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1. A systematic review and meta-analysis of GFAP gene variants in Alexander disease

Author

Alice Grossi, Francesca Rosamilia, Silvia Carestiato, Ettore Salsano, Isabella Ceccherini, and Tiziana Bachetti

Subjects
Alexander Disease, GFAP, Meta-analysis, Genotype-phenotype correlation, Variant effect, Medicine, Science
Abstract

Abstract Alexander disease (ALXDRD) is a rare neurodegenerative disorder of astrocytes resulting from pathogenic variants in the GFAP gene. The genotype-phenotype correlation remains elusive due to the variable expressivity of clinical manifestations. In an attempt to clarify the effects of GFAP variants in ALXDRD, numerous studies were collected and analyzed. In particular, we systematically searched for GFAP variants associated with ALXDRD and collected information on the location within the gene and protein, prediction of deleteriousness/pathogenicity, occurrence, sex and country of origin of patients, DNA source, genetic testing, and clinical signs. To identify possible associations, statistical analyses and meta-analyses were applied, thus revealing a higher than expected percentage of adult patients with ALXDRD. Furthermore, substitution of Arginine, the most frequently altered residue among the 550 predominantly missense causative GFAP variants collected, were mostly de novo and more prevalent in early-onset forms of ALXDRD. The effect of defective splicing in modifying the impact of GFAP variants on the age of onset of ALXDRD was also postulated after evaluating the distribution of the corresponding deleterious predictive values. In conclusion, not only previously unrecognized genotype-phenotype correlations were revealed in ALXDRD, but also subtle mechanisms could explain the variable manifestations of the ALXDRD clinical phenotype.

Published
2024
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2. Infection risk in patients with autoimmune cytopenias and immune dysregulation treated with mycophenolate mofetil and sirolimus

Author

Mattia Comella, Elena Palmisani, Marcello Mariani, Gianluca Dell’Orso, Maria Licciardello, Maria Carla Giarratana, Luca Arcuri, Sara Pestarino, Alice Grossi, Marina Lanciotti, Giorgia Brucci, Daniela Guardo, Giovanna Russo, Carlo Dufour, Francesca Fioredda, Elio Castagnola, and Maurizio Miano

Subjects
mycophenolate, sirolimus, infection, PIRDs, ALPS, ALPS-like, Immunologic diseases. Allergy, RC581-607
Abstract

IntroductionAutoimmune cytopenias (AICs) are a group of disorders characterized by immune-mediated destruction of blood cells. In children, they are often secondary to immune dysregulation that may require long-lasting immunosuppression. Mycophenolate mofetil and sirolimus represent two well-tolerated options to treat these disorders, often as a steroid-sparing option. However, no data are available on the infection risk for patients undergoing long-lasting treatments.Patients and methodsThe rate of severe infective events was calculated in episodes per 100 persons/months at risk (p/m/r) documented by the analysis of hospitalization charts between January 2015 and July 2023 of patients treated with mycophenolate mofetil or sirolimus given for isolated AIC or AICs associated with autoimmune lymphoproliferative syndrome (ALPS)/ALPS-like syndromes in two large Italian pediatric hematology units.ResultsFrom January 2015 to July 2023, 13 out of 96 patients treated with mycophenolate mofetil or sirolimus developed 16 severe infectious events requiring hospitalization. No patients died. Overall infection rate was 0.24 person/*100 months/risk (95% CI 0.09–0.3). Serious infectious events incidence was higher in patients with ALPS-like compared to others (0.42 versus 0.09; p = 0.006) and lower in patients who underwent mycophenolate treatment alone compared to those who started sirolimus after mycophenolate failure (0.04 versus 0.29, p = 0.03). Considering only patients who started treatment at the beginning of study period, overall cumulative hazard was 18.6% at 60 months (95% CI 3.4–31.4) with higher risk of infectious events after 5 years in ALPS-like patients (26.1%; 95% CI 3.2–43.5) compared to other AICs (4%; 95% CI 0–11.4; p = 0.041).DiscussionTo the best of our knowledge, this is the first study to describe the infectious risk related to mycophenolate and sirolimus chronic treatment in patients with AICs and immune dysregulation. Our data highlight that infection rate is very low and mainly related to the underlying hematological condition.ConclusionsMycophenolate and sirolimus represent a safe immunosuppressive therapy in AICs and immune dysregulation syndromes.

Published
2024
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3. P756: IMPAIRED MITOCHONDRIAL FUNCTION AND MARROW FAILURE IN PATIENTS CARRYING A MUTATION ON SRSF4 GENE

Author

Maurizio Miano, Nadia Bertola, Alice Grossi, Gianluca Dell’orso, Stefano Regis, Francesca Fioredda, Michela Lupia, Marina Lanciotti, Elena Palmisani, Maria Carla Giarratana, Luca Arcuri, Fabio Corsolini, Marta Rusmini, Paolo Uva, Diego Vozzi, Isabella Ceccherini, Silvia Ravera, Enrico Cappelli, and Carlo Dufour

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2023
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5. PB2052: THE HEMATOLOGICAL SIDE OF TNFRSF13B/TACI: A MONOCENTRIC EXPERIENCE

Author

Andrea Beccaria, Marina Lanciotti, Maria Carla Giarratana, Elena Palmisani, Isabella Ceccherini, Alice Grossi, Roberta Caorsi, Marco Gattorno, Paola Terranova, Michela Lupia, Domenico Coviello, Massimo Maffei, Sabrina Zanardi, Maurizio Miano, Carlo Dufour, and Francesca Fioredda

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2023
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6. Autoimmune Lymphoproliferative Syndrome (ALPS) Disease and ALPS Phenotype: Are They Two Distinct Entities?

Author

Elena Palmisani, Maurizio Miano, Alice Grossi, Marina Lanciotti, Michela Lupia, Paola Terranova, Isabella Ceccherini, Eugenia Montanari, Michaela Calvillo, Filomena Pierri, Concetta Micalizzi, Rosario Maggiore, Daniela Guardo, Sabrina Zanardi, Elena Facchini, Angela Maggio, Elena Mastrodicasa, Paola Corti, Giovanna Russo, Marta Pillon, Piero Farruggia, Simone Cesaro, Angelica Barone, Francesca Tosetti, Ugo Ramenghi, Nicoletta Crescenzio, Jack Bleesing, Carlo Dufour, and Francesca Fioredda

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Abstract

Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder of lymphocyte homeostasis classically due to mutation of FAS, FASL, and CASP10 genes (ALPS-FAS/CASP10). Despite recent progress, about one-third of ALPS patients does not carry classical mutations and still remains gene orphan (ALPS-U, undetermined genetic defects). The aims of the present study were to compare the clinical and immunological features of ALPS-FAS/CASP10 versus those of ALPS-U affected subjects and to deepen the genetic characteristics of this latter group. Demographical, anamnestic, biochemical data were retrieved from medical record of 46 ALPS subjects. An enlarged panel of genes (next-generation sequencing) was applied to the ALPS-U group. ALPS-U subjects showed a more complex phenotype if compared to ALPS-FAS/CASP10 group, characterized by multiorgan involvement (P = 0.001) and positivity of autoimmune markers (P = 0.02). Multilineage cytopenia was present in both groups without differences with the exception of lymphocytopenia and autoimmune neutropenia that were more frequent in ALPS-U than in the ALPS-FAS/CASP10 group (P = 0.01 and P = 0.04). First- and second-line treatments were able to control the symptoms in 100% of the ALPS-FAS/CASP10 patients, while 63% of ALPS-U needed >2 lines of treatment and remission in some cases was obtained only after target therapy. In the ALPS-U group, we found in 14 of 28 (50%) patients 19 variants; of these, 4 of 19 (21%) were known as pathogenic and 8 of 19 (42%) as likely pathogenic. A characteristic flow cytometry panel including CD3CD4-CD8-+TCRαβ+, CD3+CD25+/CD3HLADR+, TCR αβ+ B220+, and CD19+CD27+ identified the ALPS-FAS/CASP10 group. ALPS-U seems to represent a distinct entity from ALPS-FAS/CASP10; this is relevant for management and tailored treatments whenever available.

Published
2023
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7. Case Report: Susceptibility to viral infections and secondary hemophagocytic lymphohistiocytosis responsive to intravenous immunoglobulin as primary manifestations of adenosine deaminase 2 deficiency

Author

Enrico Drago, Francesca Garbarino, Sara Signa, Alice Grossi, Francesca Schena, Federica Penco, Elettra Santori, Fabio Candotti, Kaan Boztug, Stefano Volpi, Marco Gattorno, and Roberta Caorsi

Subjects
dada2, hemophagocitic lymphohistiocytosis, viral infection, therapy, immunoglobulin, Immunologic diseases. Allergy, RC581-607
Abstract

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease associated with a highly variable clinical presentation, including systemic vasculitis, immunodeficiency, and cytopenia. We report a case of a 16-year-old girl affected by recurrent viral infections [including cytomegalovirus (CMV)-related hepatitis and measles vaccine virus-associated manifestations] and persistent inflammation, which occurred after Parvovirus infection and complicated by secondary hemophagocytic lymphohistiocytosis (HLH). HLH’s first episode presented at 6 years of age and was preceded by persistent fever and arthralgia with evidence of Parvovirus B19 infection. The episode responded to intravenous steroids but relapsed during steroids tapering. High-dose intravenous immunoglobulin (IVIG) helped manage her clinical symptoms and systemic inflammation. The frequency of IVIG administration and the dosage were progressively reduced. At the age of 9, she experienced varicella zoster virus (VZV) reactivation followed by the recurrence of the inflammatory phenotype complicated by HLH with neurological involvement. Again, high-dose steroids and monthly IVIG resulted in a quick response. Targeted next-generation sequencing (NGS) for autoinflammatory diseases and immunodeficiencies revealed the homozygous Leu183Pro ADA2 mutation, which was confirmed by Sanger analysis. ADA2 enzymatic test showed a complete loss of ADA2 activity. For about 3 years, IVIG alone was completely effective in preventing flares of inflammation and neurological manifestations. Anti-TNF treatment was started at the age of 13 for the appearance of recurrent genital ulcers, with a complete response. This case further expands the clinical spectrum of DADA2 and emphasizes the importance of extensive genetic testing in clinical phenotypes characterized by persistent unspecific inflammatory syndromes. The use of high doses of IVIG might represent a possible effective immune modulator, especially in combination with anti-TNF treatment.

Published
2022
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8. Underlying Inborn Errors of Immunity in Patients With Evans Syndrome and Multilineage Cytopenias: A Single-Centre Analysis

Author

Maurizio Miano, Daniela Guardo, Alice Grossi, Elena Palmisani, Francesca Fioredda, Paola Terranova, Enrico Cappelli, Michela Lupia, Monica Traverso, Gianluca Dell’Orso, Fabio Corsolini, Andrea Beccaria, Marina Lanciotti, Isabella Ceccherini, and Carlo Dufour

Subjects
Evans syndrome, autoimmune cytopenias, inborn errors of immunity (IEI), immune dysregulation, autoimmune haemolytic anaemia (AIHA), ITP (idiopathic thrombocytopenic purpura), Immunologic diseases. Allergy, RC581-607
Abstract

BackgroundEvans syndrome (ES) is a rare disorder classically defined as the simultaneous or sequential presence of autoimmune haemolytic anaemia and immune thrombocytopenia, but it has also been described as the presence of at least two autoimmune cytopenias. Recent reports have shown that ES is often a manifestation of an underlying inborn error of immunity (IEI) that can benefit from specific treatments.AimsThe aim of this study is to investigate the clinical and immunological characteristics and the underlying genetic background of a single-centre cohort of patients with ES.MethodsData were obtained from a retrospective chart review of patients with a diagnosis of ES followed in our centre. Genetic studies were performed with NGS analysis of 315 genes related to both haematological and immunological disorders, in particular IEI.ResultsBetween 1985 and 2020, 40 patients (23 men, 17 women) with a median age at onset of 6 years (range 0–16) were studied. ES was concomitant and sequential in 18 (45%) and 22 (55%) patients, respectively. Nine of the 40 (8%) patients had a positive family history of autoimmunity. Other abnormal immunological features and signs of lymphoproliferation were present in 24/40 (60%) and 27/40 (67%) of cases, respectively. Seventeen out of 40 (42%) children fit the ALPS diagnostic criteria. The remaining 21 (42%) and 2 (5%) were classified as having an ALPS-like and an idiopathic disease, respectively. Eighteen patients (45%) were found to have an underlying genetic defect on genes FAS, CASP10, TNFSF13B, LRBA, CTLA4, STAT3, IKBGK, CARD11, ADA2, and LIG4. No significant differences were noted between patients with or without variant and between subjects with classical ES and the ones with other forms of multilineage cytopenias.ConclusionsThis study shows that nearly half of patients with ES have a genetic background being in most cases secondary to IEI, and therefore, a molecular evaluation should be offered to all patients.

Published
2022
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9. Sirolimus Restores Erythropoiesis and Controls Immune Dysregulation in a Child With Cartilage-Hair Hypoplasia: A Case Report

Author

Giovanni Del Borrello, Maurizio Miano, Concetta Micalizzi, Michela Lupia, Isabella Ceccherini, Alice Grossi, Andrea Cavalli, Stefano Gustincich, Marta Rusmini, Maura Faraci, Gianluca Dell’Orso, Ugo Ramenghi, Alessio Mesini, Erica Ricci, Maurizio Schiavone, Natascia Di Iorgi, and Carlo Dufour

Subjects
sirolimus, bone marrow failure disorders, cartilage-hair hypoplasia (CHH), pure red cell aplasia (PRCA), whole-genome sequencing (WGS), Immunologic diseases. Allergy, RC581-607
Abstract

Cartilage-hair hypoplasia (CHH) is a syndromic immunodeficiency characterized by metaphyseal dysplasia, cancer predisposition, and varying degrees of anemia. It may present as severe combined immunodeficiency in infancy, or slowly progress until fully manifesting in late adolescence/adulthood. No targeted treatment is currently available, and patients are usually managed with supportive measures, or are offered a bone marrow transplant if the clinical phenotype is severe and a suitable donor is available. We report the case of a young girl presenting with transfusion-dependent erythropoietic failure and immunological features resembling autoimmune lymphoproliferative syndrome who responded well to empirical sirolimus. She later developed a marked growth delay, which was ultimately attributed to metaphyseal dysplasia. A diagnosis of CHH was reached through whole-genome sequencing (WGS), after a less sensitive genetic diagnostic strategy failed. The patient eventually underwent a haploidentical bone marrow transplant due to progressive combined immunodeficiency manifested as cryptococcal meningoencephalitis. This case illustrates the potential role of sirolimus in correcting anemia and partially controlling the immune aberrations associated with CHH, and serves as a reminder of the invaluable role of WGS in diagnosing patients with complex and atypical presentations.

Published
2022
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10. Case Report: Atypical Manifestations Associated With FOXP3 Mutations. The 'Fil Rouge' of Treg Between IPEX Features and Other Clinical Entities?

Author

Micaela Gentile, Maurizio Miano, Paola Terranova, Stefano Giardino, Maura Faraci, Filomena Pierri, Enrico Drago, Daniela Verzola, Gianmarco Ghiggeri, Enrico Verrina, Andrea Angeletti, Barbara Cafferata, Alice Grossi, Isabella Ceccherini, Gianluca Caridi, Francesca Lugani, Lorenzo Nescis, Enrico Fiaccadori, Luca Lanino, Daniela Fenoglio, and Edoardo La Porta

Subjects
FOXP3, ALPS, IPEX, membranous glomerulopathy, regulatory T cells, NGS, Immunologic diseases. Allergy, RC581-607
Abstract

IntroductionThe Forkhead box protein P3 (FOXP3) is a transcription factor central to the function of regulatory T cells (Treg). Mutations in the FOXP3 gene lead to a systemic disease called immune dysregulation, polyendocrinopathy, and enteropathy, an X-linked syndrome (IPEX) characterized by the triad of early-onset intractable diarrhea, type 1 diabetes, and eczema. An atypical presentation of IPEX has been reported.MethodWe report rare cases with equivocal clinical associations that included inflammatory, kidney, and hematologic involvements screened with massively parallel sequencing techniques.ResultsTwo patients with hemizygous mutations of FOXP3 [c.779T>A (p.L260Q)] and [c.1087A>G (p.I363V)] presented clinical manifestations not included in typical cases of IPEX: one was a 16-year-old male patient with an initial clinical diagnosis of autoimmune lymphoproliferative syndrome (ALPS) and who developed proteinuria and decreased kidney function due to membranous nephropathy, an autoimmune renal condition characterized by glomerular sub-epithelial antibodies. The second patient was a 2-year-old child with bone marrow failure who developed the same glomerular lesions of membranous nephropathy and received a bone marrow transplantation. High levels of IgG4 in serum, bone marrow, and kidney led to the definition of IgG4-related kidney disease (IgG4 RKD) in this young boy. The circulating Treg levels were normal in the former case and very low in the second.ConclusionTwo atypical associations of functional mutations of FOXP3 that include ALPS and IgG4 RKD are described. Membranous nephropathy leading to renal failure completed in both cases the clinical phenotypes that should be included in the clinical panorama of FOXP3 failure.

Published
2022
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12. A case report of a novel compound heterozygous mutation in a Brazilian patient with deficiency of Interleukin-1 receptor antagonist (DIRA)

Author

Leonardo Oliveira Mendonça, Alice Grossi, Francesco Caroli, Robson Aguiar de Oliveira, Jorge Kalil, Fabio Fernandes Morato Castro, Alessandra Pontillo, Isabella Ceccherini, Myrthes Anna Maragna Toledo Barros, and Marco Gattorno

Subjects
DIRA, Deficiency of interleukin-1 receptor antagonist, IL1RN, Pediatrics, RJ1-570, Diseases of the musculoskeletal system, RC925-935
Abstract

Abstract Background Deficiency of the natural antagonist of interleukin-1 was first described in 2009 and so far 20 patients has been reported. In Brazil just two cases have been reported both carrying the same homozygous 15 bp deletion. Blocking interleukin-1 has changed rate survival for DIRA patients. The use of anakinra and rilonacept has been reported safe and efficient, whereas the selective blockade of interleukin-1 beta, using the monoclonal antibody canakinumab has been reported in a single case only. Case presentation Here we report a case of a 7 years old Brazilian boy that presented with recurrent episodes of systemic inflammation with severe disabling osteomyelitis with mild pustular skin rash. A Next Generation Sequencing gene panel allowed to detect two pathogenic mutations in the IL1RN gene, described in compound heterozygosity. Corticosteroids was effective in controlling inflammation and anti-IL1 beta blocker triggered disease flare. Complete clinical control could be achieved using IL-1 receptor antagonist. Conclusions DIRA is a severe, life threatening autoinflammatory condition with low numbers of patients described all over the world. The mutation p.Asp72_Ile76del in IL1RN is presented in all Brazilian DIRA patients already described and p.Q45* (rs1019766125) is a new mutation affecting the IL1RN gene. Following the pathogenesis of DIRA, blocking both subunits of interleukin one as well as antagonizing the receptor using anakinra or rilonacept seems to be effective. There is just one report using canakinumab for the treatment of DIRA and this is the first report of disease flare using this drug.

Published
2020
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13. Parental Somatic Mosaicism Uncovers Inheritance of an Apparently De Novo GFAP Mutation

Author

Alice Grossi, Federico Morelli, Marco Di Duca, Francesco Caroli, Isabella Moroni, Davide Tonduti, Tiziana Bachetti, and Isabella Ceccherini

Subjects
central nervous system diseases, genetic counseling, human genetics, DNA sequence analysis, GFAP gene, Alexander disease, Genetics, QH426-470
Abstract

Alexander disease is a leukodystrophy caused by heterozygous mutations of GFAP gene. Recurrence in siblings from healthy parents provides a confirmation to the transmission of variants through germinal mosaicism. With the use of DNA isolated from peripheral blood, next-generation sequencing (NGS) of GFAP locus was performed with deep coverage (≥500×) in 11 probands and their parents (trios) with probands heterozygous for apparently de novo GFAP mutations. Indeed, one parent had somatic mosaicism, estimated in the range of 8.9%–16%, for the mutant allele transmitted to the affected sibling. Parental germline mosaicism deserves attention, as it is critical in assessing the risk of recurrence in families with Alexander disease.

Published
2021
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14. Case Report: Deficiency of Adenosine Deaminase 2 Presenting With Overlapping Features of Autoimmune Lymphoproliferative Syndrome and Bone Marrow Failure

Author

Gianluca Dell’Orso, Alice Grossi, Federica Penco, Roberta Caorsi, Elena Palmisani, Paola Terranova, Francesca Schena, Michela Lupia, Erica Ricci, Shana Montalto, Filomena Pierri, Isabella Ceccherini, Francesca Fioredda, Carlo Dufour, Marco Gattorno, and Maurizio Miano

Subjects
bone marrow failure (BMF), primary immune regulatory disorders (PIRDS), autoimmune lymphoproliferative syndrome (ALPS), next-generation sequencing (NGS), DADA2, inborn errors of immunity (IEI), Immunologic diseases. Allergy, RC581-607
Abstract

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease associated with a highly variable clinical presentation, such as vasculitis, inflammation, and hematologic manifestations. Some associations of clinical features can mimic autoimmune lymphoproliferative syndrome (ALPS). We report a case of a female patient who fulfilled the 2009 National Institute of Health revised criteria for ALPS and received a delayed diagnosis of DADA2. During her childhood, she suffered from autoimmune hemolytic anemia, immune thrombocytopenia, and chronic lymphoproliferation, which partially responded to multiple lines of treatments and were followed, at 25 years of age, by pulmonary embolism, septic shock, and bone marrow failure with myelodysplastic evolution. The patient died from the progression of pulmonary disease and multiorgan failure. Two previously unreported variants of gene ADA2/CECR1 were found through next-generation sequencing analysis, and a pathogenic role was demonstrated through a functional study. A single somatic STAT3 mutation was also found. Clinical phenotypes encompassing immune dysregulation and marrow failure should be evaluated at the early stage of diagnostic work-up with an extended molecular evaluation. A correct genetic diagnosis may lead to a precision medicine approach consisting of the use of targeted treatments or early hematopoietic stem cell transplantation.

