Early-Onset Juvenile SLE Associated With a Novel Mutation in Protein Kinase C δ Sira Nanthapisal, MD,a Ebun Omoyinmi, PhD,a Claire Murphy, MBiolSci, MSc,a Ariane Standing, PhD,a Michael Eisenhut, MD, FRCPCH, FRCP,b Despina Eleftheriou, MBBS, PhD,a Paul A. Brogan, MB, ChB, PhDa

Juvenile systemic lupus erythematosus (jSLE) is rare before 5 years of abstract age. Monogenic causes are suspected in cases of very early onset jSLE particularly in the context of a family history and/or consanguinity. We performed whole-exome sequencing and homozygosity mapping in the siblings presented with early-onset jSLE. A novel homozygous missense mutation in protein kinase C delta (c.1294G>T; p.Gly432Trp) was identified in both patients. One patient showed a marked clinical response and a Infection, Infl ammation, and Rheumatology Section, resolution inflammation with rituximab therapy. This report demonstrates Infection, Immunity, Infl ammation and Physiological the clinical importance of identifying monogenic causes of rare disease to Medicine Programme, UCL Institute of Child Health, London, United Kingdom; bLuton & Dunstable University Hospital provide a definitive diagnosis, help rationalize treatment, and facilitate NHS Foundation Trust, Luton, United Kingdom genetic counseling. Dr Nanthapisal designed the study, carried out the analyses, and drafted the initial manuscript; Dr Omoyinmi, Ms Murphy, and Dr Standing Systemic lupus erythematosus (SLE) rash affecting the scalp, and a coordinated and supervised data analyses and is a complex, severe, chronic, and photosensitive malar rash ( Fig 1A). reviewed and revised the manuscript; Dr Eisenhut coordinated data collection and reviewed the sometimes life-threatening disease. She also had hepatosplenomegaly manuscript; Dr Eleftheriou and Prof Brogan Many factors contribute to the and bruising of the skin ( Fig 1B) and conceptualized and designed the study and critically development of juvenile SLE (jSLE), erythematous, nonpruritic, vasculitic reviewed and revised the manuscript; and all authors including genetics, immune dysfunction, rash affecting the hands and feet approved the fi nal manuscript as submitted. and environmental factors. 1 jSLE is (Fig 1 C and D). Oral mucosa was DOI: 10.1542/peds.2016-0781 rare before 5 years of age, and where normal. Other features were mild Accepted for publication Sep 6, 2016 this occurs monogenic causes should monoarthritis of the knee for >2 Address correspondence to Sira Nanthapisal, MD, be considered, particularly if there is a months (clinically not typical of septic Room 646 UCL Institute of Child Health, 30 Guilford family history of SLE or consanguinity. arthritis and hence joint not aspirated) St, London, United Kingdom. E-mail: s.nanthapisal@ There is now an ever-expanding list of and an episode of acute onset of ucl.ac.uk monogenic causes of SLE (Table 1), and fever, epistaxis, rectal bleeding, and PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, many present very early in life.2 – 6 We pancytopenia (hemoglobin 10 g/L, 1098-4275). describe 2 siblings who presented with white blood cells 3060 cells per Copyright © 2017 by the American Academy of early-onset jSLE in whom we identified milliliter, neutrophil count 1540 cells Pediatrics a homozygous missense mutation in the per milliliter, lymphocyte count 1010 FINANCIAL DISCLOSURE: The authors have PRKCD gene. This report demonstrates cells per milliliter, platelet count indicated they have no fi nancial relationships the clinical importance of identifying 87 200 cells per milliliter) at the age relevant to this article to disclose. monogenic causes of rare disease to of 3 years. Additional investigations FUNDING: Rosetrees Trust PhD studentship grant. provide a rapid and definitive diagnosis, showed elevated inflammatory POTENTIAL CONFLICT OF INTEREST: The authors help rationalize treatment, and facilitate markers (elevated erythrocyte have indicated they have no potential confl icts of genetic counseling. sedimentation rate 125 mm/hour interest to disclose. and C-reactive protein 30 mg/L), positive antinuclear antibody To cite: Nanthapisal S, Omoyinmi E, Murphy C, CASE 1:320, anti–double stranded DNA et al. Early-Onset Juvenile SLE Associated With a δ The index case presented at the age at 37 (normal < 10), and positive Novel Mutation in Protein Kinase C . Pediatrics. 2017;139(1):e20160781 of 12 months with scarring alopecia, anti–extractable nuclear antigens

