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David H Mcdermott - One of the best experts on this subject based on the ideXlab platform.
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Correction to: TREC Screening for WHIM Syndrome
Journal of Clinical Immunology, 2021Co-Authors: Martin Oman Evans, Maureen M. Petersen, Amer Khojah, Soma C. Jyonouchi, George S. Edwardson, Yasmin West Khan, James Albert Connelly, David Morris, Shamik Majumdar, David H McdermottAbstract:A Correction to this paper has been published: https://doi.org/10.1007/s10875-021-00976-x
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TREC Screening for WHIM Syndrome
Journal of Clinical Immunology, 2021Co-Authors: Martin Oman Evans, Maureen M. Petersen, Amer Khojah, Soma C. Jyonouchi, George S. Edwardson, Yasmin West Khan, James Albert Connelly, David Morris, Shamik Majumdar, David H McdermottAbstract:Purpose T cell receptor excision circle (TREC) quantification is a recent addition to newborn screening (NBS) programs and is intended to identify infants with severe combined immunodeficiencies (SCID). However, other primary immunodeficiency diseases (PID) have also been identified as the result of TREC screening. We recently reported a newborn with a low TREC level on day 1 of life who was diagnosed with WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) Syndrome, a non-SCID primary immunodeficiency caused by mutations in the chemokine receptor CXCR4. Methods We have now retrospectively reviewed the birth and clinical histories of all known WHIM infants born after the implementation of NBS for SCID. Results We identified six infants with confirmed WHIM Syndrome who also had TREC quantification on NBS. Three of the six WHIM infants had low TREC levels on NBS. All six patients were lymphopenic but only one infant had a T cell count below 1,500 cells/μL. The most common clinical manifestation was viral bronchiolitis requiring hospitalization. One infant died of complications related to Tetralogy of Fallot, a known WHIM phenotype. Conclusion The results suggest that WHIM Syndrome should be considered in the differential diagnosis of newborns with low NBS TREC levels. Trial Registration Not applicable.
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low level cxcr4 haploinsufficient hsc engraftment is sufficient to correct leukopenia in WHIM Syndrome mice
JCI insight, 2019Co-Authors: Albert Owusuansah, David H Mcdermott, Alexander Yang, Marie Siwicki, Andrea Paun, Kimberly Beacht, Philip M MurphyAbstract:Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) Syndrome immunodeficiency is caused by autosomal dominant gain-of-function mutations in chemokine receptor CXCR4. Patient WHIM-09 was spontaneously cured by chromothriptic deletion of 1 copy of 164 genes, including the CXCR4WHIM allele, presumably in a single hematopoietic stem cell (HSC) that repopulated HSCs and the myeloid lineage. Testing the specific contribution of CXCR4 hemizygosity to her cure, we previously demonstrated enhanced engraftment of Cxcr4+/o HSCs after transplantation in WHIM (Cxcr4+/w) model mice, but the potency was not quantitated. We now report graded-dose competitive transplantation experiments using lethally irradiated Cxcr4+/+ recipients in which mixed BM cells containing approximately 5 Cxcr4+/o HSCs and a 100-fold excess of Cxcr4+/w HSCs achieved durable 50% Cxcr4+/o myeloid and B cell chimerism in blood and approximately 20% Cxcr4+/o HSC chimerism in BM. In Cxcr4+/o/Cxcr4+/w parabiotic mice, we observed 80%-100% Cxcr4+/o myeloid and lymphoid chimerism in the blood and 15% Cxcr4+/o HSC chimerism in BM from the Cxcr4+/w parabiont, which was durable after separation from the Cxcr4+/o parabiont. Thus, CXCR4 haploinsufficiency likely significantly contributed to the selective repopulation of HSCs and the myeloid lineage from a single chromothriptic HSC in WHIM-09. Moreover, the results suggest that WHIM allele silencing of patient HSCs is a viable gene therapy strategy.