Published
2021
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15. Copy number variations in candidate genomic regions confirm genetic heterogeneity and parental bias in Hirschsprung disease

Author

Francesca Lantieri, Stefania Gimelli, Chiara Viaggi, Elissavet Stathaki, Michela Malacarne, Giuseppe Santamaria, Alice Grossi, Manuela Mosconi, Frédérique Sloan-Béna, Alessio Pini Prato, Domenico Coviello, and Isabella Ceccherini

Subjects
Hirschsprung disease, Copy number variations, Comparative genomic hybridization, Custom array, Candidate genes and regions, Medicine
Abstract

Abstract Background Hirschsprung Disease (HSCR) is a congenital defect of the intestinal innervations characterized by complex inheritance. Many susceptibility genes including RET, the major HSCR gene, and several linked regions and associated loci have been shown to contribute to disease pathogenesis. Nonetheless, a proportion of patients still remains unexplained. Copy Number Variations (CNVs) have already been involved in HSCR, and for this reason we performed Comparative Genomic Hybridization (CGH), using a custom array with high density probes. Results A total of 20 HSCR candidate regions/genes was tested in 55 sporadic patients and four patients with already known chromosomal aberrations. Among 83 calls, 12 variants were experimentally validated, three of which involving the HSCR crucial genes SEMA3A/3D, NRG1, and PHOX2B. Conversely RET involvement in HSCR does not seem to rely on the presence of CNVs while, interestingly, several gains and losses did co-occur with another RET defect, thus confirming that more than one predisposing event is necessary for HSCR to develop. New loci were also shown to be involved, such as ALDH1A2, already found to play a major role in the enteric nervous system. Finally, all the inherited CNVs were of maternal origin. Conclusions Our results confirm a wide genetic heterogeneity in HSCR occurrence and support a role of candidate genes in expression regulation and cell signaling, thus contributing to depict further the molecular complexity of the genomic regions involved in the Enteric Nervous System development. The observed maternal transmission bias for HSCR associated CNVs supports the hypothesis that in females these variants might be more tolerated, requiring additional alterations to develop HSCR disease.

Published
2019
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16. PAPA and FMF in two siblings: possible amplification of clinical presentation? A case report

Author

Maria Cristina Maggio, Isabella Ceccherini, Alice Grossi, Marco Gattorno, and Giovanni Corsello

Subjects
Familial Mediterranean fever, Pyogenic arthritis, pyoderma gangrenosum and acne syndrome, Colchicine, Canakinumab, Pediatrics, RJ1-570
Abstract

Abstract Background Familial Mediterranean Fever is a monogenic autoinflammatory disease, typically characterized by recurrent attacks of fever, serositis, aphthous of oral mucosa, erythema. “Pyogenic arthritis, pyoderma gangrenosum and acne syndrome” is a rare autoinflammatory disease with variable expression and typically involving joints and skin. Both the diseases are linked by the overproduction of IL-1. Case presentation We report on the case of two siblings affected by recurrent attacks of fever, oral aphthous stomatitis, abdominal pain, arthritis, undefined dermatitis at the hands, associated with increased AST, ALT, C-reactive protein, erythrocyte sedimentation rate, serum amyloid A, leucocytosis with neutrophilia. Infectious diseases were excluded. The genetic study for Familial Mediterranean Fever, tumor necrosis factor receptor-associated periodic syndrome, Mevalonate kinase deficiency, showed the homozygous mutation p.M680I of exon 10 in MEFV. Their parents were heterozygous for the same mutation p.M680I, however, the mother showed severe symptoms of FMF (recurrent attacks of fever, arthralgia and arthritis, abdominal pain, thoracic pain), the father showed recurrent pustulosis prevalent on the hands and limbs, with arthralgia and abdominal pain. Both the patients started colchicine, with an improvement in clinical manifestations and a reduction of serum amyloid A. For the atypical dermatologic signs present in the two siblings and in the father, the study of other autoinflammatory syndromes was performed with next generation sequencing and showed the heterozygous rare missense mutation of unknown significance: p.(Val408Ile) of PSTPIP1 gene in the two siblings and in the mother, the father was negative. Canakinumab treatment was started in the younger patient, with the resolution of the clinical symptoms and the normalization of serum amyloid A. Conclusions Further studies are needed to better describe the correlation between genotype and phenotype in patients with PAPA syndrome and with PAPA syndrome associated with FMF, considering that the presence of mutations in both genes may amplify clinical presentation and evolution of both diseases.

Published
2019
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17. Proceedings of the 23rd Paediatric Rheumatology European Society Congress: part one

Author

F. De Benedetti, J. Anton, M. Gattorno, H. Lachmann, I. Kone-Paut, S. Ozen, J. Frenkel, A. Simon, A. Zeft, E. Ben-Chetrit, H. M. Hoffman, Y. Joubert, K. Lheritier, A. Speziale, J. Guido, Roberta Caorsi, Federica Penco, Alice Grossi, Antonella Insalaco, Maria Alessio, Giovanni Conti, Federico Marchetti, Alberto Tommasini, Silvana Martino, Romina Gallizzi, Annalisa Salis, Francesca Schena, Francesco Caroli, Alberto Martini, Gianluca Damonte, Isabella Ceccherini, Marco Gattorno, Marie-Louise Frémond, Carolina Uggenti, Lien Van Eyck, Isabelle Melki, Darragh Duffy, Vincent Bondet, Yoann Rose, Bénédicte Neven, Yanick Crow, Mathieu P. Rodero, Yvonne Kusche, Johannes Roth, Katarzyna Barczyk-Kahlert, Giovanna Ferrara, Annalisa Chiocchetti, Silvio Polizzi, Josef Vuch, Diego Vozzi, Anna Mondino, Erica Valencic, Serena Pastore, Andrea Taddio, Flavio Faletra, Umberto Dianzani, Ugo Ramenghi, Qing Zhou, Xiaomin Yu, Erkan Demirkaya, Natalie Deuitch, Deborah Stone, Wanxia Tsai, Amanda Ombrello, Tina Romeo, Elaine F. Remmers, JaeJin Chae, Massimo Gadina, Steven Welch, Seza Ozen, Rezan Topaloglu, Mario Abinun, Daniel L. Kastner, Ivona Aksentijevich, Donatella Vairo, Rosalba Monica Ferraro, Giulia Zani, Jessica Galli, Micaela De Simone, Marco Cattalini, Elisa Fazzi, Silvia Giliani, Ebun Omoyinmi, Ariane Standing, Dorota Rowczenio, Annette Keylock, Sonia Melo Gomes, Fiona Price-Kuehne, Sira Nanthapisal, Claire Murphy, Thomas Cullup, Lucy Jenkins, Kimberly Gilmour, Despina Eleftheriou, Helen Lachmann, Philip Hawkins, Nigel Klein, Paul Brogan, Anita Dhanrajani, Mercedes Chan, Stephanie Pau, Janet Ellsworth, Jaime Guzman, Florence A. Aeschlimann, Marinka Twilt, Simon W. Eng, Shehla Sheikh, Ronald M. Laxer, Diane Hebert, Damien Noone, Christian Pagnoux, Susanne M. Benseler, Rae S. Yeung, Christoph Kessel, Katrin Lippitz, Toni Weinhage, Claas Hinze, Helmut Wittkowski, Dirk Holzinger, Niklas Grün, Dirk Föll, Pieter Van Dijkhuizen, Federica Del Chierico, Clara Malattia, Alessandra Russo, Denise Pires Marafon, Nienke M. ter Haar, Silvia Magni-Manzoni, Sebastiaan J. Vastert, Bruno Dallapiccola, Berent Prakken, Fabrizio De Benedetti, Lorenza Putignani, Berna Eren Fidanci, Kenan Barut, Serap Arıcı, Dogan Simsek, Mustafa Cakan, Ezgi D. Batu, Sezgin Şahin, Ayşenur Kısaarslan, Ebru Yilmaz, Özge Basaran, Ferhat Demir, Kubra Ozturk, Zübeyde Gunduz, Betül Sozeri, Balahan Makay, Nuray Ayaz, Onder Yavascan, Ozlem Aydog, Yelda Bilginer, Zelal Ekinci, Dilek Yıldız, Faysal Gök, Muferret Erguven, Erbil Unsal, Ozgur Kasapcopur, For the FMF Arthritis Vasculitis and Orphan Disease Research in Paediatric Rheumatology (FAVOR), Hafize E. Sönmez, Betül Sözeri, Yonatan Butbul, Seza Özen, Claudia Bracaglia, Giusi Prencipe, Manuela Pardeo, Geneviève Lapeyre, Emiliano Marasco, Walter Ferlin, Robert Nelson, Cristina de Min, N. Ruperto, H. I. Brunner, P. Quartier, T. Constantin, E. Alexeeva, K. Marzan, N. Wulffraat, R. Schneider, S. Padeh, V. Chasnyk, C. Wouters, J. B. Kuemmerle-Deschner, T. Kallinich, B. Lauwerys, E. Haddad, E. Nasonov, M. Trachana, O. Vougiouka, K. Leon, E. Vritzali, A. Martini, D. Lovell, PRINTO/PRCSG, Stefano Volpi, Claudia Pastorino, Francesca Kalli, Alessia Omenetti, Sabrina Chiesa, Arinna Bertoni, Paolo Picco, Gilberto Filaci, Elisabetta Traggiai, Marie-Louise Fremond, Naoki Kitabayashi, Olivero Sacco, Isabelle Meyts, Marie-Anne Morren, Carine Wouters, Eric Legius, Isabelle Callebaut, Christine Bodemer, Frederic Rieux-Laucat, Mathieu Rodero, Nadia Jeremiah, Alexandre Belot, Eric Jeziorski, Didier Bessis, Guilhem Cros, Gillian I. Rice, Bruno Charbit, Anne Hulin, Nihel Khoudour, Consuelo Modesto Caballero, Monique Fabre, Laureline Berteloot, Muriel Le Bourgeois, Philippe Reix, Thierry Walzer, Despina Moshous, Stéphane Blanche, Alain Fischer, Brigitte Bader-Meunier, Frédéric Rieux-Laucat, K. Annink, N. ter Haar, S. Al-Mayouf, G. Amaryan, K. Barron, S. Benseler, P. Brogan, L. Cantarini, M. Cattalini, A. Cochino, F. Dedeoglu, A. De Jesus, O. Dellacasa, E. Demirkaya, P. Dolezalova, K. Durrant, G. Fabio, R. Gallizzi, R. Goldbach-Mansky, E. Hachulla, V. Hentgen, T. Herlin, M. Hofer, H. Hoffman, A. Insalaco, A. Jansson, I. Koné-Paut, A. Kozlova, J. Kuemmerle-Deschner, R. Laxer, S. Nielsen, I. Nikishina, A. Ombrello, E. Papadopoulou-Alataki, A. Ravelli, D. Rigante, R. Russo, Y. Uziel, Nienke ter Haar, Jerold Jeyaratnam, Anna Simon, Matteo Doglio, Jordi Anton, Consuelo Modesto, Pierre Quartier, Esther Hoppenreijs, Luca Cantarini, Loredana Lepore, Inmaculada Calvo Penades, Christina Boros, Rita Consolini, Donato Rigante, Ricardo Russo, Jana Pachlopnik Schmid, Thirusha Lane, Nicolino Ruperto, Joost Frenkel, Chiara Passarelli, Elisa Pisaneschi, Virginia Messia, Antonio Novelli, Fabrizio Debenedetti, P. A. Brogan, X. Wei, Martina Finetti, Francesca Orlando, Elisabetta Cortis, Angela Miniaci, Nicola Ruperto, Charlotte Eijkelboom, Pavla Dolezalova, Isabelle Koné-Paut, Marija Jelusic-Drazic, Liliana Bezrodnik, Mari Carmen Pinedo, Valda Stanevicha, Marielle van Gijn, Silvia Federici, Hermann Girschick, Gerd Ganser, Susan Nielsen, Troels Herlin, Sulaiman Mohammed Al-Mayouf, Michael Hofer, Jasmin Kuemmerle-Deschner, Susanne Schalm, Annette Jansson, on behalf of PRINTO and Eurofever registry, Marta Marchi, Chiara Marini, Angelo Ravelli, Alberto Garaventa, Sonia Carta, Enrica Balza, Patrizia Castellani, Caterina Pellecchia, Silvia Borghini, Maria Libera Trotta, Anna Rubartelli, Andrew Henrey, Thomas Loughin, Roberta Berard, Natalie Shiff, Roman Jurencak, Susanne Benseler, Lori Tucker, on behalf of ReACCh-Out Investigators, Charalampia Papadopoulou, Ying Hong, Petra Krol, Yiannis Ioannou, Clarissa Pilkington, Hema Chaplin, Stephania Simou, Marietta Charakida, Lucy Wedderburn, Lynn R. Spiegel, Sara Ahola Kohut, Jennifer Stinson, Paula Forgeron, Miriam Kaufman, Nadia Luca, Khush Amaria, Mary Bell, J Swart, F. Boris, E. Castagnola, A. Groll, G. Giancane, G. Horneff, H. I. Huppertz, T. Wolfs, E. Alekseeva, V. Panaviene, F. Uettwiller, V. Stanevicha, L. M. Ailioaie, E. Tsitami, S. Kamphuis, G. Susic, F. Sztajnbok, B. Flato, A. Pistorio, Stephanie J. W. Shoop, Suzanne M. M. Verstappen, Janet E. McDonagh, Wendy Thomson, Kimme L. Hyrich, CAPS, Maarit Tarkiainen, Pirjo Tynjala, Pekka Lahdenne, Janne Martikainen, Acute-JIA Study Group, Meredyth Wilkinson, Christopher Piper, Georg Otto, Claire T. Deakin, Stefanie Dowle, Stefania Simou, Daniel Kelberman, Claudia Mauri, Elizabeth Jury, David Isenberg, Lucy R. Wedderburn, Kiran Nistala, I. Foeldvari, D. J. Lovell, G. Simonini, M. Bereswill, J. Kalabic, Kiem Oen, Brian M. Feldman, Brenden Dufault, Jennifer Lee, Karen Watanabe Duffy, Ciaran Duffy, ReACCh-Out Investigators, N. Tzaribachev, G. Vega-Cornejo, I. Louw, A. Berman, I. Calvo, R. Cuttica, F. Avila-Zapata, R. Cimaz, E. Solau-Gervais, R. Joos, G. Espada, X. Li, M. Nys, R. Wong, S. Banerjee, For Pediatric Rheumatology International Trials Organization (PRINTO)/Pediatric Rheumatology Collaborative Study Group (PRCSG), Rebecca Nicolai, Margherita Verardo, Adele D’Amico, Luisa Bracci-Laudiero, Gian Marco Moneta, Gillian Rice, Anne-Laure Mathieu, Sulliman O. Omarjee, Tracy A. Briggs, James O’Sullivan, Simon Williams, Rolando Cimaz, Eve Smith, Michael W. Beresford, Yanick J. Crow, GENIAL Investigators, UK JSLE Study Group, Madeleine Rooney, Nick Bishop, joyce davidson, Clarissa pilkington, Michael Beresford, Jacqui Clinch, Rangaraj Satyapal, Helen Foster, Janet Gardner Medwin, Janet McDonagh, Sue Wyatt, On Behalf of the British Society for Paediatric and Adolescent Rheumatology, Valentina Litta Modignani, Francesco Baldo, Stefano Lanni, Alessandro Consolaro, Giovanni Filocamo, Helen J. Lachmann, on behalf of Eurofever Registry, Gianmarco Moneta, Camilla Celani, Bilade Cherqaoui, Linda Rossi-Semerano, Perrine Dusser, Véronique Hentgen, Claire Grimwood, Linda Rossi, Isabelle Kone Paut, Veronique Hentgen, Denise Lasigliè, Denise Ferrera, Giulia Amico, Marco Di Duca, Laura Obici, Roberto Ravazzolo, Ryuta Nishikomori, Juan Arostegui, Andrea Petretto, Chiara Lavarello, Elvira Inglese, Federica Vanoni, Michaël Hofer, on behalf of EUROFEVER PROJECT, P. N. Hawkins, T. van der Poll, U. A. Walker, H. H. Tilson, Pascal N. Tyrrell, Raphaela Goldbach-Mansky, Norbert Blank, Hal M. Hoffman, Elisabeth Weissbarth-Riedel, Boris Huegle, Tilmann Kallinich, Ahmet Gul, Marlen Oswald, Fatma Dedeoglu, Aki Hanaya, Takako Miyamae, Manabu Kawamoto, Yumi Tani, Takuma Hara, Yasushi Kawaguchi, Satoru Nagata, Hisashi Yamanaka, Almira Ćosićkić, Fahrija Skokić, Belkisa Čolić, Sanimir Suljendić, Anna Kozlova, Irina Mersiyanova, Mariya Panina, Lily Hachtryan, Vasiliy Burlakov, Elena Raikina, Alexey Maschan, Anna Shcherbina, Banu Acar, Meryem Albayrak, Betul Sozeri, Sezgin Sahin, Amra Adrovic, Nese Inan, Serhan Sevgi, Caroline M. Andreasen, Anne Grethe Jurik, Mia B. Glerup, Christian Høst, Birgitte T. Mahler, Ellen-Margrethe Hauge, Cecilia Lazea, Laura Damian, Calin Lazar, Rodica Manasia, Chloe M. Stephenson, Vimal Prajapati, Paivi M. Miettunen, Dilek Yılmaz, Yavuz