Its name is an acronym for its main clinical manifestations. Whim syndrome is an inherited immunodeficiency caused by overactivity of cxcr4, a receptor controlling production and distribution of leukocytes in bone marrow and blood. It is a primary immunodeficiency disorder caused by irregularities in cell development or maturation. Pubmed is a searchable database of medical literature and lists journal articles that discuss whim syndrome. Individuals with whim syndrome are more susceptible to potentially lifethreatening bacterial infections. It turned out that the woman nih rare disease day 2015 teamwork of scientists and community brings treatments to fruition by lesley earl nci and emily petrus ninds eurordis. Pbs and incubated with blocking buffer 5% fatfree milk powder. Click on the link to view a sample search on this topic. Whim syndrome warts hyopogammaglobulinemia nfections. Chromothripsis chromosomal shattering resulted in clinical cure of a patient with a rare immunode. Whim syndrome epidemiology forecast report is published on june 15, 2020 and has 100 pages in it. Jun 19, 2019 according to a story from business wire, the biopharmaceutical company x4 pharmaceuticals, inc. Aug 01, 20 importantly, the whim mutant cxcr4 was refractive to ligandinduced internalization supplemental figure 1, available on the blood web site, which is a hallmark of whim syndrome. 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.
We identified a whim patient cured by chromothripsis chromosome shattering that fortuitously deleted the abnormal copy of the cxcr4 gene in a single hematopoietic stem cell, which then took over the bone marrow and restored. The past medical history revealed that whim 09 was in fact the first patient ever described with myelokathexis, the key hematopathologic feature in whim syndrome, reported in two articles published in the new england journal of medicine nejm in 1964 krill et al. The cxcr4 mutations in whim syndrome impair the stability. Warts, hypogammaglobulinemia, infections, and myelokathexis whim syndrome is a rare, autosomal. 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. In essence, the patient had deleted the bad copy of the gene and was now cured. A phase 1 clinical trial of longterm, lowdose treatment of whim syndrome with the cxcr4 antagonist plerixafor.
Treatment consists on monthly injections of intravenous immunoglobulin, which may. Chromothriptic cure of whim syndrome sciencedirect. Whim syndrome is a rare combined immunodeficiency disorder characterized by. Leukocyte analysis from whim syndrome patients reveals a. Nov, 2011 access to this database is free of charge. Treatment approaches currently include antibiotic prophylaxis. Therefore, the diagnosis of whim syndrome may be overlooked by. Whim syndrome whim is a congenital immune deficiency with characteristic. Bibliographic data, as of june 2018 only 65 cases of whim syndrome had been. A phase 1 clinical trial of longterm, lowdose treatment.
The study of inherited immunodeficiencies has proven valuable in elucidating molecular signaling cascades underlying the developmental and functional regulation of the human immune system. As a result of cxcl12 binding to mutated cxcr4 in whim syndrome, white blood cells. Warts, hypogammaglobulinemia, infections, and myelokathexis whim syndrome is a rare immunodeficiency disorder characterized by warts, hypogammaglobulinemia, infections, and abnormal retention of mature neutrophils in the bone marrow myelokathexis. This work was supported by the national committee for scientific research grant no. Whim 09 is the only patient known to have had a beneficial outcome from chromothripsis 15. She said that she and two of her three daughters, ages 21 and 23, wanted to be evaluated for whim syndrome. Murphy, md, chief, molecular signaling section, laboratory of molecular immunology. Vaccines free fulltext new insights on the emerging. Warts, hypogammaglobulinemia, infections and also myelokathexis, which refers to abnormal accumulation of mature neutrophils in the bone marrow. Moreover, malignant cells also express a selective repertoire of chemokine receptors that sustain their growth and. Test results for neutrophil antibodies, antinuclear antibodies, human immunodeficiency virus, isoagglutinin titers, and antibody responses to. Objective to evaluate serial application of the wessex head injury matrix whim in diagnosis of prolonged disorders of consciousness pdoc. The order of presentation and severity of symptoms vary from patient to patient. We identified a whim patient cured by chromothripsis chromosome shattering that fortuitously deleted the abnormal copy of the cxcr4 gene in a single hematopoietic stem cell, which then took over the bone marrow and.
