Publications by authors named "Rita Consolini"

60 Publications

A nationwide study on Sydenham's chorea: Clinical features, treatment and prognostic factors.

Eur J Paediatr Neurol 2021 Nov 6;36:1-6. Epub 2021 Nov 6.

Pediatric Rheumatology, Pediatric University Department, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Italy.

Objectives: Sydenham's Chorea (SC) is a neuropsychiatric disorder and a major manifestation of acute rheumatic fever. The erroneous assumption that SC is a benign and self-limiting disease, has led to a lack of high-quality scientific evidence of the therapeutical and prognostic features of SC.

Study Design: We retrospectively analyzed the medical records of patients <18-years old with SC in 17 Italian pediatric centers. Recorded data included clinical, instrumental and laboratory parameters. Prognostic risk factors including treatment regimens were assessed with univariate and multivariate sub-analysis.

Results: We included 171 patients with SC. 66% had generalized chorea, and 34% hemichorea. 81% had carditis (subclinical in 65%). Additional neurological symptoms were reported in 60% of the patients, mainly dysarthria and dysgraphia. 51% had neuropsychiatric symptoms at onset, which persisted after 12 months in 10%. Among psychiatric manifestations, the most common was anxiety disorder/depression (77%). Neurological remission was reached by 93% of the patients at 6 months; 9% relapsed. Patients were treated as follows: 11% penicillin alone, 37% immunomodulatory therapy, 16% symptomatic drugs (i.e. anti-seizure medication, dopamine antagonists) and 37% both symptomatic and immunomodulatory treatment. Neurological outcome did not differ between groups. Patients receiving symptomatic drugs had a higher risk of relapse on multivariate analysis (p = 0.045).

Conclusions: Treatment of SC was largely heterogeneous. Based on our results, immunomodulatory therapy did not show higher efficacy at medium term, although it was associated to a slightly lower risk of relapse compared to symptomatic therapy. Longitudinal studies are needed to assess specific risk factors and best treatment options.
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http://dx.doi.org/10.1016/j.ejpn.2021.11.002DOI Listing
November 2021

Autoimmunity in Primary Immunodeficiency Disorders: An Updated Review on Pathogenic and Clinical Implications.

J Clin Med 2021 Oct 15;10(20). Epub 2021 Oct 15.

Section of Clinical and Laboratory Immunology, Division of Pediatrics, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy.

During the last years, studies investigating the intriguing association between immunodeficiency and autoimmunity led to the discovery of new monogenic disorders, the improvement in the knowledge of the pathogenesis of autoimmunity, and the introduction of targeted treatments. Autoimmunity is observed with particular frequency in patients with primary antibody deficiencies, such as common variable immunodeficiency (CVID) and selective IgA deficiency, but combined immunodeficiency disorders (CIDs) and disorders of innate immunity have also been associated with autoimmunity. Among CIDs, the highest incidence of autoimmunity is described in patients with autoimmune polyendocrine syndrome 1, LRBA, and CTLA-4 deficiency, and in patients with STAT-related disorders. The pathogenesis of autoimmunity in patients with immunodeficiency is far to be fully elucidated. However, altered germ center reactions, impaired central and peripheral lymphocyte negative selection, uncontrolled lymphocyte proliferation, ineffective cytoskeletal function, innate immune defects, and defective clearance of the infectious agents play an important role. In this paper, we review the main immunodeficiencies associated with autoimmunity, focusing on the pathogenic mechanisms responsible for autoimmunity in each condition and on the therapeutic strategies. Moreover, we provide a diagnostic algorithm for the diagnosis of PIDs in patients with autoimmunity.
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http://dx.doi.org/10.3390/jcm10204729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8538991PMC
October 2021

OBSIDIAn - real world evidence of Originator to BioSImilar Drug switch in juvenile idiopathic arthritis.

Rheumatology (Oxford) 2021 Jul 17. Epub 2021 Jul 17.

Rheumatology Unit, Meyer Children's University Hospital; Florence, Italy.

Objectives: Limited data about use of biosimilars are available in children with Juvenile Idiopathic Arthritis (JIA). This study therefore aimed to evaluate long-term efficacy and safety of switching from etanercept (ETA) and adalimumab (ADA) originators to their biosimilars, in children with JIA, in a real-world setting.

Methods: This is a retro-prospective non-interventional multicentre Italian comparative cohort study. Medical charts of JIA children treated with biosimilars of ETA or ADA were included. Efficacy and safety of TNF-inhibitors therapy was evaluated at last follow-up during originator and at 3, 6 and 12 months following the switch to biosimilar.

Results: 59 children (42 female, median age at onset 88 months) were treated with biosimilar of ETA (21) and ADA (38). Forty-five switched from the originator to the BIO (17 ETA, 28 ADA). At time of switch, 12/17 patients on ETA and 18/28 on ADA were in remission. No significant difference has been found at 3, 6 and 12 months after the switch. Ten patients discontinued biosimilars due to disease remission (4 ETA, 3 ADA), family willing (1 ETA), occurrence of burning at injection site (1 ETA), and persistent activity (1 ADA). No statistically significant difference was observed between originator and BIOs, nor between originator and BIOs, and between ADA and ETA in time to disease remission achievement, time to relapse and number of patients who experienced AE.

Conclusion: Our real-life results seem to confirm the efficacy and safety profile of switching from originator of ADA and ETA to their respective BIOs also in paediatric patients with JIA.
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http://dx.doi.org/10.1093/rheumatology/keab572DOI Listing
July 2021

Lymphadenopathy at the crossroad between immunodeficiency and autoinflammation: An intriguing challenge.

Clin Exp Immunol 2021 Sep 20;205(3):288-305. Epub 2021 Jun 20.

