WHIM syndrome

A hereditary autosomal dominant immunologic deficiency syndrome characterized by NEUTROPENIA; AGAMMAGLOBULINEMIA, and extensive human papillomavirus (HPV) infection. Despite the peripheral neutropenia, bone marrow aspirates from affected individuals contain abundant mature MYELOID CELLS (myelokathexis). The susceptibility to HPV is disproportionate compared with other immunodeficiency conditions. Mutations in the CXCR4 gene have been identified. OMIM: 193670

Also Known As:

Networked: 84 relevant articles (3 outcomes, 14 trials/studies)

Relationship Network

Disease Context: Research Results

Related Diseases

1.	Chromothripsis
2.	Warts (Wart)
3.	Neoplasms (Cancer)
4.	Agammaglobulinemia (Hypogammaglobulinemia)
5.	Infections

Experts

1.	McDermott, David H: 18 articles (01/2022 - 10/2010)
2.	Murphy, Philip M: 18 articles (01/2021 - 10/2010)
3.	Liu, Qian: 10 articles (12/2019 - 10/2010)
4.	Bachelerie, Françoise: 7 articles (10/2017 - 07/2008)
5.	Gao, Ji-Liang: 6 articles (12/2019 - 01/2015)
6.	Malech, Harry L: 6 articles (02/2015 - 10/2010)
7.	Balabanian, Karl: 5 articles (01/2021 - 07/2008)
8.	Ulrick, Jean: 5 articles (04/2014 - 10/2010)
9.	Yim, Erin: 4 articles (12/2019 - 02/2015)
10.	Velez, Daniel: 4 articles (10/2019 - 04/2014)

Drugs and Biologics

Drugs and Important Biological Agents (IBA) related to WHIM syndrome:

