Immune system defects in DiGeorge syndrome and association with clinical course

Nain, Ercan; Kıykım, Ayça; Öğülür, İsmail; Kasap, Nurhan; Karakoç-Aydıner, Elif; Özen, Ahmet; Barış, Safa

doi:10.1111/sji.12809

Cited by 10 publications

(7 citation statements)

References 23 publications

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“…These features were also found in patients suffering simultaneously from both CVID and ITP, 22 characterized by an accumulation of CD21low B lymphocytes, responsible for IEI‐related autoimmune disorders, 8 along with defects in PAN‐B cells bone marrow production and CD4+ naїve T‐cells differentiation. These findings suit also with the individual of the cohort with DGS, showing low CD4+ naїve T‐cells%, switched memory B‐cells% and IgM levels, along with an inverted CD4+/CD8+ ratio, all biomarkers configuring an immunophenotype associated with autoimmunity, lymphoproliferation and a severe clinical course, characterized in our case by invasive and recurrent infections 23–25 …”

Section: Discussionsupporting

confidence: 87%

“…These findings suit also with the individual of the cohort with DGS, showing low CD4+ naїve T-cells%, switched memory B-cells% and IgM levels, along with an inverted CD4+/CD8+ ratio, all biomarkers configuring an immunophenotype associated with autoimmunity, lymphoproliferation and a severe clinical course, characterized in our case by invasive and recurrent infections. [23][24][25] Our hypotheses concerning the above-mentioned correlations in IEI+ group and CVID subgroup are strengthened by the fact that, in IEI− group, CD4+ naїve T-cells% showed an inverse correlation respectively milder with CD4+ effector memory T-cells% (Pearson's R = −0.545) and not significant with CD21low B-cells% (Pearson's R = −0.024). Memory and transitional B-cells % did not show a significant difference between the two groups.…”

Section: Discussionmentioning

confidence: 76%

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Immune cytopenias as a continuum in inborn errors of immunity: An in‐depth clinical and immunological exploration

Zama

Conti

Moratti

et al. 2021

Immunity Inflam & Disease

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Background Immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and autoimmune neutropenia (AIN) are disorders characterized by immune‐mediated destruction of hematopoietic cell lineages. A link between pediatric immune cytopenias and inborn errors of immunity (IEI) was established in particular in the combined and chronic forms. Objective Aim of this study is to provide clinical‐immunological parameters to hematologists useful for a prompt identification of children with immune cytopenias deserving a deeper immunological and genetic evaluation. Methods We retrospectively collected 47 pediatric patients with at least one hematological disorder among which persistent/chronic ITP, AIHA, and AIN, aged 0–18 years at onset of immune cytopenias and/or immune‐dysregulation. The cohort was divided into two groups (IEI+ and IEI−), based on the presence/absence of underlying IEI diagnosis. IEI+ group, formed by 19/47 individuals, included: common variable immune deficiency (CVID; 9/19), autoimmune lymphoproliferative syndrome (ALPS; 4/19), DiGeorge syndrome (1/19), and unclassified IEI (5/19). Results IEI prevalence among patients with ITP, AIHA, AIN, and Evans Syndrome was respectively of 42%, 64%, 36%, and 62%. In IEI+ group the extended immunophenotyping identified the presence of statistically significant (p < .05) specific characteristics, namely T/B lymphopenia, decrease in naїve T‐cells%, switched memory B‐cells%, plasmablasts%, and/or immunoglobulins, increase in effector/central memory T‐cells% and CD21low B‐cells%. Except for DiGeorge and three ALPS patients, only 2/9 CVID patients had a molecular diagnosis for IEI: one carrying the pathogenic variant CR2:c.826delT, the likely pathogenic variant PRF1:c.272C> and the compound heterozygous TNFRSF13B variants p.Ser144Ter (pathogenic) and p.Cys193Arg (variant of uncertain significance), the other one carrying the likely pathogenic monoallelic variant TNFRSF13B:p.Ile87Asn. Conclusion The synergy between hematologists and immunologists can improve and fasten diagnosis and management of patients with immune cytopenias through a wide focused clinical/immunophenotypical characterization, which identifies children worthy of IEI‐related molecular analysis, favouring a genetic IEI diagnosis and potentially unveiling new targeted‐gene variants responsible for IEI phenotype.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 76%

Immune cytopenias as a continuum in inborn errors of immunity: An in‐depth clinical and immunological exploration

Zama

Conti

Moratti

et al. 2021

Immunity Inflam & Disease

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show abstract

“…These features were also found in patients suffering simultaneously from both CVID and ITP 22 , characterized by an accumulation of auto-reactive CD21low B lymphocytes, responsible for IEI-related autoimmune disorders 8 , along with defects in PAN-B cells bone marrow production and CD4+ nayive T-cells differentiation. These findings suit also with the individual of the cohort with DGS, showing low CD4+ nayive T-cells%, switched memory B-cells% and IgM levels, along with an inverted CD4+/CD8+ ratio, all biomarkers configuring an immunophenotype associated with autoimmunity, lymphoproliferation and a severe clinical course, characterized in our case by invasive and recurrent infections [23][24][25] . Memory and transitional B-cells% did not show a significant difference between the two groups.…”