Section of Clinical and Laboratory Immunology, Division of Pediatrics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Lymphadenopathies can be part of the clinical spectrum of several primary immunodeficiencies, including diseases with immune dysregulation and autoinflammatory disorders, as the clinical expression of benign polyclonal lymphoproliferation, granulomatous disease or lymphoid malignancy. Lymphadenopathy poses a significant diagnostic dilemma when it represents the first sign of a disorder of the immune system, leading to a consequently delayed diagnosis. Additionally, the finding of lymphadenopathy in a patient with diagnosed immunodeficiency raises the question of the differential diagnosis between benign lymphoproliferation and malignancies. Lymphadenopathies are evidenced in 15-20% of the patients with common variable immunodeficiency, while in other antibody deficiencies the prevalence is lower. They are also evidenced in different combined immunodeficiency disorders, including Omenn syndrome, which presents in the first months of life. Interestingly, in the activated phosphoinositide 3-kinase delta syndrome, autoimmune lymphoproliferative syndrome, Epstein-Barr virus (EBV)-related lymphoproliferative disorders and regulatory T cell disorders, lymphadenopathy is one of the leading signs of the entire clinical picture. Among autoinflammatory diseases, the highest prevalence of lymphadenopathies is observed in patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) and hyper-immunoglobulin (Ig)D syndrome. The mechanisms underlying lymphoproliferation in the different disorders of the immune system are multiple and not completely elucidated. The advances in genetic techniques provide the opportunity of identifying new monogenic disorders, allowing genotype-phenotype correlations to be made and to provide adequate follow-up and treatment in the single diseases. In this work, we provide an overview of the most relevant immune disorders associated with lymphadenopathy, focusing on their diagnostic and prognostic implications.
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http://dx.doi.org/10.1111/cei.13620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374228PMC
September 2021

Severe COVID-19 in pediatric age: an update on the role of the anti-rheumatic agents.

Pediatr Rheumatol Online J 2021 May 4;19(1):68. Epub 2021 May 4.

Section of Rheumatology and Clinical Immunology, Division of Pediatrics, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56126, Pisa, Italy.

Background: SARS-CoV-2 can induce an immune impairment and dysregulation, finally resulting in the massive release of inflammatory mediators (cytokine storm), strongly contributing to the pulmonary and systemic manifestations in severe coronavirus disease 2019 (COVID-19). As a consequence, different drugs active on the immune system have been proposed for the treatment of the disease in adults.

Role Of The Anti-rheumatic Agents In Children: Children are more likely to develop a mild disease course, as the severe form of COVID-19 is identified in less than 5% of the pediatric patients. Moreover, in children a peculiar disease phenotype, defined as multisystem inflammatory syndrome in children (MIS-C) is observed, representing the most severe expression of the inflammatory dysregulation caused by SARS-CoV-2. The limited experience with the severe pediatric COVID-19 and MIS-C does not allow conclusions about the role of the immune pharmacological approach, and therefore the treatment of these conditions represents a considerable clinical challenge. The use of chloroquine, hydroxychloroquine, and colchicine in the early disease stages is not sufficiently supported by evidence, and there is an increasing interest in the role of biologic agents, including anti-IL-1 and anti-IL-6 agents, in the prevention and treatment of the severe manifestations of COVID-19.

Conclusion: The therapeutic approach to pediatric COVID-19 is multidisciplinary, and anti-rheumatic agents have a prominent role in severe disease. This paper reviews the rationale for the use of anti-rheumatic agents in pediatric COVID-19 and MIS-C and the clinical experience with the single drugs. Finally, the areas of potential improvement in the use of anti-rheumatic agents, including the optimization of the drug choice and the timing of administration, are discussed.
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http://dx.doi.org/10.1186/s12969-021-00559-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094984PMC
May 2021

The role of inflammatory mediators in epilepsy: Focus on developmental and epileptic encephalopathies and therapeutic implications.

Epilepsy Res 2021 05 18;172:106588. Epub 2021 Feb 18.

Pediatric Clinic, IRCCS Policlinico San Matteo Foundation, University of Pavia, Viale Golgi 19, 27100 Pavia, Italy.

In recent years, there has been an increasing interest in the potential involvement of neuroinflammation in the pathogenesis of epilepsy. Specifically, the role of innate immunity (that includes cytokines and chemokines) has been extensively investigated either in animal models of epilepsy and in clinical settings. Developmental and epileptic encephalopathies (DEE) are a heterogeneous group of epileptic disorders, in which uncontrolled epileptic activity results in cognitive, motor and behavioral impairment. By definition, epilepsy in DEE is poorly controlled by common antiepileptic drugs but may respond to alternative treatments, including steroids and immunomodulatory drugs. In this review, we will focus on how cytokines and chemokines play a role in the pathogenesis of DEE and why expanding our knowledge about the role of neuroinflammation in DEE may be crucial to develop new and effective targeted therapeutic strategies to prevent seizure recurrence and developmental regression.
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http://dx.doi.org/10.1016/j.eplepsyres.2021.106588DOI Listing
May 2021

Age-related differences in the immune response could contribute to determine the spectrum of severity of COVID-19.

Immun Inflamm Dis 2021 06 10;9(2):331-339. Epub 2021 Feb 10.

Division of Pediatrics, Department of Clinical and Experimental Medicine, Section of Rheumatology and Clinical Immunology, University of Pisa, Pisa, Italy.

