anomalies were observed, inflammatory arthritis (7.1%) and scoliosis (4.8%) occurring most frequently after pesplanus. Other spinal abnormalities included the well-documented T21 as-sociated c-spine instability, absent C2 vertebra and spondylolisthesis.Common hip and foot pathologies included dislocations, Perthes disease,slipped upper femoral epiphysis (SUFE) and hallux valgus.Ambulation and Trisomy 21. The median age our cohort walked was 28 months (12-84 months). This is comparable to the literature that re-ports children with T21 walk at 23 months (range 13-48), comparedwith 12 months (range 9-17) for the general paediatric population.Conclusion: Children with T21 are at increased risk of a number of po-tentially debilitating musculoskeletal problems. Early, regular andcontinuous musculoskeletal assessment of children with Down syn-drome is paramount to management of musculoskeletal conditions.The aim is to avoid children presenting with irreversible, preventablejoint damage and disability due to delayed or incorrect diagnosis andmanagement of these very treatable conditions.Key Message(s)Pes planus is common in children with Trisomy 21, therefore earlyconsideration of orthotics and life-long appropriate supportive foot-wear is advised.When a child with Down syndrome presents with a limp theyshould always be referred for a hip x-ray.A high index of suspicion for pathology should be employed whenassessing a child with Down syndrome presenting with change and/or deterioration in function and mobility.Inflammatory arthritis in children with Down syndrome is commonand potentially erosive and debilitating if left untreated.Significantly delayed ambulation is noted in children with T21. Vari-ability exists in the basic biomechanics of the musculoskeletal systemin children with Down syndrome in terms of motor control, coordin-ation, and skill. Multidisciplinary team assessment and managementshould be early, regular and ongoing to ensure these children reachtheir potential with regards to motor function.Compulsory annual musculoskeletal assessment for all children withT21 would enable early detection of potential problems, allowing fortimely intervention and in-turn better clinical outcomes.Disclosure of InterestNone Declared. P309Coffin-Siris syndrome with ARID1B mutations: a genetic syndromelinked with arthritis?Sonia Melo Gomes, Ebun Omoyinmi, Jane Hurst, Nathalie Canham,Despina Eleftheriou, Nigel Klein, Sandrine Lacassagne, Paul BroganRheumatology, Institute of Child Health, London, UK; Rheumatology,Great Ormond Street Hospital, London, UK; Genetics, Great OrmondStreet Hospital, London, UK; Genetics, London Northwest HealthcareNHS Trust, London, UK; Infectious Diseases, Great Ormond Street Hospital, London, UKPresenting author: Sonia Melo GomesPediatric Rheumatology 2017, 15(Suppl 1):P309 Introduction: Coffin-Siris (CSS) and Nicolaides-Baraitser (NBS) are twooverlapping syndromes caused by mutations in genes associatedwith the chromatin remodeling complex, which are associated withmultiple malformations and intellectual disability. Musculo-skeletalchanges, such as prominence of inter-phalangeal joints in hands,feet, and knee joints are very common in NBS (up to 75%), and alsoreported in CSS. These changes are usually considered to be dysplastic in nature rather than inflammatory, however.Objectives: To identify the genetic cause in a child with some clinicalfeatures suggestive of NBS and diffuse polyarthritis.Methods: We performed Whole Exome Sequencing (WES) on theproband and immediate family members. WES results were con-firmed by conventional Sanger sequencing.Results: Case reportWe present the case of a 7 year old boy with a long standing boggy polyarthritis, a previous history of developmen-tal delay, microcephaly (<4th centile), and distinct dysmorphic fea-tures that were reminiscent of Nicolaides-Baraitser Syndrome.However, Sanger sequencing of the SMARCA2 gene was negative(wild-type). There were no signs of uveitis. Laboratory tests showednormal inflammatory markers, negative autoantibody screen, and normal complement levels. Synovial biopsy confirmed the presenceof a chronic inflammatory synovitis consistent with juvenile idio-pathic arthritis. Brain MRI revealed a dysgenetic corpus callosum.Treatment was started with methotrexate (15 mg/m/week, subcuta-neously), which failed to control the polyarthritis; etanercept wassubsequently added, leading to significant improvement.Whole exome sequencing (WES) was performed on the patient andimmediate family members, revealing a novel, de novo heterozygous missense mutation in exon 20 of the ARID1B gene, resulting in a Pediatric Rheumatology 2017, 15(Suppl 1):44Page 168 of 259 premature stop codon at amino acid position 1802 (c.C5404T;p.R1802X), thus confirming the diagnosis of CSS. Sanger