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WHIM Syndrome: from Pathogenesis Towards Personalized Medicine and Cure
Journal of Clinical Immunology, 2019Co-Authors: Lauren E. Heusinkveld, David H Mcdermott, Shamik Majumdar, Ji-liang Gao, Philip M MurphyAbstract:WHIM Syndrome is a rare combined primary immunodeficiency disease named by acronym for the diagnostic tetrad of warts, hypogammaglobulinemia, infections, and myelokathexis. Myelokathexis is a unique form of non-cyclic severe congenital neutropenia caused by accumulation of mature and degenerating neutrophils in the bone marrow; monocytopenia and lymphopenia, especially B lymphopenia, also commonly occur. WHIM Syndrome is usually caused by autosomal dominant mutations in the G protein-coupled chemokine receptor CXCR4 that impair desensitization, resulting in enhanced and prolonged G protein- and β-arrestin-dependent responses. Accordingly, CXCR4 antagonists have shown promise as mechanism-based treatments in phase 1 clinical trials. This review is based on analysis of all 105 published cases of WHIM Syndrome and covers current concepts, recent advances, unresolved enigmas and controversies, and promising future research directions.
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Plerixafor for the Treatment of WHIM Syndrome.
The New England journal of medicine, 2019Co-Authors: David H Mcdermott, Diana V. Pastrana, Katherine R. Calvo, Stefania Pittaluga, Daniel Velez, Elena Cho, Qian Liu, Hugh H. Trout, João F. Neves, Pamela J. GardnerAbstract:WHIM Syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), a primary immunodeficiency disorder involving panleukopenia, is caused by autosomal dominant gain-of-function mutations in CXC chemokine receptor 4 (CXCR4). Myelokathexis is neutropenia caused by neutrophil retention in bone marrow. Patients with WHIM Syndrome are often treated with granulocyte colony-stimulating factor (G-CSF), which can increase neutrophil counts but does not affect cytopenias other than neutropenia. In this investigator-initiated, open-label study, three severely affected patients with WHIM Syndrome who could not receive G-CSF were treated with low-dose plerixafor, a CXCR4 antagonist, for 19 to 52 months. Myelofibrosis, panleukopenia, anemia, and thrombocytopenia were ameliorated, the wart burden and frequency of infection declined, human papillomavirus-associated oropharyngeal squamous-cell carcinoma stabilized, and quality of life improved markedly. Adverse events were mainly infections attributable to the underlying immunodeficiency. One patient died from complications of elective reconstructive surgery. (Funded by the National Institutes of Health.).
Philip M Murphy - One of the best experts on this subject based on the ideXlab platform.
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low level cxcr4 haploinsufficient hsc engraftment is sufficient to correct leukopenia in WHIM Syndrome mice
JCI insight, 2019Co-Authors: Albert Owusuansah, David H Mcdermott, Alexander Yang, Marie Siwicki, Andrea Paun, Kimberly Beacht, Philip M MurphyAbstract:Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) Syndrome immunodeficiency is caused by autosomal dominant gain-of-function mutations in chemokine receptor CXCR4. Patient WHIM-09 was spontaneously cured by chromothriptic deletion of 1 copy of 164 genes, including the CXCR4WHIM allele, presumably in a single hematopoietic stem cell (HSC) that repopulated HSCs and the myeloid lineage. Testing the specific contribution of CXCR4 hemizygosity to her cure, we previously demonstrated enhanced engraftment of Cxcr4+/o HSCs after transplantation in WHIM (Cxcr4+/w) model mice, but the potency was not quantitated. We now report graded-dose competitive transplantation experiments using lethally irradiated Cxcr4+/+ recipients in which mixed BM cells containing approximately 5 Cxcr4+/o HSCs and a 100-fold excess of Cxcr4+/w HSCs achieved durable 50% Cxcr4+/o myeloid and B cell chimerism in blood and approximately 20% Cxcr4+/o HSC chimerism in BM. In Cxcr4+/o/Cxcr4+/w parabiotic mice, we observed 80%-100% Cxcr4+/o myeloid and lymphoid chimerism in the blood and 15% Cxcr4+/o HSC chimerism in BM from the Cxcr4+/w parabiont, which was durable after separation from the Cxcr4+/o parabiont. Thus, CXCR4 haploinsufficiency likely significantly contributed to the selective repopulation of HSCs and the myeloid lineage from a single chromothriptic HSC in WHIM-09. Moreover, the results suggest that WHIM allele silencing of patient HSCs is a viable gene therapy strategy.
