Publications by authors named "Eleonora Gambineri"

50 Publications

Case Report: A Novel Pathogenic Missense Mutation in : A Multi-Generational Case Series of Autoimmune Lymphoproliferative Syndrome.

Front Pediatr 2021 18;9:624116. Epub 2021 Mar 18.

Department of Medicine, University of South Florida, Tampa, FL, United States.

Autoimmune Lymphoproliferative Syndrome (ALPS), commonly caused by mutations in the gene, is a disease with variable penetrance. Subjects may be asymptomatic, or they may present with lymphadenopathy, splenomegaly, cytopenias, or malignancy. Prompt recognition of ALPS is needed for optimal management. We describe a multi-generational cohort presenting with clinical manifestations of ALPS, and a previously unreported heterozygous missense variant of uncertain significance in (c.758G >T, p.G253V), located in exon 9. Knowledge of the underlying genetic defect permitted prompt targeted therapy to treat acute episodes of cytopenia. This cohort underscores the importance of genetic testing in subjects with clinical features of ALPS and should facilitate the reclassification of this variant as pathogenic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fped.2021.624116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012668PMC
March 2021

Planned hematopoietic stem cell transplantation in a 17-month-old patient with high-risk acute myeloid leukemia and persistent SARS-CoV-2 infection.

Transfusion 2021 05 25;61(5):1657-1659. Epub 2021 Mar 25.

Pediatric Haematology/Oncology and HSCT Department, Meyer Children's University Hospital, Florence, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/trf.16361DOI Listing
May 2021

Atypical Presentations of IPEX: Expect the Unexpected.

Front Pediatr 2021 5;9:643094. Epub 2021 Feb 5.

Division of Pediatric Oncology/Hematology, Meyer University Children's Hospital, Florence, Italy.

Immune dysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX) syndrome is a rare disorder that has become a model of monogenic autoimmunity. IPEX is caused by mutations in gene, a master regulator of regulatory T cells (Treg). Cases reported in the last 20 years demonstrate that IPEX clinical spectrum encompasses more than the classical triad of early-onset intractable diarrhea, type 1 diabetes (T1D) and eczema. Atypical cases of IPEX include patients with late-onset of symptoms, single-organ involvement, mild disease phenotypes or rare clinical features (e.g., atrophic gastritis, interstitial lung disease, nephropathy etc.). Several atypical presentations have recently been reported, suggesting that IPEX incidence might be underestimated. Immunosuppression (IS) treatment strategies can control the disease, however at the moment allogeneic hematopoietic stem cell transplantation (HSCT) is the only available definitive cure, therefore it is important to achieve a prompt diagnosis. This review aims to describe unusual clinical phenotypes, beyond classical IPEX. Overall, our analysis contributes to increase awareness and finally improve diagnosis and treatment intervention in IPEX in order to ensure a good quality of life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fped.2021.643094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892580PMC
February 2021

Case Report: Signal Transducer and Activator of Transcription 3 Gain-of-Function and Spectrin Deficiency: A Life-Threatening Case of Severe Hemolytic Anemia.

Front Immunol 2020 15;11:620046. Epub 2021 Jan 15.

Division of Pediatric Oncology/Hematology, Meyer University Children's Hospital, Florence, Italy.

gain-of-function (GOF) mutations can be responsible for an incomplete phenotype mainly characterized by hematological autoimmunity, even in the absence of other organ autoimmunity, growth impairment, or severe infections. We hereby report a case with an incomplete form of GOF intensified by a concomitant hereditary hematological disease, which misleads the diagnosis. The patient presented with lymphadenopathy, splenomegaly, hypogammaglobulinemia, and severe autoimmune hemolytic anemia (AIHA) with critical complications, including stroke. A Primary Immune Regulatory Disorders (PIRD) was suspected, and molecular analysis revealed a gain-of-function mutation. The response to multiple immune suppressive treatments was ineffective, and further investigations revealed a spectrin deficiency. Ultimately, hematopoietic stem cell transplantation from a matched unrelated donor was able to cure the patient. Our case shows an atypical presentation of GOF associated with hereditary spherocytosis, and how achievement of a good long-term outcome depends on a strict clinical and laboratory monitoring, as well as on prompt therapeutic intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.620046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843414PMC
January 2021

Germline IKAROS dimerization haploinsufficiency causes hematologic cytopenias and malignancies.