Coronavirus disease 2019 (COVID-19), can present with a wide spectrum of severity. Elderly patients with cardiac, pulmonary and metabolic comorbidities are more likely to develop the severe manifestations of COVID-19, which are observed in less than 5% of the pediatric patients. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is able to induce an immune impairment and dysregulation, finally resulting in the massive release of inflammatory mediators, strongly contributing to the pulmonary and systemic manifestations in COVID-19. In children, the immune dysregulation following SARS-CoV-2 can also be responsible of a severe disease phenotype defined as multisystem inflammatory syndrome in children. As the immune system undergoes a complex process of maturation from birth to adult age, differences in the immune and inflammatory response could have a significant impact in determining the spectrum of severity of COVID-19. Indeed, children show a higher ability to respond to viral infections and a reduced baseline pro-inflammatory state compared with elderly patients. Age and comorbidities contribute to disease severity through immune-mediated mechanisms, since they are associated with a chronic increase of pro-inflammatory mediators, and cause an enhanced susceptibility to develop an immune dysregulation following SARS-CoV-2 infection. Also the expression of ACE2, the receptor of SARS-CoV-2, varies with age, and is linked to the immune and inflammatory response through a complex, and not completely elucidated, network. This paper reviews the peculiar immunopathogenic aspects of COVID-19, with a focus on the differences between adult and pediatric patients.
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http://dx.doi.org/10.1002/iid3.404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014746PMC
June 2021

The Challenge of Managing Children With Periodic Fever Syndromes in the Era of COVID-19.

Front Pediatr 2020 6;8:620621. Epub 2021 Jan 6.

Center for Autoinflammatory Diseases and Immunodeficiencies, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Giannina Gaslini, Genoa, Italy.

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http://dx.doi.org/10.3389/fped.2020.620621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815684PMC
January 2021

The Italian Registry for Primary Immunodeficiencies (Italian Primary Immunodeficiency Network; IPINet): Twenty Years of Experience (1999-2019).

J Clin Immunol 2020 10 15;40(7):1026-1037. Epub 2020 Aug 15.

Department of Clinical and Molecular Medicine, Sapienza University, Rome, Italy.

Primary immunodeficiencies (PIDs) are heterogeneous disorders, characterized by variable clinical and immunological features. National PID registries offer useful insights on the epidemiology, diagnosis, and natural history of these disorders. In 1999, the Italian network for primary immunodeficiencies (IPINet) was established. We report on data collected from the IPINet registry after 20 years of activity. A total of 3352 pediatric and adult patients affected with PIDs are registered in the database. In Italy, a regional distribution trend of PID diagnosis was observed. Based on the updated IUIS classification of 2019, PID distribution in Italy showed that predominantly antibody deficiencies account for the majority of cases (63%), followed by combined immunodeficiencies with associated or syndromic features (22.5%). The overall age at diagnosis was younger for male patients. The minimal prevalence of PIDs in Italy resulted in 5.1 per 100.000 habitants. Mortality was similar to other European registries (4.2%). Immunoglobulin replacement treatment was prescribed to less than one third of the patient cohort. Collectively, this is the first comprehensive description of the PID epidemiology in Italy.
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http://dx.doi.org/10.1007/s10875-020-00844-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505879PMC
October 2020

Behçet's Disease in Children: Diagnostic and Management Challenges.

Ther Clin Risk Manag 2020 11;16:495-507. Epub 2020 Jun 11.

Laboratory of Immunology, Department of Clinical and Experimental Medicine, Division of Pediatrics, University of Pisa, Pisa, Italy.

Behçet's Disease (BD) is an inflammatory disease of unknown etiology with multisystemic involvement, being the main clinical manifestations represented by recurrent oral and genital ulcerations and uveitis. The disease has typically a chronic-relapsing course and may cause significant morbidity and mortality due to eye, vascular and neurological involvement. Although BD is more frequently diagnosed in adulthood, the disease onset can also be in pediatric age. Pediatric-onset BD is commonly featured by an incomplete clinical picture, and therefore the diagnosis represents a considerable clinical challenge for the physicians. The first classification criteria for pediatric BD, based on a scoring system, have been proposed few years ago. This work focuses on the main difficulties concerning both the diagnostic approach and the treatment of BD in pediatric age. The recommendation for the treatment of pediatric BD has been recently updated and allowed a considerable improvement of the therapeutic strategies. In particular, the use of anti-TNFα drugs as a second-line option for refractory BD, and as a first-line treatment in severe ocular and neurological involvement, has demonstrated to be effective in improving the outcome of BD patients. The knowledge about the molecular pathogenesis is progressively increasing, showing that BD shares common features with autoimmune and autoinflammatory disorders, and thus leading to the use of new biologic agents targeting the main mediators involved in the determination of BD. Anti-IL-17, anti-IL-23, anti-IL-1 and anti-IL-6 agents have shown promising results for the treatment of refractory BD in clinical trials and will represent an important alternative for the therapeutic approach to the disease.
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http://dx.doi.org/10.2147/TCRM.S232660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295757PMC
June 2020

Failure of anti Interleukin-1 β monoclonal antibody in the treatment of recurrent pericarditis in two children.

Pediatr Rheumatol Online J 2020 Jun 16;18(1):51. Epub 2020 Jun 16.

UOSD Centro Malattie Autoinfiammatorie ed Immunodeficienze, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147, Genoa, Italy.

Background: Recurrent pericarditis (RP) is a complication (15-30%) of acute pericarditis with an unknown etiology. Treatment regimen consists of a combination of non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine, with the addition of corticosteroids in resistant or intolerant cases. In the last decade anakinra was shown as an effective treatment in patients with colchicine resistant and steroid-dependent RP, initially in anecdotal reports in children and more recently in a randomized trial. Canakinumab is a monoclonal antibody selectively blocking IL-1β and its use is only anecdotally reported to treat pericarditis. We report two pediatric patients with refractory recurrent pericarditis, who presented an optimal response to anakinra treatment but prompt relapse after switch to canakinumab.

