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Wiskott Aldrich Syndrome

WAS

Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency in which eczema, recurrent infections, and thrombocytopenia are constitutive features.


Presentation

The clinical presentation of WAS includes several key findings [3]:

Generalized Lymphadenopathy
  • However, about 2 weeks after splenectomy, he developed generalized lymphadenopathy and lymphoma was misdiagnosed based on lymph node biopsy at another hospital where he was admitted for urgent care.[ncbi.nlm.nih.gov]
  • He also experienced a lymphoproliferative disorder with generalized lymphadenopathy, liver enlargement, and renal infiltration.[jamanetwork.com]
Easy Bruising
  • Symptoms Children with WAS are diagnosed most commonly in the first year of life because of easy bruising, abnormal bleeding, or low platelet counts.[seattlecca.org]
  • Severe thrombocytopenia and microthrombi causing easy bruising, bloody diarrhoea etc. 3. Profound immunodeficiency, neutropenia, decrease B and T lymphocytes.[rarediseasesindia.org]
  • Snapshot An 8-year-old boy is brought to his pediatrician for easy bruising. On physical exam, he is found with petechiae and purpura in multiple areas over his body, as well as bruises over his arms.[medbullets.com]
  • Thrasher; used with consent given by parents History & Exam Key Factors FHx of WAS easy bruising and petechiae Other Factors serious bleeding recurrent infections serious/life-threatening infection eczema autoimmunity bruises and petechiae lymphadenopathy[online.epocrates.com]
Recurrent Infection
  • We investigated two Malay boys who presented with congenital thrombocytopenia, eczema and recurrent infections. Here we report two cases of WASP mutation in Malaysia from two unrelated families.[ncbi.nlm.nih.gov]
  • Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by thrombocytopenia with microplatelets, eczema, recurrent infections, and predisposition to autoimmune disease and malignancy.[ncbi.nlm.nih.gov]
  • In our patient these two unusual manifestations preceded the onset of recurrent infections. Recognition of this rare presentation led us to an early diagnosis of WAS, associated with p.Glu31Lys mutation in the WAS protein.[ncbi.nlm.nih.gov]
  • Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency disorder characterized by recurrent infection, eczema, and microthrombocytopenia.[ncbi.nlm.nih.gov]
  • Wiskott-Aldrich syndrome (WAS) is an X-linked recessive immunodeficiency characterized by eczema, thrombocytopenia, and recurrent infections. Linkage studies have placed the gene at Xp11.22-p11.23.[ncbi.nlm.nih.gov]
Recurrent Respiratory Infections
  • Symptoms and Signs The first manifestations are often hemorrhagic (usually bloody diarrhea), followed by recurrent respiratory infections, eczema, and thrombocytopenia.[msdmanuals.com]
  • Affiliated tissues include bone, bone marrow and skin, and related phenotypes are chronic otitis media and recurrent respiratory infections Disease Ontology : 12 A X-linked recessive disease that is characterized by abnormal immune system function and[malacards.org]
Fatigue
  • Common symptoms include paleness, fatigue, and shortness of breath. Chorionic villus biopsy — A procedure used for prenatal diagnosis at 10-12 weeks gestation.[medical-dictionary.thefreedictionary.com]
  • […] bruising susceptibility 60 33 hallmark (90%) Very frequent (99-80%) HP:0000978 12 prolonged bleeding time 60 33 hallmark (90%) Very frequent (99-80%) HP:0003010 13 abnormal platelet morphology 60 33 hallmark (90%) Very frequent (99-80%) HP:0011875 14 fatigue[malacards.org]
Virilization
  • An 18-year-old fully virilized male patient with a history of Wiskott-Aldrich syndrome had undergone successful bone marrow transplantation in infancy. The donor was his older sister.[ncbi.nlm.nih.gov]
Diarrhea
  • A 7-month-old Korean boy presented with recurrent bloody diarrhea, eczema, and persistent thrombocytopenia with small platelets.[ncbi.nlm.nih.gov]
  • Next come nosebleeds and bloody diarrhea from failure of the platelets to form clots to stop the bleeding. After that, the patient is usually succeptible to numerous infections.[house.wikia.com]
  • Because the number of platelets is low, bleeding problems, usually bloody diarrhea, may be the first symptom. Eczema also develops at an early age. Life expectancy is shortened.[msdmanuals.com]