Whim syndrome is a rare, autosomal dominant immunodeficiency which is named for the four. Whim w arts, h ypogammaglobulinemia, infections, and m yelokathexis syndrome, a rare, inherited, primary immunodeficiency disease the company is targeting with its phase 3 clinical candidate mavorixafor. A database of published information on patients with whim syndrome was constructed from case and cohort reports, comprising 88 cases with patientspecific data case dataset7 and a cohort of 21 patients described by dotta et al. 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. Whim syndrome is an autosomal dominant immunodeficiency disease caused by mutations affecting the carboxyterminus of cxcr4. Whim syndrome is an autosomal dominant disorder of warts, hypogammaglobulinemia, infections, and myelokathexis caused by heterozygous gainoffunction mutations in the gene encoding the cxcr4 chemokine receptor kawai and malech, 2009. Chief, laboratory of molecular immunology, national institute o. Serial measurement of wessex head injury matrix in the. Warts, hypogammaglobulinemia, infections, and myelokathexis whim syndrome is a rare genetic disease of the immune system. The immune systems job is to keep the human body healthy, and free from infections. Familial occurrence of warts, hypogammaglobulinemia. Making the diagnosis of whim syndrome is very challenging.
Whim syndrome nord national organization for rare disorders. Sarah cohen md, medical director rare diseases, x4 pharmaceuticals, discusses the diagnostic journey of whim syndrome. A phase 1 clinical trial of longterm, lowdose treatment of. Case studies in immunology a clinical companion 7th. These whim mutations render cxcr4 hyperresponsive to its ligand cxcl12 together with impaired desensitization and internalization of the mutant receptor balabanian et al.
Whim syndrome epidemiology forecast market research. If you have problems viewing pdf files, download the latest version of adobe reader. The warts, hypogammaglobulinemia, infections, and myelokathexis whim syndrome. Whim syndrome definition of whim syndrome by medical dictionary. Based on the patient described in this article, whim 09, and subsequent mechanistic. Plerixafor for the treatment of whim syndrome request pdf. According to the orphanet report seriesprevalence of rare diseases. Warts, hypogammaglobulinemia, infections, and myelokathexis. Whim 09 to engraft can be attributed to the loss of one cxcr4 allele in that cell. X4s most advanced product candidate, mavorixafor x4p001, is in a global phase 3 pivotal trial in patients with whim syndrome, a rare, inherited, primary immunodeficiency disease, and is currently also under investigation in combination with axitinib in the phase 2a portion of an openlabel phase 12 clinical trial in clear cell renal cell carcinoma ccrcc. Whim syndrome genetic and rare diseases information center.
Whim syndrome genetic and rare diseases information. The m in the acronym whim refers to myelokathexis, the. While this treatment shows promise in treating neutropenia decreased white blood cells, this trial showe. Whim syndrome is characterized by neutropenia, lymphopenia, and. This webinar will be relevant to health care providers who specialize in immunologic, hematologic, or dermatologic disorders. It is caused by mutations in the cxcr4 gene and is inherited in an autosomal dominant manner. It is suggested that perinatal diagnostics of whim syndrome based on a molecular dna analysis of cord blood cells should be performed in cases of pregnancy of affected mothers. Specifically, to determine whether the trajectory of change predicts outcome status, and whether the current hierarchical order of whim items is correct for this context.