Case Presentation: The first patient is a girl with Recurrent Pericarditis started in April 2015, after heart surgery. NSAIDs and oral steroids were started, with prompt relapse after steroid suspension. The child showed a steroid-dependent RP; anakinra was therefore started with excellent response, but discontinued after 2 weeks for local reactions. In July 2016 therapy with canakinumab was started. She experienced four relapses during canakinumab therapy despite dosage increase and steroid treatment. In January 2018 a procedure of desensitization from anakinra was performed, successfully. Anakinra as monotherapy is currently ongoing, without any sign of flare. The second patient is a girl with an idiopathic RP, who showed an initial benefit from NSAIDs and colchicine. However, 10 days after the first episode a relapse occurred and therapy with anakinra was established. Two months later, while being in complete remission, anakinra was replaced with canakinumab due to patient's poor compliance to daily injections. She experienced a relapse requiring steroids 10 days after the first canakinumab injection. Anakinra was subsequently re-started with complete remission, persisting after 24 months follow-up.

Conclusions: We describe two cases of failure of the treatment with anti-IL-1β monoclonal antibodies in steroid- dependent idiopathic RP. This anecdotal and preliminary observation suggests a different efficacy of the two IL-1 blockers in the management of RP and support a possible pivotal role of IL-1α in the pathogenesis of this condition.
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http://dx.doi.org/10.1186/s12969-020-00438-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298800PMC
June 2020

Long-term follow-up of 168 patients with X-linked agammaglobulinemia reveals increased morbidity and mortality.

J Allergy Clin Immunol 2020 08 10;146(2):429-437. Epub 2020 Mar 10.

University Department of Pediatrics, Unit of Immune and Infectious Diseases, Bambino Gesù Children's Hospital, University of Rome Tor Vergata, and the Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.

Background: X-linked agammaglobulinemia (XLA) is the prototype of primary humoral immunodeficiencies. Long-term follow-up studies regarding disease-related complications and outcome are scarce.

Objective: Our aim was to describe the natural history of XLA.

Methods: A nationwide multicenter study based on the Italian Primary Immunodeficiency Network registry was established in 2000 in Italy. Affected patients were enrolled by documenting centers, and the patients' laboratory, clinical, and imaging data were recorded on an annual base.

Results: Data on the patients (N = 168) were derived from a cumulative follow-up of 1370 patient-years, with a mean follow-up of 8.35 years per patient. The mean age at diagnosis decreased after establishment of the Italian Primary Immunodeficiency Network registry (84 months before vs 23 months after). Respiratory, skin, and gastrointestinal manifestations were the most frequent clinical symptoms at diagnosis and during long-term follow-up. Regular immunoglobulin replacement treatment reduced the incidence of invasive infections. Affected patients developed chronic lung disease over time (47% after 40 years of follow-up) in the presence of chronic sinusitis (84%). Malignancies were documented in a minority of cases (3.7%). Overall survival for affected patients was significantly reduced when compared with that for the healthy male Italian population, and it further deteriorated in the presence of chronic lung disease.

Conclusions: This is the first detailed long-term follow-up study for patients with XLA, revealing that although immunoglobulin replacement treatment reduces the incidence of invasive infections, it does not appear to influence the development of chronic lung disease. The overall survival of affected patients is reduced. Further studies are warranted to improve patients' clinical management and increase awareness among physicians.
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http://dx.doi.org/10.1016/j.jaci.2020.03.001DOI Listing
August 2020

Clinical, Immunological, and Molecular Features of Typical and Atypical Severe Combined Immunodeficiency: Report of the Italian Primary Immunodeficiency Network.

Front Immunol 2019 13;10:1908. Epub 2019 Aug 13.

Department of Pediatric Hematology and Oncology, Bambino Gesù Children's Hospital, Rome, Italy.

Severe combined immunodeficiencies (SCIDs) are a group of inborn errors of the immune system, usually associated with severe or life-threatening infections. Due to the variability of clinical phenotypes, the diagnostic complexity and the heterogeneity of the genetic basis, they are often difficult to recognize, leading to a significant diagnostic delay (DD). Aim of this study is to define presenting signs and natural history of SCID in a large cohort of patients, prior to hematopoietic stem cell or gene therapies. To this purpose, we conducted a 30-year retro-prospective multicenter study within the Italian Primary Immunodeficiency Network. One hundred eleven patients, diagnosed as typical or atypical SCID according to the European Society for Immune Deficiencies criteria, were included. Patients were subsequently classified based on the genetic alteration, pathogenic mechanism and immunological classification. A positive relationship between the age at onset and the DD was found. SCID patients with later onset were identified only in the last decade of observation. Syndromic SCIDs represented 28% of the cohort. Eight percent of the subjects were diagnosed in Intensive Care Units. Fifty-three percent had an atypical phenotype and most of them exhibited a discordant genotype-immunophenotype. Pre-treatment mortality was higher in atypical and syndromic patients. Our study broadens the knowledge of clinical and laboratory manifestations and genotype/phenotype correlation in patients with SCID and may facilitate the diagnosis of both typical and atypical forms of the disease in countries where newborn screening programs have not yet been implemented.
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http://dx.doi.org/10.3389/fimmu.2019.01908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700292PMC
September 2020

Refractory Chronic Spontaneous Urticaria Treated With Omalizumab in an Adolescent With Common Variable Immunodeficiency.

Front Immunol 2019 17;10:1700. Epub 2019 Jul 17.

