Inflammatory Arthritis as a Possible Feature of Coffin-Siris Syndrome Sonia Melo Gomes, MD,a,b Cristina Dias, MD, PhD,c,d,e Ebun Omoyinmi, PhD,a Sandrine Compeyrot-Lacassagne, MD,b Nigel Klein, MD, PhD,a Neil J. Sebire, MD, PhD,f Paul Brogan, MD, PhDa,b

Coffin-Siris syndrome (CSS) and Nicolaides-Baraitser syndrome (NBS) are 2 abstract overlapping syndromes caused by mutations in genes of the barrier-to- autointegration factor chromatin-remodeling complex, presenting with multiple malformations and intellectual disability. Musculoskeletal changes such as noninflammatory prominence of interphalangeal joints in hands, feet, and, to a lesser extent, knee joints are common in NBS (up to 85%) and also aDepartment of Infection, Immunity, and Inflammation, reported in CSS. We present the case of a 7-year-old boy with polyarthritis of University College London Great Ormond Street Institute of several years’ duration (without uveitis), developmental delay, microcephaly, Child Health, London, United Kingdom; Departments of bRheumatology, cClinical Genetics, and fHistopathology, and dysmorphic features reminiscent of NBS. Sanger sequencing of the Great Ormond Street Hospital, London, United Kingdom; SMARCA2 gene revealed no mutations. Laboratory test results were normal. dDepartment of Medical and Molecular Genetics, School of fi fl Basic and Medical Biosciences, King’s College London, With synovial biopsy, we con rmed a chronic in ammatory synovitis. Brain London, United Kingdom; and eThe Francis Crick Institute, MRI revealed dysgenesis of the corpus callosum. Treatment with London, United Kingdom methotrexate and, subsequently, etanercept led to significant clinical Dr Melo Gomes conceptualized and designed the improvement. Whole-exome sequencing revealed a de novo heterozygous study, collected and analyzed the data, conducted the nonsense mutation in the ARID1B gene, resulting in a premature stop codon genetic analyses, and drafted the initial manuscript; 3 Dr Dias reviewed the genetics; Dr Brogan (c.C5404T; p.R1802 ), a genotype consistent with CSS. The absence of conceptualized and designed the study and significantly raised inflammatory markers and a clinical diagnosis of a genetic supervised data collection; Dr Omoyinmi supervised syndrome associated with noninflammatory joint changes may have data analysis; Dr Compeyrot-Lacassagne collected ’ data; Dr Sebire conducted the histopathological contributed to this patient s polyarthritis being missed for several years. We analysis; and all authors reviewed and revised the propose that some patients with CSS may have inflammatory arthritis (with manuscript, approved the final manuscript as or without coexisting skeletal dysplasia), which may be helped by treatment submitted, and agree to be accountable for all as described herein. Early recognition and treatment of inflammatory arthritis aspects of the work. in CSS would have a significant impact on reducing disease burden and DOI: https://doi.org/10.1542/peds.2018-1741 improving quality of life for patients with this rare genetic syndrome. Accepted for publication Mar 14, 2019 Address correspondence to Sonia Melo Gomes, MD, Department of Infection, Immunity, and Inflammation, UCL Great Ormond Street Institute of fi SMARCA2 fi Child Health, 30 Guilford St, London WC1N 1EH, United Cof n-Siris syndrome (CSS) and gene were rst linked to NBS, Kingdom. E-mail: [email protected] Nicolaides-Baraitser syndrome (NBS) and 5 other BAF SWI/SNF genes were ARID1B ARID1A PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, are 2 overlapping syndromes caused by linked to CSS ( , , 1098-4275). mutations in genes associated with the SMARCB1, SMARCA4, and SMARCE1).2–4 Copyright © 2019 by the American Academy of barrier-to-autointegration factor (BAF) Since then, these and several genes Pediatrics switch/sucrose nonfermentable encoding subunits of this complex have FINANCIAL DISCLOSURE: The authors have indicated chromatin-remodeling complex (SWI/ been associated with distinct they have no financial relationships relevant to this SNF) chromatin-remodeling complex. intellectual disability syndromes and article to disclose. 5–9 Chromatin-remodeling complexes have nonsyndromic intellectual disability. FUNDING: Funded by a Bupa Cromwell PhD been implicated in the pathogenesis of Both CSS and NBS syndromes are Studentship Grant. developmental disorders and are associated with intellectual disability, known to regulate transcription by characteristic dysmorphisms, and To cite: Melo Gomes S, Dias C, Omoyinmi E, et al. modifying chemical marks on histones congenital malformations. Although Inflammatory Arthritis as a Possible Feature of or inducing conformational changes in they are 2 distinct clinical entities, with Coffin-Siris Syndrome. Pediatrics. 2019;144(1): chromatin.1 In 2012, mutations in the distinctive features associated with e20181741