Section: Discussionsupporting

confidence: 88%

Immunophenotype identifies children with immune cytopenias at risk of inborn errors of immunity-related mutations

Zama¹,

Conti²,

Moratti³

et al. 2020

Preprint

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Background Immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA) and autoimmune neutropenia (AIN) are disorders characterized by immune-mediated destruction of hematopoietic cell lineages. A link between pediatric immune cytopenias and inborn errors of immunity (IEI) was established in particular in the combined and chronic forms. Objective Identification of predictive factors of IEI in immune cytopenic children is an important objective for a prompt immunological diagnosis and appropriate management. Aim of this study is to detect clinical and laboratory signs of IEI, in particular the latter by an extensive lymphocyte immunophenotyping. Methods We retrospectively collected 47 pediatric patients with at least one hematological disorder among which persistent/chronic ITP, AIHA and AIN, aged 0-18 years at onset of immune cytopenias and/or immune-dysregulation. The cohort was divided into 2 groups (IEI+ and IEI-), based on the presence/absence of underlying IEI diagnosis. IEI+ group, formed by 19/47 individuals, included: Common variable immune deficiency (9/19), Autoimmune lymphoproliferative syndrome (4/19), DiGeorge syndrome (1/19) and unclassified IEI (5/19). Results IEI prevalence among patients with ITP, AIHA, AIN and Evans Syndrome was respectively of 42%, 64%, 36% and 62%. In IEI+ the extended lymphocyte immunophenotyping identified the presence of statistically significant (p-value<0.05) specific characteristics, namely T/B lymphopenia, decrease in naїve T-cells%, switched memory B-cells%, plasmablasts% and/or immunoglobulins, increase in effector/central memory T-cells% and CD21low B-cells%. Conclusion A wide focused clinical/immunophenotypical characterization of pediatric patients with immune cytopenia can highlight specific signs of IEI, potentially helpful in the diagnostic and clinical management, identifying children worthy of IEI-related molecular analysis.Immunophenotype identifies children with immune cytopenias at risk of inborn errors of immunity-related mutations

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“…18 The immunodeficiency related with this syndrome has a large range from life-threatening to normal immunity. 18 Nain et al 19 defined patients with low CD4+ and CD8+ cells as "high risk patients" whereas patients with normal numbers of CD4+ and CD8+ T-cells were defined as "standard risk patients." The authors had detected more severe infections and persistent hypoparathyroidism in the high-risk group.…”

Section: Discussionmentioning

confidence: 99%

“…In five patients, absolute lymphocyte counts were low compared to age-related normal values (Table 5). Twenty-one patients had low CD3+ T-cell counts, 19…”

Section: Methodsmentioning

confidence: 99%

22q11.2 deletion syndrome: 20 years of experience from two pediatric immunology units and review of clues for diagnosis and disease management

Özen¹,

Akçal²,

Taşkırdı³

et al. 2021

aei

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Introduction and objectives: The purpose of this study was to evaluate patients diagnosed with 22q11.2 deletion syndrome and determine the clues directing to diagnosis and evaluation of immunological findings for excellent management of the disease. Material and methods: Thirty-three pediatric patients with 22q11.2 deletion syndrome diag-nosed between 1998 and 2019 at Pediatric Immunology Division of Ege University Faculty of Medicine and SBU Izmir Dr Behcet Uz Children’s Education and Research Hospital were evaluated. Results: This study includes the largest case series reported from Turkey. Congenital car-diac anomalies were the most common pathology associated with the syndrome (90.9%). Hypocalcemic symptoms were observed in 13 patients (40%). Twenty-two of the 33 (66.6%) patients were diagnosed before two years of age. Autoimmune diseases, dysmorphic facial findings, recurrent infections, growth retardation, and speech impairment were other clues for diagnosis in older patients. Clinical spectrum and immunological abnormalities of this syn-drome are quite variable. All T-cell subset counts were less than 5th percentile below median by age in one patient (3%) and 10 patients had normal all T-cell subset counts (30.3%). Overall, 69.6% of the patients had normal IgG, IgA, and IgM levels and two patients had panhypogam-maglobulinemia. Recurrent infections were revealed in 75.7% of the patients during follow-up. Conclusions: Presence of cardiac anomaly is more helpful in the diagnosis, especially under two years of age. Patients with immunologically high or standard risk did not show any differ-ence in terms of numbers and severity of infections and autoimmunity.

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Immune system defects in DiGeorge syndrome and association with clinical course

Cited by 10 publications

References 23 publications

Immune cytopenias as a continuum in inborn errors of immunity: An in‐depth clinical and immunological exploration

Immune cytopenias as a continuum in inborn errors of immunity: An in‐depth clinical and immunological exploration

Immunophenotype identifies children with immune cytopenias at risk of inborn errors of immunity-related mutations

22q11.2 deletion syndrome: 20 years of experience from two pediatric immunology units and review of clues for diagnosis and disease management

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