Tokgöz, Yasin Bulut, Harun Çakmak, Ferah Sönmez, Elif Comak, Gülşah Kaya Aksoy, Mustafa Koyun, Sema Akman, Yunus Arıkan, Ender Terzioğlu, Osman Nidai Özdeş, İbrahim Keser, Hüseyin Koçak, Ayşen Bingöl, Aygen Yılmaz, Reha Artan, X. Xu, Fatemeh F. Mehregan, Vahid Ziaee, Mohammad H. Moradinejad, Francesco La Torre, Clotilde Alizzi, Pio D’Adamo, G. Junge, J. Gregson, Hasmik Sargsyan, Hulya Zengin, Berna E. Fidanci, Cagla Kaymakamgil, Dilek Konukbay, Dilek Yildiz, Faysal Gok, Iris Stoler, Judith Freytag, Banu Orak, Christine Seib, Lars Esmann, Eva Seipelt, Faekah Gohar, Dirk Foell, Ismail Dursun, Sebahat Tulpar, Sibel Yel, Demet Kartal, Murat Borlu, Funda Bastug, Hakan Poyrazoglu, Zubeyde Gunduz, Kader Kose, Mehmet E. Yuksel, Abdullah Calıskan, Ahmet B. Cekgeloglu, Ruhan Dusunsel, Katerina Bouchalova, Jana Franova, Marcel Schuller, Marie Macku, Katerina Theodoropoulou, Raffaella Carlomagno, Annette von Scheven-Gête, Claudia Poloni, Laura O. Damian, Dan Cosma, Amanda Radulescu, Dan Vasilescu, Liliana Rogojan, Simona Rednic, Mihaela Lupse, Lien De Somer, Pierre Moens, Rocio Galindo Zavala, Laura Martín Pedraz, Esmeralda Núñez Cuadros, Gisela Díaz-Cordovés Rego, Antonio L. Urda Cardona, Ilaria Dal Forno, Sara Pieropan, Ombretta Viapiana, Davide Gatti, Gloria Dallagiacoma, Paola Caramaschi, Domenico Biasi, Daniel Windschall, Ralf Trauzeddel, Hartwig Lehmann, Rainer Berendes, Maria Haller, Manuela Krumrey-Langkammerer, Antje Nimtz-Talaska, Philipp Schoof, Ralf Felix Trauzeddel, Christine Nirschl, Estefania Quesada-Masachs, Carla Aguilar Blancafort, Sara Marsal Barril, Francisca Aguiar, Rita Fonseca, Duarte Alves, Ana Vieira, Alberto Vieira, Jorge A. Dias, Iva Brito, Gordana Susic, Vera Milic, Goran Radunovic, Ivan Boricic, Pauline Marteau, Catherine Adamsbaum, Michel De Bandt, Irène Lemelle, Chantal Deslandre, Tu Anh Tran, Anne Lohse, Elisabeth Solau-Gervais, Pascal Pillet, Julien Wipff, Cécile Gaujoux-Viala, Sylvain Breton, Valérie Devauchelle-Pensec, Sandra Gran, Olesja Fehler, Stefanie Zenker, Michael Schäfers, Thomas Vogl, Severine Guillaume Czitrom, EH Pieter Van Dijkhuizen, Silvia Magni Manzoni, Francesca Magnaguagno, Laura Tanturri de Horatio, Nienke M. Ter Haar, Annemieke S. Littooij, Vitor A. Teixeira, Raquel Campanilho-Marques, Ana F. Mourão, Filipa O. Ramos, Manuela Costa, Wafa A. Madan, Orla G. Killeen, Adriana Rodriguez Vidal, Diana Sueiro Delgado, Maria Isabel Gonzalez Fernandez, Berta Lopez Montesinos, Aleksey Kozhevnikov, Nina Pozdeeva, Mikhail Konev, Evgeniy Melchenko, Vladimir Kenis, Gennadiy Novik, Aysenur Pac Kısaarslan, Butsabong Lerkvaleekul, Suphaneewan Jaovisidha, Witaya Sungkarat, Niyata Chitrapazt, Praman Fuangfa, Thumanoon Ruangchaijatuporn, Soamarat Vilaiyuk, Dan Ø. Pradsgaard, Arne Hørlyck, Anne H. Spannow, Carsten W. Heuck, Talia Diaz, Fernando Garcia, Lorenia De La Cruz, Nadina Rubio, Joanna Świdrowska-Jaros, Elzbieta Smolewska, Mirta Lamot, Lovro Lamot, Mandica Vidovic, Edi Paleka Bosak, Ivana Rados, Miroslav Harjacek, Nikolay Tzaribachev, Polymnia Louka, Romiesa Hagoug, Chiara Trentin, Olga Kubassova, Mark Hinton, Mikael Boesen, Olena A. Oshlianska, Illya A. Chaikovsky, G. Mjasnikov, A. Kazmirchyk, Umberto Garagiola, Irene Borzani, Paolo Cressoni, Fabrizia Corona, Eszter Dzsida, Giampietro Farronato, Antonella Petaccia, Alenka Gagro, Agneza Marija Pasini, Goran Roic, Ozren Vrdoljak, Lucija Lujic, Matija Zutelija-Fattorini, Monika M. Esser, Deepthi R. Abraham, Craig Kinnear, Glenda Durrheim, Mike Urban, Eileen Hoal, Victoria B. Nikolayenko, Kubilay Şahin, Yasar Karaaslan, Adele Civino, Giovanni Alighieri, Sergio Davì, Roberto Rondelli, Andrea Magnolato, Francesca Ricci, Alma Olivieri, Valeria Gerloni, Bianca Lattanzi, Francesca Soscia, Alessandro De Fanti, Stefania Citiso, Lorenzo Quartulli, Maria Cristina Maggio, Manuela Marsili, Maria Antonietta Pelagatti, Valentino Conter, Franca Fagioli, Andrea Pession, Marco Garrone, Mariangela Rinaldi, Jaime De Inocencio, Stella Garay, Daniel J. Lovell, Berit Flato, EPOCA Study Group, Angela Aquilani, Simona Cascioli, Ivan Caiello, Denise Pires-Marafón, Rita Carsetti, Emily Robinson, Salvatore Albani, Wilco de Jager, Sytze de Roock, Trang Duong, Justine Ellis, Kimme Hyrich, Laetitia Jervis, Daniel Lovell, Lucy Marshall, Elizabeth D. Mellins, Kirsten Minden, Jane Munro, Peter A. Nigrovic, Jason Palman, Sunil Sampath, Laura E. Schanberg, Susan D. Thompson, Richard Vesely, Chris Wallace, Chris Williams, Qiong Wu, Nico Wulffraat, Rae S. M. Yeung, M. B. Seyger, D. Arikan, J. K. Anderson, A. Lazar, D. A. Williams, C. Wang, R. Tarzynski-Potempa, J. S. Hymans, Gabriele Simonini, Erika Scoccimarro, Irene Pontikaki, Teresa Giani, Alessandro Ventura, Pier Luigi Meroni, Gaetana Minnone, Marzia Soligo, Luigi Manni, Luisa Bracci Laudiero, Noortje Groot, I. Grein, N. M. Wulffraat, R. Schepp, G. Berbers, C. C. Barbosa Sandoval de Souza, V. Paes Leme Ferriani, G. Pileggi, S. de Roock, Ingrid H. R. Grein, Silvia Scala, Elisa Patrone, Casper Schoemaker, on behalf of Dutch JIA patient organization, Wendy Costello, on behalf of ENCA, Suzanne Parsons, Jean-David Cohen, Damien Bentayou, Marc-Antoine Bernard Brunel, Sonia Trope, Jens Klotsche, Miriam Listing, Martina Niewerth, Gerd Horneff, Angelika Thon, Hans-Iko Huppertz, Kirsten Mönkemöller, Ivan Foeldvari, ICON study group, Achille Marino, Stefano Stagi, Niccolò Carli, Federico Bertini, Adriana S. Díaz-Maldonado, Sally Pino, Pilar Guarnizo, Alfonso Ragnar Torres-Jimenez, Berenice Sanchez-Jara, Eunice Solis-Vallejo, Adriana Ivonne Cespedes-Cruz, Maritza Zeferino-Cruz, Julia Veronica Ramirez-Miramontes, Ankur Kumar, Anju Gupta, Deepti Suri, Amit Rawat, Nandita Kakkar, Surjit Singh, Özge A. Gücenmez, Erbil Ünsal, Bo Magnusson, Karina Mördrup, Anna Vermé, Christina Peterson, Board of the Swedish Pediatric Rheumatology Registry, Caroline Freychet, Jean Louis Stephan, Cathryn E. Harkness, Leanne Foster, Emma Henry, Pauline Taggart, Coskun F. Ozkececi, Esra Kurt, Gokalp Basbozkurt, Daiva Gorczyca, Jacek Postępski, Aleksandra Czajkowska, Bogumiła Szponar, Mariola Paściak, Anna Gruenpeter, Iwona Lachór-Motyka, Daria Augustyniak, Edyta Olesińska, Emediong S. Asuka, Tatyana Golovko, Samuel U. Aliejim, Emilio Inarejos Clemente, Estibaliz Iglesias Jimenez, Joan Calzada Hernandez, Sergi Borlan Fernandez, Clara Gimenez Roca, David Moreno Romo, Natalia Rodriguez Nieva, Juan Manuel Mosquera Angarita, Jordi Anton Lopez, Esmeralda Nuñez-Cuadros, Gisela Diaz-Cordovés, Rocío Galindo-Zavala, Antonio Urda-Cardona, Antonio Fernández-Nebro, Daniel Álvarez de la Sierra, Marina Garcia Prat, Mónica Martínez Gallo, Ricardo Pujol Borrell, Ana M. Marín Sánchez, Etienne Merlin, Sylvie Fraitag, Jean-Louis Stephan, Federico Annoni, Giancarla Di Landro, Sofia Torreggiani, Marta Torcoletti, Georgina Tiller, Jo Buckle, Angela Cox, Peter Gowdie, Roger C. Allen, Jonathan D. Akikusa, Hayde G. Hernández-Huirache, Edel R. Rodea-Montero, William Fahy, Christelle Sordet, Karin B. Berggren, Johanna T. Kembe, Joyce Bos, Wineke Armbrust, Marco van Brussel, Jeanette Cappon, Pieter Dijkstra, Jan Geertzen, Elizabeth Legger, Marion van Rossum, Pieter Sauer, Otto Lelieveld, Levent Buluc, Gur Akansel, Bahar Muezzinoglu, Ljubov Rychkova, Tatyana Knyazeva, Anna Pogodina, Tatyana Belova, Tamara Mandzyak, Ekaterina Kulesh, Alessandro Cafarotti, Cosimo Giannini, Roberta Salvatore, Giuseppe Lapergola, Caterina Di Battista, Maria Loredana Marcovecchio, Raffaella Basilico, Piernicola Pelliccia, Francesco Chiarelli, Luciana Breda, Beverley Almeida, Sarah Tansley, Harsha Gunawardena, Neil McHugh, Juvenile Dermatomyositis Research Group (JDRG), Jessie Aouizerate, Marie De Antonio, Christine Barnerias, Guillaume Bassez, Isabelle Desguerre, Romain Gherardi, Jean-Luc Charuel, François-Jérôme Authier, Cyril Gitiaux, C. H. Spencer, Rabheh Abdul Aziz, Chack-Yung Yu, Brent Adler, Sharon Bout-Tabaku, Katherine Lintner, Melissa Moore-Clingenpeel, Liza McCann, Nicola Ambrose, Mario Cortina-Borja, Juvenile Dermatomyositis Cohort and Biomarker Study (JCDBS), Prasad T. Oommen, Fabian Speth, Johannes-Peter Haas, Working Group “Juvenile Dermatomyositis” of the German Society for Paediatric and Adolescent Rheumatology (GKJR), Claudio Lavarello, Gabriella Giancane, Angela Pistorio, Lisa Rider, Rohit Aggarwal, Sheila K. Oliveira, Ruben Cuttica, Michel Fischbach, Gary Sterba, Karine Brochard, Frank Dressler, Patrizia Barone, Ruben Burgos-Vargas, Elizabeth Candell Chalom, Marine Desjonqueres, Graciela Espada, Anders Fasth, Stella Maris Garay, Rose-Marie Herbigneaux, Claire Hoyoux, Chantal Job Deslandre, Frederick W. Miller, Jiri Vencovsky, Erdal Sag, Gulsev Kale, Haluk Topaloglu, Beril Talim, Francesco Zulian, Tadej Avcin, Roberto Marini, Anne Pagnier, Michel Rodiere, Christine Soler, Rebecca Ten Cate, Yosef Uziel, Jelena Vojinovic, Ana V. Villarreal, Nydia Acevedo, Yuridiana Ramirez, Enrique Faugier, Rocio Maldonado, Bita Arabshahi, John H. Lee, Ian Leibowitz, Lawrence O. Okong’o, Jo Wilmshurst, Monika Esser, Christiaan Scott, Ezgi Deniz Batu, Nagehan Emiroglu, Hafize Emine Sonmez, Gokcen Dilsa Tugcu, Zehra Serap Arici, Ebru Yalcin, Deniz Dogru, Ugur Ozcelik, Mithat Haliloglu, Nural Kiper, Masato Yashiro, Mutsuko Yamada, Toshihiko Yabuuchi, Tomonobu Kikkawa, Nobuyuki Nosaka, Yosuke Fujii, Yukie Saito, Hirokazu Tsukahara, Sulaiman M. Al-Mayouf, Nora AlMutiari, Mohammed Muzaffer, Rawiah shehata, Adel Al-Wahadneh, Reem Abdwani, Safia Al-Abrawi, Mohammed Abu-shukair, Zeyad El-Habahbeh, Abdullah Alsonbul, Aleksandra Szabat, Monika Chęć, Violetta Opoka-Winiarska, Biman Saikia, Ranjana W. Minz, Christine Arango, Clara Malagon, Maria D. P. Gomez, Angela C. Mosquera, Ricardo Yepez, Tatiana Gonzalez, Camilo Vargas, GRIP study group, Marta Balzarin, Biagio Castaldi, Elena Reffo, Francesca Sperotto, Giorgia Martini, Alessandra Meneghel, Ornella Milanesi, Ozgur Kasapçopur, Maria Teresa Terreri, Ekaterina Alexeeva, Maria Katsicas, Mikhail Kostik, Thomas Lehman, W.-Alberto Sifuentes-Giraldo, Vanessa Smith, Flavio Sztajnbok, Tadey Avcin, Maria Jose Santos, Dana Nemcova, Cristina Battagliotti, Liora Harel, Mahesh Janarthanan, Kathryn Torok, Nicola Helmus, Eileen Baildem, Michael Blakley, Kim Fligelstone, Antonia Kienast, Clare Pain, Amanda Saracino, Gabriele Simoni, Lisa Weibel, Maria K. Osminina, Nathalia A. Geppe, Olga V. Niconorova, Olesya V. Karashtina, Oksana V. Abbyasova, Olga V. Shpitonkova, Sinem Durmus, Hafize Uzun, Angela Mauro, Eleonora Fanti, Fabio Voller, Franca Rusconi, Fernando Garcia-Rodriguez, Ana V. Villarreal-Treviño, Angel J. Flores-Pineda, Paola B. Lara-Herrea, Diego R. Salinas-Encinas, Talia Diaz-Prieto, Maria R. Maldonado-Velazquez, Sarbelio Moreno-Espinosa, Enrique Faugier-Fuentes, Mirella Crapanzano, Ilaria Parissenti, Man S. Parihar, Pandiarajan Vignesh, ManojKumar Rohit, Kavitha Gopalan, Savita V. Attri, Alan Salama, David Jayne, Mark Little, Yulia Kostina, Galina Lyskina, Olga Shpitonkova, Alena Torbyak, Olga Shirinsky, Maria Francesca Gicchino, Maria Cristina Smaldone, Mario Diplomatico, Alma Nunzia Olivieri, C H. Spencer, Richard McClead, Hiren Patel, Chung-Yung Yu, Dita Cebecauerová, Tomáš Dallos, Edita Kabíčková, Martin Kynčl, Daniela Chroustová, Jozef Hoza, Dana Němcová, Vladimír Tesař, Pavla Doležalová, Tuncay Hazirolan, Fatih Ozaltin, Fabiola Almeida, Isabela H. Faria de Paula, Maíra M. Sampaio, Fernando N. Arita, Andressa G. Alves, Maria Carolina Santos, Eunice M. Okuda, Silvana B. Sacchetti, Fernanda Falcini, Marini Francesca, Gemma Lepri, Marco Matucci-Cerinic, Maria Luisa Brandi, Hakan Kisaoglu, Sema Misir, Selim Demir, Yuksel Aliyazicioglu, Mukaddes Kalyoncu, Carlos Eduardo Ramalho, Fabiola D. Almeida, Joan Calzada-Hernández, Rosa Bou, Estíbaliz Iglesias, Judith Sánchez-Manubens, Fredy Hermógenes Prada Martínez, Clara Giménez Roca, Sergi Borlan Fernández, Marek Bohm, Kamran Mahmood, Valentina Leone, Mark Wood, Ken-Ichi Yamaguchi, Satoshi Fujikawa, Working Group of Behçet’s Disease, Pediatric Rheumatology Association of Japan (PRAJ), Kyu Yeun Kim, Do Young Kim, Dong Soo Kim, Maka Ioseliani, Ivane Chkhaidze, Maia Lekishvili, Nana Tskhakaia, Shorena Tvalabeishvili, Aleksandre Kajrishvili, Maiko Takakura, Masaki Shimizu, Natsumi Inoue, Mao Mizuta, Akihiro Yachie, Giovanni Corsello, Maryam Piram, Carla Maldini, Sandra Biscardi, Nathalie Desuremain, Catherine Orzechowski, Emilie Georget, Delphine Regnard, Isabelle Kone-Paut, Alfred Mahr, Mihaela Sparchez, Zeno Sparchez, Nydia Acevedo Silva, Ana V. Villarreal Treviño, Yuridiana Ramirez Loyola, Talia Diaz Prieto, Enrique Faugier Fuentes, Maria D. R. Maldonado Velazquez, Pilar Perez, Sagar Bhattad, Ranjana Minz, Jitendra Shandilya, Pediatric Allergy and Immunology Unit, PGIMER, Chandigarh, Ana Villarreal, Yuridiana Ramírez, Zeynep Birsin Özçakar, Suat Fitoz, Fatos Yalcinkaya, Annacarin Horne, Francesca Minoia, Francesca Bovis, Sergio Davi, Priyankar Pal, Kimo Stein, Sandra Enciso, Michael Jeng, Despoina Maritsi, Randy C. Cron, Anne Thorwarth, Sae Lim von Stuckrad, Angela Rösen-Wolff, Hella Luksch, Patrick Hundsdoerfer, Peter Krawitz, Nuray Aktay Ayaz, Doğan Simsek, Şebnem Sara Kılıc, Emine Sonmez, Aysenur Pac Kisaarslan, Ozge Altug Gucenmez, Z. Serap Arıcı, Fatih Kelesoglu, Zelal Ekinci Ekinci, Maria Miranda-Garcia, Carolin Pretzer, Michael Frosch, F. Gohar, Angela McArdle, Niamh Callan, Belinda Hernandez, Miha Lavric, Oliver FitzGerald, Stephen R. Pennington, Joachim Peitz, Joern Kekow, Ariane Klein, Anna C. Schulz, Frank Weller-Heinemann, Anton Hospach, J-Peter Haas, BIKER collaborative group, Karen Put, Jessica Vandenhaute, Anneleen Avau, Annemarie van Nieuwenhuijze, Ellen Brisse, Tim Dierckx, Omer Rutgeerts, Josselyn E. Garcia-Perez, Jaan Toelen, Mark Waer, Georges Leclercq, An Goris, Johan Van Weyenbergh, Adrian Liston, Patrick Matthys, Carine H. Wouters, Yasuo Nakagishi, Michael J. Ombrello, Victoria Arthur, Anne Hinks, Patricia Woo, International Childhood Arthritis Genetics (INCHARGE) Consortium, Barbara Stanimirovic, Biljana Djurdjevic-Banjac, Olivera Ljuboja, Boris Hugle, MArgarita Onoufriou, Olga Vougiouka, Kenza Bouayed, Sanae El Hani, Imane Hafid, Nabiha Mikou, Nunu Shelia, Mari Laan, Jaanika Ilisson, and Chris Pruunsild

