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Asian Pacific Journal of Allergy and... Mar 2012The Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency disorder characterized by thrombocytopenia with small sized platelets, eczema, and recurrent...
BACKGROUND
The Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency disorder characterized by thrombocytopenia with small sized platelets, eczema, and recurrent infections. There is paucity of information on WAS from the Indian subcontinent. We describe the clinical and molecular profile of 8 patients with WAS as seen in the Pediatric Immunodeficiency Clinic at the Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
METHODS
A detailed analysis of the clinical profiles, investigations and outcome of the 8 children diagnosed with WAS during the period 2006- 2010 was performed. Confirmation of the genetic diagnosis was done at the Service d'Hématologie, d'Immunologie et de Cytogénétique, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France and the National Defense Medical College, Saitama, Japan.
RESULTS
8 patients were diagnosed as WAS in 5 years. The ages at diagnosis ranged from 13 weeks to 9 years while the mean age of onset of the symptoms was 117 days +/- 136 days. The diagnosis was established within a mean period of 31 months (ranging 1-108 months) from the onset of symptoms. Recurrent infections and diarrhea were seen in 6 and 7 out of the 8 patients, respectively, while eczema was variable. Autoimmunity manifestations were observed in 2 children. Thrombocytopenia and small platelet size was the hallmark of the disease and the main clinical clue to diagnosis in our patients. Mutations in the WASP gene were seen in 8 children, out of which 2 were novel mutations. While one child successfully underwent bone marrow transplantation, two children are doing well on immunoglobulin replacement and cotrimoxazole prophylaxis. Out of 8 children 4 children in our cohort died--all had high WAS scores and could not be offered hematopoietic stem cell transplantation.
CONCLUSION
WAS should be suspected clinically in any male infant with persistent unexplained thrombocytopenia and especially if the platelet size is small. Clinical presentation can be very variable and it is therefore important to recognize the entire spectrum of the disease. Understanding the molecular basis has important implications for the diagnosis, treatment, and genetic counseling of patients with WAS.
Topics: Child; Child, Preschool; Humans; India; Infant; Male; Wiskott-Aldrich Syndrome
PubMed: 22523910
DOI: No ID Found -
Journal of Clinical Immunology Nov 2019We undertook a study to determine the impact of Wiskott Aldrich Syndrome (WAS) and X-linked thrombocytopenia (XLT) and their therapies upon the health-related quality of...
Quality of Life of Patients with Wiskott Aldrich Syndrome and X-Linked Thrombocytopenia: a Study of the Primary Immune Deficiency Consortium (PIDTC), Immune Deficiency Foundation, and the Wiskott-Aldrich Foundation.
BACKGROUND
We undertook a study to determine the impact of Wiskott Aldrich Syndrome (WAS) and X-linked thrombocytopenia (XLT) and their therapies upon the health-related quality of life (HRQOL) of patients and their families.
MATERIALS AND METHODS
We undertook a survey of patients and their families, who self-identified as having either WAS or XLT. We assessed the PedsQL™ 4.0, the parent proxy form, and the family impact module. These results were compared with normative data from previously published reports.
RESULTS
Sixty-eight patients (29 patients completed both the PedsQL™ 4.0 and the parent proxy form; 21 completed only the PedsQL™ 4.0; and 18 completed only the parent proxy form) were included. In contrast to patient-reported outcomes, parents of patients who had a bone marrow transplant (BMT) reported that their children had better QOL scores compared with those who did not (82.6 vs. 73.3, p = 0.023). The QOL of patients vs. previously published normative data showed decreases in patient scores for psychosocial health (72.62 vs. 86.58, p = < 0.001), emotional functioning (69.91 vs. 82.64, p = < 0.001), social functioning (77.55 vs. 91.56, p = < 0.001), and school functioning (70.46 vs. 85.67, p = < 0.001). The family impact study revealed deficits in emotional, social, and cognitive functioning, communication, and worry.
CONCLUSION
These results show that patients with WAS/XLT are significantly impacted with respect to QOL. BMT offered a better QOL for patients according to parents, but not as reported by the patients. Future studies should incorporate QOL to provide more data and a better understanding of outcomes for long-term survivors and decision-making regarding BMT.