sequencingconfirmed the presence of the mutation in the patient and segrega-tion with disease within the family.Conclusion: This case illustrates yet again the power of next-generation sequencing to provide molecular confirmation of a rarediagnosis, CSS caused by a heterozygous mutation in ARID1B. The ab-sence of significantly raised inflammatory markers, in addition to asuspected clinical diagnosis of a genetic syndrome known to be as-sociated with skeletal dysplasia almost certainly contributed to thispatient’s polyarthritis not being recognized for several years. Wepropose that inflammatory arthritis may be an important feature ofCSS and related syndromes. In general, it is increasingly recognizedthat some patients with skeletal dysplasia may also have inflamma-tory arthritis, and early recognition of this and appropriate treatmentmay reduce morbidity and long-term damage.Disclosure of InterestNone Declared. Poster Session: Immunoregulation andbasic science P310Whole transcriptome analysis confirms HLA-DRB1 as a stronglyregulated gene in systemic juvenile idiopathic arthritis inremissionAnastasia Wiener, Boris Hügle, Bernd Denecke, Ivan Costa-Filho,Johannes Peter Haas, Klaus TenbrockPediatrics, RWTH AACHEN UNIVERSITY, Aachen, Germany; Pediatrics, Deutsches Zentrum für Kinderrheumatologie, Garmisch-Partenkirchen,Germany; IZKF, RWTH AACHEN UNIVERSITY, Aachen, GermanyPresenting author: Anastasia WienerPediatric Rheumatology 2017, 15(Suppl 1):P310 Introduction: Systemic juvenile idiopathic arthritis (sJIA) is an autoin-flammatory disease characterized by arthritis and severe systemic in-flammation. Treatment with interleukin (IL)-1 antagonists has shownto be effective when introduced early in the disease. No markers thatpredict response to therapy have been identified yet.Objectives: The objective of this study was a longitudinal whole tran-scriptome analysis of children with sJIA during the early phase oftreatment with IL-1 antagonists to identify novel targets that predictresponse to therapy.Methods: From the database of the German AIDnet database, patientswith sJIA and active systemic disease treated with anakinra and subse-quent remission were identified. Clinical data was obtained by retro-spective chart review. Whole blood was drawn during active diseasebefore initiation of anakinra and after achievement of remission. RNA was extracted and subjected to Affymetrix HTA 2.0 Arrays followed byintraindividual analysis of regulated genes in each patient and com-bined analysis of the genes in all the patients including GO analysis ofdifferentially expressed genes. In addition regulatory genomics toolboxmotif enrichment analysis was performed to identify transcription fac-tors and pathways that are redulated during therapy.Results: Six children with sJIA with active systemic disease were included in the study. Using a p-value of <0.01 and a fold change of 2 orgreater, 742 genes were identified of which most were associated withimmune mediated processes. Using a fold change of higher than 3 as a more stringent criterium, still more than 100 genes remained. Our ana-lysis revealed HLADRB1 as the most strongly upregulated gene in re-mission compared to active disease (FC 6.8). This gene has beenrecently identified as a risk factor in an association study of 982 childrenwith sJIA and 8,010 healthy control subjects. Moreover besides e.g.S100A8 as known disease marker an upregulation of CD177 during active disease was identified, which is a molecule engaged in neutrophilactivation and transmigration and has not been described in previousstudies. Motif analysis revealed upregulation of promoters bound bySTAT3 and STAT4 in active disease, transcriptionfactors downstream ofIL-6 and IL-12 signaling respectively.Conclusion: Our study identifies the strong up-regulation of HLA-DRB1 in patients with sJIA in remission upon treatment with IL-1 an-tagonists. This provides a functional confirmation of a previous study,which identified HLA-DRB1 as a risk factor in sJIA. Additionally CD177was observed as a possible new marker in sJIA. Studies with largerpatient cohorts are necessary to confirm these results.Disclosure of InterestNone Declared. P311S100A8/A9 regulates immune responses in dendritic cellsDavid Popp, Arjan Boltjes, Frank Rühle, Stefanie Herresthal, Wilco deJager, Femke van Wijk, Joachim Schultze, Monika Stoll, Luisa Klotz,Thomas Vogl, Johannes RothInstitute of Immunology, Muenster, Germany; Division of Pediatrics,UMC Utrecht, Utrecht, Netherlands; Institute of Human Genetics,Muenster, Germany; LIMES-Institute, Bonn, Germany; Multiplex CoreFacility, UMC Utrecht, Utrecht, Netherlands; Institute of Neurology, Muenster, GermanyPresenting author: David PoppPediatric Rheumatology 2017, 15(Suppl 1):P31
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