Pdf chromothriptic cure of whim syndrome researchgate. Whim is an acronym for some of the characteristic symptoms of the disorder warts, hypogammaglobulinemia, infections, and myelokathexis. Print arsanis and x4 pharmaceuticals agree to merger. Hierarchical cxcr4 phosphorylation and whim syndrome most whim syndrome patients carry heterozygous mutations in the cxcr4 gene which eliminate the last 10 to 19 residues of the c terminus 45,46,47. Whim syndrome is caused by mutations of the cxcr4 gene that are inherited as an autosomal dominant trait.
Whim syndrome is a primary autosomal dominant immuno deficiency due to cxcr4 mutations characterized by mucocutaneous warts, hypogammaglobulinemia, recurrent. Pdf chromothripsis is a catastrophic cellular event recently described in cancer in which chromosomes undergo massive deletion and rearrangement find. The index patient, designated whim09, is a white female who presented at age 58 to the nih requesting evaluation for herself and 2 of her 3 daughters, designated whim10 age 21 and whim11 age 23 figure 1a. Whim syndrome in the first half of 2019, said paula ragan, phd, president and chief executive officer of x4 pharmaceuticals. Leukocyte analysis from whim syndrome patients reveals a. 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. By age 6 months, 90% of patients with scn develop bacterial infections such as skin or deep tissue abscesses, oral ulcers and.
The whim syndrome is a rare, autosomal dominant primary immunodeficiency disorder characterized by warts, hypogammaglobulinemia, recurrent infections, and myelokathexis. Hierarchical organization of multisite phosphorylation at. Pathogenesis, diagnosis and therapeutic strategies in whim. This treatment resulted in a significant increase in the. Whim syndrome aspirate american society of hematology.
Treatment of the condition currently includes gcsf a medication that stimulates the production of neutrophils. Whim syndrome is a rare primary immunodeficiency disorder, which are disorders in which the bodys immune system does not function properly. Whim syndrome definition of whim syndrome by medical dictionary. 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. Although no clinical trials have been conducted to determine the efficacy of either igrt or gcsf treatment specifically for patients with whim, case reports and. Primary immunodeficiency diseases are inherited disorders of the immune system that result in an increased susceptibility to infection and an increased morbidity and mortality. Whim syndrome myelokathexis reproduced in the nodscid mouse. Summary whim syndrome is a rare, autosomal dominant. The long term follow up of eight patients highlights the clinical heterogeneity of this disease as well as the main therapeutic approaches and remaining challenges in the. Jan 01, 2007 whim stands for warts, hypogammaglobulinemia, infections, and myelokathexis.
However, cxcr4arrestin interactions involve not only the c terminus but occur also via a shsk motif in the third intracellular loop 44. These heterogeneous mutations may be either truncating or frameshift, with potentially different clinical impact17, but are not helpful for wm diagnosis. Jci cxcr4haploinsufficient bone marrow transplantation. Whim syndrome is an inherited immunodeficiency caused by overactivity of cxcr4, a receptor controlling production and distribution of leukocytes in bone marrow and blood. The authors summarize current knowledge on molecular basis, diagnostic criteria, therapy, and clinical manifestations of whim syndrome.
Description and outcome of a cohort of 8 patients with whim. Twin to twin transfusion syndrome vici syndrome whim syndrome wiskott aldrich syndrome woods black norbury syndrome. Whim definition is a capricious or eccentric and often sudden idea or turn of the mind. Whim syndrome and oral squamous cell carcinoma article pdf available in oral surgery, oral medicine, oral pathology, oral radiology, and endodontology 1091. Pdf neutropenia, hypogammaglobulinemia, and pneumonia. Whima, in collaboration with the wisconsin healthcare association, encourage use of documentation reference guides developed by an icd10 expert for your icd10 transition. Background epidermodysplasia verruciformis ev is a rare genodermatosis associated with infections with specific human papillomaviruses hpvs belonging to the. Bone marrow exhibits arrest of neutrophil maturation at the promyelocyte or myelocyte stage of development 1. Whim syndrome ws, a rare congenital neutropenia due to mutations of the cxcr4 chemokine receptor, is associated with human papillomavirus hpvinduced warts, hypogammaglobulinemia, bacterial. Supplementary appendix this appendix has been provided by the authors to give readers additional information about their work. In support of these studies, a 2014 phase i clinical trial treated 3 patients diagnosed with whim syndrome with plerixafor twice a day for 6 months.
