Purpose to investigate the trend of antinuclear antibodies (ANA) and anti-dsDNA autoantibodies titers over time in children with a diagnosis of systemic lupus erythematosus (SLE).MethodsWe enrolled ...15 children with a diagnosis of SLE, fulfilling the SLICC criteria. For all patients included in the study ANA and anti-dsDNA antibodies testing was carried out from diagnosis every 3–4 months for 2 years. ANA were defined as negative for titers lower than 1:80. Laboratory parameters, clinical and demographic data was retrieved and analyzed. Statistical analysis was performed with software R_v. 4.0.3.ResultsFollowing two years of follow-up, all patients had ANA titers significantly lower than at time of SLE diagnosis (Mann Whitney test, p=0.0002) (figure 1A). After two years of follow-up, 11 patients (73%) still had positive ANA (group 1), while 4 patients (26%) had negative ANA (group 0). At time of diagnosis no significant differences in ANA titers (Mann Whitney test, p=0.74) (figure 1B) nor in disease activity, as measured by SLEDAI, (Mann Whitney test, p=0.88) were observed (table 1). No significant differences in organ involvement were observed (table 1). Assessing the change over time in ANA titers, the 2 groups of patients showed two different patterns: in group 0, ANA titers quickly declined and disappeared in the first 6 months after diagnosis; in group 1, ANA titers declined more slowly, remaining positive at 2-year follow-up (Figure 1C). Both C3 and C4 increased in the follow-up period, with no different patterns between the 2 groups (Figure 1C). Similarly, anti-dsDNA antibodies titers declined over time with no clear different patterns between the 2 groups (Figure 1C).Abstract PO.2.31 Figure 1Abstract PO.2.31 Table 1ConclusionsOur analysis showed two different patterns in the reduction of ANA titers over time in patients with childhood onset SLE, with 26% of patients becoming ANA negative after 6 months from diagnosis and remaining persistently negative during follow-up. Our data have important implications, specifically for the recruitment of patients into clinical trials, where the latest classification criteria of SLE require ANA positivity as entry criterion. Moreover, a seronegative state may represent a different subcategory of patients with SLE with specific pathogenetic pathways involved, possibly independently from autoantibodies. Therefore, further studies are needed to confirm and expand our data.
Purpose to identify the presence of variants in gene related to monogenic lupus and their relationship with clinical manifestations in childhood-onset systemic lupus erythematosus (cSLE) or ...lupus-like phenotype.Methodsa descriptive, observational, cross-sectional study was carried out in children with a diagnosis of cSLE or with lupus-like. The genetic analysis (Sanger/Clinical Exome Sequencing) was performed from isolated DNA obtained from blood sample.ResultsForty-two children were included in the study. The genetic analysis detected at least one variant in 11 (26.1%) children, 5 (45.4%) with cSLE and 6 (54.5%) with lupus-like phenotype. Of those who carry a genetic variant, the median age at disease onset was 11 years (range: 2–16) and 72.7% were female. Most of them were Caucasians (72.7%). Four (36.3%) and 3 (27.2%) out of 11 patients had a positive family history and/or a personal history for autoimmune diseases, respectively.Regarding the clinical manifestations at onset, musculoskeletal was the most frequent (8 patients, 72.7%), followed by hematological (6 patients, 54.5%), cutaneous (6 patients, 54.5%), constitutional with fever (5 patients, 45.45%), neurological (4 patients, 36.3%), renal (3 patients, 27.2%), cardiac (3 patients, 27.2%) and pulmonary (2 patients, 18.1%) manifestations.Related to immunological parameters, 10 (90.9%) were ANA positive, 5 (45.4%) anti-dsDNA, 4 (36.3%) ENA and 2 (18.1%) were antiphospholipid antibodies and lupus anticoagulant positive. Both C3 and C4 were low in 5 (45.4%) children and isolated C3 levels were low in 4 (36.3%) patients.Among the variants, we found that only two patients who carry a TREX variant showed normal C3 and C4 levels; one of them presented with lupus pernio as reported in literature. The same RNASEH2B (c.868G>A) variant was identified in two siblings with similar phenotype. The patient who carried the SHOC2 variant presented polyarthritis and serositis, while the patient with the TNFRSF13B variant onset with a glomerulonephritis. Those manifestations have already been described related to these gene variants. Clinical manifestations and variants are detailed in Table 1.Abstract S10.3 Table 1Gene variants, clinical and immunological features. aB2GP, anti-B2glycoprotein; aCL, anti-cardiolipin; ANA, antinuclear antibodies; APL, antiphospholipid antibodies; ENA, F, female; GG, adenopathy; GMN, glomerulonephritis; ILD, interstitial lung disease; LA, lupus anticoagulant; M, male; MAS, macrophagic activation syndrome; LN, lupus nephritis; SLE, systemic lupus erythematosus; TTP, thrombotic thrombocytopenic purpura; WMI, whiter matter hyperintensities. Highlighted in yellow, are shown the manifestations which have already been described in the literature related to the gene variantConclusionsAround 25% pediatric patients with cSLE or lupus-like phenotype in our cohort showed at least one variant in gene related to monogenic-lupus and some of them had a phenotype similar to those already described. The evidence of these variants may suggest the genetics potential contribution to the cSLE pathogenesis. Further studies in larger cohorts are necessary to confirm these data.