Subjects
Pediatrics, RJ1-570, Diseases of the musculoskeletal system, RC925-935
Published
2017
Full Text
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18. Proceedings of the 23rd Paediatric Rheumatology European Society Congress: part two

Author

Olga Lomakina, Ekaterina Alekseeva, Sania Valieva, Tatiana Bzarova, Irina Nikishina, Elena Zholobova, Svetlana Rodionovskaya, Maria Kaleda, Yasuo Nakagishi, Masaki Shimizu, Mao Mizuta, Akihiro Yachie, Yuko Sugita, Nami Okamoto, Kousuke Shabana, Takuji Murata, Hiroshi Tamai, Eve M. Smith, Peng Yin, Andrea L. Jorgensen, Michael W. Beresford, on behalf of On behalf of the UK JSLE Cohort Study, Antonio Eleuteri, Beatrice Goilav, Laura Lewandowski, Angel Phuti, Dawn Wahezi, Tamar Rubinstein, Caroline Jones, Paul Newland, Stephen Marks, Rachel Corkhill, Diana Ekdawy, Clarissa Pilkington, Kjell Tullus, Chaim Putterman, Chris Scott, Antony C. Fisher, Andrea Jorgensen, Ezgi Deniz Batu, Can Kosukcu, Ekim Taskiran, Sema Akman, Kubra Ozturk, Betul Sozeri, Erbil Unsal, Zelal Ekinci, Yelda Bilginer, Mehmet Alikasifoglu, Seza Ozen, Hanna Lythgoe, Hermine I. Brunner, Gaurav Gulati, Jordan T. Jones, Mekibib Altaye, Jamie Eaton, Mark Difrancesco, Joo Guan Yeo, Jingyao Leong, Loshinidevi D/O Thana Bathi, Thaschawee Arkachaisri, Salvatore Albani, Nagla Abdelrahman, Michael W Beresford, Valentina Leone, UK JSLE study group supported by the National Institute of Health Research Clinical Research Network, Noortje Groot, D. Shaikhani, I. E. M. Bultink, M. Bijl, R. J. E. M. Dolhain, Y. K. O. Teng, E. Zirkzee, K. de Leeuw, R. Fritsch-Stork, S. S. M. Kamphuis, Rachael D. Wright, Reem Abdawani, Laila Al Shaqshi, Ibrahim Al Zakwani, Natali W. Gormezano, David Kern, Oriany L. Pereira, Gladys C. C. Esteves, Adriana M. Sallum, Nadia E. Aikawa, Rosa M. Pereira, Clovis A. Silva, Eloisa Bonfa, Jessica Beckmann, Nora Bartholomä, Nils Venhoff, Philipp Henneke, Ulrich Salzer, Ales Janda, Alina Lucica Boteanu, Sandra Garrote Corral, Alberto Sifuentes Giraldo, Mariluz Gámir Gámir, Antonio Zea Mendoza, Amra Adrovic, Reyhan Dedeoglu, Sezgin Sahin, Kenan Barut, Aida Koka, Funda Oztunc, Ozgur Kasapcopur, Ana Luisa Rodriguez-Lozano, Francisco Rivas-Larrauri, Silvestre García de la Puente, Andressa G. F. Alves, Maria F. D. A. Giacomin, Juliana Farhat, Alfésio L. F. Braga, Adriana M. E. Sallum, Lúcia M. D. A. Campos, Luiz A. A. Pereira, Ana J. D. F. C. Lichtenfels, Clóvis A. Silva, Sylvia C. L. Farhat, Banu Acar, Z. Birsin Ozcakar, Nilgün Çakar, Nermin Uncu, Gökçe Gür, Semanur Özdel, Fatoş Yalçınkaya, Christiaan Scott, Nicky Brice, Peter Nourse, Christine Arango, Angela C. Mosquera, Clara Malagon, Ana P. Sakamoto, Marco F. C. D. Silva, Ananadreia S. Lopes, Gleice C. S. Russo, Adriana E. M. Sallum, Katia Kozu, Eloisa Bonfá, Claudia Saad-Magalhães, Rosa M. R. Pereira, Claudio A. Len, Maria T. Terreri, Deepti Suri, Siyaram Didel, Amit Rawat, Surjit Singh, Despoina Maritsi, MArgarita Onoufriou, Olga Vougiouka, Maria Tsolia, Edi Paleka Bosak, Mandica Vidović, Mirta Lamot, Lovro Lamot, Miroslav Harjaček, Erika Van Nieuwenhove, Adrian Liston, Carine Wouters, Fatemeh Tahghighi, Vahid Ziaee, Seid-Reza Raeeskarami, Francisca Aguiar, Sandra Pereira, Mariana Rodrigues, Cláudia Moura, Gustavo Rocha, Hercília Guimarães, Iva Brito, Rita Fonseca, Gerd Horneff, Ariane Klein, Kirsten Minden, Hans-Iko Huppertz, Frank Weller-Heinemann, Jasmin Kuemmerle-Deschner, J-Peter Haas, Anton Hospach, BIKER collaborative group, Ricardo Menendez-Castro, Boris Huegle, Johannes-Peter Haas, Joost Swart, Gabriella Giancane, Francesca Bovis, Elio Castagnola, Andreas Groll, Daniel J. Lovell, Tom Wolfs, Michael Hofer, Violeta Panaviene, Susan Nielsen, Jordi Anton, Florence Uettwiller, Valda Stanevicha, Maria Trachana, Denise Pires Marafon, Constantin Ailioaie, Elena Tsitsami, Sylvia Kamphuis, Troels Herlin, Pavla Doležalová, Gordana Susic, Berit Flatø, Flavio Sztajnbok, Angela Pistorio, Alberto Martini, Nico Wulffraat, Nicolino Ruperto, Marco Gattorno, Antonio Brucato, Martina Finetti, George Lazaros, Silvia Maestroni, Mara Carraro, Davide Cumetti, Alessandra Carobbio, Monia Lorini, Alessandro Rimini, Renzo Marcolongo, Anna Valenti, Gian Luca Erre, Riccardo Belli, Fiorenzo Gaita, Maria Pia Sormani, Massimo Imazio, Mario Abinun, Nicola Smith, Tim Rapley, Flora McErlane, Lianne Kearsley-Fleet, Kimme L. Hyrich, Helen Foster, Nikolay Tzaribachev, Andrew Zeft, Rolando Cimaz, John Bohnsack, Thomas Griffin, Ruy Carrasco, Jason Dare, Ivan Foeldvari, Richard Vehe, Teresa Simon, Hermine Brunner, S. Verazza, S. Davì, A. Consolaro, A. Insalaco, V. Gerloni, R. Cimaz, F. Zulian, S. Pastore, F. Corona, G. Conti, P. Barone, M. Cattalini, E. Cortis, L. Breda, A. N. Olivieri, A. Civino, R. Podda, D. Rigante, F. La Torre, G. D’Angelo, M. Jorini, R. Gallizzi, M. C. Maggio, R. Consolini, A. De Fanti, M. G. Alpigiani, A. Martini, A. Ravelli, on behalf of Italian Pediatric Rheumatology Study Group, Aysenur Pac Kısaarslan, Zubeyde Gunduz, Ruhan Dusunsel, Ismail Dursun, Hakan Poyrazoglu, Ekaterina Kuchinskaya, Farida Abduragimova, Mikhail Kostik, Erik Sundberg, Soley Omarsdottir, Lena Klevenvall, Helena Erlandsson-Harris, Gokalp Basbozkurt, Ozge Erdemli, Dogan Simsek, Fatih Yazici, Yildirim Karsioglu, Aysen Tezcaner, Dilek Keskin, Huseyin Ozkan, Cengizhan Acikel, Erkan Demirkaya, Ilonka Orbán, Krisztina Sevcic, Valentin Brodszky, Emese Kiss, Ismaiel A. Tekko, Madeleine Rooney, James McElnay, Cliff Taggart, Helen McCarthy, Ryan F. Donnelly, Drug Delivery Group, Mary Slatter, Zohreh Nademi, Mark Friswell, Sharmila Jandial, Terence Flood, Sophie Hambleton, Andrew Gennery, Andrew Cant, Phoi-Ngoc Duong, Isabelle Koné-Paut, Giovanni Filocamo, María Luz Gamir, Helga Sanner, Laura Carenini, Mesut Topdemir, Yildirim Karslioglu, Faysal Gok, Nadezhda Tsurikova, Elena Ligostaeva, Navdha R. Ramchurn, O. Kostareva, I. Nikishina, S. Arsenyeva, S. Rodionovskaya, M. Kaleda, D. Alexeev, Ismail Dursun Dursun, Sara Murias, Estefania Barral, Rosa Alcobendas, Eugenia Enriquez, Agustin Remesal, Jaime de Inocencio, Tania M. Castro, Simone A. Lotufo, Tatjana Freye, Raffaella Carlomagno, Thomas Zumbrunn, Jan Bonhoeffer, Elvira Cannizzaro Schneider, Daniela Kaiser, Michaël Hofer, Véronique Hentgen, Andreas Woerner, Juvenile Inflammatory Rheumatism (JIR) Cohort, Tobias Schwarz, Jens Klotsche, Martina Niewerth, Gerd Ganser, ICON study group, Jerold Jeyaratnam, Nienke ter Haar, Donato Rigante, Fatma Dedeoglu, Ezgi Baris, Sebastiaan Vastert, Joost Frenkel, Jonathan S. Hausmann, Kathleen G. Lomax, Ari Shapiro, Karen L. Durrant, P. A. Brogan, M. Hofer, J. B. Kuemmerle-Deschner, B. Lauwerys, A. Speziale, K. Leon, X. Wei, R. M. Laxer, Sara Signa, Marta Rusmini, Elena Campione, Sabrina Chiesa, Alice Grossi, Alessia Omenetti, Roberta Caorsi, Gianmaria Viglizzo, Isabella Ceccherini, Silvia Federici, Helen Lachmann, Nicola Ruperto, on behalf of PRINTO and Eurofever Registry, Federica Vanoni, on behalf of PRINTO and Eurofever Project, Sonia Melo Gomes, Ebun Omoyinmi, Juan I. Arostegui, Eva Gonzalez-Roca, Despina Eleftheriou, Nigel Klein, Paul Brogan, Stefano Volpi, Elettra Santori, Paolo Picco, Claudia Pastorino, Gillian Rice, Alessandra Tesser, Yanick Crow, Fabio Candotti, Ada B. Sinoplu, Gozde Yucel, Gizem Pamuk, Laura O. Damian, Cecilia Lazea, Mihaela Sparchez, Paulina Vele, Laura Muntean, Adriana Albu, Simona Rednic, Calin Lazar, Leonardo O. Mendonça, Alessandra Pontillo, Jorge Kalil, Fabio M. Castro, Myrthes T. Barros, Manuela Pardeo, Virginia Messia, Fabrizio De Benedetti, Antonella Insalaco, Giorgia Malighetti, Chiara Gorio, Francesca Ricci, Ilaria Parissenti, Paola Montesano, Barbara Bonafini, Veronica Medeghini, Marco Cattalini, Lucio Giordano, Giulia Zani, Rosalba Ferraro, Donatella Vairo, Silvia Giliani, Maria Cristina Maggio, Girolamo Luppino, Giovanni Corsello, Maria Isabel Gonzalez Fernandez, Berta Lopez Montesinos, Adriana Rodriguez Vidal, Juan I. Arostegui Gorospe, Inmaculada Calvo Penades, Nadia K. Rafiq, Karen Wynne, Khalid Hussain, Paul A. Brogan, Elizabeth Ang, Nicholas Ng, Ayla Kacar, Ozge Altug Gucenmez, Balahan Makay, Sevket Erbil Unsal, Yasin Sahin, Tufan Kutlu, Fugen Cullu-Cokugras, Hasret Ayyildiz-Civan, Tulay Erkan, Sana Al Zuhbi, Eiman Abdalla, Ricardo A. Russo, María M. Katsicas, Francesca Minoia, Angelo Ravelli, Sagar Bhattad, Anju Gupta, Vignesh Pandiarajan, Ritambhra Nada, Kaara Tiewsoh, Philip Hawkins, Dorota Rowczenio, Sarka Fingerhutova, Jana Franova, Leona Prochazkova, Eva Hlavackova, Pavla Dolezalova, Havva Evrengül, Selçuk Yüksel, Mustafa Doğan, Dolunay Gürses, Harun Evrengül, Silvia De Pauli, Serena Pastore, Anna Monica Bianco, Giovanni Maria Severini, Andrea Taddio, Alberto Tommasini, Svetlana O. Salugina, Evgeny Fedorov, Elena Kamenets, Ekaterina Zaharova, Tatiana Sleptsova, Ekaterina Alexeeva, Kirill Savostyanov, Alexander Pushkov, Tatyana Bzarova, Saniya Valieva, Rina Denisova, Kseniya Isayeva, Evgeniya Chistyakova, Margarita Soloshenko, Elena Kaschenko, Utako Kaneko, Chihaya Imai, Akihiko Saitoh, Vitor A. Teixeira, Filipa O. Ramos, Manuela Costa, Yonatan Butbul Aviel, Shafe Fahoum, Riva Brik, Zeynep Birsin Özçakar, Banu Acar Celikel, Fatos Yalcinkaya, Benedetta Schiappapietra, Sergio Davi’, Federica Mongini, Luisa Giannone, Cecilia Bava, Maria Giannina Alpigiani, Alessandro Consolaro, Dragana S. Lazarevic, Jelena Vojinovic, Jelena Basic, Valentina Muratore, Valentina Marzetti, Neus Quilis, Belen Serrano Benavente, Alessandra Alongi, Adele Civino, Lorenzo Quartulli, Giedre Januskeviciute, Pieter van Dijkhuizen, N. Groot, W. van Dijk, A. Kardolus, Raul Gutiérrez Suárez, Ellen B. Nordal, Veronika G. Rypdal, Lillemor Berntson, Maria Ekelund, Kristiina Aalto, Suvi Peltoniemi, Marek Zak, Mia Glerup, Ellen D. Arnstad, Anders Fasth, Marite Rygg, the Nordic Study Group of Pediatric Rheumatology (NoSPeR), Ana Catarina Duarte, Sandra Sousa, Lídia Teixeira, Ana Cordeiro, Mª José Santos, Ana Filipa Mourão, Maria José Santos, Mónica Eusébio, Ana Lopes, Filipa Oliveira-Ramos, Manuel Salgado, Paula Estanqueiro, José Melo-Gomes, Fernando Martins, José Costa, Carolina Furtado, Ricardo Figueira, Jaime C. Branco, João E. Fonseca, Helena Canhão, Ana F. Mourão, Maria Jose Santos, Andrea Coda, Samuel Cassidy, Kerry West, Gordon Hendry, Debra Grech, Julie Jones, Fiona Hawke, Davinder Singh Grewal, Charlene Foley, Orla Killeen, Emma MacDermott, Douglas Veale, Ursula Fearon, Dilek Konukbay, Ela Tarakci, Nilay Arman, Sezgin Şahin, Jane Munro, Esi Morgan, Meredith Riebschleger, Jennifer Horonjeff, Vibeke Strand, Clifton Bingham, Ma. Theresa M. Collante, Margarita Ganeva, Stefan Stefanov, Albena Telcharova, Dimitrina Mihaylova, Radoslava Saraeva, Reni Tzveova, Radka Kaneva, Adelina Tsakova, Katya Temelkova, GRANT Medical University, Sofia 68/, Maria Mercedes C. Picarelli, Luiz C. Danzmann, Florencia Barbé-Tuana, Lucas K. Grun, Marcus H. Jones, Marijan Frković, Karla Ištuk, Ika Birkić, Saša Sršen, Marija Jelušić, Alan Easton, Rachael Quarmby, Raju Khubchandani, Mercedes Chan, Radoslav Srp, Katerina Kobrova, Dana Nemcova, Jozef Hoza, Michal Uher, Melania Saifridova, Lenka Linkova, Sirirat Charuvanij, Isree Leelayuwattanakul, Thita Pacharapakornpong, Sakda A.-O. Vallipakorn, Butsabong Lerkvaleekul, Soamarat Vilaiyuk, Stefano Lanni, Sergio Davì, Randy Q. Cron, Chiara Passarelli, Elisa Pisaneschi, Antonio Novelli, Claudia Bracaglia, Ivan Caiello, Kathy de Graaf, Florence Guilhot, Walter Ferlin, Grant Schulert, Alexi A. Grom, Robert Nelson, Cristina de Min, Dirk Holzinger, Christoph Kessel, Ndate Fall, Alexei Grom, Wilco de Jager, Raffaele Strippoli, Anna Horne, Stephan Ehl, Sandra Ammann, Kai Lehmberg, Karin Beutel, Dirk Foell, AnnaCarin Horne, Laura Pagani, Graciela Espada, Yi-jin Gao, Susan Shenoi, Sheila Weitzman, Giusi Prencipe, Antonia Pascarella, Walter G. Ferlin, Laurence Chatel, Philippe Jacqmin, Kathy De Graaf, Maria Ballabio, Zoë Johnson, Geneviève Lapeyre, Fabrizio de Benedetti, de Min Cristina, Hiroyuki Wakiguchi, Shunji Hasegawa, Reiji Hirano, Fumiko Okazaki, Tamaki Nakamura, Hidenobu Kaneyasu, Shouichi Ohga, Kazuko Yamazaki, Tomo Nozawa, Taichi Kanetaka, Shuichi Ito, Shumpei Yokota, Kirsty McLellan, Ishbel MacGregor, Neil Martin, Joyce Davidson, Sandra Hansmann, Andreas Eikelberg, Iris Haug, Sabrina Schuller, Susanne M. Benseler, Single Hub and Access point for paediatric Rheumatology in Europe (SHARE), Liliia S. Nazarova, Kseniia V. Danilko, Viktor A. Malievsky, Tatiana V. Viktorova, Angela Mauro, Angela Barnicoat, Jane Hurst, Nathalie Canham, Sandrine Lacassagne, Anastasia Wiener, Boris Hügle, Bernd Denecke, Ivan Costa-Filho, Johannes Peter Haas, Klaus Tenbrock, David Popp, Arjan Boltjes, Frank Rühle, Stefanie Herresthal, Femke van Wijk, Joachim Schultze, Monika Stoll, Luisa Klotz, Thomas Vogl, Johannes Roth, Estefania Quesada-Masachs, Daniel Álvarez de la Sierra, Marina Garcia Prat, Ana M. Marín Sánchez, Ricardo Pujol Borrell, Sara Marsal Barril, Mónica Martínez Gallo, Consuelo Modesto Caballero, Iryna Chyzheuskaya, Lyudmyla M. Byelyaeva, Rostislav M. Filonovich, Helena K. Khrustaleva, Larisa I. Zajtseva, Tamara M. Yuraga, Thomas Giner, Lukas Hackl, Julia Albrecht, Reinhard Würzner, Juergen Brunner, Marta Minute, Fulvio Parentin, Agostino Nocerino, Mette Nørgaard, Mikel Alberdi-Saugstrup, Marek S. Zak, Susan M. Nielsen, Ellen Nordal, Klaus G. Müller, Nordic Study Group of Pediatric Rheumatology (NoSPeR), Mojca Zajc Avramovič, Vita Dolžan, Nataša Toplak, Tadej Avčin, N. Ruperto, D. J. Lovell, C. Wallace, M. Toth, I. Foeldvari, J. Bohnsack, D. Milojevic, C. Rabinovich, D. Kingsbury, K. Marzan, P. Quartier, K. Minden, E. Chalom, G. Horneff, R. M. Kuester, J. Dare, M. Heinrich, H. Kupper, J. Kalabic, H. I. Brunner, on behalf of PRINTO and PRCSG, Ruben Burgos-Vargas, Tamas Constantin, Joke Dehoorne, Valda Stanevica, Katarzyna Kobusinska, Zbigniew Zuber, Richard Mouy, Ingrida Rumba-Rozenfelde, Chantal Job-Deslandre, Ronald Pederson, Jack Bukowski, Tina Hinnershitz, Bonnie Vlahos, Paula Keskitalo, Salla Kangas, Paula Vähäsalo, Raul A. Chavez Valencia, David Martino, Anne-Louise Ponsonby, Rachel Chiaroni-Clarke, Braydon Meyer, Roger C. Allen, Jonathan D. Akikusa, Jeffrey M. Craig, Richard Saffrey, Justine A. Ellis, Carol Wallace, Yosef Uziel, Gary Sterba, Rayfel Schneider, Ricardo Russo, Athimalaipet V. Ramanan, Jana Pachlopnik Schmid, Kim E Nichols, Paivi Miettunen, Toshiyuki Kitoh, Norman T. Ilowite, Jan-Inge Henter, Alexei A Grom, Edward M. Behrens, Tadej Avcin, Maurizio Aricò, Sriharsha Grevich, Peggy Lee, Sarah Ringold, Brian Leroux, Hannah Leahey, Megan Yuasa, Jessica Foster, Jeremy Sokolove, Lauren Lahey, William Robinson, Joshua Newson, Anne Stevens, Stephanie J. W. Shoop, Suzanne M. M. Verstappen, Wendy Thomson, Janet E. McDonagh, CAPS, Timothy Beukelman, Yuki Kimura, Marc Natter, Norm Ilowite, Kelly Mieszkalski, Grendel Burrell, Brian Best, Helen Bristow, Shannon Carr, Anne Dennos, Rachel Kaufmann, Laura Schanberg, for the CARRA Registry Investigators, Gabriele Simonini, Francesca Lancini, Margaux Gerbaux, Phu-Quoc Lê, Laurence Goffin, Valérie Badot, Céline La, Laure Caspers, François Willermain, Alina Ferster, Maria Ceci, Francesco Licciardi, Marco Turco, Francesca Santarelli, Davide Montin, Claudia Toppino, Clotilde Alizzi, Bruno Papia, Beatrice Vergara, Umberto Corpora, Luca Messina, Maria Tsinti, Vasiliko Dermentzoglou, Panagiotis Tziavas, Marija Perica, Lana Tambić Bukovac, Mustafa Çakan, Nuray Aktay Ayaz, Gonca Keskindemirci, Michael Lang, Catherine Laing, Susanne Benseler, Tommy Gerschman, Nadia Luca, Heinrike Schmeling, Anastasia Dropol, Jaymi Taiani, Nicole Johnson, Brian Rusted, Panagiota Nalbanti, Polyxeni Pratsidou, Grigoris Pardalos, Vasiliki Tzimouli, Anna Taparkou, Maria Stavrakidou, Fotios Papachristou, Florence Kanakoudi-Tsakalidou, Peter Bale, Emily Robinson, Jason Palman, Elizabeth Ralph, Kimberly Gilmour, Clare Heard, Lucy R. Wedderburn, Yara Barrense-Dias, Antonarakis Gregory, Dhouib Amira, Scolozzi Paolo, Hanquinet Sylviane, Hofer Michaël, Nataliya Panko, Salah Shokry, Liudmila Rakovska, Sally Pino, Adriana Diaz-Maldonado, Pilar Guarnizo, Sofia Torreggiani, Paolo Cressoni, Umberto Garagiola, Giancarla Di Landro, Giampietro Farronato, Fabrizia Corona, Samantha Bell, Parveen Bhatti, Lee Nelson, Beth A. Mueller, T. A. Simon, A. Baheti, N. Ray, Z. Guo, Anasuya Hazra, Thomas Stock, Ronnie Wang, Charles Mebus, Christine Alvey, Manisha Lamba, Sriram Krishnaswami, Umberto Conte, Min Wang, Daniel Kingsbury, Elena Koskova, Elzbieta Smolewska, Richard K. Vehe, Daniel Lovell, Tomohiro Kubota, Junko Yasumura, Toshitaka Kizawa, Masato Yashiro, Tsuyoshi Yamatou, Yuichi Yamasaki, Syuji Takei, Yoshifumi Kawano, Ulrika Järpemo Nykvist, Bo Magnusson, Rikard Wicksell, Karin Palmblad, Gunnar L. Olsson, Mohammadreza Modaressi, Mohammad-Hassan Moradinejad, Valentina Seraya, Alisa Vitebskaya, Veronica Moshe, Gil Amarilyo, Liora Harel, Phillip J Hashkes, Amir Mendelson, Noa Rabinowicz, Yonit Reis, Zane Dāvidsone, Arina Lazareva, Ruta Šantere, Dace Bērziņa, Valda Staņēviča, Giulia Camilla Varnier, Susan Maillard, Cristina Ferrari, Silvia Zaffarano, Juvenile Dermatomyositis Research Group and European Federation of Immunological Societies, Judith Wienke, Felicitas Bellutti Enders, Lucas L. van den Hoogen, Jorre S. Mertens, Timothy R. Radstake, Henny G. Hotten, Ruth Fritsch, Lucy Wedderburn, Kiran Nistala, Berent Prakken, Annet van Royen-Kerkhof, Mohammad Alhemairi, Mohammed Muzaffer, Pieter Van Dijkhuizen, Claire T. Deakin, Stefania Simou, Maria De Iorio, Qiong Wu, Tania Amin, Lee Dossetter, Juvenile Dermatomyositis Research Group (JDRG), Raquel Campanilho-Marques, Claire Deakin, Clarissa A. Pilkington, on behalf of Juvenile Dermatomyositis Research Group (JDRG), Silvia Rosina, Sirisucha Soponkanaporn, on behalf of the UK Juvenile Dermatomyositis Research Group (JDRG), Zehra S. Arıcı, Gökçen D. Tuğcu, Ezgi D. Batu, Hafize E. Sönmez, Deniz Doğru-Ersöz, Beril Talim, Nural Kiper, Seza Özen, Alexander Solyom, Ezgi Batu, John Mitchell, Ariana Kariminejad, Fatemeh Hadipour, Zahra Hadipour, Marta Torcoletti, Carlo Agostoni, Maja Di Rocco, Pranoot Tanpaiboon, Andrea Superti-Furga, Luisa Bonafé, Nur Arslan, Norberto Guelbert, Karoline Ehlert, Giedre Grigelioniene, Ratna Puri, Edward Schuchman, Pilar Gomez, Tatiana Gonzalez, Ricardo Yepez, Camilo Vargas, GRIP study group, Falcini Fernanda, Gemma Lepri, Alessandra Ferrari, Marco Matucci-Cerinic, Antonella Meini, Gian Marco Moneta, Emiliano Marasco, Rebecca Nicolai, Luisa Bracci-Laudiero, Olga Kopchak, Alexander Mushkin, Alexey Maletin, Catalina Mosquera, Rita A. Amorim, Juliana Molina, Gustavo Moreira, Flávia H. Santos, Melissa Fraga, Livia Keppeke, Vanessa M. Silva, Camila Hirotsu, Sergio Tufik, Maria Teresa Terreri, Vinícius L. Braga, Maria Beatriz Fonseca, Vania Schinzel, Maria Teresa R. Terreri, Liliana Jorge, Liana Guerra, Edson Amaro Junior, Maria Cristina Castiglione, Alessandra Tricarico, Emily Boulter, Andre Schultz, Kevin Murray, Fernanda Falcini, Stefano Stagi, Eleonora Bellucci, Ingrid H. R. Grein, Gecilmara Pileggi, Natália B. F. Pinto, Aline L. de Oliveira, Lyudmila Belyaeva, Rostislav Filonovich, Helena Khrustaleva, Larisa Zajtseva, Jaanika Ilisson, Chris Pruunsild, Olivier Gilliaux, Francis Corazza, Christophe Lelubre, on behalf of PANLAR Pediatric Rheumatology Study Group, Zoilo Morel, Claudia Saad-Magalhães C, Luis Lira, Mabel Ladino, Ruth Eraso, Ivonne Arroyo, Clovis Silva, Carlos Rose, and PANLAR Pediatric Rheumatology Study Group

Subjects
Pediatrics, RJ1-570, Diseases of the musculoskeletal system, RC925-935
Published
2017
Full Text
View/download PDF

19. A Novel Mutation of GFAP Causing Adult-Onset Alexander Disease

Author

Andrea Ciammola, Davide Sangalli, Jenny Sassone, Barbara Poletti, Laura Carelli, Paolo Banfi, Gabriele Pappacoda, Isabella Ceccherini, Alice Grossi, Luca Maderna, Monica Pingue, Floriano Girotti, and Vincenzo Silani

Subjects
Alexander disease, GFAP-glial fibrillary acidic protein, leukodystrophy, gene mutation, adult onset, Neurology. Diseases of the nervous system, RC346-429
Abstract

Alexander disease (AxD) is a rare, autosomal dominant neurological disorder. Three clinical subtypes are distinguished based on age at onset: infantile (0–2 years), juvenile (2–13 years), and adult (>13 years). The three forms differ in symptoms and prognosis. Rapid neurological decline with a fatal course characterizes the early-onset forms, while symptoms are milder and survival is longer in the adult forms. Currently, the sole known cause of AxD is mutations in the GFAP gene, which encodes a type III intermediate filament protein that is predominantly expressed in astrocytes. A wide spectrum of GFAP mutations comprising point mutations, small insertions, and deletions is associated with the disease. The genotype-phenotype correlation remains unclear. The considerable heterogeneity in severity of disease among individuals carrying identical mutations suggests that other genetic or environmental factors probably modify age at onset or progression of AxD. Describing new cases is therefore important for establishing reliable genotype-phenotype correlations and revealing environmental factors able to modify age at onset or progression of AxD. We report the case of a 54-year-old Caucasian woman, previously diagnosed with ovarian cancer and treated with surgery and chemotherapy, who developed dysarthria, ataxia, and spastic tetraparesis involving mainly the left side. Cerebral and spinal magnetic resonance imaging (MRI) revealed a peculiar tadpole-like atrophy of the brainstem. Genetic analysis of the GFAP gene detected a heterozygous mutation in exon 1 (c.219G>C), resulting in an amino acid exchange from methionine to isoleucine at codon 73 (p.M73I). The expression of this mutant in vitro affected the formation of the intermediate filament network. Thus, we have identified a new GFAP mutation in a patient with an adult form of AxD.