The whim syndrome is no longer a whim the journal of allergy. Her white blood cells were missing a large portion of chromosome 2, where the mutated whim allele resides. Feb 06, 2019 whim syndrome is a primary immunodeficiency disorder, one of a group of disorders characterized by irregularities in the cell development andor cell maturation process of the immune system. Fortuitously, the original chromothriptic hsc in whim 09 acquired a selective advantage and repopulated both the hsc pool and the entire myeloid lineage. The mature neutrophils retained in the patients bone marrow and undergo apoptotic death, therefore resulted in the lack of neutrophils in peripheral stream 8, 9. Case studies in immunology 7th edition pdf free cites major topics of immunology as the background to a selection of real clinical cases that serve to reinforce and extend the basic science. The impact of whim mutations on lymphocytes and adaptive immunity has received less attention than.
Whim syndrome is an immunodeficiency disease characterized by neutropenia, hypogammaglobulinemia, and extensive human papillomavirus hpv infection. Whim syndrome is the acronym for warts, hypogammaglobulinemia. The truncation of the receptor protein results in the inability of downregulation after stimulation. An accurate diagnosis is essential to offer proper treatment. Whim syndrome is a rare combined primary immunodeficiency disorder. Whim syndrome caused by waldenstroms macroglobulinemia. Ijms free fulltext adaptive immunodeficiency in whim syndrome. Warts, hypogammaglobulinemia, infections, and myelokathexis whim syndrome omim 193670 is an extremely rare, combined primary immunodeficiency disorder found worldwide, that is estimated to have an incidence of 0. The immune system is divided into several components, the combined actions of which are responsible for defending against infectious agents. Interestingly, besides the germline cxcr4 mutations in whim syndrome, somatic whim like mutations are found in 30% of the patients with. Nov 05, 2019 warts, hypogammaglobulinemia, infections, and myelokathexis whim syndrome is a rare, combined primary immunodeficiency disease caused in almost all cases by autosomal dominant, gainoffunction mutations in the gene encoding chemokine receptor cxcr4 1, 2. This syndrome is very rare, with only 60 cases being reported in medical literature. Jun 14, 2020 syndrome whim warts, hypogammaglobulinemia, infections and mielocatexis is a disease dominant immune autosomal congenital characterized by abnormal retention of mature neutrophils in the bone marrow mielocatexis with occasional hypogammaglobulinemia associated with an increased risk of bacterial infections and lesions induced susceptibility to the virus human papillomavirus hpv skin. Pathogenesis, diagnosis and therapeutic strategies in whim syndrome immunodeficiency.
The patient reported that from childhood through age 38, she had had many serious infections, often requiring hospitalization, but then none in the 20 subsequent years. The clinical presentation and diagnostic journey of whim syndrome will be highlighted through the case study of a family with whim syndrome. Whim syndrome is a rare congenital immunodeficiency disorder characterized by chronic. The negative charge of the 343 site is essential for. Fda for the treatment of whim syndrome treatment is directed tow. Whim syndrome is a type of primary immunodeficiency where the bodys. The cxcr4 mutations in whim syndrome impair the stability of. World map of whim syndrome find people with whim syndrome through the map. Whim syndrome is a rare primary immunodeficiency disorder, which are disorders. Whim syndrome stands for warts, hypogammaglobulinemia, infections, and myelokathexis syndrome. In addition to these classical features, the clinical onset and complications of whim syndrome are more than initially suspected 10. Whim syndrome results from autosomal dominant mutations in the gene for the chemokine receptor, cxcr4, resulting in a carboxyterminus truncation of the receptor of between ten and 19 residues.
The treatment of whim syndrome is directed toward the specific symptoms that. Hypogammaglobulinemia is a deficiency in specific infectionfighting antibodies in the blood. Cxcr4specific nanobodies as potential therapeutics for. Aug 02, 2017 whim syndrome is a rare congenital immunodeficiency disease, named after its main clinical manifestations. Tetralogy of fallot is an uncommon manifestation of warts. Companies announce plan to offer free genetic tests for. She underwent a therapeutic splenectomy at age 9 for the. Cxcr4specific nanobodies as potential therapeutics for whim. Human papillomavirus typing of verrucae in a patient with. For language access assistance, contact the ncats public information officer.
