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

• 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 excessive hemorrhage after circumcision. In 30% of cases, life-threatening gastrointestinal or intracranial hemorrhage can occur.
• Skin changes - Eczema in infancy and childhood is a constitutive feature of WAS.
• Infections - Recurrent bacterial, viral or opportunistic infections, like eczema, are invariably reported by patients, examples being bacterial pneumonia, pneumocystis jiroveci pneumonia (PJP) and various skin infections.

• 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]

  Signs and symptoms include easy bruising or bleeding due to a decrease in the number and size of platelets ; susceptibility to infections and to immune and inflammatory disorders; and an increased risk for some cancers (such as lymphoma). [rarediseases.info.nih.gov]

• 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]

  Affiliated tissues include t cells, bone and bone marrow, and related phenotypes are thrombocytopenia and recurrent infections [malacards.org]

  Eczema and recurrent infections are common. Autoimmunity complicates up to 70% of cases. There is an increased risk of haematological malignancies. [bestpractice.bmj.com]

• Anemia

  Autoimmune hemolytic anemia was defined as acquired hemolytic anemia caused by the presence of autoantibodies that agglutinated or lysed the patient’s own red blood cells (Coombs’ test positive). [pediatrics.aappublications.org]

  The first case was an 11-month-old boy presenting with complaints of recurrent soft tissue infection, ear infection, anemia, and thrombocytopenia with a low platelet volume. [ncbi.nlm.nih.gov]

  The most common of these is autoimmune attack of the red blood cells (Autoimmune Hemolytic Anemia) or platelets (Idiopathic Thrombocytopenic Purpura) but patients may also develop arthritis or inflammation of blood vessels (vasculitis). [seattlecca.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]

  Signs and symptoms of Wilson disease include yellowing of the skin and the whites of the eyes, a gold or brown ring around the colored part of the eyes, swelling in the abdomen and legs, fatigue, loss of appetite, problems with speech and swallowing, [cancer.gov]

  […] 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]

• Recurrent Respiratory Infections

  Symptoms and Signs of Wiskott-Aldrich Syndrome The first manifestations are often hemorrhagic (usually bloody diarrhea), followed by recurrent respiratory infections, eczema, and thrombocytopenia. [merckmanuals.com]

  […] immunodeficiency characterized by eczema, thrombocytopenia, recurrent infections, and bloody diarrhea. [malacards.org]

• Dyspnea

  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 60 33 frequent (33%) Frequent (79-30%) HP:0012378 15 dyspnea [malacards.org]

• Diarrhea

  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]

  A 7-month-old Korean boy presented with recurrent bloody diarrhea, eczema, and persistent thrombocytopenia with small platelets. [ncbi.nlm.nih.gov]

  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]

• 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]

  Hemorrhagic signs can involve epistaxis, oral bleeding, hematemesis, melena, petechiae, and purpura; bleeding time is prolonged. [accessanesthesiology.mhmedical.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]

• Failure to Thrive

  Patients usually present with multiple recurrent infections and failure to thrive. Patients are susceptible to encapsulated organisms as Streptococcus pneumoniae, Neisseria meningitides, and Haemophilus influenzae. [ncbi.nlm.nih.gov]

  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]

  No graft failure was reported after gene therapy; graft-versus-host disease was not reported either, a finding that was expected because of the autologous nature of the procedure. [thelancet.com]

• 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

  Hemorrhagic signs can involve epistaxis, oral bleeding, hematemesis, melena, petechiae, and purpura; bleeding time is prolonged. [accessanesthesiology.mhmedical.com]

  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]

• 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]

  In both patients, no hepatosplenomegaly, no lymphadenopathy but a moderate eczema was seen in physical exam. After one month, no response to HBV vaccine and normal isohemagglutinin antibody was seen. [ijp.tums.pub]

  […] 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]

• Chest Pain

  These may obstruct blood flow through the heart and cause fainting, shortness of breath, chest pain and other cardiac type symptoms. [dermnetnz.org]

  Occasional (29-5%) HP:0100820 31 keratitis 60 33 occasional (7.5%) Occasional (29-5%) HP:0000491 32 blepharitis 60 33 occasional (7.5%) Occasional (29-5%) HP:0000498 33 hypoplasia of the thymus 60 33 occasional (7.5%) Occasional (29-5%) HP:0000778 34 chest [malacards.org]

• 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]

  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]

  Inheritance: X-linked recessive Gene: WAS Protein: WASp Tests: WAS Gene Sequencing, WAS Protein by Flow Key Clinical and Laboratory Features Common clinical features: Abnormal bleeding, petechiae and low platelet counts. [seattlechildrens.org]

  Affecting males almost exclusively, it manifests as persistent atopic dermatitis, increased susceptibility to infections, and thrombocytopenic purpura, ecchymoses, petechiae and bloody diarrhea. [youtube.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]

• Dermatitis

  Reaction to prostaglandin E1 injected intracutaneously was normal, but the same administration of histamine resulted in a blanching that is usually seen in patients suffering from atopic dermatitis. [jamanetwork.com]

  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]

  Affecting males almost exclusively, it manifests as persistent atopic dermatitis, increased susceptibility to infections, and thrombocytopenic purpura, ecchymoses, petechiae and bloody diarrhea. [youtube.com]

  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.com]

• 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.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 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

  Maternal cousins, uncles or nephews with small platelets and thrombocytopenia Probable Male patient with congenital thrombocytopenia (less than 70,000 platelets/mm3), small platelets and at least one of the following: Eczema Abnormal antibody response [esid.org]

  Thrombocytopenia with bleeding is frequently present immediately after birth, and any male with thrombocytopenia and small platelets should be tested for WAS. [clinicaladvisor.com]

  A 7-month-old Korean boy presented with recurrent bloody diarrhea, eczema, and persistent thrombocytopenia with small platelets. [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. [dx.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]

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].

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].

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].

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].

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].

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].

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].

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.

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.