Published
2019
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20. CD70 Deficiency due to a Novel Mutation in a Patient with Severe Chronic EBV Infection Presenting As a Periodic Fever

Author

Roberta Caorsi, Marta Rusmini, Stefano Volpi, Sabrina Chiesa, Claudia Pastorino, Angela Rita Sementa, Paolo Uva, Alice Grossi, Edoardo Lanino, Maura Faraci, Francesca Minoia, Sara Signa, Paolo Picco, Alberto Martini, Isabella Ceccherini, and Marco Gattorno

Subjects
CD70 deficiency, periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome, Immunologic diseases. Allergy, RC581-607
Abstract

Primary immunodeficiencies with selective susceptibility to EBV infection are rare conditions associated with severe lymphoproliferation. We followed a patient, son of consanguineous parents, referred to our center for recurrent periodic episodes of fever associated with tonsillitis and adenitis started after an infectious mononucleosis and responsive to oral steroid. An initial diagnosis of periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome was done. In the following months, recurrent respiratory infections and episodes of keratitis were also observed, together with a progressive reduction of immunoglobulin levels and an increase of CD20+ cells. Cell sorting and EBV PCR showed 25,000 copies for 100,000 leukocytes with predominant infection of B lymphocytes. Lymph node’s biopsy revealed reactive lymphadenopathy with paracortical involvement consistent with a chronic EBV infection. Molecular analysis of XIAP, SHA2D1A, ITK, and CD27 genes did not detect any pathogenic mutation. The patients underwent repeated courses of anti-CD20 therapy with only a partial control of the disease, followed by stem cell transplantation with a complete normalization of clinical and immunological features. Whole exome sequencing of the trio was performed. Among the variants identified, a novel loss of function homozygous c.163-2A>G mutation of the CD70 gene, affecting the exon 2 AG-acceptor splice site, fit the expected recessive model of inheritance. Indeed, deficiency of both CD27, and, more recently, of its ligand CD70, has been reported as a cause of EBV-driven lymphoproliferation and hypogammaglobulinemia. Cell surface analysis of patient-derived PHA-T cell blasts and EBV-transformed lymphoblastoid cell lines confirmed absence of CD70 expression. In conclusion, we describe a case of severe chronic EBV infection caused by a novel mutation of CD70 presenting with recurrent periodic fever.

Published
2018
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21. Underlying CTLA4 Deficiency in a Patient With Juvenile Idiopathic Arthritis and Autoimmune Lymphoproliferative Syndrome Features Successfully Treated With Abatacept—A Case Report

Author

Clara Malattia, Concetta Micalizzi, Michaela Calvillo, Marta Mazzoni, Angelo Ravelli, Alice Grossi, Elena Palmisani, Maurizio Miano, Stefania Viola, Erika Massaccesi, Francesca Fioredda, Daniela Guardo, Carlo Dufour, Paola Terranova, Isabella Ceccherini, and Gianluca Dell'Orso

Subjects
Adolescent, Arthritis, medicine.disease_cause, Abatacept, Hypogammaglobulinemia, autoimmunity, cytopenias, cytotoxic T-lymphocyte antigen 4 deficiency, immune dysregulation, juvenile idiopathic arthritis, primary immunodeficiencies, Duodenitis, medicine, Humans, CTLA-4 Antigen, Immune Checkpoint Inhibitors, business.industry, Autoimmune Lymphoproliferative Syndrome, Hematology, Immune dysregulation, Prognosis, medicine.disease, Arthritis, Juvenile, Oncology, Autoimmune lymphoproliferative syndrome, Mutation, Pediatrics, Perinatology and Child Health, Immunology, Female, Polyarthritis, Autoimmune hemolytic anemia, business, medicine.drug
Abstract

Background Functional variants of the cytotoxic T-lymphocyte antigen-4 (CTLA4) could contribute to the pathogenesis of disorders characterized by abnormal T-cell responses. Case presentation We report a case of a 13-year-old girl who first presented with polyarticular juvenile idiopathic arthritis poorly responsive to treatment. During the following years the patient developed cytopenias, chronic lymphoproliferation, high values of T-cell receptor αβ+ CD4- CD8- double-negative T cells and defective Fas-mediated T cells apoptosis. Autoimmune lymphoproliferative syndrome was diagnosed and therapy with mycophenolate mofetil was started, with good hematological control. Due to the persistence of active polyarthritis, mycophenolate mofetil was replaced with sirolimus. In the following months the patient developed hypogammaglobulinemia and started having severe diarrhea. Histologically, duodenitis and chronic gastritis were present. Using the next generation sequencing-based gene panel screening, a CTLA4 mutation was detected (p.Cys58Serfs*13). At the age of 21 the patient developed acute autoimmune hemolytic anemia; steroid treatment in combination with abatacept were started with clinical remission of all symptoms, even arthritis. Conclusions Targeted immunologic screening and appropriate genetic tests could help in the diagnosis of a specific genetically mediated immune dysregulation syndrome, allowing to select those patients who can take advantage of target therapy, as in the case of abatacept in CTLA4 deficiency.

Published
2021

24. Deficiency of Adenosine Deaminase 2 in Adults and Children: Experience From India

Author

Marco Gattorno, Amita Aggarwal, K G Chengappa, Aaadhar Dhooria, Sanjay Jain, Pankaj Gupta, Juan I. Aróstegui, Rajesh Bhojwani, Saket Jha, Vikas Sharma, V K Chaturvedi, Kusum Sharma, Pallavi Pimpale Chavan, Manphool Singhal, Manish Rathi, Pui Y. Lee, Qing Zhou, Alice Grossi, Gsrsnk Naidu, Prateek Bhatia, Rajkiran Dudam, Sathish Kumar, Vikas Gupta, Rohini Handa, Eugene P. Chambers, Jun Wang, Raju Khubchandani, Ramesh Jois, Varun Dhir, Sagar Bhattad, Durga Prasanna Misra, Banwari Sharma, Vir Singh Negi, Vishal Sharma, Michael S. Hershfield, Vikas Agarwal, Ranjana W. Minz, Sourabh Malaviya, Ivona Aksentijevich, Ritambhra Nada, Z. Huang, and Aman Sharma

Subjects
medicine.medical_specialty, Pediatrics, business.industry, Anemia, Immunology, Retrospective cohort study, medicine.disease, Rheumatology, Internal medicine, medicine, Immunology and Allergy, Age of onset, Young adult, business, Vasculitis, Immunodeficiency, Systemic vasculitis
Abstract

Objective Deficiency of adenosine deaminase 2 (DADA2) is a potentially fatal monogenic syndrome characterized by variable manifestations of systemic vasculitis, bone marrow failure, and immunodeficiency. Most cases are diagnosed by pediatric care providers, given the typical early age of disease onset. This study was undertaken to describe the clinical phenotypes and treatment response both in adults and in children with DADA2 in India. Methods A retrospective analysis of pediatric and adult patients with DADA2 diagnosed at various rheumatology centers across India was conducted. Clinical characteristics, diagnostic findings, and treatment responses were analyzed in all subjects. Results In total, 33 cases of DADA2 were confirmed in this cohort between April 2017 and March 2020. Unlike previous studies, nearly one-half of the confirmed cases presented during adulthood. All symptomatic patients exhibited features of vasculitis, whereas constitutional symptoms and anemia were more common in pediatric patients. Cutaneous and neurologic involvement were common, and 18 subjects had experienced at least one stroke. In addition, the clinical spectrum of DADA2 was expanded by recognition of novel features in these patients, including pancreatic infarction, focal myocarditis, and diffuse alveolar hemorrhage. Treatment with tumor necrosis factor inhibitors (TNFi) was initiated in 25 patients. All of the identified disease manifestations showed marked improvement after initiation of TNFi, and disease remission was achieved in 19 patients. Two cases were complicated by tuberculosis infection, and 2 deaths were reported. Conclusion This report presents the first case series of patients with DADA2 from India, diagnosed by adult and pediatric care providers. The findings raise awareness of this syndrome, particularly with regard to its presentation in adults.

Published
2020

25. Dysregulation in B‐cell responses and T follicular helper cell function in ADA2 deficiency patients

Author

Annalisa Salis, Gilberto Filaci, Claudia Pastorino, Stefano Volpi, Paola Bocca, Antonella Insalaco, Federica Penco, Francesca Kalli, Arinna Bertoni, Ignazia Prigione, Gianluca Damonte, Fabrizio De Benedetti, Alice Grossi, Roberta Caorsi, Francesca Antonini, Elisabetta Traggiai, Sara Signa, Isabella Ceccherini, Francesca Schena, Marco Gattorno, and Daniela Fenoglio

Subjects
Male, 0301 basic medicine, Adenosine Deaminase 2 Deficiency, Adenosine Deaminase, Cell, Pure red cell aplasia, Lymphocyte Activation, Hypogammaglobulinemia, 0302 clinical medicine, Agammaglobulinemia, Immunology and Allergy, Child, B-Lymphocytes, B cell, Cell Differentiation, Adenosine deaminase 2, medicine.anatomical_structure, Child, Preschool, Intercellular Signaling Peptides and Proteins, Female, Follicular helper T cells, medicine.drug, Adult, Adolescent, T Follicular Helper Cells, Immunology, In Vitro Techniques, Biology, Immunophenotyping, 03 medical and health sciences, medicine, Extracellular, Humans, Immunodeficiency, Cell Proliferation, Interleukins, Infant, Newborn, Infant, medicine.disease, Adenosine, 030104 developmental biology, Case-Control Studies, Mutation, Severe Combined Immunodeficiency, Immunologic Memory, CD8, 030215 immunology
Abstract

Adenosine deaminase 2 deficiency (DADA2) is an autoinflammatory disease characterized by inflammatory vasculopathy, early strokes associated often with hypogammaglobulinemia. Pure red cell aplasia, thrombocytopenia, and neutropenia have been reported. The defect is due to biallelic loss of function of ADA2 gene, coding for a protein known to regulate the catabolism of extracellular adenosine. We therefore investigated immune phenotype and B- and T-cell responses in 14 DADA2 patients to address if ADA2 mutation affects B- and T-cell function. Here, we show a significant decrease in memory B cells, in particular class switch memory, and an expansion of CD21low B cells in DADA2 patients. In vitro stimulated B lymphocytes were able to secrete nonfunctional ADA2 protein, suggesting a cell intrinsic defect resulting in an impairment of B-cell proliferation and differentiation. Moreover, CD4+ and CD8+ T cells were diminished; however, the frequency of circulating T follicular helper cells was significantly increased but they had an impairment in IL-21 production possibly contributing to an impaired B cell help. Our findings suggest that ADA2 mutation could lead to a B-cell intrinsic defect but also to a defective Tfh cell function, which could contribute to the immunodeficient phenotype reported in DADA2 patients.

Published
2020

26. Autoimmune Neutropenia and Immune-Dysregulation in a Patient Carrying a TINF2 Variant

Author

Benedetta Chianucci, Alice Grossi, Gianluca Dell'Orso, Elena Palmisani, Marina Lanciotti, Paola Terranova, Filomena Pierri, Michela Lupia, Luca Arcuri, Marica Laurino, Isabella Ceccherini, Fabian Beier, Carlo Dufour, Francesca Fioredda, and Maurizio Miano

Subjects
Inorganic Chemistry, Organic Chemistry, General Medicine, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy, Catalysis, Computer Science Applications
Abstract

International journal of molecular sciences 23(23), 14535 (2022). doi:10.3390/ijms232314535 special issue: "Special Issue "Unveiling the Molecular Regulations of Immunological and Allergic Diseases" / Special Issue Editor: Prof. Dr. Agnieszka Paradowska‑Gorycka, Guest Editor", Published by Molecular Diversity Preservation International, Basel

Published
2022

27. Unusual Late-onset Enteropathy in a Patient With Lipopolysaccharide-responsive Beige-like Anchor Protein Deficiency

Author

Francesca Fioredda, Concetta Micalizzi, Enrico Cappelli, Elena Palmisani, Michaela Calvillo, Serena Arrigo, Tiziana Lanza, Filomena Pierri, Isabella Ceccherini, Maurizio Miano, Rosario Maggiore, Maria C Coccia, Daniela Guardo, Andrea Beccaria, Alice Grossi, Carlo Dufour, and Paola Terranova

Subjects
Male, Protein-Losing Enteropathies, chemical and pharmacologic phenomena, medicine.disease_cause, LRBA, Autoimmunity, Abatacept, 03 medical and health sciences, 0302 clinical medicine, Immune system, Antigen, Protein Deficiency, medicine, Humans, CTLA-4 Antigen, Enteropathy, Age of Onset, Adaptor Proteins, Signal Transducing, business.industry, Common variable immunodeficiency, Immunologic Deficiency Syndromes, Hematology, Immune dysregulation, Prognosis, medicine.disease, Oncology, Child, Preschool, 030220 oncology & carcinogenesis, Pediatrics, Perinatology and Child Health, Immunology, business, Immunosuppressive Agents, 030215 immunology, medicine.drug
Abstract

In recent years, monogenic causes of immune dysregulation syndromes, with variable phenotypes, have been documented. Mutations in the lipopolysaccharide-responsive beige-like anchor (LRBA) protein are associated with common variable immunodeficiency, autoimmunity, chronic enteropathy, and immune dysregulation disorders. The LRBA protein prevents degradation of cytotoxic T-lymphocyte antigen 4 (CTLA4) protein, thus inhibiting immune responses. Both LRBA and CTLA4 deficiencies usually present with immune dysregulation, mostly characterized by autoimmunity and lymphoproliferation. In this report, we describe a patient with an atypical clinical onset of LRBA deficiency and the patient's response to abatacept, a fusion protein-drug that mimics the action of CTLA4.

Published
2019

28. Case Report: Deficiency of Adenosine Deaminase 2 Presenting With Overlapping Features of Autoimmune Lymphoproliferative Syndrome and Bone Marrow Failure

Author

Alice Grossi, Federica Penco, Gianluca Dell'Orso, Shana Montalto, Erica Ricci, Carlo Dufour, Elena Palmisani, Filomena Pierri, Marco Gattorno, Isabella Ceccherini, Francesca Schena, Francesca Fioredda, Maurizio Miano, Roberta Caorsi, Paola Terranova, and Michela Lupia

Subjects
medicine.medical_treatment, DADA2, Immunology, primary immune regulatory disorders (PIRDS), Case Report, Disease, Hematopoietic stem cell transplantation, bone marrow failure (BMF), medicine.disease_cause, autoimmune lymphoproliferative syndrome (ALPS), medicine, Immunology and Allergy, next-generation sequencing (NGS), inborn errors of immunity (IEI), business.industry, Septic shock, Bone marrow failure, RC581-607, Immune dysregulation, medicine.disease, Autoimmune lymphoproliferative syndrome, Immunologic diseases. Allergy, Autoimmune hemolytic anemia, Vasculitis, business
Abstract

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease associated with a highly variable clinical presentation, such as vasculitis, inflammation, and hematologic manifestations. Some associations of clinical features can mimic autoimmune lymphoproliferative syndrome (ALPS). We report a case of a female patient who fulfilled the 2009 National Institute of Health revised criteria for ALPS and received a delayed diagnosis of DADA2. During her childhood, she suffered from autoimmune hemolytic anemia, immune thrombocytopenia, and chronic lymphoproliferation, which partially responded to multiple lines of treatments and were followed, at 25 years of age, by pulmonary embolism, septic shock, and bone marrow failure with myelodysplastic evolution. The patient died from the progression of pulmonary disease and multiorgan failure. Two previously unreported variants of gene ADA2/CECR1 were found through next-generation sequencing analysis, and a pathogenic role was demonstrated through a functional study. A single somatic STAT3 mutation was also found. Clinical phenotypes encompassing immune dysregulation and marrow failure should be evaluated at the early stage of diagnostic work-up with an extended molecular evaluation. A correct genetic diagnosis may lead to a precision medicine approach consisting of the use of targeted treatments or early hematopoietic stem cell transplantation.

Published
2021

29. PAPA and FMF in two siblings: possible amplification of clinical presentation? A case report

Author

Marco Gattorno, Isabella Ceccherini, Alice Grossi, Giovanni Corsello, Maria Cristina Maggio, Maggio, Maria Cristina, Ceccherini, Isabella, Grossi, Alice, Gattorno, Marco, and Corsello, Giovanni

Subjects
Male, Abdominal pain, medicine.medical_specialty, Adolescent, Canakinumab, Familial Mediterranean fever, Arthritis, Case Report, 03 medical and health sciences, Settore MED/38 - Pediatria Generale E Specialistica, 0302 clinical medicine, 030225 pediatrics, Acne Vulgaris, medicine, Humans, 030212 general & internal medicine, Child, Pyogenic arthritis, pyoderma gangrenosum and acne syndrome, Arthritis, Infectious, Familial Mediterranean fever, Pyogenic arthritis, pyoderma gangrenosum and acne syndrome, Colchicine, Canakinumab, business.industry, lcsh:RJ1-570, lcsh:Pediatrics, PAPA syndrome, medicine.disease, MEFV, Dermatology, Pyoderma Gangrenosum, medicine.symptom, business, Colchicine, Serositis, Pyoderma gangrenosum, medicine.drug
Abstract

Background Familial Mediterranean Fever is a monogenic autoinflammatory disease, typically characterized by recurrent attacks of fever, serositis, aphthous of oral mucosa, erythema. “Pyogenic arthritis, pyoderma gangrenosum and acne syndrome” is a rare autoinflammatory disease with variable expression and typically involving joints and skin. Both the diseases are linked by the overproduction of IL-1. Case presentation We report on the case of two siblings affected by recurrent attacks of fever, oral aphthous stomatitis, abdominal pain, arthritis, undefined dermatitis at the hands, associated with increased AST, ALT, C-reactive protein, erythrocyte sedimentation rate, serum amyloid A, leucocytosis with neutrophilia. Infectious diseases were excluded. The genetic study for Familial Mediterranean Fever, tumor necrosis factor receptor-associated periodic syndrome, Mevalonate kinase deficiency, showed the homozygous mutation p.M680I of exon 10 in MEFV. Their parents were heterozygous for the same mutation p.M680I, however, the mother showed severe symptoms of FMF (recurrent attacks of fever, arthralgia and arthritis, abdominal pain, thoracic pain), the father showed recurrent pustulosis prevalent on the hands and limbs, with arthralgia and abdominal pain. Both the patients started colchicine, with an improvement in clinical manifestations and a reduction of serum amyloid A. For the atypical dermatologic signs present in the two siblings and in the father, the study of other autoinflammatory syndromes was performed with next generation sequencing and showed the heterozygous rare missense mutation of unknown significance: p.(Val408Ile) of PSTPIP1 gene in the two siblings and in the mother, the father was negative. Canakinumab treatment was started in the younger patient, with the resolution of the clinical symptoms and the normalization of serum amyloid A. Conclusions Further studies are needed to better describe the correlation between genotype and phenotype in patients with PAPA syndrome and with PAPA syndrome associated with FMF, considering that the presence of mutations in both genes may amplify clinical presentation and evolution of both diseases.