Section of Paediatrics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Chronic spontaneous urtcaria (CSU) can represent the leading sign of a wide spectrum of systemic diseases, including primary immunodeficiencies. We describe the case of a young adult female with coexisting CSU and common variable immunodeficiency (CVID) successfully treated with omalizumab. The patient, with a history of recurrent respiratory infections during childhood, was referred to clinical attention due to the development of refractory CSU. During the diagnostic workup for the research of secondary causes of urticaria, an immunological assessment was performed, showing markedly reduced levels of IgG and IgM, poor antibody response against vaccinating antigens in absence of a T cellular deficiency. Therefore, the diagnosis of CVID was posed. Despite the immunoglobulin replacement and a trial with intravenous immunoglobulin at immunomodulatory dosage, the patient continued to experience severe urticaria, with significant impairment in the quality of life. After 2 years from the diagnosis of CVID, a treatment with omalizumab was started, showing complete remission of cutaneous symptoms after the first injection. The drug was well-tolerated, and the patient did not experience adverse effects during a 12-months follow-up.
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http://dx.doi.org/10.3389/fimmu.2019.01700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6652742PMC
September 2020

Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis Syndrome (PFAPA): A Clinical Challenge for Primary Care Physicians and Rheumatologists.

Front Pediatr 2019 5;7:277. Epub 2019 Jul 5.

Laboratory of Immunology, Division of Pediatrics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

To show the different physician's approaches and the difficulties in the diagnosis and management of the Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis (PFAPA) syndrome, and to quantify the impact of the disease on the families and on the healthcare system. Retrospective analysis on 40 patients diagnosed with PFAPA, focusing on the clinical phenotype, the process of diagnosis, and the management of the febrile episodes. The direct and indirect annual economic cost related to PFAPA in the period preceding the diagnosis were also investigated. The median age of patients at disease onset was 1.75 years and the median time to diagnosis was 14.5 months. During the diagnostic process, only 45% of our patients was firstly addressed to rheumatologic consultation, 32.5% to otorinolaryngologist (ORL), and 22.5% to immunologic consultation. Genetic investigations were performed in the 20% of the cohort. Overall population experienced a median of 60 annual days of fever and, during the critical phase, 40% of patients received more than 5 cycles of antibiotic/year. Seventy five percent required laboratory investigations, 18 (45%) needed to access to emergency department and 15 (37.5%) have been hospitalized. The annual mean direct cost was 1659.5 € for each patient, and the estimated mean indirect cost was 5811.6 € for each parent. Despite a benign clinical course, PFAPA syndrome is associated with a significant impact on the patients, their families and the national healthcare system. PFAPA patients require a large number of medical examinations and laboratory or instrumental investigations during the diagnostic approach and often receive inappropriate treatments. Therefore, we suggest the necessity of a greater awareness and knowledge of the disease among primary care physicians and, finally, of the adoption of more specific diagnostic criteria.
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http://dx.doi.org/10.3389/fped.2019.00277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624732PMC
July 2019

Immunophenotype Anomalies Predict the Development of Autoimmune Cytopenia in 22q11.2 Deletion Syndrome.

J Allergy Clin Immunol Pract 2019 Sep - Oct;7(7):2369-2376. Epub 2019 Mar 26.

University Department of Pediatrics, Unit of Immune and Infectious Diseases, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy; Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.

Background: Patients with 22q11.2 deletion syndrome (22q11.2DS) may develop severe thrombocytopenic purpura and hemolytic anemia. There are no reliable predictors for the development of hematologic autoimmunity (HA) in these patients.

Objective: To describe the peculiar B and T subpopulation defects in patients with 22q11DS who have developed HA and test if these defects precede the development of HA.

Methods: We performed a case-control multicenter study. Patients with HA were compared with a control population of 22q11.2DS without HA (non-HA). A complete immunological evaluation was performed at diagnosis and at the last follow-up including extensive T and B phenotypes.

Results: Immunophenotype at the last follow-up was available in 23 HA and 45 non-HA patients. HA patients had significantly decreased percentage of naïve CD4 cells (26.8% vs 43.2%, P = .003) and recent thymic emigrants (48.6% vs 80.5%, P = .046); decreased class-switched B cells (2.0% vs 5.9%, P = .04) and increased naive B cells (83.5% vs 71.4%, P = .02); increased CD16+/56+ both in absolute number (312 vs 199, P = .009) and percentage (20.0% vs 13.0%, P = .03). Immunophenotype was performed in 36 patients (11 HA and 25 non-HA) at diagnosis. Odds ratio (OR) of immune cytopenia were estimated for both CD4 naïve ≤30% (OR 14.0, P = .002) and switched memory B cells ≤2% (OR 44.0, P = .01). The estimated survival curves reached statistical significance, respectively, P = .0001 and P = .002.

Conclusions: Among patients with 22q11.2DS, those with HA have characteristic lymphocyte anomalies that appear considerably before HA onset. Systematic immunophenotyping of patients with 22q11.2DS at diagnosis is advisable for early identification of patients at risk for this severe complication.
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http://dx.doi.org/10.1016/j.jaip.2019.03.014DOI Listing
October 2020

Pediatric Systemic Lupus Erythematosus: Learning From Longer Follow Up to Adulthood.

Front Pediatr 2018 16;6:144. Epub 2018 May 16.

Laboratory of Immunology, Division of Pediatrics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Pediatric systemic lupus erythematosus (pSLE) is a rare condition, representing approximately 10% of SLE cases. The aim of this study was to identify variables to improve the diagnostic awareness and management of pSLE patients. This retrospective study included 25 patients diagnosed with pSLE and followed at the University of Pisa. We collected data about clinical profile at disease onset and during a long-term follow-up, including disease activity, organ damage development, and treatments received. The mean patient age at disease onset was 14.6 ± 1.6 years, and the mean follow-up period was 14.17 ± 8.04 years. The most common initial manifestations were arthritis, malar rash, and cytopenias. The median time to diagnosis since the first symptoms was 6 months, and was significantly longer in patients with hematological onset (54 months). During follow-up, the number of patients with renal involvement showed a significant increase, from 36% at diagnosis to 72.2% after 10 years of disease evolution. Patients who developed chronic organ damage maintained a higher time-averaged disease activity during follow-up and received a significantly higher dose of corticosteroids. Patients with immune cytopenia represent a group deserving strict clinical follow-up for the risk of evolution to SLE. Intense surveillance of renal function, early treatment and steroid-sparing strategies should be strongly considered in the management of pSLE patients.
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http://dx.doi.org/10.3389/fped.2018.00144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964827PMC
May 2018

Typical Kawasaki Disease Presenting With Pancreatitis and Bilateral Parotid Gland Involvement: A Case Report and Literature Review.