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WHIM Syndrome: from Pathogenesis Towards Personalized Medicine and Cure
Journal of Clinical Immunology, 2019Co-Authors: Lauren E. Heusinkveld, David H Mcdermott, Shamik Majumdar, Ji-liang Gao, Philip M MurphyAbstract:WHIM Syndrome is a rare combined primary immunodeficiency disease named by acronym for the diagnostic tetrad of warts, hypogammaglobulinemia, infections, and myelokathexis. Myelokathexis is a unique form of non-cyclic severe congenital neutropenia caused by accumulation of mature and degenerating neutrophils in the bone marrow; monocytopenia and lymphopenia, especially B lymphopenia, also commonly occur. WHIM Syndrome is usually caused by autosomal dominant mutations in the G protein-coupled chemokine receptor CXCR4 that impair desensitization, resulting in enhanced and prolonged G protein- and β-arrestin-dependent responses. Accordingly, CXCR4 antagonists have shown promise as mechanism-based treatments in phase 1 clinical trials. This review is based on analysis of all 105 published cases of WHIM Syndrome and covers current concepts, recent advances, unresolved enigmas and controversies, and promising future research directions.
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Adaptive Immunodeficiency in WHIM Syndrome
International journal of molecular sciences, 2018Co-Authors: Shamik Majumdar, Philip M MurphyAbstract:Cysteine-X-cysteine chemokine receptor 4 (CXCR4) is a broadly expressed and multifunctional G protein-coupled chemokine receptor critical for organogenesis, hematopoiesis, and antimicrobial host defense. In the hematopoietic system, the binding of CXCR4 to its cognate chemokine ligand, CXCL12, mediates leukocyte trafficking, distribution, survival, activation, and proliferation. Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) Syndrome is a rare, autosomal dominant, combined immunodeficiency disorder caused by mutations in the C-terminus of CXCR4 that prevent receptor downregulation and therefore result in pathologically increased signaling. The “M” in the acronym WHIM refers to myelokathexis, the retention of neutrophils in the bone marrow resulting in neutropenia, which explains in part the increased susceptibility to bacterial infection. However, WHIM patients also present with B and T lymphopenia, which may explain the susceptibility to human papillomavirus (HPV), the cause of warts. The impact of WHIM mutations on lymphocytes and adaptive immunity has received less attention than myelokathexis and is the focus of this review.
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WHIM Syndrome: Immunopathogenesis, treatment and cure strategies
Immunological reviews, 2018Co-Authors: David H Mcdermott, Philip M MurphyAbstract:WHIM Syndrome is a rare, autosomal dominant immunodeficiency which is named for the four key manifestations: Warts, Hypogammaglobulinemia, Infections, and Myelokathexis. It results from heterozygous gain-of-function mutations in the chemokine receptor CXCR4 which is widely expressed on leukocytes and has profound influences on immune system homeostasis and organogenesis. New treatments for the disease using drugs to reduce CXCR4 function are excellent examples of precision medicine. Since CXCR4 and its ligand CXCL12 play an important role in a variety of infectious, inflammatory, autoimmune, and malignant diseases, the study of WHIM Syndrome provides important insights into both the physiologic and disease roles of these molecules.