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 139 , number 1 , January 2017 :e 20160781 CASE REPORT TABLE 1 Monogenic Causes of SLE Gene Locus Inheritance Clinical Features Onset of SLE SLE or SLE-like Features Specifi c Treatmenta Ref. Nos. or SLE-like Features, y Complement 1–40 Fresh-frozen 6 – 9 cascade plasma, C1QA 1p.36.12 AR SLE, ICD, RI Mucocutaneous and renal hematopoietic C1QB 1p36.12 AR SLE, ICD, RI involvement, positive ANA, anti- stem cell C1QC 1p.36.11 AR SLE, ICD, RI dsDNA, extractable nuclear transplant antigen antibodies, increased cardiovascular risk C1R 12p13 AR SLE, ICD, RI <1 Mucocutaneous, neurologic, and —10 renal involvement C1S 12p13 AR SLE, ICD, RI <1 Mucocutaneous and renal — 11,12 involvement, autoimmune thyroiditis, autoimmune hepatitis C2 6p21.3 AR SLE, RI, undifferentiated >10 Mucocutaneous, hematologic, — 1,13 –15 connective tissue disease, and renal involvement, vasculitis, Sjögren arthritis syndrome C4 6p21.3 AR SLE, ICD, RI, rheumatoid 2–40 Mucocutaneous, hematologic, —16 arthritis and renal involvement, vasculitis TREX1 3p21.31 AD SLE, familial chilblain lupus, 4–adulthood Cold-induced chilblain lupus, —17 – 19 retinal vasculopathy with photosensitive rash, cerebral leukodystrophy hematologic and neurologic involvement, arthralgia or arthritis AR AGS1 <1 Cold-induced chilblain lupus RNASAH2A 19p13 AR AGS4 <1 Cold-induced chilblain lupus — 18,19 RNASAH2B 13q14 AR AGS2 <1 Cold-induced chilblain lupus — 18,19 RNASAH2C 11q13 AR AGS3 <1 Cold-induced chilblain lupus — 18,19 SAMHD1 20q11 AR AGS5 <1 Cold-induced chilblain lupus — 18,19 AD Familial chilblain lupus Cold-induced chilblain lupus 20 ADAR 1q21.3 AR AGS6 <1 Cold-induced chilblain lupus — 21 DNASE1 16p13.3 AD Sporadic SLE 9–13 Systemic lupus, Sjögren —5 syndrome, high ANA DNASE1L3 3p14.3 AR Familial SLE 2–12 Mucocutaneous and renal —2 2 involvement, positive ANCA, and anticardiolipin antibodies PRKCD 3p21.31 AR Familial SLE <5 Cutaneous vasculitis, hematologic —2 3 involvement, positive ANA and dsDNA antibodies ACP5 19p13.2 AR Spondyloenchondrodysplasia, <1–15 Hematological and renal —2 4 skeletal dysplasia, delayed involvement, positive ANA development, intracranial calcifi cation, immune dysregulation SLC7A7 14q11.2 Lysinuric protein intolerance >10 Renal involvement, vasculitis, — 25,26 with some cases of SLE hemophagocytic lymphohistiocytosis IFIH1 2q24.2 AD SLE with immunoglobulin 6–12 Arthritis, cutaneous vasculitis, —4 A defi ciency, RI, limb hematologic involvement, spasticity positive ANA and dsDNA antibodies, secondary antiphospholipid syndrome TMEM173 5q31.2 AD Familial SLE 2–20 Arthritis, cutaneous vasculitis, —27 hematologic and pulmonary involvement, positive ANA AD, autosomal dominant; AGS, Aicardi–Goutières syndrome; ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibody; AR, autosomal recessive; dsDNA, double-stranded DNA; ICD, immune complex disease; RI, recurrent infection. a All reported treatments described are case reports.

Downloaded from www.aappublications.org/news by guest on October 1, 2021 e2 NANTHAPISAL et al repeated 2 weeks later) was given to the index case, which resulted in a rapid and sustained (13 months at the time of writing) clinical improvement, with complete normalization of the full blood count and normalization of inflammatory markers. Rituximab (at the same dosage) was then given to the older sibling, who unfortunately developed anaphylaxis during the second infusion, although still B-cell depleted successfully, and remains in clinical remission 12 months later.

