Mutations in the cxcr4 gene affecting cterminal phosphorylation sites are a hallmark of whim syndrome, a genetic disorder characterized by a gain. Two cases of disseminated mycobacterium avium infection. Whim syndrome is a rare primary immunodeficiency disorder, which are disorders in which the bodys immune system does not function properly. Background epidermodysplasia verruciformis ev is a rare genodermatosis associated with infections with specific human papillomaviruses hpvs belonging to the. The specific roles of the two major innate immune cell types neutrophils and macrophages in response to infection and sterile inflammation are areas of great interest. Multiple methods have been developed in larval zebrafish to specifically. She said that she and two of her three daughters, ages 21 and 23, wanted to be evaluated for whim syndrome. A dose determination and safety study of x4p001 mavorixafor in participants with warts, hypogammaglobulinemia, infections, and myelokathexis whim syndrome the safety and.
Whim syndrome is an autosomal dominant disorder of warts, hypogammaglobulinemia, infections, and myelokathexis caused by heterozygous gainoffunction. The warts, hypogammaglobulinemia, infections, myelokathexis whim syndrome is an immunodeficiency caused by mutations in chemokine receptor cxcr4. Whim syndrome genetic and rare diseases information. The whim syndrome is no longer a whim the journal of allergy. Warts are superficial viral infections of the skin that are extremely common in children. Whim syndrome is the acronym for warts, hypogammaglobulinemia, infections, myelokathexis. A targeted oral therapy for patients with whim syndrome david dale 1, frank firkin 2, audrey anna bolyard 3, emily dick 2, merideth l. Warts, hypogammaglobulinemia, infections, and myelokathexis. Second, the chromothripsis patient whim09 has provided direct evidence that selectively inactivating the mutant cxcr4 allele in the myeloid lineage. Twin to twin transfusion syndrome vici syndrome whim syndrome wiskott aldrich syndrome woods black norbury syndrome. We have previously shown that whimmutant t cells form unstable immunological synapses, affecting t cell activation.
Pdf chromothripsis is a catastrophic cellular event recently described in cancer in which. Whim patients suffer from recurrent bacterial infections since childhood and manifest a specific susceptibility to hpv infections. Interleukin2unresponsive immune defects in good syndrome. Whim syndrome is a rare congenital immunodeficiency disease, named after its main clinical manifestations. Oral surgery, oral medicine, oral pathology, oral radiology. Kelley 1, vahagn makaryan 1, ramsey johnson 3, lu gan 3, and. Clinical immunology vol 5, issue 3, pages 347502 june. Whim syndrome or warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis syndrome is a rare congenital immunodeficiency disorder characterized by chronic noncyclic neutropenia pathophysiology. Recently, plerixafor amd3100, mozobil, a cxcr4 antagonist, has been used to treat whim patients, resulting in partial responses in the outward appearance of skin warts. About whim syndrome whim syndrome is a rare, primary immunodeficiency disease caused by genetic mutations in the cxcr4 receptor gene and is named for the characteristic clinical symptoms of the syndrome w arts, h ypogammaglobulinemia, infections, and m yelokathexis.
Myelokathexis is key to the clinical diagnosis of whim syndrome. Clinical and genetic features of warts, hypogammaglobulinemia. Paride iannella lucia del vecchio francesco locatelli. Their high turnover rate, their finetuned killing machinery, and their arsenal of toxic vesicles leave them particularly vulnerable to various genetic. This inability to fight infection can be caused by a number of conditions including illness and disease eg, diabetes, hiv, malnutrition, and drugs.