Downloaded from www.aappublications.org/news by guest on October 2, 2021 PEDIATRICS Volume 144, number 1, July 2019:e20181741 CASE REPORT each of them, phenotypic overlap can affecting both knees with fixed flexion systemic inflammatory markers, be significant, making clinical deformity as well as wrists, elbows, negative results for autoantibodies, distinction sometimes difficult.1,10,11 and the metacarpal and and normal complement 3 and 4 Clinical signs thought to be interphalangeal joints of both hands levels. Synovial biopsy of the right characteristic of CSS include (Fig 1). A previous history of knee joint revealed chronic intellectual disability, characteristic developmental delay, especially inflammatory synovitis consistent coarse facial features, agenesis or affecting expressive speech, with inflammatory arthritis (Fig 3), dysgenesis of the corpus callosum, microcephaly (,fourth percentile), after which treatment with hirsutism, sparse scalp hair, and and dysmorphisms (coarse facial methotrexate (15 mg/m2 per week hypoplasia or aplasia of the fifth digit features with anteverted nares, thick subcutaneously) was instituted. or finger or toe nail.1 In contrast, NBS lower vermillion border, and Methotrexate, however, did not is characterized by severe intellectual abnormally set ears; prominence of control the polyarthritis. Thus, the disability, sparse scalp hair, seizures, interphalangeal and knee joints antitumor necrosis factor-a agent short stature, characteristic [Fig 1]), suggested a tentative clinical etanercept (0.8 mg/kg per week dysmorphic face with coarse features, diagnosis of NBS. However, Sanger subcutaneously) was subsequently brachydactyly, and progressive sequencing of the SMARCA2 gene commenced, leading to clinical prominence of interphalangeal associated with NBS did not reveal remission. joints.12,13 any mutations to support this clinical diagnosis. Ophthalmology and Whole-exome sequencing was Musculoskeletal changes such as audiology assessments had revealed performed on DNA extracted from prominence of the interphalangeal mild myopia and moderate peripheral blood from the patient, his joints in hands, feet, and also of large conductive hearing loss. His parents, and his unaffected brother to joints such as knee joints are common increasing behavioral difficulties led try to ascertain a genetic cause for his in NBS (up to 85%) but also observed to a diagnosis of autism spectrum phenotype. Strategies for analysis of in CSS.11,13 Approximately 25% of disorder. There were frequent the exome data included exclusion of patients with NBS show typical episodes of migraines, and epilepsy synonymous variants, variants dysplastic changes such as cone- was also suspected, but repeated EEG frequent in population databases shaped or ivory epiphysis on 14 results were normal. Brain MRI (.1% in 1000 Genomes Project ; radiologic imaging, and short revealed a dysgenic corpus callosum National Heart, Lung, and Blood metacarpals and phalanges as well as with dysplastic rostrum and genu and Institute Exome Sequencing Project broad phalanges can be more 15 13 absence of the splenium (Fig 1). A release 6500 ; and the Exome frequently seen. 16 skeletal survey was also performed Aggregation Consortium ), and These joint changes are generally and did not reveal any evidence of intersection with unaffected family progressive, occurring on skeletal dysplasia (Fig 2). member exome data as well as a background of joint laxity, and can scrutiny of exome data from 120 in- lead to significant functional Subsequent full workup for house controls. In particular, targeted impairment. However, they are polyarthritis excluded uveitis; analysis of a list of candidate genes usually considered to be dysplastic in laboratory tests revealed normal associated with differential diagnoses nature rather than inflammatory13 and hence not amenable to treatment with disease-modifying antirheumatic drugs (DMARDs). Herein, we describe the case of a young boy with clinical features overlapping NBS and CSS and true inflammatory arthritis subsequently confirmed to have CSS associated with an ARID1B mutation.