Published
2019

30. What changed in the Italian internal medicine and geriatric wards during the lockdown

Author

M. C. Nava, Ligia J. Dominguez, F. Giofre, S. Dassi, Stella Provini, Roberto Castello, Maria Elena Pipita, Raffaele Landolfi, I. Indiano, S. Schiavone, Renzo Rozzini, Matteo G. Della Porta, A. Cespiati, F. Perticone, G. Bartelloni, Miriam Gino, Maurizio Corsi, Lina Falanga, R. Di Quattro, G. Orio, Salvatore Piro, Antonio Mirijello, Alessio Molfino, L. Biondi, Leonardo A. Sechi, Luciano Ottonello, Marco Bertolotti, C. Sidoli, G. Colombo, C. Bussolino, A. Delitala, P. M. Mannucci, Luigina Guasti, Antonio Nouvenne, Marta Di Pasquale, P. Peasso, E. Favale, A. Volpini, Giulia Costanzo, C. Margaria, S. Morganti, Guido Moreo, F. Nasso, S. Dolenti, Enrico Strocchi, Laura Stefani, Cristian Petri, M. M. De Amicis, Maria Domenica Cappellini, E. Magnolfi, G. Principato, Fabio Fabbian, G. D'Aurizio, M. V. Libbra, Fabrizio Fabris, Michela Zanetti, P. Tarsitani, V. Piccinelli, R. Caruso, Andrea Artoni, G. Argiolas, A. D. Di Mauro, C. Custodero, Angela Sciacqua, Gabriella Gruden, Anna Ludovica Fracanzani, A. Falcetta, M. L. Matacena, E. Ianniello, G. Bogoni, M. Soldati, P. Agosti, Patrizia Mecocci, Benedetta Marigliano, Chiara Lonati, Luca Zanoli, Massimo Raspanti, F. Gandolfo, C. Catena, Paolo Rossi, Francesco Salerno, Carlotta Franchi, A. Gennaro, P. Bocchi, Elena Silvestri, R. Leonardi, Raffaella Rossio, M. Vanoli, V. Gioffre, L. Fondrieschi, B. D'Avanzo, N. Scaramellini, S. Del Giacco, A. da Porto, G. Serafini, I. Rossi, Giuseppe Palasciano, R. Gonella, Alice Valoriani, Antonella Afeltra, Filippo Alessandro Montalto, C. Antonucci, Giorgio Galanti, F. Montecucco, I. Aiello, Giuseppe Natoli, Antonio Brucato, C. Di Gennaro, Marco Zoli, Teresa Salvatore, Maria Ester Modeo, Mosè Bartone, Ilaria Ardoino, Flora Peyvandi, E. Simeone, Y. Grassi, Paolo Gallo, S. Leoni, S. Buffelli, Giacomo Emmi, Antonio Cittadini, Maria Teresa Guagnano, F. Corica, Giorgio Basile, G. Oberti, Giulia Grignani, G. Vannini, B. Graziella, A De Giorgi, Roberto Tarquini, G. M. De Vincenzo, M. Fogliati, G. Famularo, Antonio Picardi, Chiara Mussi, Andrea Maria Maresca, M. Pisati, Silvia Prolo, Domenico Girelli, Maurizio Muscaritoli, E. Amoruso, Silvia Ghidoni, Marco Vincenzo Lenti, Caterina Mengoli, Vanessa Bianconi, Carlo Vigorito, M. Galassi, A. Di Pino, M. Bellan, M. Girino, F. Bellone, V. Beccati, Luigi Anastasio, Laura Cortesi, M. Mattioli, Giuseppe Montalto, Gino Roberto Corazza, S. Fragapani, M. V. Rabuini, Pietro Minuz, Lara Caserza, R. Battaglia, F. Cacioppo, D. Cerminara, S. Di Marca, Gian Paolo Ceda, V. Beneduce, A. Ballestrero, Giuseppe Montrucchio, G. De Luca, G. P. Fra, Vincenzo Stanghellini, Raffaele Maio, A. Cavarape, N. Passariello, F. Berti, Patrizia Suppressa, Benedetta Stancanelli, A. Giorgi, Marta Rizzo, L. Colangelo, Massimo Montalto, A. Pilotto, Anna Licata, Francesco Violi, M. S. Pisciotta, Maria Perticone, Giuseppe Zuccalà, Virginia Boccardi, L. Ricevuti, Alessandra Marengoni, Giuseppe Romanelli, V. Saracco, Paola Riva, Giuseppe Paolisso, Alessandro Nobili, Francesco Saverio Vella, S. Tiraboschi, G. Pallini, G. Vischi, Nicola Lucio Liberato, R. Tiseo, Valter Monzani, Marcello Maggio, G. Damiani, G. Leoncini, M. Sanino, M. Cesari, Luana Castiglioni, G. Miglio, Luciano Rinaldi, M. Cilli, T. de Falco, C. Ricozzi, F. Tolloso, R. D. Diprizio, M. Berria, S. Mularo, A. Comitangelo, Carmelinda Ruggiero, Eugenio Ruggeri, Claudio Borghi, Tiziana Tognin, Antonino Catalano, A. Simili, Agostino Gaudio, Mario Barbagallo, Emanuela Miceli, Luca Pasina, A. Vignali, Alessandro Salvi, Giuseppe Delitala, Elena Succurro, Maria Antonietta Bleve, Alessio Novella, Sergio Harari, D. Sola, A. Dal Col, A. Di Sabatino, F. Ferrando, Enrico Petrillo, Francesco Baffa Bellucci, Andrea Ticinesi, L. La Malfa, Davide Firinu, Franco Arturi, Umberto Vespasiani Gentilucci, Lorenzo Malatino, Alessandra Bettiol, Valeria Savojardo, Francesca Mete, R. Quadri, Mancuso G, G. Pina, C. Poletto, G. Colussi, Sarah Damanti, Ginevra De Marchi, Graziana Lupattelli, Mario Pirisi, Pietro Castellino, A. Greco, Marta Clerici, Michela Novelli, Giulia Lancellotti, R. Volpi, R. Scurti, T. Prandini, Marco Carbone, E.A. Pulixi, Gianni Biolo, S. del Vecchio, W. Capeci, Tiziana Meschi, Luigi Fenoglio, Giovanna Fabio, R. Ghio, Francesco Cipollone, Leonardo Campiotti, G. P. Martino, Michela Pasino, Maria Grazia Serra, A. Bragagni, Roberto Pontremoli, Salvatore Corrao, Mauro Tettamanti, C. Catalano, L. Monaco, S. Berra, Alice Grossi, Giuseppe Bellelli, G. N. Imperiale, C. Principato, Gabriele Mascherini, E. Larovere, A. Pietrangelo, Giancarlo Labbadia, Fabiana Busti, I. Bertozzi, F. Napoli, Domenico Prisco, G. Nobili, Carlo Sabbà, Francesco Purrello, P. Pettinari, B. Tassone, G. Ceriani, G. Scanzi, S. Baldassarre, I. Mattioli, G. Sigon, Costanza Caccia Dominioni, Alessandro Squizzato, C. Gracin, Benedetta Boari, Roberto Manfredini, M. Grossi, Salvatore Minisola, Daniela Calipari, R. Alcidi, D. Lucente, V. Terranova, D'Avanzo B., Nobili A., Tettamanti M., Pasina L., Mannucci P.M., Pietrangelo A., Perticone F., Violi F., Corazza G.R., Corrao S., Marengoni A., Salerno F., Cesari M., Franchi C., Cortesi L., Miglio G., Ardoino I., Novella A., Prisco D., Silvestri E., Emmi G., Bettiol A., Mattioli I., Biolo G., Zanetti M., Bartelloni G., Vanoli M., Grignani G., Pulixi E.A., Lupattelli G., Bianconi V., Alcidi R., Girelli D., Busti F., Marchi G., Barbagallo M., Dominguez L., Beneduce V., Cacioppo F., Natoli G., Mularo S., Raspanti M., Zoli M., Matacena M.L., Orio G., Magnolfi E., Serafini G., Simili A., Palasciano G., Modeo M.E., Di Gennaro C., Cappellini M.D., Fabio G., de Amicis M.M., de Luca G., Scaramellini N., Rossi P.D., Damanti S., Clerici M., Leoni S., Di Mauro A.D., Di Sabatino A., Miceli E., Lenti M.V., Pisati M., Dominioni C.C., Pontremoli R., Beccati V., Nobili G., Leoncini G., Anastasio L., Carbone M., Cipollone F., Guagnano M.T., Rossi I., Mancuso G., Calipari D., Bartone M., Delitala G., Berria M., Delitala A., Muscaritoli M., Molfino A., Petrillo E., Giorgi A., Gracin C., Zuccala G., D'Aurizio G., Romanelli G., Volpini A., Lucente D., Picardi A., Gentilucci U.V., Gallo P., Bellelli G., Corsi M., Antonucci C., Sidoli C., Principato G., Arturi F., Succurro E., Tassone B., Giofre F., Serra M.G., Bleve M.A., Brucato A., de Falco T., Fabris F., Bertozzi I., Bogoni G., Rabuini M.V., Prandini T., Manfredini R., Fabbian F., Boari B., de Giorgi A., Tiseo R., Paolisso G., Rizzo M.R., Catalano C., Borghi C., Strocchi E., Ianniello E., Soldati M., Schiavone S., Bragagni A., Sabba C., Vella F.S., Suppressa P., de Vincenzo G.M., Comitangelo A., Amoruso E., Custodero C., Fenoglio L., Falcetta A., Fracanzani A.L., Tiraboschi S., Cespiati A., Oberti G., Sigon G., Peyvandi F., Rossio R., Colombo G., Agosti P., Monzani V., Savojardo V., Ceriani G., Pallini G., Montecucco F., Ottonello L., Caserza L., Vischi G., Liberato N.L., Tognin T., Purrello F., Di Pino A., Piro S., Rozzini R., Falanga L., Pisciotta M.S., Bellucci F.B., Buffelli S., Montrucchio G., Peasso P., Favale E., Poletto C., Margaria C., Sanino M., Guasti L., Castiglioni L., Maresca A., Squizzato A., Campiotti L., Grossi A., Diprizio R.D., Bertolotti M., Mussi C., Lancellotti G., Libbra M.V., Galassi M., Grassi Y., Greco A., Sciacqua A., Perticone M., Battaglia R., Maio R., Stanghellini V., Ruggeri E., del Vecchio S., Salvi A., Leonardi R., Damiani G., Capeci W., Mattioli M., Martino G.P., Biondi L., Pettinari P., Ghio R., Dal Col A., Minisola S., Colangelo L., Cilli M., Labbadia G., Afeltra A., Marigliano B., Pipita M.E., Castellino P., Zanoli L., Gennaro A., Gaudio A., Saracco V., Fogliati M., Bussolino C., Mete F., Gino M., Vigorito C., Cittadini A., Moreo G., Prolo S., Pina G., Ballestrero A., Ferrando F., Gonella R., Cerminara D., Berra S., Dassi S., Nava M.C., Graziella B., Baldassarre S., Fragapani S., Gruden G., Galanti G., Mascherini G., Petri C., Stefani L., Girino M., Piccinelli V., Nasso F., Gioffre V., Pasquale M., Sechi L., Catena C., Colussi G., Cavarape A., da Porto A., Passariello N., Rinaldi L., Berti F., Famularo G., Tarsitani P., Castello R., Pasino M., Ceda G.P., Maggio M.G., Morganti S., Artoni A., Grossi M., Del Giacco S., Firinu D., Costanzo G., Argiolas G., Montalto G., Licata A., Montalto F.A., Corica F., Basile G., Catalano A., Bellone F., Principato C., Malatino L., Stancanelli B., Terranova V., Di Marca S., Di Quattro R., la Malfa L., Caruso R., Mecocci P., Ruggiero C., Boccardi V., Meschi T., Ticinesi A., Nouvenne A., Minuz P., Fondrieschi L., Imperiale G.N., Pirisi M., Fra G.P., Sola D., Bellan M., Porta M., Riva P., Quadri R., Larovere E., Novelli M., Scanzi G., Mengoli C., Provini S., Ricevuti L., Simeone E., Scurti R., Tolloso F., Tarquini R., Valoriani A., Dolenti S., Vannini G., Volpi R., Bocchi P., Vignali A., Harari S., Lonati C., Napoli F., Aiello I., Landolfi R., Montalto M., Mirijello A., Ghidoni S., Salvatore T., Monaco L., Ricozzi C., Pilotto A., Indiano I., Gandolfo F., D'Avanzo, B, Nobili, A, Tettamanti, M, Pasina, L, Mannucci, P, Bellelli, G, D'Avanzo, B., Nobili, A., Tettamanti, M., Pasina, L., Mannucci, P. M., Pietrangelo, A., Perticone, F., Violi, F., Corazza, G. R., Corrao, S., Marengoni, A., Salerno, F., Cesari, M., Franchi, C., Cortesi, L., Miglio, G., Ardoino, I., Novella, A., Prisco, D., Silvestri, E., Emmi, G., Bettiol, A., Mattioli, I., Biolo, G., Zanetti, M., Bartelloni, G., Vanoli, M., Grignani, G., Pulixi, E. A., Lupattelli, G., Bianconi, V., Alcidi, R., Girelli, D., Busti, F., Marchi, G., Barbagallo, M., Dominguez, L., Beneduce, V., Cacioppo, F., Natoli, G., Mularo, S., Raspanti, M., Zoli, M., Matacena, M. L., Orio, G., Magnolfi, E., Serafini, G., Simili, A., Palasciano, G., Modeo, M. E., Di Gennaro, C., Cappellini, M. D., Fabio, G., de Amicis, M. M., de Luca, G., Scaramellini, N., Rossi, P. D., Damanti, S., Clerici, M., Leoni, S., Di Mauro, A. D., Di Sabatino, A., Miceli, E., Lenti, M. V., Pisati, M., Dominioni, C. C., Pontremoli, R., Beccati, V., Nobili, G., Leoncini, G., Anastasio, L., Carbone, M., Cipollone, F., Guagnano, M. T., Rossi, I., Mancuso, G., Calipari, D., Bartone, M., Delitala, G., Berria, M., Delitala, A., Muscaritoli, M., Molfino, A., Petrillo, E., Giorgi, A., Gracin, C., Zuccala, G., D'Aurizio, G., Romanelli, G., Volpini, A., Lucente, D., Picardi, A., Gentilucci, U. V., Gallo, P., Bellelli, G., Corsi, M., Antonucci, C., Sidoli, C., Principato, G., Arturi, F., Succurro, E., Tassone, B., Giofre, F., Serra, M. G., Bleve, M. A., Brucato, A., de Falco, T., Fabris, F., Bertozzi, I., Bogoni, G., Rabuini, M. V., Prandini, T., Manfredini, R., Fabbian, F., Boari, B., de Giorgi, A., Tiseo, R., Paolisso, G., Rizzo, M. R., Catalano, C., Borghi, C., Strocchi, E., Ianniello, E., Soldati, M., Schiavone, S., Bragagni, A., Sabba, C., Vella, F. S., Suppressa, P., de Vincenzo, G. M., Comitangelo, A., Amoruso, E., Custodero, C., Fenoglio, L., Falcetta, A., Fracanzani, A. L., Tiraboschi, S., Cespiati, A., Oberti, G., Sigon, G., Peyvandi, F., Rossio, R., Colombo, G., Agosti, P., Monzani, V., Savojardo, V., Ceriani, G., Pallini, G., Montecucco, F., Ottonello, L., Caserza, L., Vischi, G., Liberato, N. L., Tognin, T., Purrello, F., Di Pino, A., Piro, S., Rozzini, R., Falanga, L., Pisciotta, M. S., Bellucci, F. B., Buffelli, S., Montrucchio, G., Peasso, P., Favale, E., Poletto, C., Margaria, C., Sanino, M., Guasti, L., Castiglioni, L., Maresca, A., Squizzato, A., Campiotti, L., Grossi, A., Diprizio, R. D., Bertolotti, M., Mussi, C., Lancellotti, G., Libbra, M. V., Galassi, M., Grassi, Y., Greco, A., Sciacqua, A., Perticone, M., Battaglia, R., Maio, R., Stanghellini, V., Ruggeri, E., del Vecchio, S., Salvi, A., Leonardi, R., Damiani, G., Capeci, W., Mattioli, M., Martino, G. P., Biondi, L., Pettinari, P., Ghio, R., Dal Col, A., Minisola, S., Colangelo, L., Cilli, M., Labbadia, G., Afeltra, A., Marigliano, B., Pipita, M. E., Castellino, P., Zanoli, L., Gennaro, A., Gaudio, A., Saracco, V., Fogliati, M., Bussolino, C., Mete, F., Gino, M., Vigorito, C., Cittadini, A., Moreo, G., Prolo, S., Pina, G., Ballestrero, A., Ferrando, F., Gonella, R., Cerminara, D., Berra, S., Dassi, S., Nava, M. C., Graziella, B., Baldassarre, S., Fragapani, S., Gruden, G., Galanti, G., Mascherini, G., Petri, C., Stefani, L., Girino, M., Piccinelli, V., Nasso, F., Gioffre, V., Pasquale, M., Sechi, L., Catena, C., Colussi, G., Cavarape, A., da Porto, A., Passariello, N., Rinaldi, L., Berti, F., Famularo, G., Tarsitani, P., Castello, R., Pasino, M., Ceda, G. P., Maggio, M. G., Morganti, S., Artoni, A., Grossi, M., Del Giacco, S., Firinu, D., Costanzo, G., Argiolas, G., Montalto, G., Licata, A., Montalto, F. A., Corica, F., Basile, G., Catalano, A., Bellone, F., Principato, C., Malatino, L., Stancanelli, B., Terranova, V., Di Marca, S., Di Quattro, R., la Malfa, L., Caruso, R., Mecocci, P., Ruggiero, C., Boccardi, V., Meschi, T., Ticinesi, A., Nouvenne, A., Minuz, P., Fondrieschi, L., Imperiale, G. N., Pirisi, M., Fra, G. P., Sola, D., Bellan, M., Porta, M., Riva, P., Quadri, R., Larovere, E., Novelli, M., Scanzi, G., Mengoli, C., Provini, S., Ricevuti, L., Simeone, E., Scurti, R., Tolloso, F., Tarquini, R., Valoriani, A., Dolenti, S., Vannini, G., Volpi, R., Bocchi, P., Vignali, A., Harari, S., Lonati, C., Napoli, F., Aiello, I., Landolfi, R., Montalto, M., Mirijello, A., Ghidoni, S., Salvatore, T., Monaco, L., Ricozzi, C., Pilotto, A., Indiano, I., and Gandolfo, F.

Subjects
2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Aged, Humans, Italy, Hospitals, Internal Medicine, MEDLINE, geriatric, Socio-culturale, law.invention, lockdown, Hospital, Patient Transport, law, Pandemic, Hospital discharge, medicine, Aged, Hospitals, Humans, Internal Medicine, Italy, Letter to the Editor, Internal medicine, LS7_9, business.industry, geriatric patients, medicine.disease, Intensive care unit, Internal medicine, geriatric patients, lockdown, covid-19, covid-19, Medical emergency, business, Human
Abstract

A total of 48 internal medicine or geriatric wards among the 93 adhering to the register REPOSI answered an online questionnaire aimed to investigate the characteristics and activities of converted and non-converted wards in the crucial period of the first wave of the epidemic, 22 February-4 May 2020

Published
2021

31. Collapsing Glomerulopathy as a Complication of Type I Interferon–Mediated Glomerulopathy in a Patient With RNASEH2B-Related Aicardi-Goutières Syndrome

Author

Paola Romagnani, Giovanni Maria Rossi, Augusto Vaglio, Maria Lucia Angelotti, Stefano Volpi, Lorenzo Lodi, Samuela Landini, Giulia Antonelli, Paride Fenaroli, Alice Grossi, and Marco Delsante

Subjects
Pathology, medicine.medical_specialty, kidney biopsy, 030232 urology & nephrology, case report, Collapsing glomerulopathy (CG), genetic mutation, interferon, parietal epithelial cells, RNASEH2B, systemic lupus erythematosus (SLE), 03 medical and health sciences, 0302 clinical medicine, Membranous nephropathy, Interferon, Glomerulopathy, Biopsy, medicine, 030212 general & internal medicine, Kidney, medicine.diagnostic_test, biology, business.industry, CD44, medicine.disease, medicine.anatomical_structure, Nephrology, biology.protein, Aicardi–Goutières syndrome, Synaptopodin, business, medicine.drug
Abstract

Aicardi-Goutieres syndrome (AGS) is a well-characterized monogenic type I interferonopathy presenting with prominent neurologic manifestations. Among extraneurologic features, renal involvement has been described in only 1 patient with an IFIH1 mutation in whom membranous nephropathy developed. The pathogenic role of augmented interferon (IFN) signaling in tissues other than the central nervous system remains to be elucidated. We report a case of collapsing glomerulopathy in a 15-year-old girl affected by AGS with RNASEH2B mutation (an alanine-to-threonine change at amino acid 177), which led to kidney failure. The patient had no lupus-like features and lacked the APOL1 G1 and G2 risk alleles. Kidney biopsy showed findings consistent with collapsing glomerulopathy. MxA, a protein involved in antiviral immunity and induced by type I IFNs, was selectively expressed in CD133-positive parietal epithelial cells (PECs) but not in podocytes that stained for synaptopodin or in other glomerular cells. MxA also colocalized within pseudocrescents with CD44, a marker of PEC activation involved in cellular proliferation, differentiation, and migration and in glomerular scarring. Our findings suggest that collapsing glomerulopathy can be a complication of the type I interferonopathy AGS and that a constitutively enhanced type I IFN response in CD133-positive PECs can drive collapsing glomerulopathy.

Published
2021

32. Genetic screening of children with marrow failure. The role of primary Immunodeficiencies

Author

Francesca Fioredda, Paola Terranova, Silvia Ravera, Alice Grossi, Maurizio Miano, Carlo Dufour, Andrea Beccaria, Elena Palmisani, Fiorina Giona, Michelina Santopietro, Tiziana Lanza, Marina Lanciotti, Enrico Cappelli, Isabella Ceccherini, Vanessa Cossu, Gianluca Dell'Orso, and Daniela Guardo

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, medicine.medical_treatment, Primary Immunodeficiency Diseases, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Fanconi anemia, Bone Marrow, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Young adult, Child, Preschool, Genetic testing, Retrospective Studies, medicine.diagnostic_test, business.industry, Incidence (epidemiology), High-Throughput Nucleotide Sequencing, Infant, Immunosuppression, Retrospective cohort study, Hematology, Bone Marrow Failure Disorders, medicine.disease, Child, Preschool, Female, 030220 oncology & carcinogenesis, Primary immunodeficiency, Differential diagnosis, business, 030215 immunology
Abstract

The differential diagnosis of marrow failure (MF) is crucial in the diagnostic work-up, since genetic forms require specific care. We retrospectively studied all patients with single/multi-lineage MF evaluated in a single-center to identify the type and incidence of underlying molecular defects. The diepoxybutane test was used to screen Fanconi Anemia. Other congenital MFs have been searched using Sanger and/or Next Generation Sequencing analysis, depending on the available tools over the years. Between 2009-2019, 97 patients (aged 0-32 years-median 5) with single-lineage (29%) or multilineage (68%) MF were evaluated. Fifty-three (54%) and 28 (29%) were diagnosed with acquired and congenital MF, respectively. The remaining 16 (17%), with trilinear (n=9) and monolinear (n=7) MF, were found to have an underlying primary immunodeficiency (PID) and showed clinical and biochemical signs of immune-dysregulation in 10/16 (62%) and in 14/16 (87%) of cases, respectively. Clinical signs were also found in 22/53 (41%) and 8/28 (28%) patients with idiopathic and classical cMF, respectively. Eight out of 16 PIDs patients were successfully transplanted, four received immunosuppression, two did not require treatment, and the remaining two died. We show that patients with single/multi-lineage MF may have underlying PIDs in a considerable number of cases and that MF may represent a relevant clinical sign in patients with PIDs, thus widening their clinical phenotype. An accurate immunological work-up should be performed in all patients with MF, and PID-related genes should be considered when screening MF in order to identify disorders that may receive targeted treatments and/or appropriate conditioning regimens before transplant.