WORKUP FOR SUSPECTED MONOGENIC SLE All experimental work was FIGURE 1 performed with ethical approval A, A 3-year-old with early-onset jSLE caused by homozygous mutation of PRKCD manifesting with alopecia and rash affecting the scalp and face, with sparing of the nasolabial folds. B, Hepatosplenomegaly (ethics number 08H071382) and and bruising from thrombocytopenia. C, D, Erythematous, nonpruritic, vasculitic rash affecting the with written informed consent palms and soles. from all participants. Both patients were screened via conventional Sanger sequencing for known (ribonucleoprotein, Smith and of pancytopenia or other organ monogenic causes of SLE for TREX1, ribosomal P protein). Complement involvement. SAMHD1, C1qA, C1qB, and C1qC, assays were normal: C1q 42 mg/L Both siblings were received a all of which were negative (wild- (normal range 50–250 mg/L), diagnosis of familial SLE, with type). Homozygosity mapping C3 0.66 g/L (normal range 0.75– fulfillment of 6 out of 11 of the was therefore performed in both 1.65 g/L), C4 0.1 g/L (normal range American College of Rheumatology patients and both parents (see 0.14–0.54 g/L); functional classic classification criteria: malar Supplemental Materials). Whole- complement pathway assay activity rash, photosensitivity, arthritis, exome sequencing (WES) was was 75% (normal > 40%), and hematologic disorder, immunologic subsequently performed only in functional alternative complement disorder, and positive antinuclear the index case (see Supplemental pathway assay activity was 99% antibody. 28 Both patients were Materials). These studies revealed (normal > 10%). Renal function and initially treated in the first instance a homozygous missense mutation transaminase levels were entirely with pulse methylprednisolone (c.1294G>T; p.Gly432Trp) in normal. (30 mg/kg for 3 days followed by the PRKCD in the index case (see The pedigree of the family is shown oral prednisolone 2 mg/kg per day), Supplemental Materials for more in Fig 2A. She was the second child hydroxychloroquine (5 mg/kg details), subsequently confirmed via of consanguineous parents (first per day), and azathioprine (2 mg/kg Sanger sequencing. The c.1294G>T cousins once removed, ie, the father per day). However, over the substitution is a novel mutation not was the child of the mother’s first next 6 months both children yet annotated in the single nucleotide cousin) originally from Pakistan. progressively deteriorated with polymorphism database, the ClinSeq The 5-year-old sister of the index pancytopenia, with a platelet count database, 29 6500ESP, 30 or the 1000 case had identical symptoms and in the range of 60 000 to 84 000 Genomes Project databases. 31 This signs, which started at the age cells per milliliter. Both siblings homozygous c.1294G>T mutation of 12 months. Her parents were demonstrated only a transient was also confirmed in her affected initially healthy, although the response to additional pulses of sister via Sanger sequencing ( Fig 2B). mother subsequently developed intravenous methylprednisolone and Her currently asymptomatic 1-year- SLE during her third pregnancy. It intravenous immunoglobulin (2 g/kg, old brother was also homozygous manifested as mild cutaneous malar for persistent thrombocytopenia). for the same mutation. As expected, rash and arthralgia but no evidence Therefore, rituximab (750 mg/m2, both parents were confirmed to be

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 139 , number 1 , January 2017 e3 FIGURE 2 A, Pedigree of the family. The index case is V-2; the affected sister is V-1. B, Sanger sequencing chromatogram of PRKCD at position c.1294 (in the red- dashed box). The reference base in wild type is G shown above the chromatogram. The chromatogram shows a heterozygous pattern with 2 peaks of T and G in parents, and a homozygous T in patient, affected sister, and unaffected brother. (T is red and G is black.) heterozygous carriers of the same 349 and 603.36 Thus, this mutation transfected lymphoblastoid cell mutation. is likely to cause a loss of function lines were found to be resistant to of the kinase activity of PKCδ. The apoptosis, reversible by coexpression p.Gly432Trp mutation is predicted of nonmutant protein. In the Belot DISCUSSION to be deleterious in pathogenicity study, primary B cells from patients prediction algorithms (Supplemental and heterozygous carriers also PRKCD is located on chromosome Table 2). One limitation of our study exhibited a higher proliferation 3p21.31. It encodes protein kinase was that we did not perform any rate than wild-type individuals C δ (PKCδ), a member of serine/ functional experiments to assess after stimulation of the B-cell threonine kinase family that plays a protein expression or function or receptor, CD40, and Toll-like role in apoptosis and proliferation detailed B cell immunotyping (for receptor 9 compared with wild-type of cells. 32 PKCδ is also known to play various practical reasons, including B cells. a role in B-cell negative selection 33 limited access to clinical samples). and has been shown to prevent However, we suggest that the Rituximab, a monoclonal antibody proliferation of B and T cells in clinical features are explained by the against CD20 present on pre-B response to stimulation in the mutations we identified in PRKCD, and mature B lymphocytes, was mouse model. 34 PKCδ-deficient mice particularly because WES did not (fortuitously) the optimal therapeutic were found to have features of SLE identify any other plausible genetic drug of choice in these patients including anti–double strand DNA cause. because of the possible immunologic autoantibodies, glomerulonephritis defects in B cells caused by the with immunoglobulin G containing Mutation of PRKCD (p.Gly510Ser) mutation in PRKCD. Because 1 sibling immune complex deposition, and has previously been identified developed anaphylaxis to rituximab, lymphocyte infiltration in multiple as the cause of early-onset jSLE other B-cell targeted therapies such organs. 34, 35 by Belot et al 23 in 3 children of as ofatumumab (an alternative fully consanguineous unions. Mutations humanized monoclonal antibody The p.Gly432Trp mutation affects identified were shown to cause against CD20) 37 or belimumab the protein kinase activity domain, reduction of PKCδ expression (a fully humanized monoclonal which is located between amino acid and phosphorylation activity, and antibody against B-lymphocyte