Bartter syndrome is a rare, genetically heterogeneous, mainly autosomal recessively inherited condition characterized by hypochloremic hypokalemic metabolic alkalosis. Warts, hypogammaglobulinemia, infections, and myelokathexis whim is an immunodeficiency with autosomal dominant inheritance. Of the 60 known individuals with whim syndrome, 29 of whom are patients at the nih, there had been no record of a patient recovering. X4 pharmaceuticals initiates pivotal phase 3 clinical. Whim syndrome is a rare combined primary immunodeficiency disease named by acronym for the diagnostic tetrad of warts, hypogammaglobulinemia, infections, and myelokathexis. The disease is primarily caused by cterminal truncation mutations of the chemokine receptor cxcr4, giving these cxcr4 whim. Whim patient adaptive immunity defects remain largely unexplained. In most kindred gain of function mutations of the chemokine receptor cxcr4 have been identified as the cause of the disease. Whim syndrome ws, a rare congenital neutropenia due to mutations of the cxcr4 chemokine receptor, is associated with human papillomavirus hpvinduced warts. Adaptive immunodeficiency in whim syndrome ncbi nih. The chemokine receptor cxcr4 regulates cell migration during ontogenesis and disease states including cancer and inflammation.
The three patients who received long term gcsf therapy, interrupted treatment. Metagenomic discovery of 83 new human papillomavirus types in. Whim syndrome warts hyopogammaglobulinemia nfections. To the best of our knowledge, this is the first report of whim syndrome in korea. Jul 16, 2019 whim syndrome is usually caused by autosomal dominant mutations in the g proteincoupled chemokine receptor cxcr4 that impair desensitization, resulting in enhanced and prolonged g protein and. While this treatment shows promise in treating neutropenia decreased white blood cells, this trial. The whimlike cxcr4 s338x somatic mutation activates akt and. Frontiers dysplasia of granulocytes in a patient with hpv. Abstract myers kc, bolyard aa, leung j, moore j, loveless s, mount l, harris re, davies sm, keel s, dale dc, shimamura a. Whim syndrome is a rare immunodeficiency disorder characterized by papillomavirusinduced w arts, h ypogammaglobulinemia, recurrent bacterial i nfection, and m yelokathexis, a type of neutropenia associated with the retention and death of mature neutrophils in the bone marrow.
Monomac syndrome in a patient with a gata2 mutation. A report of whim syndrome myelokathexis clinical features and bone marrow morphology. Whim syndrome is a primary immunodeficiency disease caused by a mutation in the cxc receptor type 4 cxcr4 gene resulting in susceptibility to certain types of infections. Review article congenital defects in neutrophil dynamics martonkeszeiandlisas. Given the variability in clinical presentation, the discovery of whim syndrome was. Treatment consists on monthly injections of intravenous immunoglobulin, which may reduce the incidence.
Pathogenesis, diagnosis and therapeutic strategies in whim. There currently are no approved treatments for whim syndrome. In one patient with whim syndrome, the natural deletion of one copy of the gene reportedly resulted in a cure, with spontaneous and complete remission of warts, sustained correction of neutropenia and monocytopenia, and normalization of bone marrow pathology. Chemokine receptors are gpcrs that are critically involved in leukocyte migration, and their mutation can lead to altered signaling and migratory behavior, leading to immune system impairment. A retrospective and prospective natural history study of patients with whim syndrome the safety and scientific validity of this study is the responsibility of the study sponsor and. Jul 19, 2011 a report of whim syndrome myelokathexis clinical features and bone marrow morphology. There was no family history of susceptibility to infection or neutropenia. This treatment resulted in a significant increase in the. Second, the chromothripsis patient whim09 has provided direct evidence that selectively inactivating the mutant cxcr4 allele in the myeloid lineage can eliminate the main clinical manifestations of the disease. Myelokathexis refers to the retention of mature neutrophils in the bone marrow bm, which accounts for degenerative changes and hypersegmentation. Whim syndrome is an immunodeficiency disease characterized by neutropenia, hypogammaglobulinemia, and extensive human papillomavirus hpv infection. Whim syndrome suffer from an extremely rare genetic immunode. Acute myeloid leukemia arising after hodgkin lymphoma in a.