  • In addition to that, the brothers also had bouts of bloody diarrhea, eczema (which is itchy and inflamed patches of skin), and frequent ear infections.[study.com]
Hematemesis
  • The clinical presentation of WAS includes several key findings: Bleeding abnormalities - As a result of thrombocytopenia, petechiae, epistaxis, hematemesis and melena are seen in the majority of patients and one of the earliest diagnostic clues may be[symptoma.com]
  • […] agents: Streptococcus pneumonia, Haemophilus influenza, Neisseria meningitides viral agents: varicella and CMV fungal infections: Candida albicans thrombocytopenia recurrent bleeding, especially in first days of life petechiae purpura easy bruising hematemesis[medbullets.com]
  • […] agents: Streptococcus pneumonia, Haemophilus influenza, Neisseria meningitides viral agents: varicella and CMV fungal infections: Candida albicans thrombocytopenia recurrent bleeding , especially in first days of life petechiae purpura easy bruising hematemesis[step1.medbullets.com]
  • […] vasculitis more Immunology: lymphopenia moderately depressed antibody response to polysaccharide antigens abnormal delayed hypersensitivity skin test absent microvilli on the surface of peripheral blood lymphocytes Abdomen Gastrointestinal: diarrhea hematemesis[malacards.org]
Failure to Thrive
  • Failure to thrive in a 14-month-old boy with lymphopenia and eosinophilia. Klin Padiatr. 2004;216(1):24–5. doi: 10.1055/s-2004-817993.[doi.org]
  • […] to thrive, Inflammatory indexes/vasculitis, hepatosplenomegaly GE reflux/food adversion (fed by naso-gastric tube), allergy WAS mutation Exon 10: C T 995 (R321X) IVS10del11nt 37C T (R13X) WASP expression Zhu score 3 4 4 Age at treatment (y) 5.9 1.6 1.1[ncbi.nlm.nih.gov]
  • All three had failure to thrive, platelet abnormalities, eosinophilia, eczema and other indicators of inflammatory/immune disease including elevated IgA and IgE, and anti-neutrophil autoantibodies. Only Patient 1 had chronic infections and colitis.[doi.org]
Blood in Stool
  • At one month of life, Knowah had blood streaked stools and was treated for amoebasis with metronidazole. However, the blood-streaked stools have persisted. At two months of life, Knowah had another fever.[globalgenes.org]
Oral Bleeding
  • In most cases the first clinical features are hemorrhagic manifestations with petechiae, bruising, purpura, epistaxis, oral bleeding, bloody diarrhea and intracranial bleeding. Acute or chronic eczema is the second characteristic finding of WAS.[orpha.net]
  • Hemorrhage – petechiae/purpura/oral bleeding (Mild bleeding under skin) to intestinal/intercranial bleeding Eczema – Abnormal priming of antigen specific T-cells in the skin, caused by defective chemotaxis of dendritic cells.[slideshare.net]
  • Life-threatening bleeding, including severe oral bleeding, gastrointestinal bleeding, and intracranial haemorrhage, has been reported in up to 30% of patients. Compromised humoral and cellular adaptive immunity is a hallmark of classical WAS.[atlasgeneticsoncology.org]
Hepatosplenomegaly
  • An Epstein-Barr virus (EBV)-associated post-transplantation lymphoproliferative disorder (PTLD) of donor cell origin and hemophagocytosis syndrome with fever, lymphadenopathy, hepatosplenomegaly, seizures, involuntary movements and pancytopenia developed[ncbi.nlm.nih.gov]
  • […] influenza, Neisseria meningitides viral agents: varicella and CMV fungal infections: Candida albicans thrombocytopenia recurrent bleeding, especially in first days of life petechiae purpura easy bruising hematemesis epistaxis hematuria chronic eczema hepatosplenomegaly[medbullets.com]
  • […] influenza, Neisseria meningitides viral agents: varicella and CMV fungal infections: Candida albicans thrombocytopenia recurrent bleeding , especially in first days of life petechiae purpura easy bruising hematemesis epistaxis hematuria chronic eczema hepatosplenomegaly[step1.medbullets.com]
  • Hepatosplenomegaly is commonly found but lymphadenopathy is unusual. Later in the course of the disease, complications due to chronic infections arise, such as bronchiectasis and chronic keratitis.[ijdvl.com]
  • Thrombocytopenia manifestations Skin petechiae Skin petechiae, GI bleeding Skin petechiae, GI bleeding, epistaxis Eczema Moderate-severe Moderate-severe Severe Other Developmental disorder, allergy Failure to thrive, Inflammatory indexes/vasculitis, hepatosplenomegaly[ncbi.nlm.nih.gov]
Retinal Hemorrhage