Blood 2021 01;137(3):349-363

Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD.

IKAROS is a transcription factor forming homo- and heterodimers and regulating lymphocyte development and function. Germline mutations affecting the IKAROS N-terminal DNA binding domain, acting in a haploinsufficient or dominant-negative manner, cause immunodeficiency. Herein, we describe 4 germline heterozygous IKAROS variants affecting its C-terminal dimerization domain, via haploinsufficiency, in 4 unrelated families. Index patients presented with hematologic disease consisting of cytopenias (thrombocytopenia, anemia, neutropenia)/Evans syndrome and malignancies (T-cell acute lymphoblastic leukemia, Burkitt lymphoma). These dimerization defective mutants disrupt homo- and heterodimerization in a complete or partial manner, but they do not affect the wild-type allele function. Moreover, they alter key mechanisms of IKAROS gene regulation, including sumoylation, protein stability, and the recruitment of the nucleosome remodeling and deacetylase complex; none affected in N-terminal DNA binding defects. These C-terminal dimerization mutations are largely associated with hematologic disorders, display dimerization haploinsufficiency and incomplete clinical penetrance, and differ from previously reported allelic variants in their mechanism of action. Dimerization mutants contribute to the growing spectrum of IKAROS-associated diseases displaying a genotype-phenotype correlation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020007292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819759PMC
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10875-020-00844-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505879PMC
October 2020

Allogeneic Hematopoietic Stem Cell Transplantation for Congenital Immune Dysregulatory Disorders.

Front Pediatr 2019 13;7:461. Epub 2019 Nov 13.

NEUROFARBA Department, University of Florence, University of Florence, Florence, Italy.

Primary immunodeficiency disorders that predominantly affect immune regulation and mechanisms of self-tolerance have come into the limelight, because at least for a subgroup of monogenetic disorders, a targeted therapy has become available. Nevertheless, their management often involves the treatment of severely compromising, refractory, multi-organ autoimmunity, leading to further increased susceptibility to infections and complications of long-term immune suppressive treatment, including the risk of malignancy. While evidence for allogeneic hematopoietic stem cell transplantation (alloHSCT) as a curative treatment option for severely affected patients by this disease category accumulates, clear indications, and guidelines for alloHSCT are lacking. Predictive and stratification-relevant tools such as disease activity scores are largely missing and often there is not a consistent genotype-phenotype correlation within the same family to facilitate the decision whether to transplant or not. In this review, we provide a literature-based update on indications and outcomes of alloHSCT for congenital immune dysregulative inborn errors of immunity according to the IUIS classification 2017.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fped.2019.00461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865355PMC
November 2019

Multisystem autoimmune disease caused by increased STAT3 phosphorylation and dysregulated gene expression.

Haematologica 2019 07 9;104(7):e322-e325. Epub 2019 May 9.

Clinica Pediatrica and "A. Nocivelli" Institute for Molecular Medicine, Department of Clinical and Experimental Sciences, University of Brescia, Spedali Civili Hospital, Brescia

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2018.202374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601097PMC
July 2019

CD25 deficiency: A new conformational mutation prevents the receptor expression on cell surface.

Clin Immunol 2019 04 8;201:15-19. Epub 2019 Feb 8.

Department of "NEUROFARBA", Section of Child's Health, University of Florence, Italy; Department of Haematology-Oncology "Anna Meyer" Children's Hospital, Florence, Italy. Electronic address:

CD25 deficiency is a very rare autosomal recessive disorder that shows a clinical phenotype highly overlapping IPEX syndrome with an increased susceptibility to viral, bacterial, and fungal infections. It is due to mutations in the IL2Rα gene that codes for the α subunit of the IL2 receptor complex. Here we report the characterization of a novel IL2Rα gene mutation leading to a severe protein conformational alteration that abrogates its cell surface expression in a child presenting with early-onset IPEX-like disorder. Cytofluorimetric analysis revealed the total absence of CD25 cell surface expression and addressed IL2Rα molecular investigation. The early clinical and molecular diagnosis of CD25 deficiency in this patient promptly led to hematopoietic stem cell transplantation (HSCT), allowing complete resolution of the symptoms and definitive cure of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clim.2019.02.003DOI Listing
April 2019

Two male siblings with a novel mutation presenting with different findings of IPEX syndrome.