Primary cutaneous follicle center lymphoma in a patient with. The larval zebrafish model of innate immunity, and the imaging capabilities it provides, is a source of new research and discoveries in this field. Whim is an acronym for some of the characteristic symptoms of the disorder warts, h ypogammaglobulinemia, i nfections. Whim syndrome is one of only a few diseases directly and primarily caused by an aberrant chemokine, making its molecular biology important in understanding the role of cell signaling and trafficking. Since whim syndrome is a subtype of severe congenital neutropenia scn, patients are commonly treated with granulocyte colonystimulating factor gcsffilgrastim, neupogen. Two cases of disseminated mycobacterium avium infection associated with a new immunode. Whim syndrome is an acronym for a rare immunodeficiency disorder with each letter representing a predominant feature of the condition.
These include the warts, hypogammaglobulinemia, infections, and myelokathexis whim syndrome, which results from dominant gain of function mutations in chemokine receptor cxcr4 leading to retention of mature neutrophils in the bone marrow. First, only one cxcr4 allele is mutated in the disease. Further controlled assessment of the safety and efficacy of plerixafor in patients with whim syndrome is a challenge because the disease is extremely rare. Description and outcome of a cohort of 8 patients with. Our murine experiments suggest this would be safe and ef. Warts, hypogammaglobulinemia, infections and myelokathexis, which is abnormal retention of mature neutrophils in the bone marrow. The infection usually lasts more than 1 year and can be moderately contagious in specific settings. Cxcr4specific nanobodies as potential therapeutics for. Mcdermott and colleagues administered the cxcr4 antagonist, plerixafor, to 3 patients with whim syndrome in a phase 1 study. Upon stimulation by the endogenous ligand cxcl12, cxcr4 becomes phosphorylated at multiple sites in its cterminal domain. Dale 1, audrey anna bolyard 2, emily dick 2, merideth l.
Westerberg department of microbiology tumor and cell biology, karolinska institutet, stockholm, sweden. Mar 03, 2008 pdf abstract leukocytes from individuals with warts, hypogammaglobulinemia, infections, and myelokathexis whim syndrome, a rare immunodeficiency, and bearing a wildtype cxcr4 orf whimwt display impaired cxcr4 internalization and desensitization upon exposure to cxcl12. Review articletrends in medicine tim october, 2008. Since the root cause of whim syndrome is a mutation in a specific gene cxcr4, gene editing techniques may provide a promising avenue for research. Jul 17, 2019 the case is interesting because the patient exemplifies widely known aspects of the disease, demonstrating classic features of whim syndrome, while at the same time manifests aspects of the syndrome which clinicians unfamiliar with the disease may not be aware of such as biological combined immune deficiency or a history of tetralogy of fallot. But knowing about this unique case suggests that manipulation of bone marrow stem cells to inactivate the mutant gene, perhaps using the crisprcas system see copy editing. Pdf chromothriptic cure of whim syndrome researchgate.
Md, a distinguished professor of medicine in cardiology, both at mayo clinic in rochester, minnesota. Hierarchical organization of multisite phosphorylation at. Frontiers cxcl12 mediates aberrant costimulation of b. Longterm clinical remission of whim syndrome and evidence for somatic. Whim syndrome is a rare congenital immune deficiency, characterized by warts, hypogammaglobulinemia, infections, and myelokathexisthat form the acronym of its name. Here, we show that, in whim patients and whim cxcr4 knockin. Whim syndrome is due to heterozygous mutations affecting the cterminus of cxcr4, a chemokine receptor mapped on 2q21 locus and expressed by both hematopoietic and nonhematopoietic cells. Accordingly, cxcr4 antagonists have shown promise as mechanismbased treatments in phase 1 clinical trials. Karyotype of a woman spontaneously cured of whim syndrome. Waldenstrom macroglobulinemia wm is a distinct clinicopathologic entity characterized by the presence of a lymphoplasmacytic lymphoma, a nonhodgkin lymphoma, and igm monoclonal gammopathy. Pdf a report of whim syndrome myelokathexis clinical. Cerebellar involvement in warts hypogammaglobulinemia. Letter to the editor successful hematopoietic stem cell transplantation for myelo. Whim syndrome ws, a rare congenital neutropenia due to.