  • The clinical course was complicated by severe CMV retinitis with bilateral retinal hemorrhages and renal vasculitis. He underwent unrelated UCBT resulting in a rapid resolution of autoimmunity and thrombocytopenia.[ncbi.nlm.nih.gov]
Eczema
  • 2 WISKOTT-ALDRICH SYNDROME Eczema thrombocytopenia immunodeficiency syndrome edit English Wiskott-Aldrich syndrome rare disease Wiskott syndrome WAS Immunodeficiency 2 Aldrich Syndrome WISKOTT-ALDRICH SYNDROME; WAS Wiskott-Aldrich Syndrome 1 Eczema-Thrombocytopenia-Immunodeficiency[wikidata.org]
  • The Wiskott-Aldrich syndrome is a rare X-linked immunodeficiency characterized by microplatelet thrombocytopenia and eczema. Eczema may be severe and facilitate entry of microorganism into the host.[ncbi.nlm.nih.gov]
  • We investigated two Malay boys who presented with congenital thrombocytopenia, eczema and recurrent infections. Here we report two cases of WASP mutation in Malaysia from two unrelated families.[ncbi.nlm.nih.gov]
  • It causes eczema (a type of skin inflammation), a decrease in the number of platelets (blood cells that help prevent bleeding), and frequent bacterial infections.[icd9data.com]
  • Skin changes - Eczema in infancy and childhood is a constitutive feature of WAS.[symptoma.com]
Petechiae
  • Thrasher; used with consent given by parents History & Exam Key Factors FHx of WAS easy bruising and petechiae Other Factors serious bleeding recurrent infections serious/life-threatening infection eczema autoimmunity bruises and petechiae lymphadenopathy[online.epocrates.com]
  • Wiskott-Aldrich syndrome (WAS) is a rare immunodeficiency disease with a characteristic phenotype that includes: X-linked recessive petechiae, bloody diarrhea, epistaxis due to thrombocytopenia with small platelets eczema starts in first month of life[radiopaedia.org]
  • On physical exam, he is found with petechiae and purpura in multiple areas over his body, as well as bruises over his arms. Eczematous patches are also found on his flexural surfaces. Laboratory results reveal thrombocytopenia to 30,000/mm 3.[medbullets.com]
  • On physical exam, he is found with petechiae and purpura in multiple areas over his body, as well as bruises over his arms. Eczematous patches are also found on his flexural surfaces. Laboratory results reveal thrombocytopenia to 30,000/mm 3 .[step1.medbullets.com]
Dermatitis
  • WAS is a rare X-linked recessive disorder characterized by primary progressive T cell immunodeficiency, impaired antipolysaccharide antibody response, thrombocytopenia with small platelet, and eczematoid dermatitis.[ncbi.nlm.nih.gov]
  • The lesion is essentially indistinguishable from that of atopic dermatitis except for the presence of purpura and petechiae. A bloody crust can be seen on the red papules.[emedicine.medscape.com]
  • At a Glance Male infants, boys, or young men with recurrent or chronic eczematous dermatitis; recurrent, chronic, or severe infections; thrombocytopenia with abnormal bleeding; and small platelets should be considered for the diagnosis of Wiskott-Aldrich[clinicaladvisor.com]
  • Eczema that resembles an atopic dermatitis. A bleeding tendency due to thrombocytopenia and platelet dysfunction.[patient.info]
Cutaneous Manifestation
  • Cutaneous manifestations in patients with Wiskott-Aldrich syndrome submitted to haematopoietic stem cell transplantation. Arch Dis Child. 2013 Apr. 98(4):304-7. [Medline]. Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA.[emedicine.com]
  • Cutaneous manifestations in patients with Wiskott-Aldrich syndrome submitted to haematopoietic stem cell transplantation. Arch Dis Child . 2013 Apr. 98(4):304-7. [Medline] . Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA.[emedicine.medscape.com]
Epistaxis
  • Wiskott-Aldrich syndrome (WAS) is a rare immunodeficiency disease with a characteristic phenotype that includes: X-linked recessive petechiae, bloody diarrhea, epistaxis due to thrombocytopenia with small platelets eczema starts in first month of life[radiopaedia.org]
  • Further questioning reveals a past medical history of multiple hospital stays due to pneumonia and otitis media infections as well as recurrent epistaxis.[medbullets.com]
  • The clinical presentation of WAS includes several key findings: Bleeding abnormalities - As a result of thrombocytopenia, petechiae, epistaxis, hematemesis and melena are seen in the majority of patients and one of the earliest diagnostic clues may be[symptoma.com]