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cxcr4 haploinsufficient bone marrow transplantation corrects leukopenia in an unconditioned WHIM Syndrome model
Journal of Clinical Investigation, 2018Co-Authors: Marie Siwicki, David H Mcdermott, Alexander Yang, Ari B. Azani, Albert Owusuansah, Philip M MurphyAbstract:For gene therapy of gain-of-function autosomal dominant diseases, either correcting or deleting the disease allele is potentially curative. To test whether there may be an advantage of one approach over the other for WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) Syndrome — a primary immunodeficiency disorder caused by gain-of-function autosomal dominant mutations in chemokine receptor CXCR4 — we performed competitive transplantation experiments using both lethally irradiated WT (Cxcr4+/+) and unconditioned WHIM (Cxcr4+/w) recipient mice. In both models, hematopoietic reconstitution was markedly superior using BM cells from donors hemizygous for Cxcr4 (Cxcr4+/o) compared with BM cells from Cxcr4+/+ donors. Remarkably, only approximately 6% Cxcr4+/o hematopoietic stem cell (HSC) chimerism after transplantation in unconditioned Cxcr4+/w recipient BM supported more than 70% long-term donor myeloid chimerism in blood and corrected myeloid cell deficiency in blood. Donor Cxcr4+/o HSCs differentiated normally and did not undergo exhaustion as late as 465 days after transplantation. Thus, disease allele deletion resulting in Cxcr4 haploinsufficiency was superior to disease allele repair in a mouse model of gene therapy for WHIM Syndrome, allowing correction of leukopenia without recipient conditioning.
Raffaele Badolato - One of the best experts on this subject based on the ideXlab platform.
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Cerebellar involvement in warts Hypogammaglobulinemia immunodeficiency myelokathexis patients: neuroimaging and clinical findings
Orphanet journal of rare diseases, 2019Co-Authors: Jessica Galli, Laura Dotta, Lucia Dora Notarangelo, Vassilios Lougaris, Lorenzo Pinelli, Serena Micheletti, Giovanni Palumbo, Elisa Fazzi, Raffaele BadolatoAbstract:Warts Hypogammaglobulinemia Immunodeficiency Myelokathexis (WHIM) Syndrome is a primary immunodeficiency characterized by recurrent bacterial infections, severe chronic neutropenia, with lymphopenia, monocytopenia and myelokathexis which is caused by heterozygous gain of functions mutations of the CXC chemokine receptor 4 (CXCR4). WHIM patients display an increased incidence of non-hematopoietic conditions, such as congenital heart disease suggesting that abnormal CXCR4 may put these patients at increased risk of congenital anomalies. Studies conducted on CXCR4 and SDF-1-deficient mice have demonstrated the role of CXCR4 signaling in neuronal cell migration and brain development. In particular, CXCR4 conditional knockout mice display abnormal cerebellar morphology and poor coordination and balance on motor testing. In order to evaluate a possible neurological involvement in WHIM Syndrome subjects, we performed neurological examination, including International Cooperative Ataxia Rating Scale, cognitive and psychopathological assessment and brain Magnetic Resonance Imaging (MRI) in 6 WHIM patients (age range 8–51 years) with typical gain of functions mutations of CXCR4 (R334X or G336X). In three cases (P3, P5, P6) neurological evaluation revealed fine and global motor coordination disorders, balance disturbances, mild limb ataxia and excessive talkativeness. Brain MRI showed an abnormal orientation of the cerebellar folia involving bilaterally the gracilis and biventer lobules together with the tonsils in four subjects (P3, P4, P5, P6). The neuropsychiatric evaluation showed increased risk of internalizing and/or externalizing problems in four patients (P2, P3, P4, P6). Taken together, these observations suggest CXCR4 gain of function mutations can be associated with cerebellar malformation, mild neuromotor and psychopathological dysfunction in WHIM patients.