Front Pediatr 2018 11;6:90. Epub 2018 Apr 11.

Section of Pediatrics Immunology and Rheumatology, Department of Pediatrics, University of Pisa, Pisa, Italy.

We describe the case of a 3-year child in which pancreatic and parotid gland involvement preceded the development of the classical clinical phenotype of a typical Kawasaki disease (KD). The child was referred to the Emergency Department with a story of 3 days of continuous fever associated with abdominal pain and bilaterally swelling in the parotid regions; laboratory evaluation identified markedly increased levels of total amylase, pancreatic amylase, lipase, and transaminase, and diagnosis of pancreatitis was posed. After 9 days of fever and persistence of the clinical features, the classical signs of KD appeared, and the child was treated with intravenous immunoglobulins (IVIG), showing a dramatic response with complete resolution of the clinical picture. In this work, we reviewed the literature about gastrointestinal (GI) symptoms in KD, focusing on pancreatic and hepatic involvement. This analysis highlighted that, in case of fever associated with pancreatic inflammation, KD must be considered in the spectrum of differential diagnosis, and that GI involvement in KD is frequently associated with an incomplete response to IVIG treatment.
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http://dx.doi.org/10.3389/fped.2018.00090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5904203PMC
April 2018

Correction to: A national cohort study on pediatric Behçet's disease: cross-sectional data from an Italian registry.

Pediatr Rheumatol Online J 2018 04 23;16(1):29. Epub 2018 Apr 23.

Pediatric Rheumatology Unit, AOU Meyer, University of Florence, Florence, Italy.

Following publication of the original article [1], the authors reported that the names of two institutional authors - EUROFEVER and the Paediatric Rheumatology International Trials Organisation (PRINTO) - had been unintentionally omitted in the final online version of the manuscript. The corrected author list is shown in this Correction..
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http://dx.doi.org/10.1186/s12969-018-0241-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911960PMC
April 2018

The Italian version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR).

Rheumatol Int 2018 Apr 7;38(Suppl 1):251-258. Epub 2018 Apr 7.

Clinica Pediatrica e Reumatologia, Paediatric Rheumatology International Trials Organisation (PRINTO), Istituto Giannina Gaslini, Via Gaslini 5, 16147, Genoa, Italy.

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Italian language.The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents.The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the 3 Likert assumptions, floor/ceiling effects, internal consistency, Cronbach's alpha, interscale correlations, test-retest reliability, and construct validity (convergent and discriminant validity).A total of 1296 JIA patients (7.2% systemic, 59.5% oligoarticular, 21.4% RF negative polyarthritis, 11.9% other categories) and 100 healthy children, were enrolled in 18 centres. The JAMAR components discriminated well healthy subjects from JIA patients except for the Health Related Quality of Life (HRQoL) Psychosocial Health (PsH) subscales. All JAMAR components revealed good psychometric performances.In conclusion, the Italian version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and clinical research.
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http://dx.doi.org/10.1007/s00296-018-3960-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5893696PMC
April 2018

A national cohort study on pediatric Behçet's disease: cross-sectional data from an Italian registry.

Pediatr Rheumatol Online J 2017 Dec 21;15(1):84. Epub 2017 Dec 21.

Pediatric Rheumatology Unit, AOU Meyer, University of Florence, Florence, Italy.

Background: Behçet's disease is a rare multi-systemic inflammatory disease with unknown etiology which involves principally oral and genital mucosa, skin and eyes. Average age at onset of the disease is about 25-30 years, but it may be diagnosed before the age of 16. It is not very rare in Italy, even though there are limited data concerning epidemiology. Aim of this study is to describe the baseline data of an Italian cohort of patients with as having BD or probable BD.

Methods: We described the baseline data of the first national epidemiological study on children coming from 16 Italian Pediatric Rheumatologic Centers diagnosed by the treating physicians as having Behçet's Disease. Data on demographic characteristics, clinical features and therapy were collected. We then compared our findings to those of international pediatric cohort studies and also retrospectively evaluated the ability to diagnose BD using ISG, ICBD and, for the first time, the new PEDBD criteria.

Results: The study included 110 patients (62 M, 48F). Average age at onset was 8.34±4.11 years. The frequencies of signs/symptoms were: recurrent oral aphtosis 94.5%, genital ulcers 33.6%, ocular 43.6%, gastrointestinal 42.7%, musculoskeletal 42.7%, neurological 30.9% and vascular involvement 10%. Thirty-two patients (29.1%) fulfilled ISG, 78 (70.9%) ICBD, 50 (45.5%) PEDBD criteria and 31 (28%) didn't fulfill any of them. The most frequently used treatments were colchicine and corticosteroids followed by immunosuppressants. Four patients received biologic therapy (anti TNF-α and anti-IL-1) to treat severe organ involvement.

Conclusions: Recurrent oral aphtosis was the most frequent clinical manifestation, followed by ocular involvement. Gastrointestinal lesions were more frequent in Italy than in non-European countries as opposed to genital ulcers. Skin, ocular and vascular manifestations had a higher frequency in males and genital ulcers in females. Constitutional symptoms were present in 44.5% and recurrent fever in one third of our population.
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http://dx.doi.org/10.1186/s12969-017-0213-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740899PMC
December 2017

Significant Improvement of Clinical Symptoms, Bone Lesions, and Bone Turnover after Long-Term Zoledronic Acid Treatment in Patients with a Severe Form of Camurati-Engelmann Disease.

