How I manage patients with Wiskott Aldrich syndrome

Abstract

Wiskott Aldrich syndrome (WAS) is a primary immunodeficiency disease resulting in recurrent infections, eczema and microthrombocytopaenia. In its classical form, significant combined immune deficiency, autoimmune complications and risk of haematological malignancy necessitate early correction with stem cell transplantation or gene therapy. A milder form, X-linked thrombocytopaenia (XLT), shares similar bleeding risk from thrombocytopaenia but is not associated with other significant clinical features and is generally managed conservatively. Here, we detail our approach to the diagnosis and treatment of classical WAS and XLT.

Keywords: Wiskott Aldrich syndrome; X-linked thrombocytopenia; haematopoietic stem cell transplant; immunodeficiency.

Fig 1

Classical presentation of WAS. Case presentation: Severe hand-foot-and-mouth disease on a background of eczema since birth, cow’s milk protein allergy and having a previous diagnosis of idiopathic thrombocytopaenia. Subsequently developed autoimmune haemolytic anaemia and thrombocytopenia. Initial investigations: Low CD8⁺ T-cells but otherwise normal lymphocyte numbers, with normal response to phytohaemagglutinin and vaccine response to tetanus. Platelet count was 27 × 10⁹/l with normal mean platelet volume (automated). WAS protein expression was found to be absent and mutation in WAS gene [c.374G>A hemizygote, substitution of glycine for glutamic acid p.(Gly125Glu)] confirmed diagnosis. Treatment: matched unrelated donor haematopoietic stem cell transplantation at 9 months old.

Fig 2

WAS and CMV infection. Case presentation: Monochorionic diamniotic twins presented with cytomegalovirus (CMV) pneumonitis at 5 months old on a background of persistent thrombocytopenia, infected eczema, reflux and colitis in the context of cow’s milk protein allergy. One twin subsequently developed pre-B infant acute lymphoblastic leukaemia. Initial investigations: normal lymphocyte numbers and response to phytohaemagglutinin stimulation with normal vaccine responses to tetanus and pneumococcus (conjugate vaccine) but absent response to CD3 stimulation. Platelet counts were low, at 37 × 10⁹/l, with low mean platelet volume of 6·9. WAS protein expression was absent by flow and immunoblot, with mutation in WAS gene (c777+1G>A splice site mutation) confirming diagnosis. CMV viral loads were 302 888 and 122 834 copies/ml at presentation. Treatment: Haplo (T-cell receptor/CD19 depleted) haematopoietic stem cell transplantation at 21 months old.

Fig 3

WAS and autoimmunity. Case presentation: Thrombocytopenia was noted following an upper respiratory tract infection at 8 months old, with small amounts of blood in the stool, mild eczema and suspicion of cow’s milk protein allergy. Subsequently developed molloscum contagiosum and warts but remained well until 8 years old with a phenotype otherwise consistent with attenuated Wiskott-Aldrich syndrome (WAS) (X-linked thrombocytopenia). Initial investigations: Normal lymphocyte numbers, response to phytohaemagglutinin and vaccine responses to tetanus and pneumococcus (conjugate vaccine), but absent response to CD3 stimulation. Platelet count was low at 40 × 10⁹/l. Raised IgA and IgG (not on replacement immunoglobulin therapy). Normal WAS protein expression by flow cytometry and mutation in WAS identified as c.1498T>C, (p.Trp500Arg). Treatment: Splenectomy (age 3 years). Progress: At 8 years old, remains well from infection and inflammation point of view but developed cola-coloured urine (left) with subsequent episodes of frank haematuria (right), associated with hypertension and mildly elevated creatinine (56 μmol/l) consistent with IgA nephropathy (confirmed on biopsy). Normalisation of platelet number and size occurred post-splenectomy, with no relapse of thrombocytopenia.