Here we describe a korean child with whim syndrome who had a novel cxcr4 mutation. Of course, restricting editing to the mutant cxcr4 allele would be key to safety. Sep 01, 2012 the result is believed to be overactivation and uncontrolled signaling, which is known to promote bone marrow neutrophil retention in mice. Description and outcome of a cohort of 8 patients with whim. Plerixafor for the treatment of whim syndrome nejm. Warts, hypogammaglobulinemia, infections, and myelokathexis whim syndrome immunodeficiency is caused by autosomal dominant gainoffunction mutations in chemokine receptor cxcr4. Warts, hypogammaglobulinemia, infections, and myelokathexis whim syndrome is a rare, autosomal dominant, combined immunodeficiency disorder caused by mutations in the cterminus of cxcr4 that. Jun 10, 2014 the use of cxcr4 antagonists may therefore offer a targeted approach to therapy of wm patients with whim like somatic mutations, particularly given their success in patients with whim syndrome. Warts hypogammaglobulinemia immunodeficiency myelokathexis whim syndrome is a rare primary immunodeficiency characterized by recurrent bacterial infections, severe congenital.
Whim syndrome may be particularly amenable to gene editing as a cure strategy for three reasons. Primary cutaneous follicle center lymphoma in a patient with whim syndrome. A novel molecularlytargeted oral therapy for whim syndrome david c. Neutrophil granulocytes are key effector cells of the vertebrate immune system.
Scott wright, a professor of medicine in cardiology facilitates a conversation with dr. In the literature clinical infectious diseases oxford. The acronym whim resumes the main features of the syndrome. Results cure of a patient with whim syndrome the index patient, designated whim 09, is a white female who presented at age 58 to the nih requesting evaluation for herself and two of her three daughters, designated whim. Whim syndrome is a rare, autosomal dominant immunodeficiency which is named for the four key manifestations. Whim syndrome is a condition in which affected persons have chronic peripheral neutropenia, lymphopenia, abnormal susceptibility to human papilloma virus infection, and myelokathexis.
An immunocompromised host is a patient who does not have the ability to respond normally to an infection due to an impaired or weakened immune system. Whim syndrome with a novel cxcr4 variant in a korean child. Myelokathexis is amongst the diseases treated with bone marrow transplantation and cord blood stem cells. Whim is an abbreviation for the characteristic clinical symptoms of the syndrome. Aug 14, 2019 cxcr4 plays a physiological role in hematopoiesis 73,74, leukocyte trafficking 7577, cell migration and embryo development, as well as a pathological function in hiv pathogenesis, whim syndrome and cancer 81,82. Most patients present heterozygous autosomal dominant mutations. Recommendations are initially drafted by clinical editors including. Review article congenital defects in neutrophil dynamics. A retrospective and prospective natural history study of. Warts hypogammaglobulinemia immunodeficiency myelokathexis whim syndrome is a rare primary immunodeficiency characterized by recurrent bacterial infections, severe congenital neutropenia, with lymphopenia and monocytopenia, associated with myelokathexis in the bone marrow, the latter resulting from the abnormal retention of neutrophils that become senescent 1,2,3,4.
Gene editingbased gene therapy is also now under investigation as a cure strategy in whim syndrome, as in other inherited diseases of the blood. Determining macrophage versus neutrophil contributions to. The case is interesting because the patient exemplifies widely known aspects of the disease, demonstrating classic features of whim syndrome, while at the same time manifests aspects of the syndrome. Whim syndrome is a rare congenital immunodeficiency disorder characterized by chronic noncyclic neutropenia. Unlimited viewing of the articlechapter pdf and any.
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