PurposeInterferonopathies are conditions characterized by excessive production of type 1 interferon. Several diseases, autoinflammatory or autoimmune, are classified as type1 interferonopathies such ...as Aicardi-Goutieres, Sting associated vasculopathy with onset in Infancy, monogenic Systemic lupus erythematosus (SLE) and Dermatomyositis. The aim of this study is to evaluate the role of MMF in modulating the activation of the interferon pathway describing its clinical and laboratory effects in a cohort of patients with defined and undefined interferonopathyMethodsWe included patients aged 0–18 years with defined (genetically confirmed) and undefined interferonopathy (evocative clinical picture, interferon signature (IS)> 2 in at least 3 samples 3 months apart, negative genetic test) followed at Bambino Gesù Children’s Hospital treated with MMF. For each patient demographic, clinical, laboratory parameters and IS were collected every 3 months starting from the year before the MMF treatment until the date of the last follow up. In vitro the effect of MMF on the IFN-pathway was evaluated by adding MMF to peripheral mononuclear cells of the patients.ResultsNine patients were enrolled, 4 with defined and 5 with undefined interferonopathy. When therapy was started, 78% of patients had recurrent febrile episodes, 57% polyarthritis, 67% skin and/or neurological involvement. A pathological brain MRI was found in 44% of patients. Persistent anemia, lymphopenia and autoantibody positivity were detected in 44% of patients and increased ESR in 67%. All patients had a positive IS(median 46.9; IQR 23.5–133.8). Three months after the beginning of MMF we observed a resolution of febrile episodes and skin manifestations in 86% of cases, remission of joint involvement in all patients, improvement of neurological symptoms in 1 patient, resolution of the anemia and normalization of the ESR in 50% and 66% respectively. During MMF therapy, as reported in patients with SLE, ANA titers decline or normalized in 75% of patients and anti dsDNA in 66% of patients. Cerebral MRI improved in patient with radiological alterations. MMF therapy allowed to completely withdraw glucocorticoid therapy in 4 patients and to reduce the dosage in other 3. No significant reduction in IS was detected during a median follow-up of 36 months (IQR 25–45). Nevertheless these data contrasted with our ex vivo experiments in which the incubation with MMF of peripheral mononuclear cells of our patients (and of patients with other interferonopathies including SLE and dermatomyositis) showed a significant reduction in the INF-a pathway activation after cells stimulationConclusionsThis is the first study evaluating the effects of MMF in a cohort of patients with type I interferonopathy. The results, although preliminary, seem to suggest a role of the drug in improving clinical, laboratory and radiological findings of our patients, allowing also a significant glucocorticoid sparing. These data, if confirmed in larger and prospective studies, should encourage the use of MMF especially for those patients in which standard treatment with JAK inhibitor could be contraindicated or ineffective
BackgroundAutoinflammatory disorders (AIDs) represent a group of complex diseases characterized by periodic or chronic systemic inflammations with involvement of various organs and systems in the ...absence of evidence of autoimmunity or infections. Mutations in more than 15 genes, affecting several distinct pathways, have been associated with autoinflammatory recessive/dominant syndromes 1. The molecular genetic analysis of these diseases based just on the candidate gene has low efficiency and it's time consuming and expensive. Next Generation Sequencing (NGS) has emerged in the last year as new diagnostic tool in this field.ObjectivesTo share data obtained by the application of NGS in a cohort of patients affected by an AIDs of undefined origin evaluated at our center.MethodsIn this study we enrolled 145 patients evaluated at our center from 2010 to 2014,affected by undefined AIDs. In order to improve variant detection, to reduce diagnosis time and to correlate phenotype of patients with their genotype on multiple genes, we developed NGS approaches starting with 11 genes (divided into two panels), already known to be involved in AID (Panel 1: MVK, MEFV, NRLP12, NRLP3, NOD2, TNFRSF1A and PSTPIP1; Panel 2: IL1RN, LPIN2, IL36RN, PSMB8). Targeted resequencing was performed using a uniquely customized panel and analyzed with the MiSeq® sequencing platform (Illumina, San Diego, CA). All variants identified have been confirmed by Sanger sequencing and,when possible,family members were tested to study the segregation of identified variants.ResultsNGS analysis led to the identification of 61 patients with different variants in the genes of panel 1, with a detection rate of 42%. 