Topics: Adolescent; Bone Marrow Transplantation; Caregivers; Child; Child, Preschool; Decision Making; Genetic Diseases, X-Linked; Humans; Male; Parents; Patient Reported Outcome Measures; Quality of Life; Surveys and Questionnaires; Survivors; Thrombocytopenia; Wiskott-Aldrich Syndrome; Young Adult
PubMed: 31620947
DOI: 10.1007/s10875-019-00689-2 -
Clinical and Experimental Immunology Mar 1967Wiskott–Aldrich syndrome is a sex-linked recessive antibody-deficiency syndrome characterized by thrombocytopenia, eczema and increased susceptibility to infection....
Wiskott–Aldrich syndrome is a sex-linked recessive antibody-deficiency syndrome characterized by thrombocytopenia, eczema and increased susceptibility to infection. All forms of therapy are notably unsuccessful and these patients succumb in the first decade. Three cases of this syndrome are presented from a large family in which nine male infants have succumbed with manifestations of this disease. Two of the infants died at ages 10 months and 4 years respectively. A third child is alive at age 2. Serial quantitative immune globulin studies performed in two cases demonstrated markedly elevated γA, decreased γM and normal γG; levels of γM were initially normal but fell progressively as γA levels increased. The low levels of γM are probably a factor in their low or absent isoagglutinins, poor response to injected antigens, and increased susceptibility to infection; elevated γA levels may indicate immunologic unresponsiveness and/or a compensatory mechanism for the defect in γM synthesis. In two of these patients prolonged trials (17 and 23 months) of periodic plasma infusions (15 ml/kg at 6-week intervals), accompanied by γ-globulin injections (0·1 ml/kg) were undertaken. Although no remarkable effects on the platelets or their resistance to infection was noted, we feel that some benefit might have accrued and that further trails are indicated.
Topics: Humans; Infant; Infant, Newborn; Male; Wiskott-Aldrich Syndrome; gamma-Globulins
PubMed: 4166240
DOI: No ID Found -
Frontiers in Immunology 2019Wiskott-Aldrich syndrome (WAS) is a rare and severe X-linked disorder with variable clinical phenotypes correlating with the type of mutations in the gene. The...
Wiskott-Aldrich syndrome (WAS) is a rare and severe X-linked disorder with variable clinical phenotypes correlating with the type of mutations in the gene. The syndrome is difficult to differentiate from idiopathic thrombocytopenic purpura (ITP) before genetic diagnosis. We retrospectively reviewed patients suspected to have WAS who were referred to our hospital from 2004 to 2016 and compared the clinical features and laboratory examination of genetically confirmed WAS patients and of patients diagnosed with ITP in order to seek some clues to distinguish WAS and ITP before genetic diagnosis. Seventy-eight children suspected to have WAS from 78 unrelated families were enrolled in this study. The clinical data and laboratory examination of children were reviewed in the present study. The distribution of lymphocyte subsets from peripheral blood was examined by how cytometry. mutations were identified by direct sequencing of PCR-amplified genomic DNA. Forty-two patients were finally diagnosed with WAS genetically. The median onset age of these patients was 1 month (range: 1 day-10 months). The median diagnosis lag was 4.6 months (range: 0 months-9.42 years). Fifteen patients (35.71%) had positive family histories. More than half of the patients ( = 23, 54.76%) had diarrhea. Twenty-three (54.76%) had pneumonia, 7 with severe symptoms. Major bleeding events included skin spots or petechiae ( = 27, 64.29%), per-rectal bleeding ( = 21, 50.00%), epistaxis ( = 7, 16.67%) and intracranial bleeding ( = 2, 4.76%). Twenty-nine patients (69.05%) had eczema, and one patient had a drug allergy. Three patients had autoimmune diseases, among whom 2 had autoimmune hemolytic anemia and one had autoimmune hemolytic anemia and IgA nephropathy. A total of 42 mutations in were identified, including 19 novel mutations. Eight patients received hematopoietic stem cell transplantation (HSCT) and all survived. Compared with the 30 patients diagnosed with ITP, the WAS patients had higher EOS counts and elevated IgE level, increased NK cell numbers but fewer CD8T lymphocytes. The gene diagnosis should be considered in all males with ITP-like features, especially for patients with a very early onset age, decreased MPV (<6.5 fl), higher EOS counts and elevated IgE level, increased NK cell number, diminished CD8T lymphocyte count.