1.	plerixaforFDA Link 10/01/2011 - "WHIM mutations may potentiate CXCR4 signalling, suggesting that the United States Food and Drug Administration (FDA)-approved CXCR4 antagonist AnorMED3100 (AMD3100) (also known as Plerixafor) may be beneficial in WHIM syndrome. " 10/01/2019 - "Plerixafor for the Treatment of WHIM Syndrome." 01/01/2019 - "Plerixafor for the Treatment of WHIM Syndrome. " 01/01/2019 - "Plerixafor for the Treatment of WHIM Syndrome." 01/01/2017 - "Plerixafor is FDA-approved for hematopoietic stem cell (HSC) mobilization and has shown preliminary safety and efficacy in phase I clinical trials in WHIM syndrome. "
2.	mavorixaforIBA 12/24/2020 - "We report the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mavorixafor from a phase 2 open-label dose-escalation and extension study in 8 adult patients with genetically confirmed WHIM syndrome. " 06/29/2023 - "Results of a phase 2 trial of an oral CXCR4 antagonist, mavorixafor, for treatment of WHIM syndrome. " 12/24/2020 - "Results of a phase 2 trial of an oral CXCR4 antagonist, mavorixafor, for treatment of WHIM syndrome." 12/24/2020 - "This study demonstrates that mavorixafor, 400 mg once daily, mobilizes neutrophil and lymphocytes in adult patients with WHIM syndrome and provides preliminary evidence of clinical benefit for patients on long-term therapy. "
3.	Chemokine ReceptorsIBA 07/06/2023 - "WHIM syndrome is an autosomal dominant immunodeficiency disorder caused by gain-of-function mutations in chemokine receptor CXCR4 that promote severe panleukopenia because of retention of mature leukocytes in the bone marrow (BM). " 01/01/2023 - "The pathophysiology of WHIM syndrome is due to an autosomal dominant gain of function mutation in the CXCR4 chemokine receptor resulting in increased activity that impairs neutrophil migration from the bone marrow into the peripheral blood. " 01/01/2022 - "While several gain-of-function mutations that lead to C-terminal truncations, frame shifts and point mutations in the chemokine receptor CXCR4 have been identified in WHIM syndrome patients, the functional effect of these mutations are not fully understood. " 01/01/2022 - "Characterization of a new WHIM syndrome mutant reveals mechanistic differences in regulation of the chemokine receptor CXCR4." 01/01/2018 - "WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is a genetic autoimmune disorder that results from gain-of-function mutations in the gene encoding chemokine receptor CXCR4. "
4.	ArrestinIBA 01/01/2022 - "Taken together, these studies identify a new WHIM syndrome mutant, CXCR4-S339fs5, which promotes enhanced signaling, reduced phosphorylation, β-arrestin binding and endocytosis, and a very high basal rate of degradation that is not protected by antagonist treatment." 01/01/2017 - "Together, these studies demonstrate the role Ser-346/7 plays in arrestin recruitment and initiation of receptor desensitization and provide insight into the dysregulation of CXCR4 observed in patients with various forms of WHIM syndrome." 01/01/2023 - "Reduced G protein signaling despite impaired internalization and β-arrestin recruitment in patients carrying a CXCR4Leu317fsX3 mutation causing WHIM syndrome." 01/01/2019 - "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. "
5.	Granulocyte Colony-Stimulating Factor (G-CSF)IBA 10/01/2019 - "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. " 10/02/2023 - "A phase III randomized crossover trial of plerixafor versus G-CSF for treatment of WHIM syndrome." 10/01/2019 - "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. " 10/02/2023 - "The CXCR4 antagonist plerixafor mobilizes leukocytes to the blood; however, its safety and efficacy in WHIM syndrome are undefined.METHODSIn this investigator-initiated, single-center, quadruple-masked phase III crossover trial, we compared the total infection severity score (TISS) as the primary endpoint in an intent-to-treat manner in 19 patients with WHIM who each received 12 months treatment with plerixafor and 12 months treatment with granulocyte CSF (G-CSF, the standard of care for severe congenital neutropenia). "
6.	GTP-Binding Proteins (G-Protein)IBA 01/23/2021 - "Studies have clarified that the loss of phosphorylation sites in the C-terminus of truncated CXCR4 impairs the desensitization process, enhances the activation of G-protein, prolongs downstream signaling pathways and introduces over immune responses, thereby causing WHIM syndrome. " 01/01/2023 - "Reduced G protein signaling despite impaired internalization and β-arrestin recruitment in patients carrying a CXCR4Leu317fsX3 mutation causing WHIM syndrome." 04/10/2014 - "Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare immunodeficiency disorder caused by gain-of-function mutations in the G protein-coupled chemokine receptor CXCR4. " 01/01/2019 - "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. " 01/01/2014 - "The G-protein coupled chemokine (C-X-C motif) receptor CXCR4 is linked to cancer, HIV, and WHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome. "
7.	LigandsIBA 01/01/2019 - "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." 12/01/2009 - "Leukocytes from patients with WHIM syndrome display impaired CXCR4 internalization and enhanced chemotaxis in response to its unique ligand SDF-1/CXCL12, which likely contribute to the clinical manifestations. " 02/01/2011 - "Both clinical observations initially appeared to be very similar to WHIM syndrome (Warts, Hypogammaglobulinemia, Infection, Myelokathexis), a rare immunodeficiency disease correlated with CXC chemokine receptor 4 (CXCR4) mutation leading to an impaired internalization of the receptor upon its ligand CXCL12. " 01/01/2005 - "These primary immunodeficiencies are caused by germline mutations in seven genes: ELA2, encoding a neutrophil elastase, and GFI1, encoding a regulator of ELA2 (mutations associated with severe congenital neutropenia); CXCR4, encoding a chemokine receptor (warts, hypogammaglobulinemia, infections and myelokathexis syndrome); LCRR8, encoding a key protein for B-cell development (agammaglobulinemia); IFNGR1, encoding the ligand-binding chain of the interferon-gamma receptor; STAT1, encoding the signal transducer and activator of transcription 1 downstream from interferon-gammaR1 (Mendelian susceptibility to mycobacterial diseases); and IKBA, encoding IkappaBalpha, the inhibitor alpha of NF-kappaB (anhidrotic ectodermal dysplasia with immunodeficiency). "
8.	ChemokinesIBA 06/01/2013 - "These conditions encompass defects in the steps that are required for leukocyte motility: from the response to chemokines, which is altered in warts, hypogammaglobulinemia, infections, and myelokathexis syndrome, to the impairment of leukocyte adhesion and migration found in leukocyte adhesion deficiency syndrome, and finally to abnormal actin filament formation, which is affected in leukocytes of Wiskott-Aldrich syndrome patients. " 12/01/2003 - "The identification of chemokine receptor CXCR4 as the causative gene of WHIM syndrome yields new interest in the study of this disease as a model for the comprehension of CXCR4 biology in humans and highlights the importance of the chemokine network for inducing effective immune responses and governing leukocyte trafficking. " 01/01/2018 - "The broad importance of CXCL12 is revealed by the complex lethal developmental phenotypes in mice lacking either Cxcl12 or either one of its two known 7-transmembrane domain receptors Cxcr4 and Ackr3, as well as by gain-of-function mutations in human CXCR4, which cause WHIM syndrome, a multisystem and combined immunodeficiency disease and the only Mendelian condition caused by a chemokine system mutation. "
9.	CXCR4 Receptors (CXCR4 Receptor)IBA 01/01/2016 - "In this review, we discuss of CXCR4 receptor properties and signaling in health and diseases, focusing on the WHIM syndrome, an inherited immunodeficiency caused by mutations of the CXCR4 gene." 07/01/2008 - "WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is an immune deficiency linked in many cases to heterozygous mutations causing truncations in the cytoplasmic tail of CXC chemokine receptor 4 (CXCR4). " 10/01/2019 - "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). " 01/01/2019 - "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). " 08/22/2008 - "For instance, CXCL12 has been shown to mediate human immunodeficiency virus-induced neurotoxicity, proliferative retinopathy and chronic inflammation, whereas its receptor CXCR4 is involved in human immunodeficiency virus infection, cancer metastasis and in the rare disease known as the warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis (WHIM) syndrome. "
10.	G-Protein-Coupled Receptors (Receptors, G Protein Coupled)IBA 12/01/2013 - "G protein-coupled receptor kinase-3-deficient mice exhibit WHIM syndrome features and attenuated inflammatory responses." 12/01/2010 - "CXCR4 is a G-protein coupled receptor for CXCL12 that plays an important role in human immunodeficiency virus infection, cancer growth and metastasization, immune cell trafficking and WHIM syndrome. " 12/01/2009 - "Since beta-Arrestins and Grks play critical roles in phosphorylation and internalization of agonist-activated G protein-coupled receptors, these results provide a molecular basis for CXCR4 dysfunction in WHIM syndrome." 03/05/2010 - "The chemokine receptor CXCR4 is a widely expressed G protein-coupled receptor that has been implicated in a number of diseases including human immunodeficiency virus, cancer, and WHIM syndrome, with the latter two involving dysregulation of CXCR4 signaling. "