Workup

The diagnosis mandates a thorough patient history regarding the course of symptoms, but establishing their presence in other family members may significantly aid in making the diagnosis. To confirm WAS, however, laboratory studies identifying thrombocytopenia and a smaller diameter of platelets is necessary, coupled with genetic testing to determine WASP mutations [3].

Anergy
  • Although negative selection mechanisms including deletion, anergy, and receptor editing were relatively unperturbed, WASp-deficient transitional B cells showed enhanced proliferation in vivo mediated by antigen- and Myd88-dependent signals.[ncbi.nlm.nih.gov]
  • .: Lymphocyte-macrophage interaction in antigen induced in vitro lymphocyte transformation in patients with the Wiskott-Aldrich syndrome and other diseases with anergy. Cell. Immunol. 4 , 228–242 (1972) PubMed CrossRef Google Scholar 37.[link.springer.com]
Small Platelets
  • Despite the heterogeneity of genetic and clinical findings, a correlation with small platelet size is routinely observed.[ncbi.nlm.nih.gov]
  • WAS is a rare X-linked recessive disorder characterized by primary progressive T cell immunodeficiency, impaired antipolysaccharide antibody response, thrombocytopenia with small platelet, and eczematoid dermatitis.[ncbi.nlm.nih.gov]
  • A 7-month-old Korean boy presented with recurrent bloody diarrhea, eczema, and persistent thrombocytopenia with small platelets.[ncbi.nlm.nih.gov]
  • Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by thrombocytopenia, small platelets, eczema, increased susceptibility to infection, and immunodeficiency.[ncbi.nlm.nih.gov]
  • The Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive immunodeficiency disorder, caused by mutations in the WAS protein (WASP) gene and characterised by thrombocytopenia, small platelets, eczema, and recurrent infections associated with increased[ncbi.nlm.nih.gov]
Immunoglobulin A Increased
  • Abnormal immunoglobulin levels (increased IgM in Patient 1 and decreased IgG in Patient 2) normalized after gene therapy.[doi.org]
Decreased Platelet Count
  • Diagnosis Presentation: Children 1-2 years present with easy bruising, bleeding tendencies, decreased platelet counts. Bacterial infection is also seen. There are 4 types: a. Classic WAS b. X linked thrombocytopenia c.[rarediseasesindia.org]

Treatment

Hematopoietic cell transplantation (HCT) is currently the only therapeutic procedure for WAS, but it is associated with significant complications - an increased frequency of autoimmune events, development of hematologic malignancies (B-cell lymphoma, large-cell lymphoma, myelodysplasia and lymphoproliferative disorders have all been documented) and infections (particularly viral) [4]. Stem-cell gene therapy for WAS is a novel therapeutic modality that is still in the phase of research, but its application in clinical practice might substantially increase survival and reduce the burden of WAS [5] [6].

Prognosis

With current therapy, the prognosis of patients suffering from WAS is poor, as median survival rates are approximately 15 years and most common causes of death are an infection, bleeding and the appearance of malignant diseases (mainly lymphoproliferative disorders) [2].

Etiology

X-linked mutations of WASP in hematopoietic cells is the underlying cause of WAS, but the events that trigger these mutations remain unknown [1] [4].

Epidemiology

An incidence rate of 1-4 per 1 million patients is established and the diagnosis is most frequently made around 24 months of age in patients without a positive family history [4]. Given the fact that WAS is an X-linked disorder, virtually all patients are males and very few cases of female WAS have been described in the literature [7].