CASE REPORT A 7-year-old boy presented to our FIGURE 1 rheumatology department with Dysmorphic features. A, Short metacarpals and prominence of interphalangeal joints caused by a long-standing polyarthritis for inflammatory arthritis. B, Sandal gap and hypoplastic fifth-digit toenail. C, Brain MRI revealing .3 years with “boggy” synovitis a dysgenetic corpus callosum.

Downloaded from www.aappublications.org/news by guest on October 2, 2021 2 MELO GOMES et al FIGURE 2 The skeletal survey revealed no signs of skeletal dysplasia. A, Soft tissue swelling was identified in knees. B, Soft tissue swelling was identified in knees. C, Xxx. D, Soft tissue swelling was identified in ankles. E, Xxx. F, Xxx. G, Xxx. H, Xxx. I, Xxx. of NBS was performed, as was With dideoxynucleotide sequencing, nonsyndromic intellectual disability.6 analysis of genes known to be we confirmed the presence of this ARID1B encodes AT-rich interactive associated with monogenic mutation in a heterozygous state in domain protein 1B (BAF250A), autoinflammation.17 This strategy the patient and its absence in the a component of the BAF SWI/SNF revealed the presence of a de novo clinically unaffected first-degree chromatin-remodeling complex, heterozygous single-nucleotide family members. The same variant which acts as an epigenetic modifier substitution in the ARID1B gene has previously been reported at least by altering chromatin structure and resulting in a premature stop codon 3 times in public databases in facilitating access of transcription in all Reference Sequence association with developmental factors to DNA. It is ubiquitously database–annotated isoforms. disease,19,20 additionally supporting expressed in mammalian Specifically, in the primary transcript, the diagnosis. development and postnatal tissues at predicted to be highly expressed in moderate levels,21 and, specifically in human brain (and other somatic the developing brain, its highest DISCUSSION tissues),18 it results in a nonsense expression is identified in cortical mutation in exon 20 ARID1B mutations have been linked layers 4 and 5 and the lateral ([ENST00000346085] NM_020732, to CSS since 20123,4 and account ganglionic eminences.22 It has been c.5404C.T; p.R18023). A loss-of- for 44% of CSS cases and are now shown to play an essential role in function mutation in ARID1B is also recognized to be 1 of the dendritic arborization and synapse consistent with a diagnosis of CSS. most frequent causes (0.9%) of formation of the cortex and