Therapies and Procedures

1.	Therapeutics 01/01/2021 - "This study aimed to employ WHIM syndrome pathogenesis as an inspirational approach to reinforce cell therapies. " 11/01/2022 - "The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. " 01/01/2017 - "WHIM syndrome may be particularly amenable to mechanism-based therapeutics for three reasons: 1) CXCR4 has been validated as the molecular target in the disease by Mendelian genetics; 2) the biochemical abnormality is excessive CXCR4 signaling; and 3) antagonists selective for CXCR4 have been developed. " 06/24/2007 - "The authors summarize current knowledge on molecular basis, diagnostic criteria, therapy, and clinical manifestations of WHIM syndrome. " 12/24/2020 - "This study demonstrates that mavorixafor, 400 mg once daily, mobilizes neutrophil and lymphocytes in adult patients with WHIM syndrome and provides preliminary evidence of clinical benefit for patients on long-term therapy. "
2.	Hematopoietic Stem Cell Mobilization 04/10/2014 - "The CXCR4 antagonist plerixafor, which is approved by the US Food and Drug Administration (FDA) for stem cell mobilization in cancer and administered for that indication at 0.24 mg/kg, has been shown in short-term (1- to 2-week) phase 1 dose-escalation studies to correct neutropenia and other cytopenias in WHIM syndrome. "
3.	Drug Therapy (Chemotherapy) 04/03/2020 - "These mutations closely resemble those occurring in Warts, Hypogammaglobulinemia, Immunodeficiency, and Myelokathexis (WHIM) syndrome, an immunodeficiency associated with CXCR4 aberrant expression and activity and with chemotherapy resistance in clinical trials. "
4.	Transplantation 02/12/2015 - "In competitive mouse bone marrow (BM) transplantation experiments, Cxcr4 haploinsufficiency was sufficient to confer a strong long-term engraftment advantage of donor BM over BM from either wild-type or WHIM syndrome model mice, suggesting a potential mechanism for the patient's cure. " 09/01/2023 - "He underwent allogeneic cord blood transplantation for warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome and developed intestinal late-onset aGVHD 31 months after transplantation. " 01/01/2018 - "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. "
5.	Bone Marrow Transplantation (Transplantation, Bone Marrow) 01/01/2015 - "Chromothriptic cure of WHIM syndrome: Implications for bone marrow transplantation." 01/01/2018 - "Cxcr4-haploinsufficient bone marrow transplantation corrects leukopenia in an unconditioned WHIM syndrome model."