JMM Case Rep 2018 Oct 15;5(10):e005167. Epub 2018 Oct 15.

Department of Pediatric Immunology, Ege University Faculty of Medicine, Izmir, Turkey.

Introduction: LPS-responsive beige-like anchor (LRBA) protein deficiency is a disease of immune dysregulation with autoimmunity affecting various systems.

Case Presentation: Two male siblings with a novel mutation had different primary findings at admission: the younger sibling had chronic early-onset diarrhoea and the elder one had autoimmune haemolytic anaemia. During long-term follow-up for IPEX phenotype, both developed hypogammaglobulinaemia, enteropathy and lung involvement. The patients partially responded to immunosuppressive therapies. A homozygous c.2496C>A, p.Cys832Ter (p.C832*) mutation in the gene causing a premature stop codon was detected. After molecular diagnosis, abatacept, as a target-specific molecule, was used with promising results.

Conclusion: LRBA deficiency is a recently defined defect, with variable presentations in different patients; a single, definitive treatment option is thus not yet available.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1099/jmmcr.0.005167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249428PMC
October 2018

Clinical, Immunological, and Molecular Heterogeneity of 173 Patients With the Phenotype of Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX) Syndrome.

Front Immunol 2018 1;9:2411. Epub 2018 Nov 1.

Seattle Children's Research Institute, University of Washington, Seattle, WA, United States.

Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) Syndrome is a rare recessive disorder caused by mutations in the gene. In addition, there has been an increasing number of patients with wild-type gene and, in some cases, mutations in other immune regulatory genes. To molecularly asses a cohort of 173 patients with the IPEX phenotype and to delineate the relationship between the clinical/immunologic phenotypes and the genotypes. We reviewed the clinical presentation and laboratory characteristics of each patient and compared clinical and laboratory data of mutation-positive (IPEX patients) with those from mutation-negative patients (IPEX-like). A total of 173 affected patients underwent direct sequence analysis of the gene while 85 IPEX-like patients with normal FOXP3 were investigated by a multiplex panel of "Primary Immune Deficiency (PID-related) genes." Forty-four distinct variants were identified in 88 IPEX patients, 9 of which were not previously reported. Among the 85 IPEX-like patients, 19 different disease-associated variants affecting 9 distinct genes were identified. We provide a comprehensive analysis of the clinical features and molecular bases of IPEX and IPEX-like patients. Although we were not able to identify major distinctive clinical features to differentiate IPEX from IPEX-like syndromes, we propose a simple flow-chart to effectively evaluate such patients and to focus on the most likely molecular diagnosis. Given the large number of potential candidate genes and overlapping phenotypes, selecting a panel of PID-related genes will facilitate a molecular diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2018.02411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223101PMC
October 2019

Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study.

J Allergy Clin Immunol 2018 03 11;141(3):1036-1049.e5. Epub 2017 Dec 11.

Department of Pediatric Hematology and Oncology, Baylor College of Medicine Texas Children's Hospital, Houston, Tex.

Background: Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined.

Objective: This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors.

Methods: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed.

Results: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS.

Conclusions: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2017.10.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050203PMC
March 2018

Novel molecular defects associated with very early-onset inflammatory bowel.

Curr Opin Allergy Clin Immunol 2017 Oct;17(5):317-324

aDepartment of 'NEUROFARBA', Section of Child's Health, University of Florence bHematology-Oncology Department, 'Anna Meyer Children's Hospital', Florence, Italy.

Purpose Of Review: Immune dysregulation disorders present with common clinical features of multiorgan autoimmunity. Gastrointestinal involvement is the hallmark of an impaired immune homeostasis. This review will give an overview on the novel phenotypes, highlighting the major points that will help to enable early diagnosis and treatment.

Recent Findings: The rapid progress on DNA sequencing technologies have led to the identification of monogenic defects that adversely impact the control of immune homeostasis. Lymphocytes may be present but dysfunctional, allowing for the development of excessive autoreactivity and resultant autoimmune disease. Regulatory T cells (Tregs) play an essential role in enforcing immune tolerance. Here we illustrate disorders caused by impairment of mechanisms ensuring Tregs function (Tregs related) in which autoimmunity is a hallmark of the clinical disease presentation and other disorders, affecting molecules more broadly involved in immune responses and indirectly causing immune dysregulation (Tregs unrelated). Clinical presentation is sometime mischievous and often symptoms are analogous in different diseases and can mislead diagnosis.