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How I treat warts, hypogammaglobulinemia, infections, and myelokathexis Syndrome
Blood, 2017Co-Authors: Raffaele Badolato, Jean DonadieuAbstract:Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) Syndrome is a genetic disease characterized by neutropenia, lymphopenia, susceptibility to infections, and myelokathexis, which describes degenerative changes of mature neutrophils and hyperplasia of bone marrow myeloid cells. Some patients present with hypogammaglobulinemia and/or refractory warts of skin and genitalia. Congenital cardiac defects constitute uncommon manifestations of the disease. The disorder, which is inherited as an autosomal dominant trait, is caused by heterozygous mutations of the chemokine receptor CXCR4. These mutations lead to an increased sensitivity of neutrophils and lymphocytes to the unique ligand CXCL12 and to an increased accumulation of mature neutrophils in the bone marrow. Despite greatly improved knowledge of the disease, therapeutic choices are insufficient to prevent some of the disease outcomes, such as development of bronchiectasis, anogenital dysplasia, or invasive cancer. The available therapeutic measures aimed at preventing the risk for infection in WHIM patients are discussed. We critically evaluate the diagnostic criteria of WHIM Syndrome, particularly when WHIM Syndrome should be suspected in patients with congenital neutropenia and lymphopenia despite the absence of hypogammaglobulinemia and/or warts. Finally, we discuss recent results of trials evaluating plerixafor, a selective antagonist of CXCR4, as a mechanism-oriented strategy for treatment of WHIM patients.
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Hypogammaglobulinemia, Infections, Myelokathexis (WHIM) Syndrome Altered leukocyte response to CXCL12 in patients with Warts
2013Co-Authors: D Notarangelo, Raffaele Badolato, Daniele Moratto, Silvano Sozzani, Silvia Pirovano, Lucia Dora Notarangelo, Roberta Soresina, Evelina Mazzolari, David L. Nelson, Patrizia CavadiniAbstract:Abstract The chemokine receptor CXCR4 and its functional ligand CXCL12 are essential regulators of development and homeostasis of hematopoietic and lymphoid organs. Heterozygous truncating mutations in the CXCR4 intracellular tail cause a rare genetic disease known as WHIM Syndrome (Warts, Hypogammaglobulinemia, Infections, Myelokathexis), whose pathophysiology remains unclear. We report CXCR4 function in three patients with WHIM Syndrome carrying heterozygous truncating mutations of CXCR4. We show that CXCR4 gene mutations in WHIM patients do not affect cell surface expression of the chemokine receptor and its internalization upon stimulation with CXCL12. Moreover, no significant differences in calcium mobilization in response to CXCL12 are found. However, the chemotactic response of both polymorphonuclear cells and T lymphocytes in response to CXCL12 is increased. Furthermore, immunophenotypic analysis of circulating T and B lymphocytes reveals a decreased number of memory B cells and of naive T cells, and an accumulation of effector memory T cells, associated with a restricted T-cell repertoire. Based on our results, we suggest that the altered leukocyte response to CXCL12 may account for the pathological retention of mature polymorphonuclear cells in the bone marrow (myelokathexis) and for an altered lymphocyte trafficking, which may cause the immunophenotyping abnormalities observed in WHIM patients. (badolato@med.unibs.it )From bloodjournal.hematologylibrary.org by guest on May 29, 2013. For personal use only.
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Tetralogy of fallot is an uncommon manifestation of warts, hypogammaglobulinemia, infections, and myelokathexis Syndrome.
The Journal of pediatrics, 2012Co-Authors: Raffaele Badolato, Laura Tassone, Françoise Bachelerie, Laura Dotta, Lucia Dora Notarangelo, Fulvio Porta, Giovanni Amendola, Franco Locatelli, Yves Bertrand, Jean DonadieuAbstract:Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) Syndrome is a rare immunodeficiency disorder. We report three patients with WHIM Syndrome who are affected by Tetralogy of Fallot (TOF). This observation suggests a possible increased risk of TOF in WHIM Syndrome and that birth presentation of TOF and neutropenia should lead to suspect WHIM Syndrome.
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Clinical and genetic features of Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) Syndrome.