36% of the patients showed variants in the NLRP3 gene, 19% in NOD2, 31% in NLRP12, 23% in MEFV, 8% in MVK and TNFRSF1A, 6% in PSTPIP1. Some of these variants are novel and others are already known or polymorphisms. In 29% of patients the combination of variants in two different genes was found. Several variants are of unknown pathogenic significance,while some of them are described as risk factors. We performed 15 familial study to unravel the segregation of some variants.ConclusionsNGS leads to the identification of many genetic variants that could be associated with disease susceptibility. The major challenge is in the interpretation of the clinical relevance of identified variants, particularly of variants that are found at low, but >1%, frequency in various populations. These may function as susceptibility alleles to inflammation rather than disease-associated mutations 2. Some patients show variants in multiple analyzed genes: it can be assumed that different variants in different genes may cooperate to determine a pathological phenotype.This will necessitate large-scale population studies, in vitro functional assay and careful correlation of genetic information with phenotypic data 3. Crucial is close collaboration with clinicians.ReferencesMartinon F, Aksentijevich I. New players driving inflammation in monogenic autoinflammatory diseases. Nat Rev Rheumatol 2015 Jan;11(1):11-20.Shinar Y, et al. Guidelines for the genetic diagnosis of hereditary recurrent fevers. Ann Rheum Dis 2012 Oct;71(10):1599-605.Aksentijevich I, Kastner D. Genetics of monogenic autoinflammatory diseases: past successes, future challenges. Nat Rev Rheumatol 2011 Jul 5;7(8):469-78.Disclosure of InterestNone declared
BackgroundChronic nonbacterial osteomyelitis (CNO)is the most common autoinflammatory bone disorders in childhood (1). CNO remains a diagnosis of exclusion because of the absence of specific clinical ...or laboratory findings.An important role in the diagnosis could be provided by whole body imaging techniques as TC-99 bone scintigraphy and/or whole body MRI. The treatment is not standardized;non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, bisphosphonates and tumour necrosis factor neutralizing agents have been used until now with variable response (2).ObjectivesTo describe clinical, biological and radiological response to treatment with IL-1 receptor antagonist (anakinra) in a cohort of patients with CNO.MethodsSeven patients with CNO refractory to NSAIDs, glucocorticoids and bisphosphonate (pamidronate) were treated with anakinra for at least 6 months in our institution. Response of treatment was evaluated assessing clinical manifestations (pain, local swelling, functional impairment), laboratory findings (C-reactive protein CRP, erythrocyte sedimentation rate ESR and serum amyloid A level SAA) and number of bone lesions on TC-99 bone scintigraphy at the start of treatment and in a 6 months follow-up.ResultsSeven patients (4 females and 3 males) were included in this study. The median age at diagnosis was 9.7 years (IQR 7.8-14.7) and the median age before starting anakinra treatment was 13.3 years (IQR 8.0-15.9). All the patients were treated with NSAIDs and bisphosphonates as first-line therapy. Glucocorticoid therapy was required in one patients with concomitant recurrent fever and pleural effusion. These patients did not respond satisfactorily and we decide to use anakinra (2 mg/kg/day) to control disease activity. At the start of treatment 7/7 patients (100%) had pain, 3/7 (43%) local swelling and 5/7 (71%) functional impairment; at 6 months of follow up 6/7 patients (86%) were completely asymptomatic, with