Sex distribution
Age distribution

Pathophysiology

WAS protein (WASP) is one of the key proteins involved in the polymerization of actin in hematopoietic cells, influencing processes such as cell signaling, locomotion, and formation of immunologic synapses [6]. In the setting of mutations that impair its function, the activity of B and T cells, as well as the formation of platelets, is suppressed, leading to various forms of immunodeficiency, depending on the severity of mutations [4].

Prevention

Current prevention strategies are aimed at reducing the risk of infections by prophylactic use of antibiotics and antiviral agents, immunosuppressive therapy if there is clinical suspicion of autoimmunity, and platelet transfusion to minimize the risk of bleeding [3].

Summary

Wiskott-Aldrich syndrome (WAS) is a rare form of primary immunodeficiency that stems from X-linked mutations in the WAS gene, coding for WAS protein (WASP) expressed only in hematopoietic cells [1]. WASP is involved in the polymerization of actin, which is essential for cell locomotion and signaling, but specific mutations lead to its dysfunction and absence in hematopoietic lineages [2]. As a result, impaired B and T cell activity, defects in phagocytosis and platelet abnormalities develop, causing immunodeficiency [2]. Hence, recurrent pyogenic, viral or opportunistic infections occurring exclusively in males are a clinical hallmark of WAS, as are thrombocytopenia, eczema and an increased incidence of lymphoproliferative disease [3]. The diagnosis is made based on clinical findings and laboratory studies, but it should be mentioned that a strong correlation between genotypes and phenotypes exist (milder mutations are associated with X-linked thrombocytopenia and X-linked neutropenia, or XLT and XLN, respectively) [4]. Hematopoietic cell transplantation is currently the mainstay of therapy [3], but the prognosis of WAS patients is rather poor, with median survival being around 15 years despite available therapy [2]. Gene therapy, however, has been evaluated in the treatment of WAS and is showing promising results [5] [6].

Patient Information

Wiskott-Aldrich syndrome is a rare genetic disorder seen in approximately 1-4 per 1 million individuals, and stems from mutations in WAS protein, one of the key molecules involved in maintaining the structure of red and white blood cells, as well as platelets. Because mutations are located on the X chromosome, only male individuals can develop WAS, as they carry only one copy of the genes that code for the aberrant protein. Consequences of mutations are a very early onset of eczema, recurrent infections (including viral, bacterial and fungal) and episodes of bleeding due to reduced platelet count, which may be life-threatening if not recognized on time. The initial diagnosis is made on clinical grounds and patient history, whereas confirmation requires laboratory studies to confirm low platelet count (and a very small size of platelets) and genetic tests. Transplantation of hematopoietic stem cells is the only therapeutic measure, but the overall prognosis is poor, as patients infrequently reach adulthood.

References

Article

  1. Ochs HD, Filipovich AH, Veys P, Cowan MJ, Kapoor N. Wiskott-Aldrich syndrome: diagnosis, clinical and laboratory manifestations, and treatment. Biol Blood Marrow Transplant. 2009;15(1):84-90.
  2. Thrasher AJ, Kinnon C. The Wiskott–Aldrich syndrome. Clin Exp Immunol. 2000;120(1):2-9.
  3. Massaad MJ, Ramesh N, Geha RS. Wiskott-Aldrich syndrome: a comprehensive review. Ann N Y Acad Sci. 2013;1285:26-43.
  4. Buchbinder D, Nugent DJ, Fillipovich AH. Wiskott–Aldrich syndrome: diagnosis, current management, and emerging treatments. Appl Clin Genet. 2014;7:55-66.
  5. Bosticardo M, Ferrua F, Cavazzana M, Aiuti A. Gene therapy for Wiskott-Aldrich Syndrome. Curr Gene Ther. 2014;14(6):413-21.
  6. Boztug K, Schmidt M, Schwarzer A, et al. Stem-Cell Gene Therapy for the Wiskott–Aldrich Syndrome. N Engl J Med. 2010;363(20):1918-1927.
  7. Boonyawat B, Dhanraj S, Al Abbas F, Zlateska B, Grunenbaum E, Roifman CM, et al. Combined de-novo mutation and non-random X-chromosome inactivation causing Wiskott-Aldrich syndrome in a female with thrombocytopenia. J Clin Immunol. 2013;33(7):1150-1155.

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Last updated: 2019-07-11 20:38