Current molecular medicine, 2011Co-Authors: Laura Dotta, Laura Tassone, Raffaele BadolatoAbstract:WHIM Syndrome is a dominantly inherited primary immunodeficiency disorder representing the first identified example of human disease caused by mutations in the gene encoding for the chemokine receptor CXCR4. Pathogenesis is mediated by CXCR4 hyperfunction, leading to increased responsiveness to its unique ligand CXCL12 (also known as SDF-1). The altered CXCR4/CXCL12 interaction likely impairs cellular homeostasis and trafficking, resulting in immunological dysfunctions. The acronym WHIM resumes the main features of the Syndrome: Warts, Hypogammaglobulinemia, Infections and Myelokathexis, which is abnormal retention of mature neutrophils in the bone marrow. WHIM patients suffer from recurrent bacterial infections since childhood and manifest a specific susceptibility to HPV infections. Hematological findings include neutropenia, lymphopenia and hypogammaglobulinemia. Because of the rarity of the disease and the heterogeneity in clinical presentation, diagnosis is often delayed. In the majority of patients, the phenotype is incomplete at the onset and WHIM Syndrome is not suspected. Early identification may improve clinical and therapeutic management. Symptomatic treatments include G-CSF, substitutive immunoglobulins and antibiotic prophylaxis. A new therapeutic strategy might include the potent inhibitor of CXCR4 function plerixafor (Mozobil), as an agent specifically targeting the molecular defect in order to attenuate the phenotypic manifestations of the Syndrome.
George A Diaz - One of the best experts on this subject based on the ideXlab platform.
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Released on a WHIM
Blood, 2011Co-Authors: George A DiazAbstract:In this issue of Blood , 2 groups (McDermott et al 1 and Dale et al 2 ) independently report the results of phase 1 clinical trials using the CXCR4-specific chemokine receptor antagonist plerixafor (Mozobil) to target the hyperfunctional CXCR4 signaling axis in patients with the rare immunodeficiency disease WHIM Syndrome.
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Oligoclonality, impaired class switch and B cell memory responses in WHIM Syndrome
Clinical immunology (Orlando Fla.), 2010Co-Authors: Peter J. Mc Guire, Charlotte Cunningham-rundles, Hans D. Ochs, George A DiazAbstract:Heterozygous truncating mutations in CXCR4 have been identified as a cause of WHIM Syndrome (warts, hypogammaglobulinemia, immunodeficiency and myelokathexis). The receptor truncations have been proposed to lead to altered lymphocyte trafficking. The purpose of the described studies was to characterize the B-cell repertoire in WHIM subjects. We confirmed profound B-cell lymphopenia and demonstrated oligoclonality of the circulating B-cell pool by HCDR3 spectratyping. The response to immunization was studied in one subject utilizing a bacteriophage PhiX174 immunization protocol. Spectratyping showed oligoclonality at baseline with normalization of the HCDR3 length distribution by 5 months after immunization with PhiX174 with eventual return to the baseline state. Isotype switching from phage specific neutralizing antibody of the IgM class to IgG was markedly reduced. Overall, these data suggest that impaired CXCR4 signaling in WHIM Syndrome results in defective B-cell function and abnormal isotype switching, possibly through effects on germinal center trafficking of lymphocytes.
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Sporadic case of warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis Syndrome
The Journal of allergy and clinical immunology, 2005Co-Authors: M. D. Tarzi, George A Diaz, Michael Jenner, Keith Hattotuwa, Asma Faruqi, Hilary LonghurstAbstract:The term WHIM Syndrome (WHIMS) is an acronym describing a rare primary immunodeficiency disorder characterized by warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis, the unusual association of neutropenia with bone marrow myeloid hypercellularity. WHIMS was recently associated with mutations in the gene encoding the chemokine receptor CXCR4 and as such is the first disease ascribed to abnormalities of chemokine signaling. We report a sporadic case of WHIMS in a woman presenting with recurrent infections and human papilloma virus–related genital dysplasia.
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WHIM Syndrome: A defect in CXCR4 signaling
Current Allergy and Asthma Reports, 2005Co-Authors: George A Diaz, A. Virginia GulinoAbstract:The study of inherited immunodeficiencies has proven valuable in elucidating molecular signaling cascades underlying the developmental and functional regulation of the human immune system. The first example of a human immunologic disease caused by mutation of a chemokine receptor was provided by WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) Syndrome, a rare, combined immunodeficiency featuring an unusual form of neutropenia. Subsequent studies following the initial description of mutations in the CXCR4 gene have revealed a striking concordance in the types of mutations observed, suggesting that impaired regulation of receptor signaling by truncation of the cytoplasmic tail domain is an essential aspect in disease pathogenesis. Biochemical studies have provided support for the model that impaired receptor downregulation leads to the characteristic immunologic and hematologic disturbances. Interestingly, these genetic studies have also identified phenocopies with the same clinical features but without mutation of CXCR4, suggesting that mutations in as yet uncharacterized downstream regulators of the receptor may be involved in a proportion of cases.