Published
2021

33. Recessive NLRC4-autoinflammatory disease reveals an ulcerative colitis locus

Author

Jorge Kalil, Fiona Moghaddas, Alice Grossi, Florian N. Gohr, Matthias Geyer, Sophia Davidson, Gunther Hartmann, Leonardo Oliveira Mendonça, Seth L. Masters, Fabio Fernandes Morato Castro, Isabella Ceccherini, Thomas Reygaerts, Eva Bartok, Thomas Zillinger, Alessandra Pontillo, Marco Gattorno, Francesco Caroli, Jonas Moecking, Florian I. Schmidt, and Annemarie Steiner

Subjects
Enterocolitis, education.field_of_study, ATIVAÇÃO ENZIMÁTICA, business.industry, Immunology, Population, Immune dysregulation, medicine.disease, medicine.disease_cause, Systemic inflammation, Ulcerative colitis, Diarrhea, NLRC4, Macrophage activation syndrome, Immunology and Allergy, Medicine, medicine.symptom, business, education
Abstract

PurposeNLRC4-associated autoinflammatory disease (NLRC4-AID) is an autosomal dominant condition presenting with a range of clinical manifestations which can include macrophage activation syndrome (MAS) and severe enterocolitis. We now report the first homozygous mutation inNLRC4(c.478G > A, p.A160T) causing autoinflammatory disease with immune dysregulation and find that heterozygous carriers in the general population are at increased risk of developing ulcerative colitis.MethodsCirculating immune cells and inflammatory markers were profiled and historical clinical data interrogated. DNA was extracted and sequenced using standard procedures. Inflammasome activation assays for ASC speck formation, pyroptosis, and IL-1β/IL-18 secretion confirmed pathogenicity of the mutation in vitro. Genome-wide association of NLRC4 (A160T) with ulcerative colitis was examined using data from the IBD exomes portal.ResultsA 60-year-old Brazilian female patient was evaluated for recurrent episodes of systemic inflammation from six months of age. Episodes were characterized by recurrent low-grade fever, chills, oral ulceration, uveitis, arthralgia, and abdominal pain, followed by diarrhea with mucus and variable skin rash. High doses of corticosteroids were somewhat effective in controlling disease and anti-IL-1β therapy partially controlled symptoms. While on treatment, serum IL-1β and IL-18 levels remained elevated. Genetic investigations identified a homozygous mutation inNLRC4(A160T), inherited in a recessive fashion. Increased ASC speck formation and IL-1β/IL-18 secretion confirmed pathogenicity when NLRC4 (A160T) was analyzed in human cell lines. This allele is significantly enriched in patients with ulcerative colitis: OR 2.546 (95% 1.778–3.644),P = 0.01305.ConclusionNLRC4 (A160T) can either cause recessively inherited autoinflammation and immune dysregulation, or function as a heterozygous risk factor for the development of ulcerative colitis.

Published
2021

34. A case report of a novel compound heterozygous mutation in a Brazilian patient with deficiency of Interleukin-1 receptor antagonist (DIRA)

Author

Jorge Kalil, Fabio Fernandes Morato Castro, Myrthes Toledo Barros, Isabella Ceccherini, Robson Aguiar de Oliveira, Francesco Caroli, Alessandra Pontillo, Marco Gattorno, Leonardo Oliveira Mendonça, and Alice Grossi

Subjects
lcsh:Diseases of the musculoskeletal system, medicine.drug_class, Interleukin-1beta, Deficiency of interleukin-1 receptor antagonist, Review, Compound heterozygosity, Antibodies, Monoclonal, Humanized, DIRA, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Adrenal Cortex Hormones, medicine, IL1RN, Immunology and Allergy, Humans, 030212 general & internal medicine, Genetic Testing, Child, 030203 arthritis & rheumatology, Anakinra, business.industry, Hereditary Autoinflammatory Diseases, Homozygote, lcsh:RJ1-570, Interleukin, lcsh:Pediatrics, Osteomyelitis, Receptor antagonist, Symptom Flare Up, Rash, Rilonacept, Radiography, Canakinumab, Interleukin 1 Receptor Antagonist Protein, Interleukin 1 receptor antagonist, Treatment Outcome, Antirheumatic Agents, Pediatrics, Perinatology and Child Health, Immunology, Mutation, lcsh:RC925-935, medicine.symptom, business, medicine.drug
Abstract

Background Deficiency of the natural antagonist of interleukin-1 was first described in 2009 and so far 20 patients has been reported. In Brazil just two cases have been reported both carrying the same homozygous 15 bp deletion. Blocking interleukin-1 has changed rate survival for DIRA patients. The use of anakinra and rilonacept has been reported safe and efficient, whereas the selective blockade of interleukin-1 beta, using the monoclonal antibody canakinumab has been reported in a single case only. Case presentation Here we report a case of a 7 years old Brazilian boy that presented with recurrent episodes of systemic inflammation with severe disabling osteomyelitis with mild pustular skin rash. A Next Generation Sequencing gene panel allowed to detect two pathogenic mutations in the IL1RN gene, described in compound heterozygosity. Corticosteroids was effective in controlling inflammation and anti-IL1 beta blocker triggered disease flare. Complete clinical control could be achieved using IL-1 receptor antagonist. Conclusions DIRA is a severe, life threatening autoinflammatory condition with low numbers of patients described all over the world. The mutation p.Asp72_Ile76del in IL1RN is presented in all Brazilian DIRA patients already described and p.Q45* (rs1019766125) is a new mutation affecting the IL1RN gene. Following the pathogenesis of DIRA, blocking both subunits of interleukin one as well as antagonizing the receptor using anakinra or rilonacept seems to be effective. There is just one report using canakinumab for the treatment of DIRA and this is the first report of disease flare using this drug.

Published
2020

35. Author response for 'Dysregulation in B cell responses and T follicular helper cell function in ADA2 deficiency patients'

Author

Arinna Bertoni, Annalisa Salis, Isabella Ceccherini, Claudia Pastorino, Roberta Caorsi, Daniela Fenoglio, Ignazia Prigione, Francesca Antonini, Elisabetta Traggiai, Gianluca Damonte, Federica Penco, Sara Signa, Fabrizio De Benedetti, Alice Grossi, Paola Bocca, Francesca Schena, Gilberto Filaci, Francesca Kalli, Marco Gattorno, Stefano Volpi, and Antonella Insalaco

Subjects
medicine.anatomical_structure, Immunology, Follicular phase, medicine, ADA2 DEFICIENCY, Biology, Cell function, B cell
Published
2020

36. Late-onset and long-lasting autoimmune neutropenia: An analysis from the Italian Neutropenia Registry

Author

Lucia Dora Notarangelo, Giovanna Russo, Angelica Barone, Angela Trizzino, Maurizio Miano, Francesca Fioredda, Andrea Finocchi, Alice Grossi, Gioacchino Andrea Rotulo, Gianluca Boscarol, Nicoletta Marra, Laura Porretti, Ugo Ramenghi, Fabian Beier, Roberta Ghilardi, Baldassare Martire, Sabrina Zanardi, Marina Lanciotti, Paola Giordano, Federico Verzegnassi, Marta Pillon, Tiziana Lanza, Laura Luti, Francesca Dagliano, Daniela Onofrillo, Marinella Veltroni, Saverio Ladogana, Piero Farruggia, Elena Mastrodicasa, Isabella Ceccherini, Paola Terranova, Sonia Bonanomi, and Carlo Dufour

Subjects
Adult, medicine.medical_specialty, Neutropenia, Late onset, Autoimmunity, 030204 cardiovascular system & hematology, Gastroenterology, 03 medical and health sciences, Phagocytes, Granulocytes, and Myelopoiesis, Child, Child, Preschool, Congenital Bone Marrow Failure Syndromes, Humans, Italy, Registries, 0302 clinical medicine, Internal medicine, White blood cell, medicine, Preschool, Immunodeficiency, Autoimmune disease, Leukopenia, business.industry, Hematology, medicine.disease, medicine.anatomical_structure, Autoimmune neutropenia, Lymphocytopenia, medicine.symptom, business, 030215 immunology
Abstract

Primary autoimmune neutropenia (pAN) is typified by onset in early infancy and a mild/moderate phenotype that resolves within 3 years of diagnosis. In contrast, secondary AN is classically an adult disease associated with malignancy, autoimmunity, immunodeficiency, viral infection, or drugs. This study describes a cohort of 79 children from the Italian Registry who, although resembling pAN, did not fully match the criteria for pAN because neutropenia either appeared after age 5 years (LO-Np) or lasted longer than 3 years (LL-Np). These 2 categories compared with classical pAN showed a far inferior rate of resolution (P < .001), lower severity of neutropenia (P = .03), leukopenia (P < .001), lymphopenia (P < .001) with low B+ (P = .001), increased need of granulocyte colony-stimulating factor (P = .04), and increased frequency of autoimmunity over the disease course (P < .001). A paired comparison between LO-Np and LL-Np suggested that LO-Np had a lower rate of resolution (P < .001) and lower white blood cell (P < .001) and lymphocyte (P < .001) values, higher occurrence of apthae (P = .008), and a stronger association with autoimmune diseases/markers (P = .001) than LL-Np, thus suggesting a more pronounced autoimmune signature for LO-Np. A next-generation sequencing panel applied in a small subgroup of LO-Np and LL-Np patients identified variants related to immune dysregulations. Overall, these findings indicate that there are important differences among pAN LL-Np and LO-Np. Forms rising after 3 years of age, with low tendency to resolution, require tight monitoring and extensive immune investigations aimed to early identify underlying immunologic disease.

Published
2020

37. Atypical Autoimmune Neutropenia: Data from The Italian Neutropenia Registry

Author

Fioredda, Francesca, Farruggia, Piero, Rotulo, Andrea, Pillon, Marta, Trizzino, Angela, Notarangelo, Lucia Dora, Luti, Laura, Lanza, Tiziana, Lanciotti, Marina, Isabella, Ceccherini, Alice, Grossi, Porretti, Laura, Matrodicasa, Elena, Barone, Angelica, Russo, Giovanna, Bonanomi, Sonia, Boscarol, Gianluca, Finocchi, Andrea, Veltroni, Marinella, Ramenghi, Ugo, Onofrillo, Daniela, Verzegnassi, Federico, Martire, Baldo, Ghilardi, Roberta, Lassandro, Giuseppe, La Dogana, Saverio, Marra, Nicoletta, PAOLA TERRANOVA, Zanardi, Sabrina, Dufour, Carlo, and Miano, Maurizio

Published
2020

38. Recessive NLRC4-Autoinflammatory Disease Reveals an Ulcerative Colitis Locus

Author

Annemarie, Steiner, Thomas, Reygaerts, Alessandra, Pontillo, Isabella, Ceccherini, Jonas, Moecking, Fiona, Moghaddas, Sophia, Davidson, Francesco, Caroli, Alice, Grossi, Fabio Fernandes Morato, Castro, Jorge, Kalil, Florian N, Gohr, Florian I, Schmidt, Eva, Bartok, Thomas, Zillinger, Gunther, Hartmann, Matthias, Geyer, Marco, Gattorno, Leonardo Oliveira, Mendonça, and Seth L, Masters

Subjects
CARD Signaling Adaptor Proteins, Inflammasomes, Calcium-Binding Proteins, Hereditary Autoinflammatory Diseases, Humans, Colitis, Ulcerative, Female, Middle Aged, Genome-Wide Association Study
Abstract

NLRC4-associated autoinflammatory disease (NLRC4-AID) is an autosomal dominant condition presenting with a range of clinical manifestations which can include macrophage activation syndrome (MAS) and severe enterocolitis. We now report the first homozygous mutation in NLRC4 (c.478G A, p.A160T) causing autoinflammatory disease with immune dysregulation and find that heterozygous carriers in the general population are at increased risk of developing ulcerative colitis.Circulating immune cells and inflammatory markers were profiled and historical clinical data interrogated. DNA was extracted and sequenced using standard procedures. Inflammasome activation assays for ASC speck formation, pyroptosis, and IL-1β/IL-18 secretion confirmed pathogenicity of the mutation in vitro. Genome-wide association of NLRC4 (A160T) with ulcerative colitis was examined using data from the IBD exomes portal.A 60-year-old Brazilian female patient was evaluated for recurrent episodes of systemic inflammation from six months of age. Episodes were characterized by recurrent low-grade fever, chills, oral ulceration, uveitis, arthralgia, and abdominal pain, followed by diarrhea with mucus and variable skin rash. High doses of corticosteroids were somewhat effective in controlling disease and anti-IL-1β therapy partially controlled symptoms. While on treatment, serum IL-1β and IL-18 levels remained elevated. Genetic investigations identified a homozygous mutation in NLRC4 (A160T), inherited in a recessive fashion. Increased ASC speck formation and IL-1β/IL-18 secretion confirmed pathogenicity when NLRC4 (A160T) was analyzed in human cell lines. This allele is significantly enriched in patients with ulcerative colitis: OR 2.546 (95% 1.778-3.644), P = 0.01305.NLRC4 (A160T) can either cause recessively inherited autoinflammation and immune dysregulation, or function as a heterozygous risk factor for the development of ulcerative colitis.

Published
2019

39. ABCC6 mutations and early onset stroke: Two cases of a typical Pseudoxanthoma Elasticum

Author

Marco Pavanello, Alessia Aiello, Maria Stella Vari, Alessandro Rimini, Paolo Moretti, Valeria Capra, Antonella Palmieri, Alice Grossi, Sara Uccella, Pasquale Striano, Silvia Pederzoli, Maja Di Rocco, Luca A. Ramenghi, Isabella Ceccherini, Thea Giacomini, Giulia Prato, Domenico Tortora, Andrea Moscatelli, Carlo Gandolfo, Paolo Picco, Francesca Minoia, Marta Bertamino, Clara Malattia, Mariasavina Severino, Laura Banov, Paola Lanteri, Marta Rusmini, Angelo Claudio Molinari, and Andrea Rossi

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Adolescent, ABCC6, Pediatrics, 03 medical and health sciences, Magnetic resonance imaging, 0302 clinical medicine, Pathognomonic, Genetics, medicine, Humans, Pediatric stroke, Pseudoxanthoma Elasticum, Child, Preschool, Stroke, biology, business.industry, Genetic disorder, High-Throughput Nucleotide Sequencing, General Medicine, Perinatology and Child Health, medicine.disease, Pseudoxanthoma elasticum, Dermatology, Next-generation sequencing, Child, Preschool, Female, Multidrug Resistance-Associated Proteins, Mutation, Pediatrics, Perinatology and Child Health, Neurology (clinical), Angioid streaks, 030104 developmental biology, biology.protein, Age of onset, business, 030217 neurology & neurosurgery
Abstract

Pseudoxanthoma elasticum (PXE) is a rare genetic disorder characterized by fragmented and mineralized elastic fibers in the mid-dermis of the skin, eye, digestive tract and cardiovascular system. Clinical presentation includes typical skin lesions, ocular angioid streaks, and multisystem vasculopathy. The age of onset varies considerably from infancy to old age, but the diagnosis is usually made in young adults due to frequent absence of pathognomonic skin and ocular manifestations in early childhood. We report two children with PXE presenting with isolated multisystem vasculopathy and early-onset stroke. In the first patient, diagnosis was delayed until typical dermatologic alterations appeared; in the second patient, next-generation sequencing (NGS) study led to early diagnosis and specific follow-up, underlying the crucial role in idiopathic pediatric stroke of early genetic testing using NGS-based panels.

Published
2018

40. Late Onset and Long Lasting Idiopathic and Autoimmune Neutropenia As Epiphenomena of Immune Dysregulation: Preliminary Data Study from the Italian Neutropenia Registry

Author

Francesca Fioredda, Marina Lanciotti, Cecilia Contratto, Giovanni Del Borrello, Michela Lupia, Paola Terranova, Eleonora Rotondo, Domenico Coviello, Maurizio Miano, Antonio Marzollo, Adele Civino, Francesca Bagnasco, Alice Grossi, Andrea Beccaria, and Carlo Dufour

Subjects
Long lasting, business.industry, Immunology, Late onset, Epiphenomenon, Cell Biology, Hematology, Neutropenia, Immune dysregulation, medicine.disease, medicine.disease_cause, Biochemistry, Autoimmune neutropenia, medicine, business
Abstract

INTRODUCTION: Idiopathic neutropenia (IN) of childhood is a benign, self-limiting disorder usually occurring in the first 3 years of life that differs from primary autoimmune neutropenia (AIN) because anti neutrophil antibodies are not detected on repeated indirect testing over time(1). Chronic idiopathic neutropenia (CIN) is a well characterized disorder of elderly with a peculiar immunological pattern(2). Pediatric AIN patients, with atypical features represented by longer disease duration (Long Lasting) or diagnosed later (Late Onset), were recently shown by our group to display a different immune-hematological profile vs typical primary AIN(3). Atypical pediatric IN subjects, i.e. diagnosed later or with longer disease duration, though occasionally reported, were never systematically investigated. In the present study we analyzed a cohort of young patients with atypical IN and AIN, diagnosed after the age of 3 years or with longer disease duration, aiming to identify an immunological signature that might predict their different outcome from classical AIN and IN of infancy. PURPOSE OF THE STUDY: to analyze a cohort of patients affected with AIN and IN rising > 3 years of age and with duration >12 months or rising MATERIALS AND METHODS: Clinical, immunological and genetic data (NGS panel of 160 immunodeficiency/disimmunity genes) of eligible patients were collected from the database of the Italian Neutropenia Registry. RESULTS: From 2005 to 2020, data from 46 patients (24F, 24 autoimmune and 22 Idiopathic Neutropenia) were retrieved. Median age at onset was 11.2 years (IQR13.2-16.7), median follow-up was 4.3 years (IQR 3.2-6.8). Neither autoimmunity nor additional cytopenias to neutropenia were present at onset. Cumulative incidence at 5 years of autoimmune manifestations (thyroiditis, arthritis, vitiligo, recurrent skin rash) was 11.8% (CI 95% 4.3-30). Throughout the follow up, infections occurred in 32/46 (70%) subjects and in only 16% were severe (meningitis, recurrent pneumonia, sepsis and pericarditis). Infections sites were upper respiratory (in 84% of subjects mouth and gums (47%), and skin (40%) ear (25%), lung (19%) and urinary tract (12%). Fever of unknown origin was detected in 40% of patients. Recurrent infections (more than 3/y) involved mouth (85%) and ear (88%). White Blood Cell, Absolute Neutrophil and Lymphocyte counts retrieved at the beginning of the study, in the middle and at the end of follow up are shown in Table 1. Leucocytes and Lymphocytes at the end of follow up were significantly lower than values seen at diagnosis (p < 0.001) whereas neutrophil count remained stable (p=ns). One third of the cohort had lower values than normal of CD19+ and CD3-CD56+CD16+ cells. B switched memory CD27+/IgD-/IgM- (in 94%) were lower, while marginal zone B lymphocytes CD27+/IgD+/IgM+ (62%) and Tγδ cells (70%) were increased than the normal population according to a pattern comparable to that described in chronic idiopathic neutropenia (CIN). Immunoglobulin serum levels (IgA, IgG and IgM) were below the normal value in 7.5% of the population, but specularly a small subset (7.5%) of IN showed an increase of IgM was seen, similar to what already descibed in adult CIN. The genetic study carried out in 32 patients showed in 5 (16%) pathogenic variants: of immunodeficit/dysregulation (2 TACI, 1 TINF2, 1 CARD11) and in 9 cases (28%) VUS in genes of the same groups (1CARD11, 4CASP10,1DDX41/SOCS1, 1TSR2/DCLRE1c, 1PIK3D, 1TERT/TACI). CONCLUSIONS: Atypical IN and AIN (of longer duration or occurring in advanced pediatric age) are different from those appearing in early infancy. They seem to display dysimmune/autoimmune features that is some case is proven to rely on a genetic dysimmune background. They might represent an anticipation of more complex autoimmune disorders which may fully manifest later in life. Interstingly these patients seem to share some features with CIN of adults. Definitive conclusions will be drawn by applying more comprehensive genetic nalysis (WES and WGS) on larger group of subjects. References: 1. Farruggia et al, Am J Hematol. 2019, 94:216-222 2. Mavroudi I et al, Clin Immunol. 2017 Oct;183:75-84 3. Fioredda F et al, Blood Adv 2020 Nov 24;4:5644-5649 Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Published
2021

41. Genetic Screening of Patients with Evans Syndrome: A Single Centre Analysis

Author

Alice Grossi, Carlo Dufour, Francesca Fioredda, Marina Lanciotti, Elena Palmisani, Paola Terranova, Enrico Cappelli, Michela Lupia, Gianluca Dell'Orso, Isabella Ceccherini, Daniela Guardo, and Maurizio Miano

Subjects
Pediatrics, medicine.medical_specialty, Single centre, Evans syndrome, business.industry, Immunology, Medicine, Cell Biology, Hematology, business, medicine.disease, Biochemistry
Abstract

Background: Evans syndrome (ES) is a rare disorder defined as the simultaneous or sequential presence of autoimmune haemolytic anemia and immune thrombocytopenia but it can also be considered as the presence of at least two autoimmune cytopenias. Recent reports have shown that ES is often a manifestation of an underlying congenital immune dysregulation syndrome that, in some case, can benefit from specific treatments. Aims: The aim of this study is to investigate the clinical/immnunological characteristics and the underlying genetic background of a single centre cohort of patients with ES. Methods: Data were obtained from a retrospective charts' review of patients with a diagnosis of ES in our centre. Genetic studies were performed with NGS analysis of 315 genes related to both hematologic and immunological disorders as congenital bone marrow failure syndromes, primary immunodeficiencies, and primary immune regulatory disorders. Results: Fourteen patients (23 males, 17 females) with a median age at onset of 6 years (range 0-16) were studied. ES was concomitant and sequential in 18 (45%) and 22 (55%) patients, respectively. Nine/40 (8%) patients had a family history of autoimmunity. Other abnormal immunological features and signs of lymphoproliferation were present in 24/40 (60%) and 29/40 (72%) of cases, respectively. Seventeen out of 40 (42%) children fitted the ALPS diagnostic criteria. The remaining 15 (37%) and 9 (22%) were classified as having an ALPS-like phenotype and an isolated ES, respectively. Twenty patients (50%) were found to have an underlying genetic defect on TNFRSF13B, FAS, CTLA4, IKBGK, CARD11, LIG4, LRBA, STAT3, CASP10 and ADA2 genes. Table 1 shows the details of clinical/immunological characteristics of patients with or without a genetic diagnosis. No significant differences were noted between the two groups. Conclusions: This study shows that half of patients with ES have a genetic background, secondary to Primary Immunodeficiencies. Therefore, an immunological screening and an extended molecular evaluation should be offered to all patients, since specific genetic diagnosis may benefit from targeted treatments. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Published
2021

42. Copy number variations in candidate genomic regions confirm genetic heterogeneity and parental bias in Hirschsprung disease

Author

Alessio Pini Prato, Chiara Viaggi, Giuseppe Santamaria, Francesca Lantieri, Domenico Coviello, Manuela Mosconi, Stefania Gimelli, Michela Malacarne, Alice Grossi, Isabella Ceccherini, Elissavet Stathaki, and Frédérique Sloan-Béna

Subjects
Male, 0301 basic medicine, Candidate gene, DNA Copy Number Variations, Hirschsprung disease, lcsh:Medicine, Disease, 030105 genetics & heredity, Biology, Polymorphism, Single Nucleotide, Aldehyde Dehydrogenase 1 Family, Genetic Heterogeneity, 03 medical and health sciences, Humans, Genetic Predisposition to Disease, Pharmacology (medical), Copy number variations, Copy-number variation, Candidate genes and regions, Gene, Genetics (clinical), Chromosome Aberrations, Genetics, Comparative genomic hybridization, Genetic heterogeneity, Research, lcsh:R, Inheritance (genetic algorithm), Retinal Dehydrogenase, Candidate genes and regions, Comparative genomic hybridization, Copy number variations, Custom array, Hirschsprung disease, General Medicine, Human genetics, 030104 developmental biology, Custom array, Female, Genome-Wide Association Study
Abstract

Background Hirschsprung Disease (HSCR) is a congenital defect of the intestinal innervations characterized by complex inheritance. Many susceptibility genes including RET, the major HSCR gene, and several linked regions and associated loci have been shown to contribute to disease pathogenesis. Nonetheless, a proportion of patients still remains unexplained. Copy Number Variations (CNVs) have already been involved in HSCR, and for this reason we performed Comparative Genomic Hybridization (CGH), using a custom array with high density probes. Results A total of 20 HSCR candidate regions/genes was tested in 55 sporadic patients and four patients with already known chromosomal aberrations. Among 83 calls, 12 variants were experimentally validated, three of which involving the HSCR crucial genes SEMA3A/3D, NRG1, and PHOX2B. Conversely RET involvement in HSCR does not seem to rely on the presence of CNVs while, interestingly, several gains and losses did co-occur with another RET defect, thus confirming that more than one predisposing event is necessary for HSCR to develop. New loci were also shown to be involved, such as ALDH1A2, already found to play a major role in the enteric nervous system. Finally, all the inherited CNVs were of maternal origin. Conclusions Our results confirm a wide genetic heterogeneity in HSCR occurrence and support a role of candidate genes in expression regulation and cell signaling, thus contributing to depict further the molecular complexity of the genomic regions involved in the Enteric Nervous System development. The observed maternal transmission bias for HSCR associated CNVs supports the hypothesis that in females these variants might be more tolerated, requiring additional alterations to develop HSCR disease.