one patient complaining of arthralgia. Before starting anakinra the median CRP, ESR and SAA were 2.7 mg/dl (IQR 1.7-4.9) 26 mm/h (IQR 12-46) and 53 mg/dl (IQR 27-112); at 6 months 5/7 patients (71%) have normalized CRP, ESR and SAA, 2/7 had a decrease in inflammatory markers. Before anakinra 59 osseous lesions were detected on TC-99 bone scintigraphy. After 6 months of therapy 24/59 lesions (40%) had completely resolved, 1/59 lesions (2%) had partially improved and 29/59 lesions (49%) remained stable. In two patients with persistent high biological inflammatory markers, new lesions (14) developed during treatment.ConclusionsOur data suggest that anakinra appears effective in CNO patient, who have not responded to standard of care, in controlling symptoms and laboratory findings, although subclinical bone inflammation was still detectable by bone scintigraphy after 6 months of treatment. Long-term follow-up studies with a larger number of patients are needed.ReferencesSara M. Stern, Polly J. Ferguson. Autoinflammatory Bone Diseases. Rheum Dis Clin N Am 39 (2013) 735-749.H J Girschick, P Raab, S Surbaum, A Trusen, et al. Chronic non-bacterial osteomyelitis in children. Ann Rheum Dis 2005;64:279-285.Disclosure of InterestNone declared
BackgroundChronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disorder of unknown ethiology. The clinical manifestations of CRMO are highly variable. One to 20 sites can be ...affected at one time. Since CNO is a systemic disorder that can affect multiple skeletal sites, whole-body imaging techniques (Tc-99 bone scintigraphy or MRI) provide major contribution to the initial diagnostic approach, as well as during follow-up (1-2).ObjectivesTo evaluate typical patterns of bone involvement on MRI in paediatric patients with CRMO.MethodsWe retrospectively reviewed 112 MRI performed at the diagnosis and during follow-up from 2010 to 2014 of 40 children with CRMO. Thirty-two patients underwent bone biopsy that confirmed the diagnosis. 28/40 (70%) underwent one or more WBMRI. Coronal STIR images were obtained in all children. Additional sequences were performed in doubtful cases.ResultsA total of 360 lesions were detected. Lesions were multifocal in 36/40 patients (90%) and were symmetric in at least one localization in 24/40 patients (60%). In 30/40 patients (75%) lesions were located on the metaphyses of long bones (especially femur and tibia) close to one or both sides of an epiphyseal or apophyseal growth plate and/or on pelvic bones (particularly on the sacro-iliac joints and close to the triradiate cartilage) and/or on clavicle/sternum. The spine was involved in 14/40 (34.1%) patients, in all but 2 in combination to the submentioned locations. No patients had carpal or head bone involvement, 16/40 had tarsal involvement.ConclusionsMRI, and particularly WBMRI, should be considered the diagnostic modality of choice in patients with clinical multifocal pain. Simmetricity, multifocality and particularly specific patterns of lesions appear highly suggestive of CRMO.ReferencesDe Somer L. et al. Total body MRI, a guide to diagnosis in patients with osteo-articular pain and inflammation. Arthritis Rheumatol. 2014 March;66(S3):S119Falip C. et al. Chronic recurrent multifocal osteomyelitis (CRMO): a longitudinal case series review. Pediatr Radiol. 2013 Mar;43(3):355-75.Disclosure of InterestNone declared
BackgroundSystemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of antinuclear antibodies (ANA). Monitoring of anti-DNA antibody levels may reflect disease ...activity, by contrast a single anti-RBP antibody determination is thought to suffice for clinical purposes. Recent data suggests that ANA levels may decrease over time secondary to the natural history or to treatments.ObjectivesTo investigate the trend of ANA and anti-dsDNA titers over time in children with a diagnosis of SLE.MethodsWe enrolled 15 children with SLE. ANA and anti-dsDNA testing were carried out in all patients from diagnosis every 3-4 months for 2 years. ANA were defined as negative for titers < 1:80. Laboratory parameters, clinical and demographic data was retrieved and analyzed. Interferon Gene Signature (IGS was assessed by the expression of 6 interferon-induced genes (IFI27, IFI44L, IFIT1, ISG15, RSAD2, SIGLEC1) in