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CXCR4 mutations in WHIM Syndrome: a misguided immune system?
Immunological reviews, 2005Co-Authors: George A DiazAbstract:Chemokines and their receptors are key molecules in the development and function of immune cell populations and the organization of lymphoid organs. Despite their central role in immunologic function, genetic studies exploring the intersection of chemokines or their receptors and human health have revealed few associations of unambiguous significance. The best-characterized examples have revealed striking selective advantage conferred by loss of receptors used as portals of entry by pathogens. Recently, mutations in the CXCR4 chemokine receptor gene were identified in a dominantly inherited immunodeficiency disease, WHIM Syndrome. Genetic and biochemical evidences suggest that the loss of the receptor cytoplasmic tail domain results in aberrant signaling. Analyses of mutant cell responses to the receptor ligand CXCL12 have revealed enhanced chemotaxis, confirming the gain-of-function effect of the truncation mutations. The clinical features and potential mechanism of immunodeficiency in WHIM Syndrome patients are discussed in this review.
Laura Dotta - One of the best experts on this subject based on the ideXlab platform.
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Cerebellar involvement in warts Hypogammaglobulinemia immunodeficiency myelokathexis patients: neuroimaging and clinical findings
Orphanet journal of rare diseases, 2019Co-Authors: Jessica Galli, Laura Dotta, Lucia Dora Notarangelo, Vassilios Lougaris, Lorenzo Pinelli, Serena Micheletti, Giovanni Palumbo, Elisa Fazzi, Raffaele BadolatoAbstract:Warts Hypogammaglobulinemia Immunodeficiency Myelokathexis (WHIM) Syndrome is a primary immunodeficiency characterized by recurrent bacterial infections, severe chronic neutropenia, with lymphopenia, monocytopenia and myelokathexis which is caused by heterozygous gain of functions mutations of the CXC chemokine receptor 4 (CXCR4). WHIM patients display an increased incidence of non-hematopoietic conditions, such as congenital heart disease suggesting that abnormal CXCR4 may put these patients at increased risk of congenital anomalies. Studies conducted on CXCR4 and SDF-1-deficient mice have demonstrated the role of CXCR4 signaling in neuronal cell migration and brain development. In particular, CXCR4 conditional knockout mice display abnormal cerebellar morphology and poor coordination and balance on motor testing. In order to evaluate a possible neurological involvement in WHIM Syndrome subjects, we performed neurological examination, including International Cooperative Ataxia Rating Scale, cognitive and psychopathological assessment and brain Magnetic Resonance Imaging (MRI) in 6 WHIM patients (age range 8–51 years) with typical gain of functions mutations of CXCR4 (R334X or G336X). In three cases (P3, P5, P6) neurological evaluation revealed fine and global motor coordination disorders, balance disturbances, mild limb ataxia and excessive talkativeness. Brain MRI showed an abnormal orientation of the cerebellar folia involving bilaterally the gracilis and biventer lobules together with the tonsils in four subjects (P3, P4, P5, P6). The neuropsychiatric evaluation showed increased risk of internalizing and/or externalizing problems in four patients (P2, P3, P4, P6). Taken together, these observations suggest CXCR4 gain of function mutations can be associated with cerebellar malformation, mild neuromotor and psychopathological dysfunction in WHIM patients.