Downloaded from www.aappublications.org/news by guest on October 1, 2021 e4 NANTHAPISAL et al stimulator) 38 are being considered particularly for consanguineous mutations. Genes Immun. for future treatment. 39 Alternatively, families. 2011;12(8):626–634 it is possible that hematopoietic 9. Arkwright PD, Riley P, Hughes SM, stem cell transplantation may Alachkar H, Wynn RF. Successful cure ultimately be needed, although ABBREVIATIONS of C1q defi ciency in human subjects to the best of our knowledge it has jSLE: juvenile systemic lupus treated with hematopoietic stem J Allergy Clin not yet been performed in SLE erythematosus cell transplantation. PRKCD Immunol. 2014;133(1):265–267 caused by mutations in PKCδ: protein kinase C δ (A. Belot, MD, PhD, personal ROH: runs of homozygosity 10. Wu YL, Brookshire BP, Verani RR, communication, 2016). SLE: systemic lupus Arnett FC, Yu CY. Clinical presentations erythematosus and molecular basis of complement Interestingly the mother, who is a C1r defi ciency in a male African- SNP: single nucleotide heterozygous carrier of the mutation, American patient with systemic polymorphism developed SLE during pregnancy lupus erythematosus. Lupus. with her third child. The combined WES: whole-exome sequencing 2011;20(11):1126–1134 contribution of heterozygous 11. Dragon-Durey MA, Quartier P, carriage and hormonal changes Frémeaux-Bacchi V, et al. Molecular occurring during pregnancy may REFERENCES basis of a selective C1s defi ciency be responsible for the new onset associated with early onset multiple of SLE during pregnancy. 40 The 1. Hauck F, Lee-kirsch MA, Aust D, autoimmune diseases. J Immunol. youngest brother, aged 18 months Roesler J, Pessler F. Complement C2 2001;166(12):7612–7616 defi ciency disarranging innate and at the time of writing, also has the adaptive humoral immune responses 12. Amano MT, Ferriani VP, Florido MP, homozygous mutation and is thus in a pediatric patient: treatment et al. Genetic analysis of complement far asymptomatic but will be closely with rituximab. Arthritis Care Res C1s defi ciency associated with monitored for the development of (Hoboken). 2011;63(3):454–459 systemic lupus erythematosus symptoms. highlights alternative splicing of ü 2. Lee-Kirsch MA, Wolf C, G nther C. normal C1s gene. Mol Immunol. è Aicardi–Gouti res syndrome: a model 2008;45(6):1693–1702 disease for systemic autoimmunity. CONCLUSIONS ö ö Clin Exp Immunol. 2014;175(1):17–24 13. J nsson G, Sj holm AG, Truedsson L, Bengtsson AA, Braconier JH, We have described a rare monogenic 3. Truedsson L, Bengtsson AA, Sturfelt G. Sturfelt G. Rheumatological form of jSLE caused by a novel but Complement defi ciencies and systemic manifestations, organ damage damaging homozygous mutation lupus erythematosus. Autoimmunity. and autoimmunity in hereditary C2 PRKCD affecting the active region of . 2007;40(8):560–566 defi ciency. Rheumatology (Oxford). Identification of this additional 2007;46(7):1133–1139 disease-causing variant of PRKCD 4. Van Eyck L, De Somer L, Pombal D, et al. Brief report: IFIH1 mutation 14. J önsson G, Truedsson L, Sturfelt G, provides additional supportive causes systemic lupus erythematosus Oxelius VA, Braconier JH, Sjöholm evidence for this gene to be included with selective IgA defi ciency. Arthritis AG. Hereditary C2 defi ciency in in routine genetic screening for Rheumatol. 2015;67(6):1592–1597 Sweden: frequent occurrence of suspected monogenic SLE. Securing invasive infection, atherosclerosis, this molecular diagnosis not only 5. Yasutomo K, Horiuchi T, Kagami S, and rheumatic disease. Medicine provided us with a definitive et al. Mutation of DNASE1 in people (Baltimore). 2005;84(1):23–34 with systemic lupus erythematosus. diagnosis but also explained the á Nat Genet. 2001;28(4):313–314 15. Litzman J, Freiberger T, Bartonkov dramatic and complete therapeutic D, Vlková M, Thon V, Lokaj J. Early response to B-cell depletion (despite 6. van Schaarenburg RA, Schejbel L, manifestation and recognition failing other therapies) and will Truedsson L, et al. Marked variability in of C2 complement defi ciency in direct the choices made for future clinical presentation and outcome of the form of pyogenic infection in treatment options. Because the patients with C1q immunodefi ciency. infancy. J Paediatr Child Health. list of monogenic causes of SLE is J Autoimmun. 2015;62:39–44 2003;39(4):274–277 increasing ( Table 1), next-generation 7. Walport MJ, Davies KA, Botto M. C1q 16. Yang Y, Chung EK, Zhou B, et al. sequencing offers the opportunity and systemic lupus erythematosus. The intricate role of complement to screen all known genetic causes Immunobiology. 1998;199(2):265–285 component C4 in human systemic lupus erythematosus. Curr Dir rapidly, and for a fraction of the 8. Schejbel L, Skattum L, Hagelberg S, Autoimmun. 2004;7:98–132 cost of conventional sequencing, et al. Molecular basis of hereditary C1q and should be considered in all defi ciency—revisited: identifi cation 17. Yamashiro K, Tanaka R, Li Y, Mikasa M, cases of early-onset (<5 years) jSLE, of several novel disease-causing Hattori N. A TREX1 mutation causing