Accordingly, cxcr4 antagonists have shown promise as mechanismbased treatments in phase 1 clinical trials. Apr 10, 2014 whim syndrome is a rare primary immunodeficiency disorder whose name is an acronym of its main clinical features. Treatment consists on monthly injections of intravenous immunoglobulin, which may reduce the incidence. Myelokathexis refers to the failure of neutrophils. Many whim syndrome patients develop widespread hpvinduced warts that are often difficult to treat, generally starting on hands and feet. Nov 17, 2020 hsct in whim syndrome is limited by the availability of immunologically matched donors and by the significant short and longterm risks of allotransplantation. This new edition vividly illustrates the importance of an understanding of immunology in diagnosis and therapy. Abnormal newborn screen in a whim syndrome infant j clin immunol. Chemotaxis defects also include the previously mentioned deficiency of the adhesion molecules and defects. Feb 28, 2019 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. Dec 18, 2018 whim syndrome is a rare, autosomal dominant immunodeficiency which is named for the four key manifestations. Review of case report literature highlights that whim.
Design analysis of prospectively gathered clinical cohort data. Whim syndrome is a rare congenital immune deficiency, characterized by warts, hypogammaglobulinemia, infections, and myelokathexisthat form the acronym of its name. Genetic and rare diseases information center gard po box 8126, gaithersburg, md 208988126 toll free. Authors martin o evans 2nd 1, david h mcdermott 2, philip m murphy 2, maureen m petersen 3 affiliations 1 walter reed national military. The hypogammaglobulinemia of whim syndrome is inconsistent, and recurrent bacterial infections include sinus infections, cellulitis, periodontitis, and meningitis. To characterize novel genetic causes of the syndrome, we recruited a pediatric patient with possible whim syndrome, performed cxcr4 gene sequencing and compared his clinical phenotype and cxcr4 tail amino acid sequences with other patients with whim syndrome carrying. Cancers express a complex chemokine network influencing leucocyte infiltration and angiogenesis. Feb 12, 2015 the past medical history revealed that whim 09 was in fact the first patient ever described with myelokathexis, the key hematopathologic feature in whim syndrome, reported in two articles published in the new england journal of medicine nejm in 1964 krill et al.
Whim syndrome was presented by philip murphy, md on september 26, 2020. Whim syndrome is a primary immunodeficiency disorder, one of a group of disorders characterized by irregularities in the cell development andor cell maturation process of the immune system. The first example of a human immunologic disease caused by. Pathogenesis, diagnosis and therapeutic strategies in whim.
X4 pharmaceuticals to host 2020 analyst day webinar. Clinical symptoms in whim syndrome are dependent on myeloid deficits. Ijms free fulltext adaptive immunodeficiency in whim. Whim syndrome definition of whim syndrome by medical. Warts, hypogammaglobulinemia, infections, and myelokathexis whim syndrome is a rare, autosomal dominant, combined immunodeficiency disorder caused by mutations in the cterminus of cxcr4 that prevent receptor downregulation and therefore result in pathologically increased signaling. Lowlevel cxcr4haploinsufficient hsc leukopenia in whim. Deciphering the molecular alterations leading to disease initiation and progression is currently crucial to identify the most relevant targets for precision therapy in cancer patients. How i treat warts, hypogammaglobulinemia, infections, and. Cxcr4 is a receptor a sort of antenna found on the surface of cells see figure 1 that binds to a signaling molecule called cxcl12, a molecule released by cells in the bone marrow known as stromal cells. Request pdf plerixafor for the treatment of whim syndrome whim syndrome warts, hypogammaglobulinemia, infections, and myelokathexis, a primary immunodeficiency disorder involving. Treatment may include medications that replace antibodies. Niaid researchers discovered why a woman with whim syndrome was spontaneously cured of the disease. Cerebellar involvement in warts hypogammaglobulinemia. Whim syndrome have the mutation in every cell in their body.
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