Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome with NK dysfunction and EBV-driven malignancy treated with stem cell transplantation

Burk, Caitlin M.; Coffey, Kara; Mace, Emily M.; Bostwick, Bret L.; Chinn, Iván K.; Coban‐Akdemir, Zeynep; Jhangiani, Shalini N.; Lupski, James R.; Ortiz, Damara; Barnum, Jessie L.; Allen, Steven W.; Robertson, Leanna-Marie; Chong, Hey

doi:10.1016/j.jaip.2019.08.040

Cited by 10 publications

(4 citation statements)

References 14 publications

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“…On the other hand, he had B cell lymphopenia with particularly low counts of post-germinal B cells, similar to what has been previously reported in these patients ( 9 ). Interestingly, five other ICF2 patients have been reported with EBV infection: the first was described as having “severe mononucleosis” ( 9 ), the second had persistent EBV infection ( 10 ), the third had an EBV-induced hemophagocytic lymphohystiocytosis ( 11 ), the fourth had a chronic EBV infection and developed an aggressive Hodgkin lymphoma ( 4 ) and the last one had an EBV-driven lymphoproliferative disorder with features of a CD20-negative large B-cell lymphoma ( 12 ) (Table S3) This susceptibility to EBV seems to be particular of ICF-2 as it has not been described in the other types of ICF. Similar to our patient, one patient had EBV+ T-cell lymphoproliferation ( 9 ) and other had progression of the disease despite rituximab ( 10 ).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Primary Immunodeficiencies, Massive EBV+ T-Cell Lympoproliferation Leading to the Diagnosis of ICF2 Syndrome

et al. 2021

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In immunocompromised patients, EBV may elicit B-cell transformation and proliferation. A 5-year-old microcephalic boy was admitted with fever and non-malignant polymorphic T-cell lymphoproliferative disease associated with EBV. A presumptive diagnosis of primary immunodeficiency with inability to control EBV was made and next-generation sequencing led to the identification of a novel ZBTB24 mutation (ICF2-syndrome). This case shows that susceptibility to EBV seems to be particular of ICF-2 as it has not been described in the other types of ICF. It is mandatory to raise the hypothesis of an underlying PID in case of severe EBV infection.

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Section: Discussionmentioning

confidence: 99%

Case Report: Primary Immunodeficiencies, Massive EBV+ T-Cell Lympoproliferation Leading to the Diagnosis of ICF2 Syndrome

et al. 2021

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“…Another option, that was considered in other clinical cases, is an allo-HSCT [29,30,33]. There are only a few reports of performed allo-HSCT in patients with ICF type 1, who were successfully cured, and even fewer that presented the same outcome in patient with ICF type 2 [9,29,[34][35][36]. Positive results presented in those papers give premises to take allo-HSCT under consideration in patients, whose clinical state allows performing that procedure.…”

Section: Mds and Allo-hsctmentioning

confidence: 99%

Myelodysplastic syndrome and pulmonary alveolar proteinosis in a 6-year-old girl with mutation of the ZBTB24 gene

Homa,

Janiuk

et al. 2023

Acta Haematol Pol.

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In this article, we would like to present rare diseases, which are immunodeficiency, centromeric instability and facial dysmorphism syndrome (ICF), and myelodysplastic neoplasm (MDS), with possible complications of their course and treatment with particular emphasis on pulmonary alveolar proteinosis (PAP). We are basing that review on our experience that we have gained through the diagnostic and treatment process of our pediatric patient. MDS is a rare disease among children that has a different and uncharacteristic clinical course and genetic background in comparison to MDS occurring in adults. Regarding the uncharacteristic clinical picture, the differential diagnosis can be a challenge for clinicians. In that process also diseases characterized by immunodeficiency should be taken into account, including the ICF. ICF type 2 is an autosomal recessive disease that manifests by agammaglobulinemia or hypogammaglobulinemia, developmental delay, and facial anomalies. Both ICF and MDS can be treated with an allogeneic hematopoietic stem cell transplantation. One of the possible complications in the course and treatment of MDS and ICF can be PAP. Its pathogenesis is based on the accumulation of surfactant in alveoli that leads to pulmonary insufficiency. As hematologic diseases and their treatment are known for their impact on multiple systems, we find the unique value of this article in being the first description of the coexistence of ICF type 2 with PAP.

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“…Given the intriguing NK cell lymphocytosis, we set out to define the developmental and functional status of P1 NK cells by assessing the expression of CD56, maturation (CD27, CD57, CD94), adhesion (CD16), and activation (CD8, CD25) markers [33][34][35] As NK cells mediate their effector functions through the release of proinflammatory cytokines and cytolysis 33 , we studied whether these roles were affected in P1. In response to stimulation, P1 had significantly elevated IFN-γ + NK cells (Figure 3Q, Figure S1O), but comparable TNF-α + NK cells (Figure 3R, Figure S1P).…”

Section: P1 Nk Cells Are Phenotypically Immature and Functionally Abn...mentioning

confidence: 99%

A germline heterozygous dominant negativeIKZF2variant causing syndromic primary immune regulatory disorder and ICHAD

Lu,

Vaseghi-Shanjani,

Lam

et al. 2023

Preprint

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Monogenic defects that impair the control of inflammation and tolerance lead to profound immune dysregulation, including autoimmunity and atopy. Studying these disorders reveals important molecular and cellular factors that regulate human immune homeostasis and identifies potential precision medicine targets. Here, we provide a detailed immunological assessment of a pediatric patient with a recently discovered syndrome causing Immunodysregulation, Craniofacial anomalies, Hearing impairment, Athelia, and Developmental delay (or ICHAD syndrome). The immunodysregulation resulted in autoimmune hemolytic anemia (AIHA) and atopic dermatitis. The patient carried ade novogermline heterozygous c.406+540_574+13477dup;p.Gly136_Ser191dup variant inIKAROS family zinc finger 2(IKZF2), which encodes Helios. This variant led to reduced Helios protein expression and dominant interference of wild-type Helios-mediated repression of theIL2promoter. Multi-parameter flow cytometric analyses of patient peripheral blood mononuclear cells revealed strongly impaired natural killer cell differentiation and function, and increased CD8+T cell activation and cytokine secretion. Strikingly, patient CD4+T cells were hyperactive, produced elevated levels of nearly all T helper (TH) cytokines, and readily proliferated in response to stimulation. Patient regulatory T cells (Tregs) developed normally but aberrantly produced high levels of many THcytokines. Single-cell RNA sequencing revealed largely normal Tregs (albeit mostly memory), but naïve CD4+T cells that were more enriched in genes related to activation, proliferation, metabolism, and THdifferentiation. This work describes the immunological phenotype of one of the first reported cases of germline dominant negative Helios deficiency, expands our understanding of the pathogenesis of AIHA on a single cell level, and provides valuable insights into Helios function in a variety of lymphocyte subsets.

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Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome with NK dysfunction and EBV-driven malignancy treated with stem cell transplantation

Cited by 10 publications

References 14 publications

Case Report: Primary Immunodeficiencies, Massive EBV+ T-Cell Lympoproliferation Leading to the Diagnosis of ICF2 Syndrome

Case Report: Primary Immunodeficiencies, Massive EBV+ T-Cell Lympoproliferation Leading to the Diagnosis of ICF2 Syndrome

Myelodysplastic syndrome and pulmonary alveolar proteinosis in a 6-year-old girl with mutation of the ZBTB24 gene

A germline heterozygous dominant negativeIKZF2variant causing syndromic primary immune regulatory disorder and ICHAD

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