Summary: The increasing comprehension of immunological concepts behind immune dysregulation diseases will allow better and in some cases possibly even targeted treatment. A genetic diagnosis therefore becomes important information in this group of patients, especially as some patients might require hematopoietic stem cell transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/ACI.0000000000000393DOI Listing
October 2017

Low IgE Is Insufficiently Sensitive to Guide Genetic Testing of Gain-of-Function Mutations.

Clin Chem 2017 09 30;63(9):1539-1540. Epub 2017 Jun 30.

Adult Immunodeficiency Unit Infectious Diseases, Inflammation Center and Rare Diseases Center Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1373/clinchem.2017.273458DOI Listing
September 2017

Timely follow-up of a GATA2 deficiency patient allows successful treatment.

J Allergy Clin Immunol 2016 11 29;138(5):1480-1483.e4. Epub 2016 Jul 29.

Department of "NEUROFARBA," Section of Child's Health, University of Florence, Florence, Italy; Hematology-Oncology Department, "Anna Meyer Children's Hospital," Florence, Italy. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2016.06.004DOI Listing
November 2016

Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation in autoimmune lymphoproliferative syndrome.

Blood 2016 07 20;128(2):227-38. Epub 2016 Apr 20.

Department of Internal Medicine 5, Haematology and Oncology, University Hospital Erlangen, Erlanger, Germany;

Autoimmune lymphoproliferative syndrome (ALPS) is a human disorder characterized by defective Fas signaling, resulting in chronic benign lymphoproliferation and accumulation of TCRαβ(+) CD4(-) CD8(-) double-negative T (DNT) cells. Although their phenotype resembles that of terminally differentiated or exhausted T cells, lack of KLRG1, high eomesodermin, and marginal T-bet expression point instead to a long-lived memory state with potent proliferative capacity. Here we show that despite their terminally differentiated phenotype, human ALPS DNT cells exhibit substantial mitotic activity in vivo. Notably, hyperproliferation of ALPS DNT cells is associated with increased basal and activation-induced phosphorylation of serine-threonine kinases Akt and mechanistic target of rapamycin (mTOR). The mTOR inhibitor rapamycin abrogated survival and proliferation of ALPS DNT cells, but not of CD4(+) or CD8(+) T cells in vitro. In vivo, mTOR inhibition reduced proliferation and abnormal differentiation by DNT cells. Importantly, increased mitotic activity and hyperactive mTOR signaling was also observed in recently defined CD4(+) or CD8(+) precursor DNT cells, and mTOR inhibition specifically reduced these cells in vivo, indicating abnormal programming of Fas-deficient T cells before the DNT stage. Thus, our results identify the mTOR pathway as a major regulator of lymphoproliferation and aberrant differentiation in ALPS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2015-11-685024DOI Listing
July 2016

Gut immune reconstitution in immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome after hematopoietic stem cell transplantation.

J Allergy Clin Immunol 2015 Jan 25;135(1):260-2. Epub 2014 Oct 25.

Institute of Cellular Medicine, University of Newcastle, Newcastle upon Tyne, United Kingdom; Department of Pediatric Immunology, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2014.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282727PMC
January 2015

Late-onset of immunodysregulation, polyendocrinopathy, enteropathy, x-linked syndrome (IPEX) with intractable diarrhea.

Ital J Pediatr 2014 Oct 18;40:68. Epub 2014 Oct 18.

Pediatric Oncology and Haematology Unit "Lalla Seràgnoli", Department of Pediatrics, University of Bologna Sant'Orsola-Malpighi Hospital, Via Massarenti, 11, Bologna, 40138, Italy.

The syndrome of immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) is a rare disorder caused by mutations in the FOXP3 gene. Diarrhea, diabetes and dermatitis are the hallmark of the disease, with a typical onset within the first months of life. We describe the case of a twelve-year old male affected by a very late-onset IPEX with intractable enteropathy, which markedly improved after starting Sirolimus as second-line treatment. This case suggests that IPEX should always be considered in the differential diagnosis of watery intractable diarrhea, despite its unusual onset.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13052-014-0068-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4421998PMC
October 2014

Langerhans cell histiocytosis in IPEX syndrome: possible role for natural regulatory T cells?