Downloaded from www.aappublications.org/news by guest on October 2, 2021 PEDIATRICS Volume 144, number 1, July 2019 3 associated with joint hypermobility13 and thus not amenable to treatment with DMARDs. We speculate that inflammatory arthritis may be under- recognized in CSS and NBS. This could account for the observation that patients with NBS tend to lose joint mobility with age13; thus, although true arthritis has not been described thus far in CSS, to what extent this has been investigated remains uncertain. FIGURE 3 A, Synovial biopsy revealing florid chronic inflammatory changes, including a mixed mononuclear Coexistence of inflammatory arthritis inflammatory infiltrate composed of predominant lymphocytes but with large numbers of plasma and dysplastic skeletal changes is fi 3 cells admixed (original magni cation 20; hematoxylin and eosin). B, The features are those of well described in other genetic a chronic inflammatory process consistent with immune dysregulation (original magnification 3200; hematoxylin and eosin). syndromes. For example, chronic infantile neurologic cutaneous hippocampus.23 Furthermore, the corpus callosum is a frequent articular (also known as neonatal haploinsufficiency of murine ARID1B feature of inpatients with CSS and onset multisystem inflammatory leads to aberrant development of ARID1B mutations, but the absence of disease) syndrome is a multisystemic cortical interneurons and abnormal hypoplasia of the fifth digit and/or autoinflammatory syndrome with cognitive and social behavior,24 finger or toe nail and presence of chronic arthropathy caused by highlighting its importance in enlarged interphalangeal joints are heterozygous gain-of-function neurodevelopment. more common in NBS.1,11,13 In some mutations in the NLRP3 gene.34 One cases, clinical distinction between of the hallmarks of this syndrome is The vast majority of reported NBS and CSS can be difficult, bony overgrowth due to enlargement ARID1B pathogenic mutations are especially in early childhood, because of the nonossified portion of the heterozygous loss-of-function some features of NBS such as coarse physis followed by splaying and mutations (microdeletions or face and broad phalanges tend to cupping of the metaphysis and nonsense or frameshift variants) and progress and become more prominent subsequent ossification of the are sporadic de novo, consistent with over time. Molecular testing is resulting paraphyseal mass.35 an extremely low tolerance of this therefore usually required to reliably Another example is Blau syndrome, fi 25,26 gene to haploinsuf ciency. distinguish CSS from NBS in these which is an agranulomatous Exceptionally, 1 case of transmission instances. Interestingly, 3 patients inflammatory disease characterized 27 from an affected parent and 1 of with a clinical diagnosis of NBS found by the classic clinical triad of skin recurrence due to germ-line to have mutations in ARID1B were rash (granulomatous dermatitis), 28 mosaicism have been described, and classified as CSS after clinical re- arthritis, and uveitis and caused by a few individuals with potentially evaluation.1 Likewise, patients with an heterozygous mutations in the pathogenic splice and missense variants initial clinical diagnosis of CSS and nucleotide-binding oligomerization 19,20,29–31 have also been reported. SMARCA2 mutations were reclassified domain-containing 2 gene.36 A The mutation described in this patient as NBS after detailed clinical multicenter observational study leads to a premature stop codon in the assessment.2,4,10,32 following 31 patients with Blau last coding exon that may escape syndrome found radiologic evidence The association with arthritis has not nonsense-mediated decay, resulting of dysplastic bony changes in two- been thoroughly addressed in in a truncated protein disrupting the thirds of the patients.37 These reported cases. We found a single C-terminal BAF250_C domain dysplastic changes included patient with early arthritis of the predicted to have a role in protein camptodactyly, carpal dysplasia, 4 large joints reported in the interactions. “plump” or short ulna, and abnormal literature,33 although no indication of diaphysis of the second metacarpal Although retrospective review of the the nature of the arthritis or clinical bone and are thought to be not patient’s phenotypic features outcomes were detailed. Although caused by postinflammatory bone revealed they are consistent with the joint enlargement of interphalangeal remodeling but rather an integral genetic diagnosis of CSS, we recognize and larger joints is frequently part of the phenotype.37 that the polyarticular involvement described in these syndromes, these made clinical distinction from NBS have been considered to be dysplastic Although our patient did not have difficult. For example, hypoplasia of in nature (at least in NBS), frequently marked systemic inflammation,

Downloaded from www.aappublications.org/news by guest on October 2, 2021 4 MELO GOMES et al a scenario not uncommon in patients appropriate treatment with ABBREVIATIONS with juvenile idiopathic arthritis,38 DMARDs.39 the presence of chronic inflammatory BAF: barrier-to-autointegration arthritis was confirmed with synovial Therefore, we propose that clinicians factor biopsy, and response to therapy was be vigilant to the possibility that CSS: Coffin-Siris syndrome positive. The absence of significantly patients with BAF SWI/SNF DMARD: disease-modifying raised inflammatory markers and intellectual disability syndromes antirheumatic drug early joint features suggestive of NBS could have coexistent inflammatory NBS: Nicolaides-Baraitser in a nonverbal developmentally arthritis. Early recognition of syndrome delayed child with behavioral changes inflammatory arthritis enables the SWI/SNF: switch/sucrose in the autistic spectrum probably timely institution of therapy with nonfermentable contributed to a delay of several years DMARDs, with significant chromatin-remodeling in the detection of this patient’s improvement of clinical outcomes complex polyarthritis and, hence, access to and quality of life.

POTENTIAL CONFLICT OF INTEREST: Dr Brogan has received a grant from Novartis, consulting fees from Roche, speaker fees from UCB, committee fees and an institutional grant from Swedish Orphan Biovitrum for gene hunting in autoinflammation, an institutional grant from Novimmune for a clinical trial, and other institutional fees from ChemoCentryx; the other authors have indicated they have no potential conflicts of interest to disclose.