Murphy, chief of niaids laboratory of molecular immunology, were intrigued and began a quest to unravel this medical mystery. These chromosome pairings, which are from her white blood cells, show a normal chromosome 2 on the left, and a truncated chromosome 2 on the right. In this genetic form of whim syndrome, impaired cxcr4 desensitization. This article is from orphanet journal of rare diseases, volume 7. Whim syndrome ws, a rare congenital neutropenia due to mutations of the cxcr4 chemokine receptor, is associated with human papillomavirus hpvinduced warts, hypogammaglobulinemia, bacterial infections and myelokathexis. Patients with ev usually have a selective defect in cellmediated. Nov, 2011 a collection of disease information resources and questions answered by our genetic and rare diseases information specialists for whim syndrome. Plerixafor for the treatment of whim syndrome nejm. Treatment may include injection of granulocyte colony. A dose determination and safety study of x4p001 mavorixafor. This extremely rare inherited immunodeficiency disease later came to be known as whim syndrome warts, hypogammaglobulinemia low concentrations of immunoglobulins, infections, and myelokathexis white blood cells trapped in the bone marrow. Treatment consists on monthly injections of intravenous immunoglobulin, which may reduce the incidence of infectious episodes.
Cxcr4 ad whim syndrome dkc1 xr dyskeratosis congenita or hoyeraal hreidarsson syndrome elane ela2 ad scn1 g6pc3 ar scn4, nonsyndromic scn, dursun syndrome gata1 x linked gata1related xlinked cytopenia gata2 ad gata2 deficiency gfi1 ad scn2 hax1 ar scn3, kostmann syndrome lamtor2 robld3 ar p14 deficiency lyst ar chediak higashi syndrome. B spontaneous and complete remission of warts in patient whim09. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a pdf plugin installed and enabled in your browser. Primary immunodeficiency diseases are inherited disorders that affect human adaptive and innate immunity. In 1964, wolf zuelzer 1 first used the term myelokathexis to describe a 10yearold girl with severe neutropenia who had abundant mature and hypersegmented neutrophils in the bone marrow, but severe peripheral neutropenia. 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. 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. X4 pharma screening for and treatment in whim syndrome principal investigator on pediatric studies with hyqvia shire what will we learn. 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. Karyotype of a woman spontaneously cured of whim syndrome. Whim syndrome genetic and rare diseases information. Warts, hypogammaglobulinemia low immunoglobulin levels, immunodeficiency susceptibility to infections, myelokathexis trapping of white blood cells in the bone marrow.
Familial occurrence of warts, hypogammaglobulinemia, infections, and myelokathexis whim syndrome, archivum immunologiae et therapiae. This susceptibility appears to be associated with a high degree of cellular activation caused by the inability of stromal derived factor 1 sdf1, the natural. At the time of designation, whim syndrome affected approximately 0. What is the estimated number of patients affected by the condition. Listing a study does not mean it has been evaluated by the u. As whim syndrome is a molecular disease arising from gainoffunction mutations in cxcr4, preclinical studies identified plerixafor, a specific cxcr4 antagonist, as a potential mechanismbased therapeutic for the disease. Research open access description and outcome of a cohort of 8 patients with whim syndrome from the french severe chronic neutropenia registry sarah beaussant cohen1,2, odile fenneteau3, emmanuel plouvier2, pierresimon rohrlich2, gerard daltroff4. Whim syndrome genetic and rare diseases information center. Whim syndrome warts hyopogammaglobulinemia nfections. Whim syndrome is a serious, genetic primary immunodeficiency disease that is caused by a mutation in the cxcr4 receptor, the precise pathway targeted by. Cxcr4haploinsufficient bone marrow transplantation corrects leukopenia in an unconditioned whim syndrome model. 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. Chromothriptic cure of whim syndrome sciencedirect. Final protocol page s 4490 of this document summary of changes page 91 of this document the study analysis plan is described in section 5 of the protocols and the method is the same.
The term whim is an acronym for the main signs of the syndrome. Chemotaxis defects also include the previously mentioned deficiency of the adhesion molecules and defects. Whim syndrome is a rare immunodeficiency disorder, characterized in part by disproportionate susceptibility of epithelial cells to human papillomavirus hpv induced warts. Treatment consists on monthly injections of intravenous immunoglobulin, which may reduce the incidence. They have been utilized by practicing physicians and were found to be functional and effective. 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 investigators. A woman with spontaneous remission of her whim syndrome due to chromothripsis in one of her blood stem cells has been identified. Whim syndrome is a long term debilitating and life threatening condition because of the recurrent infections which increase the risk of developing cancer. Whim syndrome is a clinically variable disorder with a spectrum of features that give it its name.
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. Whim syndrome is an acronym for a rare immunodeficiency disorder with each letter representing a predominant feature of the condition. Pdfs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%. Icd10 affects diagnosis and inpatient procedure coding for everyone covered by the health insurance portability accountability act hipaa, not just those who submit medicare or medicaid claims. 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. Aug 31, 2006 whim syndrome is characterized by w arts, h ypogammaglobulinemia, recurrent bacterial i nfection, and m yelokathexis severe chronic neutropenia with marrow hyperplasia and inappropriate apoptosis of mature myeloid cells in the bone marrow bm. Genetic variation in cxcr4 and risk of chronic lymphocytic. 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. The whim syndrome is no longer a whim the journal of allergy. Whim syndrome whim is a congenital immune deficiency with characteristic clinical features that include. The primary objectives of this phase 2 study are to determine the safety, tolerability, and dose selection of mavorixafor in participants with whim syndrome.