Pediatr Allergy Immunol 2014 Oct 16;25(6):601-3. Epub 2014 Mar 16.

Department of Pediatric Gastroenterology, Konya Training and Research Hospital, Konya, Turkey.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/pai.12219DOI Listing
October 2014

ICON: the early diagnosis of congenital immunodeficiencies.

J Clin Immunol 2014 May 12;34(4):398-424. Epub 2014 Mar 12.

Department of Pediatrics, Medical College of Wisconsin, and Children's Research Institute, Milwaukee, WI, 53226-4874, USA,

Primary immunodeficiencies are intrinsic defects in the immune system that result in a predisposition to infection and are frequently accompanied by a propensity to autoimmunity and/or immunedysregulation. Primary immunodeficiencies can be divided into innate immunodeficiencies, phagocytic deficiencies, complement deficiencies, disorders of T cells and B cells (combined immunodeficiencies), antibody deficiencies and immunodeficiencies associated with syndromes. Diseases of immune dysregulation and autoinflammatory disorder are many times also included although the immunodeficiency in these disorders are often secondary to the autoimmunity or immune dysregulation and/or secondary immunosuppression used to control these disorders. Congenital primary immunodeficiencies typically manifest early in life although delayed onset are increasingly recognized. The early diagnosis of congenital immunodeficiencies is essential for optimal management and improved outcomes. In this International Consensus (ICON) document, we provide the salient features of the most common congenital immunodeficiencies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10875-014-0003-xDOI Listing
May 2014

The evolution of cellular deficiency in GATA2 mutation.

Blood 2014 Feb 17;123(6):863-74. Epub 2013 Dec 17.

Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;

Constitutive heterozygous GATA2 mutation is associated with deafness, lymphedema, mononuclear cytopenias, infection, myelodysplasia (MDS), and acute myeloid leukemia. In this study, we describe a cross-sectional analysis of 24 patients and 6 relatives with 14 different frameshift or substitution mutations of GATA2. A pattern of dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency (DCML deficiency) with elevated Fms-like tyrosine kinase 3 ligand (Flt3L) was observed in all 20 patients phenotyped, including patients with Emberger syndrome, monocytopenia with Mycobacterium avium complex (MonoMAC), and MDS. Four unaffected relatives had a normal phenotype indicating that cellular deficiency may evolve over time or is incompletely penetrant, while 2 developed subclinical cytopenias or elevated Flt3L. Patients with GATA2 mutation maintained higher hemoglobin, neutrophils, and platelets and were younger than controls with acquired MDS and wild-type GATA2. Frameshift mutations were associated with earlier age of clinical presentation than substitution mutations. Elevated Flt3L, loss of bone marrow progenitors, and clonal myelopoiesis were early signs of disease evolution. Clinical progression was associated with increasingly elevated Flt3L, depletion of transitional B cells, CD56(bright) NK cells, naïve T cells, and accumulation of terminally differentiated NK and CD8(+) memory T cells. These studies provide a framework for clinical and laboratory monitoring of patients with GATA2 mutation and may inform therapeutic decision-making.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2013-07-517151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916878PMC
February 2014

CACP syndrome: identification of five novel mutations and of the first case of UPD in the largest European cohort.

Eur J Hum Genet 2014 Feb 12;22(2):197-201. Epub 2013 Jun 12.

Department of 'NEUROFARBA', Section of Child's Health, University of Florence and Anna Meyer Children's Hospital, Florence, Italy.

Camptodactyly-Arthropathy-Coxa vara-Pericarditis (CACP) syndrome is a rare autosomal recessive disorder caused by mutations in PRG4 gene that encodes for proteoglycan 4, a mucin-like glycoprotein that is the major lubricant for joints and tendon surfaces. The molecular studies reported so far have described the identification of 15 mutations associated with this syndrome and the majority of them were found in families of Arabian origin. Here we report the molecular investigation of the largest European cohort that comprises 13 patients, and allowed the identification of 5 novel mutations and of the first case of CACP syndrome resulting from uniparental disomy of chromosome 1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ejhg.2013.123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895642PMC
February 2014

Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome.

J Allergy Clin Immunol 2013 Jun 25;131(6):1611-23. Epub 2013 Mar 25.