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 139 , number 1 , January 2017 e5 cerebral vasculopathy in a patient interferon expression signature. Nat activation mechanisms and functions. with familial chilblain lupus. J Neurol. Genet. 2011;43(2):127–131 J Biochem. 2002;132(6):831–839 2013;260(10):2653–2655 25. Aoki M, Fukao T, Fujita Y, et al. 33. Limnander A, Depeille P, Freedman 18. Bronson PG, Chaivorapol C, Ortmann W, Lysinuric protein intolerance TS, et al. STIM1, PKC-δ and RasGRP Behrens TW, Graham RR. The genetics in siblings: complication of set a threshold for proapoptotic Erk of type I interferon in systemic lupus systemic lupus erythematosus signaling during B cell development. erythematosus. Curr Opin Immunol. in the elder sister. Eur J Pediatr. Nat Immunol. 2011;12(5):425–433 2012;24(5):530–537 2001;160(8):522–523 34. Miyamoto A, Nakayama K, Imaki H, 19. Crow YJ, Rehwinkel J. Aicardi– 26. Kamoda T, Nagai Y, Shigeta M, et al. et al. Increased proliferation of B Goutieres syndrome and related Lysinuric protein intolerance and cells and auto-immunity in mice phenotypes: linking nucleic acid systemic lupus erythematosus. Eur J lacking protein kinase Cdelta. Nature. metabolism with autoimmunity. Hum Pediatr. 1998;157(2):130–131 2002;416(6883):865–869 Mol Genet. 2009;18(R2):R130–R136 27. Jeremiah N, Neven B, Gentili M, 35. Gorelik G, Sawalha AH, Patel D, 20. Ravenscroft JC, Suri M, Rice GI, et al. Inherited STING-activating Johnson K, Richardson B. T cell PKCδ Szynkiewicz M, Crow YJ. Autosomal mutation underlies a familial kinase inactivation induces lupus-like dominant inheritance of a infl ammatory syndrome with lupus- autoimmunity in mice. Clin Immunol. heterozygous mutation in SAMHD1 like manifestations. J Clin Invest. 2015;158(2):193–203 causing familial chilblain lupus. Am J 2014;124(12):5516–5520 36. InterPro. Protein sequence analysis & Med Genet A. 2011;155A(1):235–237 28. Hochberg MC. Updating the American classifi cation. Available at: www. ebi. ac. 21. La Piana R, Uggetti C, Olivieri I, et al. College of Rheumatology revised uk/ interpro/ protein/ Q05655. Accessed Bilateral striatal necrosis in two criteria for the classifi cation of June 25, 2015 subjects with Aicardi–Goutières systemic lupus erythematosus. 37. Thornton CC, Ambrose N, Ioannou Y. syndrome due to mutations in Arthritis Rheum. 1997;40(9):1725 Ofatumumab: a novel treatment for ADAR1 (AGS6). Am J Med Genet A. 29. Biesecker LG, Mullikin JC, Facio FM, severe systemic lupus erythematosus. 2014;164A(3):815–819 et al; NISC Comparative Sequencing Rheumatology (Oxford). 22. Al-Mayouf SM, Sunker A, Abdwani R, Program. The ClinSeq Project: piloting 2015;54(3):559–560 et al. Loss-of-function variant in large-scale genome sequencing 38. Belimumab: anti-BLyS human DNASE1L3 causes a familial form of for research in genomic medicine. monoclonal antibody, anti-BLyS systemic lupus erythematosus. Nat Genome Res. 2009;19(9):1665–1674 monoclonal antibody, BmAb, Genet. 2011;43(12):1186–1188 30. NHLBI Exome Sequencing Project (ESP). human monoclonal antibody to 23. Belot A, Kasher PR, Trotter EW, Exome Variant Server. Available at: B-lymphocyte stimulator. Drugs R D. et al. Protein kinase cδ defi ciency http:// evs. gs. washington. edu/ EVS/ . 2008;9(3):197–202 causes mendelian systemic lupus Accessed May 2015 39. Batu ED, Karadag O, Taskiran EZ, et al. erythematosus with B cell–defective 31. Abecasis GR, Auton A, Brooks LD, et al; A case series of adenosine deaminase 2– apoptosis and hyperproliferation. 1000 Genomes Project Consortium. An defi cient patients emphasizing treatment Arthritis Rheum. 2013;65(8):2161–2171 integrated map of genetic variation and genotype–phenotype correlations. 24. Briggs TA, Rice GI, Daly S, et al. from 1, 092 human genomes. Nature. J Rheumatol. 2015;42(8):1532–1534 Tartrate-resistant acid phosphatase 2012;491(7422):56–65 40. Baer AN, Witter FR, Petri M. Lupus defi ciency causes a bone dysplasia 32. Kikkawa U, Matsuzaki H, Yamamoto and pregnancy. Obstet Gynecol Surv. with autoimmunity and a type I T. Protein kinase C delta (PKC delta): 2011;66(10):639–653