REFERENCES

1. Wieczorek D, Bögershausen N, Beleggia intellectual disability. Am J Hum Genet. phenotype. AmJMedGenetPartA. F, et al. A comprehensive molecular 2012;90(3):565–572 149A(8):1628–1640 study on Coffin-Siris and Nicolaides- 7. Dias C, Estruch SB, Graham SA, et al; 13. Sousa SB, Hennekam RC; Nicolaides- Baraitser syndromes identifies a broad DDD Study. BCL11A haploinsufficiency Baraitser Syndrome International molecular and clinical spectrum causes an intellectual disability Consortium. Phenotype and genotype in converging on altered chromatin syndrome and dysregulates Nicolaides-Baraitser syndrome. Am remodeling. Hum Mol Genet. 2013; transcription. Am J Hum Genet. 2016; J Med Genet C Semin Med Genet. 2014; 22(25):5121–5135 99(2):253–274 166C(3):302–314 2. Van Houdt JK, Nowakowska BA, Sousa 8. Marom R, Jain M, Burrage LC, et al. 14. 1000 Genomes Project Consortium; SB, et al. Heterozygous missense Heterozygous variants in ACTL6A, Auton A, Brooks LD, Durbin RM, et al. A mutations in SMARCA2 cause encoding a component of the BAF global reference for human genetic Nicolaides-Baraitser syndrome. Nat complex, are associated with variation. Nature. 2015;526(7571):68–74 Genet. 2012;44(4):445, S1–449, S1 intellectual disability. Hum Mutat. 2017; 15. National Heart, Lung, and Blood 3. Santen GW, Aten E, Sun Y, et al. 38(10):1365–1371 Institute. National Heart, Lung, and Mutations in SWI/SNF chromatin 9. Vasileiou G, Vergarajauregui S, Endele Blood Institute Exome Sequencing remodeling complex gene ARID1B cause S, et al; Deciphering Developmental Project Exome Variant Server release Coffin-Siris syndrome. Nat Genet. 2012; Disorders Study. Mutations in the BAF- ESP6500. Available at: http://evs.gs. 44(4):379–380 complex subunit DPF2 are associated washington.edu/EVS/. Accessed August 1, 2018 4. Tsurusaki Y, Okamoto N, Ohashi H, et al. with Coffin-Siris syndrome. Am J Hum Mutations affecting components of the Genet. 2018;102(3):468–479 16. Broad Institute. EXaC browser (beta), SWI/SNF complex cause Coffin-Siris 10. Tsurusaki Y, Okamoto N, Ohashi H, et al. Exome Aggregation Consortium. syndrome. Nat Genet. 2012;44(4): Coffin-Siris syndrome is a SWI/SNF Available at: http://exac.broadinstitute. 376–378 complex disorder. Clin Genet. 2014; org/. Accessed August 1, 2018 – 5. Halgren C, Kjaergaard S, Bak M, et al. 85(6):548 554 17. Omoyinmi E, Standing A, Keylock A, et al. Corpus callosum abnormalities, 11. Santen GWE, Aten E, Vulto-van Silfhout Clinical impact of a targeted next- intellectual disability, speech AT, et al; Coffin-Siris Consortium. Coffin- generation sequencing gene panel for fl impairment, and autism in patients Siris syndrome and the BAF complex: autoin ammation and vasculitis. PLoS with haploinsufficiency of ARID1B. Clin genotype-phenotype study in 63 One. 2017;12(7):e0181874 Genet. 2012;82(3):248–255 patients. Hum Mutat. 2013;34(11): 18. National Institutes of Health. GTExPortal. 1519–1528 6. Hoyer J, Ekici AB, Endele S, et al. Available at: https://gtexportal.org/ Haploinsufficiency of ARID1B, a member 12. Sousa SB, Abdul-Rahman OA, Bottani home/. Accessed August 1, 2018 of the SWI/SNF-a chromatin-remodeling A, et al. Nicolaides-Baraitser 19. National Center for Biotechnology complex, is a frequent cause of syndrome: delineation of the Information. ClinVar database. Available