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Long-Term Outcome of WHIM Syndrome in 18 Patients: High Risk of Lung Disease and HPV-Related Malignancies
The journal of allergy and clinical immunology. In practice, 2019Co-Authors: Laura Dotta, Daniele Moratto, Lucia Dora Notarangelo, C. I. Edvard Smith, Fulvio Porta, Vassilios Lougaris, Alessandro Plebani, Rajesh Kumar, Annarosa Soresina, Ac NorlinAbstract:Background In the warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) Syndrome, variable phenotypic expression may delay diagnosis. Panleukopenia, malignancy, and chronic lung disease all affect morbidity and mortality risks. Routinely used treatments include immunoglobulins, granulocyte-colony stimulating factor (G-CSF), and antibiotics; recent trials with a target C-X-C chemokine receptor type 4 (CXCR4) antagonist show promising results. Objective We sought to characterize the largest cohort of patients with WHIM and evaluate their diagnostic and therapeutic management. Methods Data were collected from an international cohort of 18 patients with CXCR4 mutations. Results The clinical features manifested at 2.2 ± 2.6 years of age, whereas the disease diagnosis was delayed until 12.5 ± 10.4 years of age. Patients with WHIM commonly presented with a severe bacterial infection (78%). Pneumonia recurrence was observed in 61% of patients and was complicated with bronchiectasis in 27%. Skin warts were observed in 61% of patients at a mean age of 11 years, whereas human papilloma virus (HPV)-related malignancies manifested in 16% of patients. All the patients had severe neutropenia (195 ± 102 cells/mm3 at onset), whereas lymphopenia and hypogammaglobulinemia were detected in 88% and 58% of patients, respectively. Approximately 50% of patients received antibiotic prophylaxis, whereas G-CSF and immunoglobulin treatments were used in 72% and 55% of patients, respectively. Conclusions The WHIM Syndrome onsets early in life and should be suspected in patients with chronic neutropenia. Patients with WHIM need careful monitoring and timely intervention for complications, mainly lung disease and HPV-related malignancies. We suggest that immunoglobulin therapy should be promptly considered to control the frequency of bacterial infections and prevent chronic lung damage.
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Tetralogy of fallot is an uncommon manifestation of warts, hypogammaglobulinemia, infections, and myelokathexis Syndrome.
The Journal of pediatrics, 2012Co-Authors: Raffaele Badolato, Laura Tassone, Françoise Bachelerie, Laura Dotta, Lucia Dora Notarangelo, Fulvio Porta, Giovanni Amendola, Franco Locatelli, Yves Bertrand, Jean DonadieuAbstract:Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) Syndrome is a rare immunodeficiency disorder. We report three patients with WHIM Syndrome who are affected by Tetralogy of Fallot (TOF). This observation suggests a possible increased risk of TOF in WHIM Syndrome and that birth presentation of TOF and neutropenia should lead to suspect WHIM Syndrome.
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Clinical and genetic features of Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) Syndrome.
Current molecular medicine, 2011Co-Authors: Laura Dotta, Laura Tassone, Raffaele BadolatoAbstract:WHIM Syndrome is a dominantly inherited primary immunodeficiency disorder representing the first identified example of human disease caused by mutations in the gene encoding for the chemokine receptor CXCR4. Pathogenesis is mediated by CXCR4 hyperfunction, leading to increased responsiveness to its unique ligand CXCL12 (also known as SDF-1). The altered CXCR4/CXCL12 interaction likely impairs cellular homeostasis and trafficking, resulting in immunological dysfunctions. The acronym WHIM resumes the main features of the Syndrome: Warts, Hypogammaglobulinemia, Infections and Myelokathexis, which is abnormal retention of mature neutrophils in the bone marrow. WHIM patients suffer from recurrent bacterial infections since childhood and manifest a specific susceptibility to HPV infections. Hematological findings include neutropenia, lymphopenia and hypogammaglobulinemia. Because of the rarity of the disease and the heterogeneity in clinical presentation, diagnosis is often delayed. In the majority of patients, the phenotype is incomplete at the onset and WHIM Syndrome is not suspected. Early identification may improve clinical and therapeutic management. Symptomatic treatments include G-CSF, substitutive immunoglobulins and antibiotic prophylaxis. A new therapeutic strategy might include the potent inhibitor of CXCR4 function plerixafor (Mozobil), as an agent specifically targeting the molecular defect in order to attenuate the phenotypic manifestations of the Syndrome.