Published
2019

43. Thrombotic thrombocytopenic purpura and defective apoptosis due to CASP8/10 mutations: the role of mycophenolate mofetil

Author

A. Mariani, Filomena Pierri, Concetta Micalizzi, Alice Grossi, Isabella Ceccherini, Flora Peyvandi, Elena Palmisani, Michaela Calvillo, Andrea Beccaria, Francesca Fioredda, Ilaria Mancini, Fabio Corsolini, Roberta Venè, Enrico Cappelli, Maurizio Miano, and Carlo Dufour

Subjects
Adolescent, Thrombotic thrombocytopenic purpura, ADAMTS13 Protein, Apoptosis, Mycophenolate, medicine.disease_cause, Disease susceptibility, medicine, Humans, Caspase 10, Mutation, Caspase 8, Antibiotics, Antineoplastic, Purpura, Thrombotic Thrombocytopenic, business.industry, Hematology, Mycophenolic Acid, medicine.disease, Purpura, Immunology, Proteolysis, Exceptional Case Report, Female, Disease Susceptibility, medicine.symptom, business, Biomarkers
Abstract

Key Points Immunological dysregulation may underlie unusual autoimmune diseases, which also deserve to be investigated from a genetic point of view.

Published
2019

44. THU0505 INTRINSIC AND EXTRINSIC B CELL DEFECT IN DADA2 PATIENTS

Author

Federica Penco, Elisabetta Traggiai, Francesca Kalli, Alice Grossi, Isabella Ceccherini, Stefano Volpi, Francesca Antonini, Alberto Martini, Marco Gattorno, Roberta Caorsi, Annalisa Salis, Antonella Insalaco, Francesca Schena, Gianluca Damonte, Paola Bocca, Daniela Fenoglio, Gilberto Filaci, Claudia Pastorino, Arinna Bertoni, and Ignazia Prigione

Subjects
CD40, biology, Polyarteritis nodosa, business.industry, T cell, medicine.disease, Immunophenotyping, medicine.anatomical_structure, Immunology, biology.protein, medicine, Antibody, business, CD8, B cell, Immunodeficiency
Abstract

Background: ADA2 Deficiency is an autoinflammatory disease characterized by systemic vasculopathy, strokes and mild immunodeficiency. The defect is due to a mutation in ADA2 gene. It regulates the catabolism of extracellular adenosine, which is an important regulator of Class Switch Recombination in B lymphocytes. Objectives: We addressed if ADA2 mutation affects directly B-cell function and the capacity of helper T cells to support B cells. Methods: 14 patients carrying LOF mutations in ADA2 were examined. We analyzed immunophenotype by flow cytometry. B cells isolated from DADA patients or HD have been cultured alone or in co-culture with CD4+ T cells and in vitro B cell proliferation has been evaluated by CFSE dilution, whereas B cell differentiation to Immunoglobulins secreting cells in response to TLR9 agonist and T cell help has been evaluated by ELISA assay. Results: Flow-cytometric analysis showed a significant reduction of switched memory B cells and of CD4+/CD8+ T cells. We identified an significant expansion of circulating Tfh cells in DADA2. Then we investigated a role of ADA2 in B cells: we found that it is expressed, secreted but the activity is strongly impaired in DADA2. We also addressed the interaction between B and T cells; we found that proliferation and differentiation of patients’ B cells were not sustained from patient’s T cells. Moreover DADA2 T cells showed an impairment in the IL21 production and a downregulation of CD40L. Conclusion: Our findings suggest that ADA2 mutation could affects directly B cell function and T cell help functions. References: [1] Zhou Q, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med 2014 Mar 6;370(10):911-20. [2] Navon EP, et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med 2014 Mar 6;370(10):921-31. [3] Schepp J, et al.Screening of 181 Patients with Antibody Deficiency for Deficiency of Adenosine Deaminase 2 sheds new lights on the disease in Adulthood. Arthritis and Rheum 2017 August; Vol. 69, 8:1689–1700. [4] Caorsi R, Monogenic polyarteritis: the lesson of ADA2 deficiency. Pediatr Rheumatol Online J 2016;14(1):51. [5] Caorsi R. et al.ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study. Ann Rheum Dis 2017; 0:1-9. Disclosure of Interests: Francesca Schena: None declared, Federica Penco: None declared, Stefano Volpi: None declared, Claudia Pastorino: None declared, Roberta Caorsi: None declared, Francesca Kalli: None declared, Daniela Fenoglio: None declared, Annalisa Salis: None declared, Arinna Bertoni: None declared, Ignazia Prigione: None declared, Paola Bocca: None declared, Antonella Insalaco: None declared, Francesca Antonini: None declared, Alice Grossi: None declared, Gianluca Damonte: None declared, Isabella Ceccherini: None declared, Gilberto Filaci: None declared, Alberto Martini Consultant for: I do not have any conflict of interest to declare since starting from 1 March 2016 I became the Scientific Director of the G. Gaslini Hospital; therefore, my role does not allow me to render private consultancies resulting in personal income. I perform consultancy activities on behalf of the Gaslini Institute for the companies listed below: AbbVie, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, EMD Serono, Janssen, Novartis, Pfizer, R-Pharm. The money received for these activities are directly transferred to the Gaslini Institute’s bank account. Before March 2016, I was the head of the Pediatric Rheumatology Department at the G. Gaslini Hospital, where the PRINTO Coordinating Centre is located. For the coordination activity of the PRINTO network, the Gaslini Hospital received contributions from the industries listed in this section. This money has been reinvested for the research activities of the hospital in fully independent manners besides any commitment with third parties., Elisabetta Traggiai Employee of: Novartis, Marco Gattorno Grant/research support from: MG has received unrestricted grants from Sobi and Novartis

Published
2019

45. AB0974 A CASE OF ADENOSINE DEAMINASE 2 DEFICIENCY (DADA2) WITH AN UNCOMMON CLINICAL PRESENTATION AND RESPONSE TO IV IG

Author

Francesca Garbarino, Alice Grossi, Stefano Volpi, Isabella Ceccherini, Roberta Caorsi, and Marco Gattorno

Subjects
Hepatitis, Adenosine Deaminase 2 Deficiency, Anakinra, Polyarteritis nodosa, business.industry, medicine.disease, Hypogammaglobulinemia, Lethargy, Immunology, medicine, medicine.symptom, business, Immunodeficiency, medicine.drug, Livedo reticularis
Abstract

Background DADA2 is an autoinflammatory disease with autosomal recessive inheritance characterized by a heterogeneous clinical phenotype ranging from multisystemic inflammation (fever, polyarteritis nodosa, cerebral stroke, livedo reticularis etc.) to immune-dysregulation and immunodeficiency. Objectives To extend the clinical spectrum of DADA2 reporting a case of isolated nonspecific systemic inflammatory syndrome associated with signs of immune-dysregulation in a patient with a novel ADA2 mutation. Methods In a patient with nonspecific inflammatory phenotype associated to susceptibility to viral infections, Next Generation Sequencing (NGS) panel was performed; mutations detected were confirmed by Sanger analysis. ADA2 enzymatic activity was analyzed in monocyte isolated from the patient and incubated with adenosine and an ADA1 inhibitor. Results The girl, adopted and of Asian origin, began to suffer from nonspecific systemic inflammatory symptoms (persistent fever and arthralgias) at the age of 6. In past history recurrent respiratory infections and impaired immunological response to viruses (CMV related hepatitis, measles after vaccination) were reported. After few months the patient developed clinical and laboratory findings of HLH (Hemophagocytic Lympho-Histocytosis), confirmed on bone marrow samples; treatment with intravenous (IV) high dose (HD) steroids was started, with prompt response. During steroids tapering fever and systemic inflammation reappeared; anti-IL1 treatment (anakinra) was not effective. Immunologic assessment demonstrated mild hypogammaglobulinemia and moderate NK deficiency on lymphocyte subsets. HD IV Immunoglobulins (IG) (2 g/kg every month) allowed to achieve a complete control of the clinical picture; the frequency of administration was progressively reduced to every 4 months due to persistent wellbeing. At the age of 9, after switching IG to the substitutive dosage, the patient experienced Herpes Zoster virus reactivation (requiring prolonged antiviral treatment), followed by the reappearance of the inflammatory phenotype complicated by HLH with neurological involvement (irritability and lethargy), responsive to HD steroids and IG. A later cerebral MRI evidenced a small gliotic area in left Centrum Ovale. After steroids suspension, monthly HD IV IG administrations maintained clinical remission. Further immunological studies confirmed a reduction of NK cells with normal function. Hereditary HLH, Autoimmune Lympho-Proliferative Syndrome (ALPS) and main primary immunodeficiencies were ruled out. Given the clinical picture, a large NGS diagnostic panel (courtesy by K. Botzug, Vienna) for autoinflammatory diseases and immunodeficiencies was performed revealing the homozygous LEU141PRO ADA2 mutation, confirmed by Sanger analysis. Being this mutation novel, an ADA2 enzymatic activity test was performed revealing a complete loss of ADA2 activity. The parents refused anti-TNF treatment and the patient is still on monthly HD IG with a complete wellbeing after 3 years of follow-up. Conclusion The current report enlarges the clinical spectrum associated with DADA2 to a persistent unspecific inflammatory syndrome, complicated by HLH. This case further emphasizes the possibility that NGS could unravel unusual phenotypes of already known inflammatory syndromes. Even if further reports are required, the response to HD IG observed in the present case it is of interest. Even if anti-TNF is the treatment of choice HD IG could be a possible treatment in DADA2, especially during the acute phase. References [1] Caorsi R, et al. Ann Rheum Dis. 201776(10):1648-1656 Disclosure of Interests Francesca Garbarino: None declared, Roberta Caorsi: None declared, Stefano Volpi: None declared, Alice Grossi: None declared, Isabella Ceccherini: None declared, Marco Gattorno Grant/research support from: MG has received unrestricted grants from Sobi and Novartis

Published
2019

46. FRI0568 THE USE OF NEXT GENERATION SEQUENCING PANEL IN UNDIFFERENTIATED AUTOINFLAMMATORY DISEASES IDENTIFY A SEPARATE SUBSET OF COLCHICINE-RESPONDER RECURRENT FEVERS DISTINCT FROM PFAPA SYNDROME

Author

Stefano Volpi, Cinzia Castana, Marco Gattorno, Paolo Picco, Angelo Ravelli, Francesca Bovis, Marielle E. van Gijn, Valeria Musso, Francesco Caroli, Alice Grossi, Isabella Ceccherini, Marta Rusmini, Roberta Caorsi, Laura Obici, and Riccardo Papa

Subjects
030203 arthritis & rheumatology, 0301 basic medicine, PFAPA syndrome, medicine.medical_specialty, business.industry, Chronic inflammatory disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Recurrent fever, Internal medicine, On demand, Medicine, business
Abstract

Background The number of monogenic innate immune system disorders classified as systemic autoinflammatory diseases (SAID) has increased during the recent years. However, more than 70% of patients with clinical manifestations of SAID not achieved a molecular diagnosis, thus getting into the so-called undifferentiated or undefined SAID (uSAID). Objectives The aim of the present study is to characterize a subgroup of patients with recurrent fever episodes distinct to PFAPA that turned out to be negative to a large 41-gene NGS panel. Methods We designed an NGS panel including 41 genes clustered in seven subpanels. Results Fifty patients were enrolled in the study. 34 patients (72%) displayed recurrent fevers and sixteen presented a chronic inflammatory disease course. A total of 100 gene variants were found (mean 2 per patient; range 0-6). Mutations with a sure or possible diagnostic impact were detected in five patients (10%). Differently from PFAPA syndrome (table), genetically negative patients with recurrent fevers presented episodes that lasted on average of six days (P Conclusion Even with a low molecular diagnostics rate, an NGS-based approach is able to provide a final diagnosis in a proportion of uSAID patients. It also allows the identification of a subgroup of genetically negative patients with recurrent fever responding to steroid on demand and colchicine. References [1] Rusmini M, et al. Next-generation sequencing and its initial applications for molecular diagnosis of systemic auto-inflammatory diseases. Ann Rheum Dis. 2016Aug;75(8):1550-7. Disclosure of Interests Riccardo Papa: None declared, Marta Rusmini: None declared, Stefano Volpi: None declared, Roberta Caorsi: None declared, Paolo Picco: None declared, Alice Grossi: None declared, Francesco Caroli: None declared, Francesca Bovis: None declared, Valeria Musso: None declared, Laura Obici: None declared, Cinzia Castana: None declared, Angelo Ravelli Grant/research support from: Angelini, AbbVie, Bristol-Myers Squibb, Johnson & Johnson, Novartis, Pfizer, Reckitt Benkiser, and Roche, Consultant for: Angelini, AbbVie, Bristol-Myers Squibb, Johnson & Johnson, Novartis, Pfizer, Reckitt Benkiser, and Roche, Speakers bureau: Angelini, AbbVie, Bristol-Myers Squibb, Johnson & Johnson, Novartis, Pfizer, Reckitt Benkiser, and Roche, Marielle E van Gijn: None declared, Isabella Ceccherini: None declared, Marco Gattorno Grant/research support from: MG has received unrestricted grants from Sobi and Novartis

Published
2019

47. 10th Congress of International Society of Systemic Auto-Inflammatory Diseases (ISSAID)

Author

Lorenza Pugni, Sofia Torreggiani, Alice Grossi, Roberta Caorsi, Francesca Minoia, Carlo Pietrasanta, Stefano Volpi, Andrea Ronchi, Giovanni Filocamo, Fabio Mosca, Marco Gattorno, Isabella Ceccherini, and Francesco Caroli

Subjects
Pathology, medicine.medical_specialty, business.industry, Interstitial lung disease, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Mevalonic aciduria, Pediatrics, Perinatology and Child Health, medicine, Immunology and Allergy, 030212 general & internal medicine, business, 030217 neurology & neurosurgery
Published
2019

48. Next generation sequencing panel in undifferentiated autoinflammatory diseases identifies patients with colchicine-responder recurrent fevers

Author

Riccardo Papa, Francesco Caroli, Laura Obici, Paolo Picco, Marielle E. van Gijn, Marco Gattorno, Stefano Volpi, Francesca Bovis, Angelo Ravelli, Roberta Caorsi, Cinzia Castana, Isabella Ceccherini, Alice Grossi, Valeria Musso, and Marta Rusmini

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, relapsing fever, Adolescent, Fever, recurrent fevers, DNA sequencing, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, 0302 clinical medicine, Rheumatology, Recurrence, On demand, Internal medicine, medicine, Colchicine, Cluster Analysis, Humans, In patient, Pharmacology (medical), Child, 030203 arthritis & rheumatology, Response rate (survey), next generation sequencing, business.industry, Hereditary Autoinflammatory Diseases, High-Throughput Nucleotide Sequencing, medicine.disease, Phenotype, Tubulin Modulators, 030104 developmental biology, chemistry, Recurrent fever, systemic autoinflammatory diseases, Child, Preschool, Mutation, Female, colchicine, business
Abstract

Objectives The number of innate immune system disorders classified as systemic autoinflammatory diseases (SAID) has increased in recent years. More than 70% of patients with clinical manifestations of SAID did not receive a molecular diagnosis, thus being classed as so-called undifferentiated or undefined SAID (uSAID). The aim of the present study was to evaluate a next-generation sequencing (NGS)-based clinically oriented protocol in patients with uSAID. Methods We designed a NGS panel that included 41 genes clustered in seven subpanels. Patients with uSAID were classified into different groups according to their clinical features and sequenced for the coding portions of the 41 genes. Results Fifty patients were enrolled in the study. Thirty-four patients (72%) displayed recurrent fevers not consistent with a PFAPA phenotype. Sixteen patients displayed a chronic inflammatory disease course. A total of 100 gene variants were found (mean 2 per patient; range 0–6), a quarter of which affected suspected genes. Mutations with a definitive diagnostic impact were detected in two patients. Patients with genetically negative recurrent fevers displayed a prevalent gastrointestinal, skin and articular involvement. Patients responded to steroids on demands (94%) and colchicine, with a response rate of 78%. Conclusion Even with a low molecular diagnostic rate, a NGS-based approach is able to provide a final diagnosis in a proportion of uSAID patients with evident cost-effectiveness. It also allows the identification of a subgroup of genetically negative patients with recurrent fever responding to steroid on demand and colchicine.

Published
2019

50. FAS-mediated apoptosis impairment in patients with ALPS/ALPS-like phenotype carrying variants on CASP10 gene

Author

Chiara Vernarecci, Alice Grossi, Marina Lanciotti, Francesca Fioredda, Agnese Pezzulla, Concetta Micalizzi, Daniela Guardo, Fabio Corsolini, Maurizio Miano, Enrico Cappelli, Rosario Maggiore, Tiziana Lanza, Giovanna Russo, Isabella Ceccherini, Elena Palmisani, Carlo Dufour, Paola Terranova, Andrea Beccaria, Michaela Calvillo, Roberta Venè, and Filomena Pierri

Subjects
Adult, Male, Programmed cell death, Heterozygote, Fas Ligand Protein, Biology, Compound heterozygosity, medicine.disease_cause, Autoimmunity, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, autoimmune diseases, fas Receptor, Caspase 10, Mutation, Caspase 8, Polymorphism, Genetic, immune-dysregulation, Homozygote, apoptosis, autoimmune lymphoproliferative syndrome, caspases, Hematology, Immune dysregulation, medicine.disease, Fas receptor, Phenotype, 030220 oncology & carcinogenesis, Autoimmune lymphoproliferative syndrome, Immunology, Female, 030215 immunology
Abstract

Autoimmune lymphoproliferative syndrome (ALPS) is a congenital disorder that results in an apoptosis impairment of lymphocytes, leading to chronic lymphoproliferation and autoimmunity, mainly autoimmune cytopenias. FAS gene defects are often responsible for the disease, the phenotype of which can vary from asymptomatic/mild forms to severe disease. More rarely, defects are associated to other genes involved in apoptosis pathway, such as CASP10. Few data are available on CASP10-mutated patients. To date, two CASP10 mutations have been recognized as pathogenic (I406L and L258F) and others have been reported with controversial result on their pathogenicity (V410l, Y446C) or are known to be polymorphic variants (L522l). In this study, we evaluated apoptosis function in patients with an ALPS/ALPS-like phenotype carrying CASP10 variants. Molecular findings were obtained by next generation sequencing analysis of genes involved in immune dysregulation syndromes. Functional studies were performed after inducing apoptosis by FAS-ligand/TRIAL stimulation and analysing cell death and the function of CASP10, CASP8 and PARP proteins. We identified 6 patients with an ALPS (n = 2) or ALPS-like (n = 4) phenotype, carrying I406L (n = 1),V410l (n = 2),Y446C (n = 1) heterozygous CASP10 variants or the L522l polymorphisms (n = 2) associated with another polymorphic homozygote variant on CASP8 or a compound heterozygous mutation on TNFRSF13C. Apoptosis was impaired in all patients showing that such variants may play a role in the development of clinical phenotype.

Published
2019

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