Longterm clinical remission of whim syndrome and evidence for somatic mosaicism in patient whim09 a family pedigree. As whim syndrome is a molecular disease arising from gainoffunction mutations in cxcr4, preclinical studies identified plerixafor, a specific cxcr4 antagonist, as a. Whim syndrome nord national organization for rare disorders. Ijms free fulltext adaptive immunodeficiency in whim. Review of case report literature highlights that whim. A phase 1 clinical trial of longterm, lowdose treatment of whim syndrome with the cxcr4 antagonist plerixafor.
Whim syndrome is a rare, autosomal dominant immunodeficiency which is named for the four key manifestations. Here, we report a case in which chromothripsis spontaneously cured a patient with whim syndrome, an autosomal dominant combined immunodeficiency disease caused by gainoffunction mutation of the chemokine receptor cxcr4. Whim stands for warts skin growths, hypogammaglobulinemia low level of antibodies, infections. Whim syndrome is a hereditary condition in which the immune sy stem the bodys natural defences does not work properly, making patients more susceptible to viral and bacterial infections. This is a phase 2 study with an initial 24week treatment period and an extension phase. Whim syndrome is a serious, genetic primary immunodeficiency disease that is caused by a mutation in the cxcr4 receptor, the precise pathway targeted by x4p001. Chromothriptic cure of whim syndrome pubmed central pmc. If you have problems viewing pdf files, download the. Cxcr4 is a gproteincoupled receptor involved in a number of physiological processes in the hematopoietic and immune systems. 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. Moreover, a perinatal diagnosis of whim syndrome made by sequencing the cxcr4 gene should be performed in cases where either parent is known to be affected with this disease. 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. Description and outcome of a cohort of 8 patients with. Research open access description and outcome of a cohort of 8.
These mutations occur after the last of the seven transmembrane helices, destroying. The first example of a human immunologic disease caused by. Severe congenital neutropenia scn is characterized by severe neutropenia at birth 1. A retrospective and prospective natural history study of. Whim syndrome is an autosomal dominant immunodeficiency disease caused by mutations affecting the carboxyterminus of cxcr4. The index patient, designated whim 09, is a white female who presented at age 58 to the nih requesting evaluation for herself and 2 of her 3 daughters, designated whim 10 age 21 and whim 11 age 23 figure 1a. Claims for services provided on or after october 1, 2015 should be submitted with icd10 diagnosis codes. Current clinical management of whim includes treatment with gcsf, ivig, prophylactic antibiotics, and aggressive surveillance for and surgical extirpation of. The sdf1cxcr4 axis is significantly associated with several diseases, such as hiv, cancer, whim syndrome, rheumatoid arthritis, pulmonary fibrosis and lupus.
Whim syndrome ws, a rare congenital neutropenia due to. Truncating mutations in the cterminus cytoplasmic tail of cxcr4 cause the whim syndrome warts, hypogammaglobulinemia, infections, and myelokathexis, characterized by bcell dysfunction. Table 3 shows the tests that could be helpful in patients with wm. The results indicate that genetic defects connected with whim syndrome may influence not only the granulocyte, but also the monocytic lineage.
Whim syndrome is unusual in being 1 the only mendelian condition caused by a chemokine receptor. Familial occurrence of warts, hypogammaglobulinemia. Chromothripsis is a catastrophic cellular event recently described in cancer in which chromosomes undergo massive deletion and rearrangement. Prompt diagnosis and early aggressive treatment of infections is important to reduce long term damage. Summary whim syndrome warts, hypogammaglobulinemia, infections, and myelokathexis, a primary immunodeficiency disorder involving.
Whim syndrome associated cxcr4 truncation mutants lacking the s346347 phosphosite and the recently identified e343k whim mutant displayed strongly. If you have not installed and configured the adobe acrobat reader on your system. The study of inherited immunodeficiencies has proven valuable in elucidating molecular signaling cascades underlying the developmental and functional regulation of the human immune system. Whim syndrome is an autosomal dominant disorder of warts. In most cases, affected individuals experience recurrent infections, but they may also suffer from autoimmune diseases and malignancies. A read is counted each time someone views a publication summary such as the title, abstract, and list of authors, clicks on a figure, or views or downloads the fulltext. Warts, hypogammaglobulinemia, infections, and myelokathexis. Whim warts, hypogammaglobulinemia, infections, and myelokathexis syndrome is a congenital autosomal dominant immune deficiency characterized by abnormal retention of mature neutrophils in the bone marrow myelokathexis and occasional hypogammaglobulinemia, associated with an increased risk for bacterial infections and a susceptibility to.
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