whole blood RNA. Statistical analysis was performed with SW R_v. 4.0.3.ResultsFollowing 2 years of follow-up, all patients had ANA titers significantly lower than at time of the onset (MWW, p=0.0002) (Figure 1A). After two years of follow-up, 11 patients (73%) remained ANA positive (group 1), while 4 patients (26%) became negative (group 0). At time of diagnosis no significant differences in ANA titers (MWW, p=0.74) nor in disease activity, measured by SLEDAI, (MWW, p=0.88) were observed (table 1; Figure 1E). No significant differences in organ involvement were observed (Table 1). Assessing the change over time in ANA titers, the 2 groups of patients showed 2 different patterns: in group 0, ANA titers quickly declined and disappeared in the first 6 months after diagnosis; in group 1, ANA titers declined more slowly, remaining positive at 2 years (Figure 1C). ANA pattern (by IFA) was also evaluated, changes from homogenous pattern to speckled was observed during follow up (Figure 1B). Both C3 and C4 increased, with no different patterns between the 2 groups (Figure 1D). Similarly, anti-dsDNA antibodies titers declined over time with no clear different patterns between the groups (Figure 1C). We also analyzed the levels of IGS at last of follow-up, observing significant differences between the groups (MWW, p=0.018) with higher levels of IGS in ANA+ patients (Figure 1F).ConclusionOur analysis showed 2 different patterns in the reduction of ANA titers over time in children with SLE, with 26% of them becoming ANA negative after 6 months from diagnosis and remaining persistently negative during follow-up. Our data have important implications, specifically for the recruitment of patients into clinical trials, where the latest classification criteria of SLE require ANA positivity as entry criterion. A seronegative state may represent a different subcategory of patients with SLE with specific pathogenetic pathways, possibly independently from autoantibodies. Therefore, further studies are needed to confirm our data.Reference1 Pisetsky DS, Nat Rev Rheumatol. 2020.Table 1.ANA- at 2yANA+ at 2yPatients, n411Female, n (%)3 (25)10 (9)Age, mean ± SD (years)13.80 ± 1.9113.45 ± 2.72Disease duration, mean ± SD (years)6.47 ± 4.226.17 ± 2.71EULAR/ACR 2019 criteriaFever, n (%)3 (75)8 (73)Acute cutaneous, n (%)4 (100)6 (55)Chronic cutaneous, n (%)0 (0)0 (0)Non-scarring alopecia, n (%)0 (0)1 (9)Oral/nasal ulcers, n (%)2 (50)7 (64)Joint involvement, n, (%)3 (75)4 (36)Serositis, n (%)0 (0)2 (18)Renal, n (%)1 (25)2 (18)Neurological, n (%)0 (0)0 (0)Hemolytic anemia, n (%)1 (25)4 (36)Leukopenia, n (%)4 (100)9 (82)Thrombocytopenia, n (%)3 (75)5 (45)Anti-dsDNA, n (%)4 (100)11 (100)Anti-Sm, n (%)1 (25)2 (18)LA, n (%)0 (0)1 (9.1)aCL, n (%)2 (50)2 (18)aB2GPI, n (%)2(50)2 (18)Low complement, n (%)4 (100)11 (100)C3, mean ± SD (mg/dl)40.25 ± 5.5152.73 ± 20.81C4, mean ± SD (mg/dl)3.67 ± 2.894.60 ± 2.72SLEDAI at diagnosis, mean ± SD12.75 ± 4.5012.18 ± 7.14SLEDAI at last follow-up, mean ± SD0.00 ± 0.001.36 ± 1.43Damage (SDI at last follow-up >0), n (%)0 (100)0 (100)TreatmentPDN, n (%)3 (75)11 (100)HCQ, n (%)4 (100)11 (100)MMF, n (%)4 (100)11 (100)RTX, n (%)0 (0)2 (18)Figure 1.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
BackgroundPediatric Antiphospolipid Syndrome (APS) is an autoimmune disease characterized by venous and/or arterial thrombotic events (TE) associated with 2 consecutive positive determinations (at ...least 12 weeks apart) of antiphospholipid antibodies (aPL), IgG/IgM anticardiolipin (aCL), IgG/IgM β2-glycoprotein I (aβ2GPI) and/or lupus anticoagulant (LA). Recent data suggests that aPL levels may decrease over time due to the natural history of the disease or to treatments. Therefore, monitoring of aPL levels may represent a strategy to evaluate disease activity and response to therapies.ObjectivesTo investigate the trend over time of aPL titers in children with APS, comparing patients under immunomodulatory therapies and those without them.MethodsA descriptive, observational, cross-sectional study was carried out in children with APS. aPLs testing was carried out in all patients from diagnosis every 3-4 months for 2 years. Interferon Gene Signature (IGS) was assessed as described by Crow1. Laboratory