Downloaded from www.aappublications.org/news by guest on October 2, 2021 PEDIATRICS Volume 144, number 1, July 2019 5 at: https://preview.ncbi.nlm.nih.gov/ genome. PLoS Genet. 2010;6(10): 33. Santen GW, Clayton-Smith J; ARID1B-CSS clinvar/. Accessed August 1, 2018 e1001154 Consortium. The ARID1B phenotype: what we have learned so far. Am J Med 20. Firth HV, Richards SM, Bevan AP, et al. 27. Smith JA, Holden KR, Friez MJ, Jones JR, Genet C Semin Med Genet. 2014;166C(3): DECIPHER: database of chromosomal Lyons MJ. A novel familial autosomal 276–289 imbalance and phenotype in humans dominant mutation in ARID1B causing using ensembl resources. Am J Hum neurodevelopmental delays, short 34. Feldmann J, Prieur AM, Quartier P, et al. Genet. 2009;84(4):524–533 stature, and dysmorphic features. Chronic infantile neurological Am J Med Genet A. 2016;170(12): cutaneous and articular syndrome is 21. Flores-Alcantar A, Gonzalez-Sandoval A, – caused by mutations in CIAS1, a gene Escalante-Alcalde D, Lomelí H. Dynamics 3313 3318 highly expressed in polymorphonuclear of expression of ARID1A and ARID1B 28. Ben-Salem S, Sobreira N, Akawi NA, cells and chondrocytes. Am J Hum subunits in mouse embryos and in cells et al. Gonadal mosaicism in ARID1B Genet. 2002;71(1):198–203 during the cell cycle. Cell Tissue Res. gene causes intellectual disability and 2011;345(1):137–148 dysmorphic features in three siblings. 35. Hill SC, Namde M, Dwyer A, Poznanski A, Canna S, Goldbach-Mansky R. 22. Backx L, Seuntjens E, Devriendt K, Am J Med Genet A. 2016;170A(1): 156–161 Arthropathy of neonatal onset Vermeesch J, Van Esch H. A balanced multisystem inflammatory disease translocation t(6;14)(q25.3;q13.2) 29. Deciphering Developmental Disorders (NOMID/CINCA). Pediatr Radiol. 2007; leading to reciprocal fusion transcripts Study. Large-scale discovery of novel 37(2):145–152 in a patient with intellectual disability genetic causes of developmental 36. Wouters CH, Maes A, Foley KP, Bertin J, and agenesis of corpus callosum. disorders. Nature. 2015;519(7542): Rose CD. Blau syndrome, the prototypic Cytogenet Genome Res. 2011;132(3): 223–228 135–143 auto-inflammatory granulomatous 30. Grozeva D, Carss K, Spasic-Boskovic O, disease. Pediatr Rheumatol Online J. 23. Ka M, Chopra DA, Dravid SM, Kim WY. et al; Italian X-Linked Mental 2014;12:33 Essential roles for ARID1B in dendritic Retardation Project; UK10K Consortium; arborization and spine morphology of 37. Rosé CD, Pans S, Casteels I, et al. Blau GOLD Consortium. Targeted next- syndrome: cross-sectional data from developing pyramidal neurons. generation sequencing analysis of 1,000 J Neurosci. 2016;36(9):2723–2742 a multicentre study of clinical, individuals with intellectual disability. radiological and functional outcomes. – 24. Jung EM, Moffat JJ, Liu J, Dravid SM, Hum Mutat. 2015;36(12):1197 1204 Rheumatology (Oxford). 2015;54(6): Gurumurthy CB, Kim WY. Arid1b 31. Mignot C, Moutard ML, Rastetter A, et al. 1008–1016 haploinsufficiency disrupts cortical ARID1B mutations are the major genetic 38. Amin T, Davidson J. JIA subtypes and interneuron development and mouse cause of corpus callosum anomalies in their clinical presentation. In: Foster H, behavior. Nat Neurosci. 2017;20(12): patients with intellectual disability. Brogan PA, eds. Paediatric 1694–1707 Brain. 2016;139(11):e64 Rheumatology. 1st ed. Oxford, United 25. Samocha KE, Robinson EB, Sanders SJ, 32. Kosho T, Okamoto N; Coffin-Siris Kingdom: Oxford University Press; 2012: et al. A framework for the – Syndrome International Collaborators. 141 145 interpretation of de novo mutation in Genotype-phenotype correlation of 39. Genik LM, McMurtry CM, Breau LM. human disease. Nat Genet. 2014;46(9): Coffin-Siris syndrome caused by Caring for children with intellectual 944–950 mutations in SMARCB1, SMARCA4, disabilities part 1: experience with the 26. Huang N, Lee I, Marcotte EM, Hurles ME. SMARCE1, and ARID1A. Am J Med Genet population, pain-related beliefs, and Characterising and predicting C Semin Med Genet. 2014;166C(3): care decisions. Res Dev Disabil. 2017;62: haploinsufficiency in the human 262–275 197–208

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Downloaded from www.aappublications.org/news by guest on October 2, 2021 Inflammatory Arthritis as a Possible Feature of Coffin-Siris Syndrome Sonia Melo Gomes, Cristina Dias, Ebun Omoyinmi, Sandrine Compeyrot-Lacassagne, Nigel Klein, Neil J. Sebire and Paul Brogan Pediatrics originally published online June 26, 2019;

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