Topics: CD8-Positive T-Lymphocytes; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin E; Killer Cells, Natural; Male; Mutation; Purpura, Thrombocytopenic, Idiopathic; Retrospective Studies; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 31354712
DOI: 10.3389/fimmu.2019.01549 -
Blood Jun 2009Wiskott-Aldrich syndrome (WAS) is a severe X-linked immunodeficiency caused by mutations in the gene encoding for WASP, a key regulator of signaling and cytoskeletal... (Review)
Review
Wiskott-Aldrich syndrome (WAS) is a severe X-linked immunodeficiency caused by mutations in the gene encoding for WASP, a key regulator of signaling and cytoskeletal reorganization in hematopoietic cells. Mutations in WASP result in a wide spectrum of clinical manifestations ranging from the relatively mild X-linked thrombocytopenia to the classic full-blown WAS phenotype characterized by thrombocytopenia, immunodeficiency, eczema, and high susceptibility to developing tumors and autoimmune manifestations. The life expectancy of patients affected by severe WAS is reduced, unless they are successfully cured by bone marrow transplantation from related identical or matched unrelated donors. Because many patients lack a compatible bone marrow donor, the administration of WAS gene-corrected autologous hematopoietic stem cells could represent an alternative therapeutic approach. In the present review, we focus on recent progress in understanding the molecular and cellular mechanisms contributing to the pathophysiology of WAS. Although molecular and cellular studies have extensively analyzed the mechanisms leading to defects in T, B, and dendritic cells, the basis of autoimmunity and thrombocytopenia still remains poorly understood. A full understanding of these mechanisms is still needed to further implement new therapeutic strategies for this peculiar immunodeficiency.
Topics: Adolescent; Animals; Autoimmune Diseases; Child; Dendritic Cells; Eczema; Genetic Predisposition to Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Lymphocyte Subsets; Male; Mice; Neoplastic Syndromes, Hereditary; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein; Young Adult
PubMed: 19351959
DOI: 10.1182/blood-2008-12-115253 -
British Journal of Haematology Jun 2001Mutations in the gene encoding the Wiskott-Aldrich syndrome protein (WASp) give rise to Wiskott-Aldrich syndrome (WAS), a condition that exhibits a wide spectrum of...
Mutations in the gene encoding the Wiskott-Aldrich syndrome protein (WASp) give rise to Wiskott-Aldrich syndrome (WAS), a condition that exhibits a wide spectrum of clinical severity. Patients may develop mild thrombocytopenia or suffer from a wide range of associated disorders including eczema, immune dysfunction, autoimmune disease and malignancy. The clinical diagnosis of Wiskott-Aldrich syndrome (WAS) can be difficult and is usually supported by the detection of WASp gene mutations using genetic analysis. Recently, protein-based assays have been used to demonstrate the absence of WASp in patients known to have WASp gene mutations. We have now reversed this approach and report on the use of immunoblot assays to rapidly diagnose WAS in 13 patients. There was a complete absence of WASp in 10 out of 13 patients and an abnormal protein form was detected in the remaining three patients. In all cases, subsequent genetic analysis confirmed the presence of a WASp gene mutation. We believe that protein-based assays should be employed as the first line of investigation in the diagnosis of WAS spectrum disorders.
Topics: Aged; Child; Child, Preschool; Female; Humans; Immunoblotting; Infant; Male; Middle Aged; Mutation; Proteins; Thrombocytopenia; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein; X Chromosome
PubMed: 11442475
DOI: 10.1046/j.1365-2141.2001.02832.x -
Journal of Autoimmunity May 2014Wiskott-Aldrich Syndrome protein (WASp) regulates the cytoskeleton in hematopoietic cells and mutations in its gene cause the Wiskott-Aldrich Syndrome (WAS), a primary...
Wiskott-Aldrich Syndrome protein (WASp) regulates the cytoskeleton in hematopoietic cells and mutations in its gene cause the Wiskott-Aldrich Syndrome (WAS), a primary immunodeficiency with microthrombocytopenia, eczema and a higher susceptibility to develop tumors. Autoimmune manifestations, frequently observed in WAS patients, are associated with an increased risk of mortality and still represent an unsolved aspect of the disease. B cells play a crucial role both in immune competence and self-tolerance and defects in their development and function result in immunodeficiency and/or autoimmunity. We performed a phenotypical and molecular analysis of central and peripheral B-cell compartments in WAS pediatric patients. We found a decreased proportion of immature B cells in the bone marrow correlating with an increased presence of transitional B cells in the periphery. These results could be explained by the defective migratory response of WAS B cells to SDF-1α, essential for the retention of immature B cells in the BM. In the periphery, we observed an unusual expansion of CD21(low) B-cell population and increased plasma BAFF levels that may contribute to the high susceptibility to develop autoimmune manifestations in WAS patients. WAS memory B cells were characterized by a reduced in vivo proliferation, decreased somatic hypermutation and preferential usage of IGHV4-34, an immunoglobulin gene commonly found in autoreactive B cells. In conclusion, our findings demonstrate that WASp-deficiency perturbs B-cell homeostasis thus adding a new layer of immune dysregulation concurring to the increased susceptibility to develop autoimmunity in WAS patients.