Mol Syndromol 2017 Nov 9;8(6):294-302. Epub 2017 Sep 9.

Pediatric Unit, Department of Obstetrics, Gynecology and Pediatrics, University Hospital, Pisa, Italy.

Camurati-Engelmann disease (CED) is an ultrarare autosomal dominant bone dysplasia. Cortical thickening of the diaphyses of the long bones with narrowing of the medullary cavity are associated with bone pain, waddling gait, muscular weakness, easy fatigability, and a marfanoid body habitus. There is no specific treatment for CED. Nonsteroidal anti-inflammatory drugs or glucocorticoids are ineffective in improving bone lesions. A family with a mild to severe form of CED is described. Two patients received long-term bisphosphonate treatment: the 19-year-old female proband was treated with zoledronic acid for 2.2 years; the 4-year-old male proband was treated with neridronic acid for 16 months and with zoledronic acid for an additional 18 months. In both probands, zoledronic acid treatment significantly improved the clinical symptoms, bone lesions, ambulation, and body habitus. Before treatment, both probands showed a marked increase in serum levels of osteocalcin, procollagen type I N-terminal propeptide, and cross-linked carboxyterminal telopeptide of type I collagen, reflecting an increased bone turnover. Bone marker levels returned to their normal values during treatment. Zoledronic acid treatment may be an important therapeutic option in patients with severe CED. Biochemical markers of bone turnover could be considered as surrogate indexes of CED activity.
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http://dx.doi.org/10.1159/000479859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701277PMC
November 2017

Cryopyrin-associated Periodic Syndromes in Italian Patients: Evaluation of the Rate of Somatic NLRP3 Mosaicism and Phenotypic Characterization.

J Rheumatol 2017 Nov 15;44(11):1667-1673. Epub 2017 Sep 15.

From these departments of the Istituto Giannina Gaslini, Genoa: Unità Operativa Complessa (UOC) Genetica Medica, UO Pediatria II, Laboratorio Fisiopatologia dell'Uremia, Core facilities, and Neuroradiology Unit; Institute for Maternal and Child Health, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Burlo Garofolo, Trieste; Department of Pediatrics, Immunology and Rheumatology Section, University of Pisa, Pisa; Division of Rheumatology, Department of Pediatric Medicine, Bambino Gesù Children's Hospital, IRCCS, Rome; Pediatric Clinic, Azienda Socio Sanitaria Territoriale (ASST) Spedali Civili and University of Brescia, Brescia; Amyloidosis Research and Treatment Centre, Biotechnology Research Laboratories, Fondazione IRCCS Policlinico San Matteo, Pavia; Department of Pediatrics, Azienda G. Martino, University of Messina, Messina; Department of Pediatrics, Immunology and Rheumatology, University of Torino, Torino; Cell Biology Unit, IRCCS L'Azienda Ospedaliera Universitaria (AOU) San Martino, San Martino, Italy; Department of Immunology, Hospital Clínic-Institut d'Investigacions Biomdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Objective: To evaluate the rate of somatic mosaicism in an Italian cohort of mutation-negative patients with cryopyrin-associated periodic syndrome (CAPS).

Methods: The study enrolled 14 patients with a clinical phenotype consistent with CAPS in whom Sanger sequencing of the gene yielded negative results. Patients' DNA were subjected to amplicon-based deep sequencing.

Results: Low-level somatic mosaicism has been detected in 4 patients, 3 affected with chronic infantile neurological cutaneous and articular syndrome and 1 with Muckle-Wells syndrome. Identified nucleotide substitutions encode for 4 different amino acid exchanges, with 2 of them being novel (p.Y563C and p.G564S). functional studies confirmed the deleterious behavior of the 4 somatic NLRP3 mutations. Among the different neurological manifestations detected, 1 patient displayed mild loss of white matter volume on brain magnetic resonance imaging.

Conclusion: The allele frequency of somatic mutations occurs generally under 15%, considered the threshold of detectability using the Sanger method of DNA sequencing. Consequently, routine genetic diagnostic of CAPS should be currently performed by next-generation techniques ensuring high coverage to identify also low-level mosaicism, whose actual frequency is yet unknown and probably underestimated.
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http://dx.doi.org/10.3899/jrheum.170041DOI Listing
November 2017

The Centenary of Immune Thrombocytopenia-Part 2: Revising Diagnostic and Therapeutic Approach.

Front Pediatr 2017 21;5:179. Epub 2017 Aug 21.

Clinical Immunology and Allergy Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Primary immune thrombocytopenia (ITP) is the most common cause of thrombocytopenia in children and adolescents and can be considered as a paradigmatic model of autoimmune disease. This second part of our review describes the clinical presentation of ITP, the diagnostic approach and overviews the current therapeutic strategies. Interestingly, it suggests an algorithm useful for differential diagnosis, a crucial process to exclude secondary forms of immune thrombocytopenia (IT) and non-immune thrombocytopenia (non-IT), which require a different therapeutic management. Advances in understanding the pathogenesis led to new therapeutic targets, as thrombopoietin receptor agonists, whose role in treatment of ITP will be discussed in this work.
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http://dx.doi.org/10.3389/fped.2017.00179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566994PMC
August 2017

Effects of Anakinra on Health-Related Quality of Life in a Patient with 1129G>A/928G>A Mutations in MVK Gene and Heterozygosity for the Mutation 2107C>A in CIAS1 Gene.

Front Pediatr 2017 7;5:128. Epub 2017 Jun 7.