Laboratory of Clinical Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1684, USA.

Background: Mutations in signal transducer and activator of transcription (STAT) 1 cause a broad spectrum of disease, ranging from severe viral and bacterial infections (amorphic alleles) to mild disseminated mycobacterial disease (hypomorphic alleles) to chronic mucocutaneous candidiasis (CMC; hypermorphic alleles). The hypermorphic mutations are also associated with arterial aneurysms, autoimmunity, and squamous cell cancers.

Objective: We sought to investigate the role of STAT1 gain-of-function mutations in phenotypes other than CMC.

Methods: We initially screened patients with CMC and autoimmunity for STAT1 mutations. We functionally characterized mutations in vitro and studied immune profiles and regulatory T (Treg) cells. After our initial case identifications, we explored 2 large cohorts of patients with wild-type forkhead box protein 3 and an immune dysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX)-like phenotype for STAT1 mutations.

Results: We identified 5 children with polyendocrinopathy, enteropathy, and dermatitis reminiscent of IPEX syndrome; all but 1 had a variety of mucosal and disseminated fungal infections. All patients lacked forkhead box protein 3 mutations but had uniallelic STAT1 mutations (c.629 G>T, p.R210I; c.1073 T>G, p.L358W, c.796G>A; p.V266I; c.1154C>T, T385M [2 patients]). STAT1 phosphorylation in response to IFN-γ, IL-6, and IL-21 was increased and prolonged. CD4(+) IL-17-producing T-cell numbers were diminished. All patients had normal Treg cell percentages in the CD4(+) T-cell compartment, and their function was intact in the 2 patients tested. Patients with cells available for study had normal levels of IL-2-induced STAT5 phosphorylation.

Conclusions: Gain-of-function mutations in STAT1 can cause an IPEX-like phenotype with normal frequency and function of Treg cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2012.11.054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672257PMC
June 2013

Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.

Clin Immunol 2013 Mar 24;146(3):248-61. Epub 2013 Jan 24.

San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy.

Cell-surface CD25 expression is critical for maintaining immune function and homeostasis. As in few reported cases, CD25 deficiency manifests with severe autoimmune enteritis and viral infections. To dissect the underlying immunological mechanisms driving these symptoms, we analyzed the regulatory and effector T cell functions in a CD25 deficient patient harboring a novel IL2RA mutation. Pronounced lymphoproliferation, mainly of the CD8(+) T cells, was detected together with an increase in T cell activation markers and elevated serum cytokines. However, Ag-specific responses were impaired in vivo and in vitro. Activated CD8(+)STAT5(+) T cells with lytic potential infiltrated the skin, even though FOXP3(+) Tregs were present and maintained a higher capacity to respond to IL-2 compared to other T-cell subsets. Thus, the complex pathogenesis of CD25 deficiency provides invaluable insight into the role of IL2/IL-2RA-dependent regulation in autoimmunity and inflammatory diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clim.2013.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594590PMC
March 2013

Does NADPH oxidase deficiency cause artery dilatation in humans?

Antioxid Redox Signal 2013 Apr 7;18(12):1491-6. Epub 2012 Dec 7.

Divisione I Clinica Medica, Department of Internal Medicine and Medical Specialities, University of Rome La Sapienza, Rome, Italy.

NADPH oxidase is known to modulate the arterial tone, but the role of its specific subunits is still unclear. The objective of this study was to compare the role of p47 and gp91phox (NOX2) on artery dilatation. We conducted a multicenter study enrolling 30 patients with chronic granulomatous disease (CGD) (25 with NOX2 deficiency and 5 with p47(phox) deficiency) and 30 healthy subjects (HS), matched for gender and age, in whom flow-mediated dilation (FMD), serum activity of NOX2 (soluble NOX2-derived peptide [sNOX2-dp]), urinary isoprostanes (8-iso-PGF2α), and platelet production of isoprostanes and NOX2 were determined. Compared to HS, patients with CGD had significantly higher FMD and lower sNOX2-dp and 8-iso-PGF2α levels. Compared to patients with NOX2 deficiency and HS, patients with p47(phox) hereditary deficiency had intermediate FMD and oxidative stress, that is, higher and lower FMD and lower and higher isoprostanes compared to HS and patients with NOX2 deficiency, respectively. In agreement with this finding, an ex vivo study showed higher inhibition of NOX2 activity and lower isoprostane formation in platelets from patients with NOX2 deficiency compared to platelets from ones with p47(phox) deficiency. Our observations lead to the hypothesis that oxidants are implicated in artery vasoconstriction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/ars.2012.4987DOI Listing
April 2013

Two novel patients with Bohring-Opitz syndrome caused by de novo ASXL1 mutations.

