|LETTER TO EDITOR
|Ahead of print publication
Atypical presentation of Wiskott–Aldrich syndrome with autoimmune arthritis and macrothrombocytopenia
Sunil Vishan Kapur, Jitendra S Oswal
Department of Immunology and Rheumatology, Bharati Vidyapeeth University Medical College Hospital and Research Centre, Pune, Maharashtra, India
|Date of Submission||17-Sep-2020|
|Date of Acceptance||16-Mar-2021|
|Date of Web Publication||28-Oct-2021|
Sunil Vishan Kapur,
Department of Immunology and Rheumatology, Bharati Vidyapeeth University Medical College Hospital and Research Centre, Pune, Maharashtra
Source of Support: None, Conflict of Interest: None
Wiskott–Aldrich syndrome (WAS) is an X-linked recessive disorder affecting 1–10 babies per million male infants, characterized by a triad of immunodeficiency, eczema, and chronic microthrombocytopenia. WAS gene has been linked to the region Xp11.22–23, encodes a 502-amino acids intracellular protein which is constitutively expressed in nonerythroid hematopoietic cells. These patients have a high susceptibility for autoimmune disorders and malignancies which is usually associated with a poor outcome. In this case report, we describe a young child with chronic infantile onset macrothrombocytopenia and autoimmune arthritis in a mutation-proven WAS.
A 3-year-old male child presented to us with mucosal bleeding and bilateral wrist swelling of 8-week duration. Since the age of 11 months, he had recurrent bleeding tendency (bruising and purpura) and consistently low platelet counts (<25,000/mm3). Antenatal, birth history, and family history were not contributory. Immunization was complete and uneventful. His past reports indicated the presence of persistent macrothrombocytopenia (mean platelet volume [MPV] >16fl), absence of eczema, or repeated infections. He had been treated initially for presumed immune thrombocytopenic purpura with corticosteroids and mycophenolate mofetil without significant response. Our examination revealed marked swelling and tenderness in bilateral wrists with restricted movements [Figure 1], failure to thrive, purpura with no hepatosplenomegaly, or lymphadenopathy. Investigations revealed thrombocytopenia (haemoglobin – 9.4 g/dL, white blood cell count – 8600/mm3, and platelet count – 15,000/mm3) and a MPV (immediately after sampling) of 18.4fl (5–7 fl). Screening for Epstein–Barr virus was negative. Direct Coombs test, coagulation profile, toxoplamosis, rubella, cytomegalovirus, herpes simplex panel, anti-nuclear antibody, and rheumatoid factor were negative. Peripheral blood smear showed giant platelets and bone marrow aspirate evidenced megakaryocytic thrombopoiesis with no other abnormalities. Imaging studies revealed X-ray right wrist showing peri-articular osteopenia and ultrasonography revealed synovitis which responded to naproxen and oral corticosteroids. Immunological studies revealed serum immunoglobulins IgA and IgE to be raised to 128 mg/dl (8–91 mg/dl) and 42 IU/mL (<15 IU/mL), respectively, with normal IgG 396 mg/dL (295–1156 mg/dL) and IgM 168 mg/dL (37–184 mg/dL). Lymphocyte subset analysis was normal. Despite the lack of classical presentation, the refractory infantile onset thrombocytopenia and raised IgA and IgE levels raised our suspicion for WAS. Genetic analysis showed a known pathogenic nonsense mutation in exon 1, c. 37C>T (p.R13X) in WAS gene confirming our diagnosis. Our patient (WAS score 5) was referred for hematopoietic stem cell transplantation (HSCT).
Autoimmune diseases are reported from 22% to 72% of WAS patients and include autoimmune hemolytic anemia, vasculitis, arthritis, neutropenia, inflammatory bowel disease, and IgA nephropathy. In a detailed analysis of the clinical profiles of the eight children diagnosed with WAS in North India, autoimmunity in the form of leukocytoclastic vaculitis was observed in two children. Clinically, the course of wrist arthritis in our patient is likely of autoimmune origin given the periarticular osteopenia and synovitis on imaging and the prompt response to anti-inflammatory drugs. Any WAS patient developing autoimmunity or tumors is given a clinical score of 5 based on Zhu et al. The treatment options reported for autoimmune manifestations in WAS patients include corticosteroids and other immunosuppressants such as azathioprine, cyclophosphamide, cyclosporine, tacrolimus, and rituximab. Our patient is similar to the case of WAS reported by Skoric et al. with hemolytic anemia, as an autoimmune phenomenon associated with macrothrombocytopenia. [Table 1] presents case reports in the literature of WAS with macrothrombocytopenia. The molecular mechanisms underlying microthrombocytopenia seen in typical WAS patients is not clear but is related to cytoskeletal defects, F-actin distribution, and pro-platelet formation. However, the clinical phenotype of WAS including the platelet size itself is very varied, and some WAS patients have been found to have normal to elevated MPV depending on the WAS mutation (similar to our patient). Our case is probably the first reported from India, wherein WAS is associated with both autoimmune arthritis and macrothrombocytopenia. At present, HSCT is the only curative therapy for WAS with gene therapy emerging as an option in future.
|Table 1: Case reports of Wiskott-Aldrich syndrome with macrothrombocytopenia|
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We report this case to emphasize WAS mutation testing in all unexplained cases of thrombocytopenia even in the absence of characteristic triad. Increased pediatrician awareness may lead to more recognition of the autoimmune manifestations of WAS.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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