Department of Pediatrics, Faculty of Medicine, University of Pisa, Pisa, Italy.

Mevalonate kinase deficiency impairs several aspects of the patient's quality of life, thus early diagnosis and treatment are required to improve health-related quality of life (HRQOL). A 15-year-old patient with double heterozygosity for the mutations 1129G>A and 928G>A in MVK gene, heterozygosity for the mutation 2107C>A in CIAS1 gene and hyper-IgD syndrome phenotype, has been treated with anakinra with a reduction of 50% in the number of fever episodes per month, a reduction of 33% in the days of fever for each attack and normal blood tests in the intercritical phase. The RAND 36-Item Health Survey has been used for the assessment of HRQOL before and after the treatment with anakinra. The patient's quality of life showed an overall improvement of 27%; results showed a better improvement in role limitations due to physical health (50%).
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http://dx.doi.org/10.3389/fped.2017.00128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461265PMC
June 2017

Deletion Extents Are Not the Cause of Clinical Variability in 22q11.2 Deletion Syndrome: Does the Interaction between DGCR8 and miRNA-CNVs Play a Major Role?

Front Genet 2017 1;8:47. Epub 2017 May 1.

Cytogenetics and Molecular Genetics Unit, Department of Laboratory Medicine, Azienda Ospedaliera Univeristaria PisanaPisa, Italy.

In humans, the most common genomic disorder is the hemizygous deletion of the chromosome 22q11.2 region, that results in the "22q11.2 deletion syndrome" (22q11.2DS). A peculiarity of 22q11.2DS is its great phenotypic variability that makes this pathology a classic example of a syndrome with variable expressivity and incomplete penetrance. The reasons for this variability have not been elucidated yet, and the molecular substrates underlying the different clinical features of 22q11.2DS are still debated. A cohort of 21 patients has been analyzed by array CGH in order to detect some of the genetic differences that may influence this variability. Two aspects have been investigated: (1) the precise localization of the deletion breakpoints within the low copy repeats (LCRs), (2) the additional Copy Number Variations (CNVs) elsewhere in the genome, by analyzing their gene content. Both protein-coding genes and miRNAs were considered, in order to discover possible epistatic interactions between genes of the 22q11.2 region and the rest of the genome. Eighteen out of twenty-one patients had a deletion of ~3 Mb mediated by LCR22-A and D, whereas 3/21 had a smaller deletion. The breakpoints within the LCR22-A and D do not have a major role in the phenotypic variability since they are rather clustered and the small differences concern genes that are not directly related to clinical signs of 22q11.2DS. A detailed analysis of the gene content of 22q11.2 deleted region indicates that this syndrome could be a bioenergetic disorder or consequence of an altered post-transcriptional gene regulation, due to the presence of , a major player of the microRNA (miRNA) biogenesis. Only four genes with mitochondrial function are harbored in the additional CNVs, whereas 11 miRNA, all related to biological pathways present in the 22q11.2DS, have been detected in 19/21 patients. CNVs and miRNAs are new entities that have changed the order of complexity at the level of gene expression and regulation, thus CNV-miRNAs (miRNA harbored in the CNVs) are potential functional variants that should be considered high priority candidate variants in genotype-phenotype association studies. Deletion of , the main actor in miRNA biogenesis, amplifies this variability. To our knowledge, this is the first report that focus on the miRNA-CNVs in 22q11.2DS, with the aim of trying to better understand their role in the variable expressivity and incomplete penetrance.
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http://dx.doi.org/10.3389/fgene.2017.00047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410573PMC
May 2017

A Case of 22q11 Deletion Syndrome (22q11DS) with a Panayiotopoulos Epileptic Pattern: Are Additional Copy-Number Variations a Possible Second Hit in Modulating the 22q11DS Phenotype?

Front Pediatr 2017 21;5:48. Epub 2017 Mar 21.

Section of Pediatric Neurology, Azienda Ospedaliero-Universitaria Pisana , Pisa , Italy.

"22q11 deletion syndrome" (22q11DS) is a rare genetic syndrome, in which most patients share the same deletion, but their clinical features may vary a great deal. The genetic mechanisms underlying the variable expressivity and reduced penetrance of 22q11DS still have to be fully elucidated. Epilepsy has been reported in about 15.2% of the patients; however, few studies have focused on this topic, and in most cases, a detailed epileptic profile is missing. Since only a minority of patients experience epileptic seizures, 22q11deletion can be considered a predisposing factor, which is not sufficient "" to cause epilepsy; to date, no candidate gene for epilepsy has been identified in the deleted region. We report on a 6-year-old girl with 22q11DS presenting a form of epilepsy that can be classified as "Panayiotopoulos syndrome." Array CGH revealed an additional microduplication of 172 kb in 2q37, harboring three genes. One of these, (diacylglycerol kinase delta), is interrupted by the distal breakpoint of the duplication. encodes a cytoplasmic enzyme that phosphorylates diacylglycerol to produce phosphatidic acid. This is an important second messenger in a pathway of lipid signaling that has been implicated in epilepsy and other neurological diseases. Disruption of by a t(X;2) has been previously reported in a patient with epilepsy. The 2q37 microduplication was inherited from her mother, who never experienced epileptic seizures, thus this imbalance is not "" sufficient to cause epilepsy. It can be hypothesized that the epileptic phenotype is provoked by the simultaneous presence of 22q11.2 deletion and 2q37 duplication. It has been shown that rare additional copy-number variations (CNVs) outside the 22q11.2 region may modulate the risk of congenital heart defects. It is possible that also for the epileptic phenotype, the additional CNVs may represent an important modifying factor underlying the variable expressivity and incomplete penetrance in the 22q11DS.
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http://dx.doi.org/10.3389/fped.2017.00048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5359231PMC
March 2017
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