Downloaded from www.aappublications.org/news by guest on October 1, 2021 e6 NANTHAPISAL et al Early-Onset Juvenile SLE Associated With a Novel Mutation in Protein Kinase C δ Sira Nanthapisal, Ebun Omoyinmi, Claire Murphy, Ariane Standing, Michael Eisenhut, Despina Eleftheriou and Paul A. Brogan Pediatrics originally published online December 21, 2016;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2016/12/19/peds.2 016-0781 References This article cites 38 articles, 3 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2016/12/19/peds.2 016-0781#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Genetics http://www.aappublications.org/cgi/collection/genetics_sub Rheumatology/Musculoskeletal Disorders http://www.aappublications.org/cgi/collection/rheumatology:musculo skeletal_disorders_sub Collagen Vascular & Other Multisystem Disorders http://www.aappublications.org/cgi/collection/collagen_vascular_-_o ther_multisystem_disorders_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on October 1, 2021 Early-Onset Juvenile SLE Associated With a Novel Mutation in Protein Kinase C δ Sira Nanthapisal, Ebun Omoyinmi, Claire Murphy, Ariane Standing, Michael Eisenhut, Despina Eleftheriou and Paul A. Brogan Pediatrics originally published online December 21, 2016;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/early/2016/12/19/peds.2016-0781

Data Supplement at: http://pediatrics.aappublications.org/content/suppl/2016/12/19/peds.2016-0781.DCSupplemental

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2016 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

Downloaded from www.aappublications.org/news by guest on October 1, 2021