Topics: Autoimmunity; B-Cell Activating Factor; B-Lymphocytes; Bone Marrow; Cell Differentiation; Cell Movement; Chemokine CXCL12; Disease Susceptibility; Gene Expression; Homeostasis; Humans; Immunoglobulin Heavy Chains; Immunologic Memory; Receptors, Complement 3d; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 24369837
DOI: 10.1016/j.jaut.2013.10.006 -
Blood Nov 1995The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by thrombocytopenia, small platelets, eczema, recurrent infections, and... (Comparative Study)
Comparative Study
The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by thrombocytopenia, small platelets, eczema, recurrent infections, and immunodeficiency. Besides the classic WAS phenotype, there is a group of patients with congenital X-linked thrombocytopenia (XLT) who have small platelets but only transient eczema, if any, and minimal immune deficiency. Because the gene responsible for WAS has been sequenced, it was possible to correlate the WAS phenotypes with WAS gene mutations. Using a fingerprinting screening technique, we determined the approximate location of the mutation in 13 unrelated WAS patients with mild to severe clinical symptoms. Direct sequence analysis of cDNA and genomic DNA obtained from patient-derived cell lines showed 12 unique mutations distributed throughout the WAS gene, including insertions, deletions, and point mutations resulting in amino acid substitutions, termination, exon skipping, or splicing defects. Of 4 unrelated patients with the XLT phenotype, 3 had missense mutations affecting exon 2 and 1 had a splice-site mutation affecting exon 9. Patients with classic WAS had more complex mutations, resulting in termination codons, frameshift, and early termination. These findings provide direct evidence that XLT and WAS are caused by mutations of the same gene and suggest that severe clinical phenotypes are associated with complex mutations.
Topics: Base Sequence; Blood Platelets; Cell Line; Cell Size; DNA Fingerprinting; DNA Mutational Analysis; DNA, Complementary; Exons; Humans; Molecular Sequence Data; Mutation; Phenotype; Proteins; Sequence Alignment; Sequence Analysis, DNA; Sequence Homology, Nucleic Acid; Thrombocytopenia; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein; X Chromosome
PubMed: 7579347
DOI: No ID Found -
Journal of Medical Case Reports Jul 2022Wiskott-Aldrich syndrome is a rare X-linked primary immunodeficiency that mostly presents with a classic triad of eczema, microthrombocytopenia, recurrent infections,...
INTRODUCTION
Wiskott-Aldrich syndrome is a rare X-linked primary immunodeficiency that mostly presents with a classic triad of eczema, microthrombocytopenia, recurrent infections, and increased risk of autoimmunity/malignancies.
CASE PRESENTATION
We present an 8-month-old African male, born from nonconsanguineous parents and who presented with a history of eczematous skin rash since day 9 of life, with recurrent sinus infections, otitis media, and skin abscesses. An elder male sibling who had similar symptoms passed away during infancy. Investigations were consistent with microthrombocytopenia and significantly raised immunoglobulin E, while immunoglobulin A and immunoglobulin G were moderately elevated with normal immunoglobulin M. Genetic testing revealed the patient to be hemizygous for a pathogenic Wiskott-Aldrich syndrome gene variant (NM_000377.2:c.403C>T). He was managed conservatively with supportive treatment until he died a year later.
CONCLUSION
Despite Wiskott-Aldrich syndrome being a rare disease, it should be considered as a differential in any male child who presents with microthrombocytopenia and recurrent infections, especially in low-resource settings where genetic testing is not routinely available.
Topics: Africa, Eastern; Aged; Child; Humans; Immunoglobulin G; Infant; Male; Mutation; Reinfection; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 35897083
DOI: 10.1186/s13256-022-03517-1 -
Journal of Immunology (Baltimore, Md. :... Jun 2018
Topics: Humans; Immunity; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 29784762
DOI: 10.4049/jimmunol.1800518