Bloody Stool and Recurrent Infections

Abstract

• Mutations in the WAS gene can result in either of the three main phenotypes: classic Wiskott-Aldrich syndrome (WAS), X-linked thrombocytopenia (XLT), and X-linked neutropenia

• WAS/XLT should be considered in every male presenting with bleeding associated with congenital or early-onset thrombocytopenia and small platelets

A 6-month-old boy presented to our clinic with bloody stool and recurrent upper respiratory tract infections. Born from a 21-year-old mother after an uncomplicated pregnancy, he is the first child of consanguineous parents with no family history of similar conditions. In his neonatal period blood was frequently observed in stool and family physician prescribed therapy for anal fissure but the bleeding persisted. At three months of age he was admitted to a local hospital with bloody stool where he was diagnosed with idiopathic thrombocytopenic purpura (ITP) and received intravenous immunoglobulin and steroids. Thrombocytopenia persisted regardless of the therapy and he experienced an episode of otitis media and pneumonia between 3 and 6 months of age. On his admission to clinic, mild eczema, petechia and hepatosplenomegaly were detected during the physical exam. Laboratory evaluation revealed hypochrome microcytic anemia and thrombocytopenia (Hb: 8.1 g/dL, MCV: 70 fL, RDW: 15.2, WBC: 8200/μL, platelet: 18,000,000/μL, MPV: 5.7 fL) and low IgM levels. His peripheral blood smear did not show any blasts.

FormalPara Q1. What is the most likely diagnosis?

• A. Chronic Idiopathic thrombocytopenic purpura

• B. Wiskott-Aldrich syndrome

• C. Evans syndrome

• D. Leukemia

FormalPara Answer:

The correct answer is B.

Wiskott-Aldrich syndrome (WAS) is a primary immune deficiency having an X-linked inheritance pattern and classically characterized by thrombocytopenia with small platelets, eczema and recurrent infections [1]. The disease is caused by mutations in the WAS gene coding the WAS protein (WASp) which is involved in cell signaling and cytoskeleton reorganization. Three different phenotype of the disease are described: Classic WAS, X-linked thrombocytopenia (XLT) and X-linked neutropenia (XLN), depending on the type and/or site of mutation and its effect on protein expression, albeit with some exceptions. Early manifestations of WAS and XLT consist of petechia, bruises and bloody diarrhea often present from neonatal period. Characteristic finding at diagnosis both in classic WAS and XLT is microthrombocytopenia. Infections including purulent otitis media are frequent during the first 6 month of life [2]. Because of the wide spectrum of the clinical presentation, WAS/XLT should be considered in every male presenting with bleeding associated with congenital or early-onset thrombocytopenia and small platelets. Evaluation of WASp expression by flow cytometry and screening the WAS gene by sequence analysis are warranted to confirm the diagnosis and assess the disease severity [3]. Mutations that cause decreased WASp levels result in XLT, whereas mutations that abolish WASp expression or result in the expression of a truncated protein are associated with WAS.

The most common cause of acute onset of thrombocytopenia in an otherwise well child is ITP [4]. There is a history of a preceding viral infection 1–4 weeks before the onset of thrombocytopenia. Findings on physical examination are petechia and purpura and rarely splenomegaly, lymphadenopathy, bone pain, and pallor. Severe thrombocytopenia (platelet count <20,000,000/μL) is common, and platelet size is normal or increased, reflecting increased platelet turnover. We do not expect a reduction in hemoglobin value or WBC count, in acute ITP. Approximately 20% of patients who present with acute ITP have persistent thrombocytopenia for more than 12 months and develop chronic ITP. At that time, a careful reevaluation for associated disorders should be performed, especially for autoimmune disease, such as SLE, chronic infectious disorders, such as HIV, and nonimmune causes of chronic thrombocytopenia, such as type 2B and platelet-type von Willebrand disease, XLT, autoimmune lymphoproliferative syndrome, common variable immunodeficiency syndrome and WAS [4].

Primary Evans syndrome (ES) is defined by the concurrent or sequential occurrence of Coombs-positive autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia in the absence of underlying etiology [5]. Although many cases are idiopathic in origin, ES has been associated with a number of other conditions in approximately one-half of the cases, including infections (e.g. HCV, HIV), systemic lupus erythematosus, lymphoproliferative disorders, common variable immunodeficiency, and autoimmune lymphoproliferative syndrome, LRBA deficiency and following allogeneic hematopoietic stem cell transplantation (HSCT). ES is often either resistant to standard treatment for AIHA or ITP (i.e. glucocorticoids, IVIG, splenectomy), or follows a chronic, relapsing course.

FormalPara Q2. Which of the following findings should rise suspicion of Wiskott-Aldrich syndrome in a boy with chronic thrombocytopenia?

• A. Hepatosplenomegaly

• B. Mean platelet volume less than 7 fL

• C. Normal megakaryocytes in bone marrow

• D. Low serum IgM levels

FormalPara Answer:

The correct answer is B.

WAS is a unique disease with microthrombocytopenia. Although rare, exceptions have been described. Typically, platelets are of small volume, which is considered a pathognomonic sign of the disease [1].

FormalPara Q3. After confirming the underlying diagnosis, what is most appropriate next step in follow-up of this patient?

• A. Avoid all live vaccines, initiate antiviral, antifungal antibacterial prophylaxis and prophylactic IVIG

• B. Donor search and bone marrow transplant

• C. Prepare the patient for gene therapy

• D. Answers A and B are correct

FormalPara Answer:

The correct answer is D.

Allogeneic HSCT, preferably from an HLA-identical sibling, is currently the established therapeutic option. HSCT performed at an early age, particularly under 2-years-old when autoimmunities and malignancies have not yet developed, has a promising overall survival of >90% [6]. If a full-matched donor is present, HSCT is the first-line treatment. Mismatched donors and older patients are factors associated with higher mortality and morbidity. Recently, gene therapy has offered a therapeutic option for high-risk patients [7].

FormalPara Practical Points

• Mutations in the WAS gene can result in either of the three main phenotypes: classic Wiskott-Aldrich syndrome (WAS), X-linked thrombocytopenia (XLT), and X-linked neutropenia

• WAS/XLT should be considered in every male presenting with bleeding associated with congenital or early-onset thrombocytopenia and small platelets