Am J Med Genet A 2012 Apr 14;158A(4):917-21. Epub 2012 Mar 14.

Dipartimento di Scienze Ginecologiche, Ostetriche e Pediatriche, Università di Bologna, Policlinico Sant'Orsola Malpighi, U.O. Genetica Medica, Bologna, Italy.

Bohring-Opitz syndrome (BOS) is a rare condition characterized by facial anomalies, multiple malformations, failure to thrive and severe intellectual disabilities. Recently, the cause was identified on the basis of de novo heterozygous mutations in the ASXL1 gene. We report on two novel cases carrying two previously undescribed mutations (c.2407_2411del5 [p.Q803TfsX17] and c.2893C>T [p.R965X]). These new data further support ASXL1 as cause of BOS and may contribute to a more precise definition of the phenotype caused by the disruption of this gene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.35265DOI Listing
April 2012

Congenital and acquired neutropenias consensus guidelines on therapy and follow-up in childhood from the Neutropenia Committee of the Marrow Failure Syndrome Group of the AIEOP (Associazione Italiana Emato-Oncologia Pediatrica).

Am J Hematol 2012 Feb 27;87(2):238-43. Epub 2011 Dec 27.

Haematology Unit, G. Gaslini Children's Hospital, Genova, Italy.

The management of congenital and acquired neutropenias presents some differences according to the type of the disease. Treatment with recombinant human granulocyte-colony stimulating factor (G-CSF) is not standardized and scanty data are available on the best schedule to apply. The frequency and the type of longitudinal controls in patients affected with neutropenias are not usually discussed in the literature. The Neutropenia Committee of the Marrow Failure Syndrome Group (MFSG) of the Associazione Italiana di Emato-Oncologia Pediatrica (AIEOP) elaborated this document following design and methodology formerly approved by the AIEOP board. The panel of experts reviewed the literature on the topic and participated in a conference producing a document that includes recommendations on neutropenia treatment and timing of follow-up.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajh.22242DOI Listing
February 2012

New frontiers in primary immunodeficiency disorders: immunology and beyond….

Cell Mol Life Sci 2012 Jan 19;69(1):1-5. Epub 2011 Oct 19.

Department of Sciences for Woman and Child's Health, Anna Meyer Children's Hospital, Haematology-Oncology Department, BMT Unit, University of Florence, Viale Gaetano Pieraccini, 24, 50139 Florence, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00018-011-0833-0DOI Listing
January 2012

Genetic disorders with immune dysregulation.

Cell Mol Life Sci 2012 Jan 9;69(1):49-58. Epub 2011 Oct 9.

Department of Sciences for Woman and Child's Health, Anna Meyer Children's Hospital, University of Florence, Florence, Italy.

We summarize the clinical presentation and molecular basis of a unique group of congenital immunodeficiency disorders in which defects in immune tolerance mechanisms result in severe autoimmunity. Patients with severe, familial forms of multi-organ autoimmunity have been recognized and clinically described for more than 40 years (Clin Exp Immunol 1: 119-128, 1966; Clin Exp Immunol 2: 19-30, 1967). Some are characterized primarily by autoimmunity and others by autoimmunity combined with susceptibility to specific infectious organisms. The first mechanistic understanding of these disorders began to emerge approximately 10 years ago with the initial identification of causative genes. As a result, our understanding of how immune tolerance is established and maintained in humans has expanded dramatically. Data generated over the last 3-4 years including identification of additional gene defects and functional characterization of each identified gene product in human and animal models have added clarity. This, in turn, has improved our ability to diagnose and effectively treat these severe, life-threatening disorders. Inherited disorders characterized by immune dysregulation have dramatically expanded our understanding of immune tolerance mechanisms in humans. Recognition and diagnosis of these disorders in the clinic allows timely initiation of life-saving therapies that may prevent death or irreversible damage to vital organs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00018-011-0838-8DOI Listing
January 2012