parameters, clinical and demographic data was retrieved and analyzed. Statistical analysis was performed with software R_v. 4.0.3.ResultsSixteen children with a diagnosis of APS were included in this study. The median age at disease onset was 11.5 years (range: 6 months – 17 years) and 62.5% were female; 87.5% Caucasians. Thirteen patients (81.2%) had a diagnosis of primary APS and 3 (18.8%) out of 16 of secondary APS.Regarding clinical manifestations, 11 children developed at least one TE (7 arterial and 5 venous). Cerebral territory was the most frequently involved with 5 thrombosis, followed by 3 deep vein thrombosis, 1 pulmonary thromboembolism and 2 arterial renal thrombosis. Most of the patients received an antiaggregant and/or anticoagulant therapy (13 and 8 patients, respectively). However, 1 patient presented a new TE after the antiaggregant withdrawal.A total of 12 (75%) children developed at least one non-criterion manifestation: 7 patients (44%) cardiac (Libman-Sacks endocarditis or valvular heart disease), 7 patients (44%) neurological (chorea or white matter lesions), 6 patients (37.5%) hematological (thrombocytopenia, hemolytic anemia or Evans syndrome) and 1 patient (3.8%) a renal thrombotic microangiopathy.Related to immunological parameters, 4 (25%) were positive for only 1 aPL, 5 (42%) for 2 aPL subtypes and 7 (44%) for all 3 aPL subtypes, showing the highest rates IgG aβ2GP (87.5%) and IgG aCL (81.25%). Lower rates were identified for LA (44%), IgM aCL (18.7%) and IgM aB2GP (12.5%). Four (25%) had ANA positivity (3 secondary and 1 primary APS).Regarding treatment, 13 children (81.25%) received at least one immunomodulatory drug (13 patients mycophenolate; 4 rituximab) and 3 (18.7%) were not treated with them.During the 2-year-follow-up, 11 patients (68.8%) showed a reduction of aPL titers compared to the onset, with becoming 9 negative (56.3%) at the end of follow-up (Figure 1A). Of those who were negative, 8 children were under immunomodulatory therapies and only 1 did not receive any treatment. Five patients (31.2%) showed stable titers of aPLs during follow-up. Of them, 2 were not treated with immunomodulatory therapies and 2 were under mycophenolate but with poor compliance (reduction of titers with the restart of therapy were observed).We also evaluated the presence of the IGS in 11 patients with APS for whom a whole blood RNA sample was available: the IGS was positive in 9 (81.8%) of 11 children (7 with primary APS and 2 with secondary APS).ConclusionOur data suggest the possible effect of immunomodulatory therapies in reducing antibody titers in APS. Therefore, it may represent a strategy to control the disease activity leading to a better prognosis. Further studies are needed to confirm and expand our data.Reference1Rice GI, et al. Lancet Neurol 2013; 12:1159-69.Figure 1.A. Trend of IgG aB2GP during 2 years of follow-up. B. Trend of IgG aCL during 2 years of follow-up.Red line (0): children without immunomodulatory (IMM) therapies; blue line (1): children with IMM therapies.Figure omitted. See PDFAcknowledgements:NIL.Disclosure of InterestsNone Declared.
Hemophagocytic lymphohistiocytosis (HLH) is characterized by immune dysregulation due to inadequate restraint of overactivated immune cells and is associated with a variable clinical spectrum having ...overlap with more common pathophysiologies. HLH is difficult to diagnose and can be part of inflammatory syndromes. Here, we identify a novel hematological/autoinflammatory condition (NOCARH syndrome) in four unrelated patients with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. Patients shared the same de novo
mutation (Chr1:22417990C>T, p.R186C) and altered hematopoietic compartment, immune dysregulation, and inflammation.
mutations had been associated with syndromic neurodevelopmental disorders. In vitro and in vivo assays documented unique effects of p.R186C on CDC42 localization and function, correlating with the distinctiveness of the trait. Emapalumab was critical to the survival of one patient, who underwent successful bone marrow transplantation. Early recognition of the disorder and establishment of treatment followed by bone marrow transplant are important to survival.
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