Clinical Phenotype and Long Term Outcome in a Large Cohort of X-Linked Thrombocytopenia (XLT)/Mild Wiskott-Aldrich-Syndrome Patients
Authors: Albert Michael H , Bittner Tanja , Stachel Daniel , Nonoyama Shigeaki , Notarangelo Lucia , Burns Siobhan , Pellier Isabelle , Strauss Gabriele , Morio Tomohiro , Imai Kohsuke , Espanol Teresa , Gathmann Benjamin , Hönig Manfred , Noordzij Jeroen G , Nathrath Michaela , Meindl Alfons , Wintergerst Uwe , Fischer Alain , Thrasher Adrian , Belohradsky Bernd H , Ochs Hans D 
Published: October 2019

Abstract
A large proportion of patients with mutations in the Wiskott Aldrich syndrome (WAS) protein gene exhibit the milder phenotype termed X-linked thrombocytopenia (XLT). Intravenous immunoglobulin and antibiotic prophylaxis until stem cell transplantation (SCT) at an early age is the treatment of choice for classical WAS patients. For patients with XLT the optimal treatment is much less clear. Most of them reach adulthood without significant problems. However, severe complications such as infections, bleeding, autoimmune disorders and malignancies have been observed in these patients, albeit at a lower rate than in classical WAS patients. In order to provide a basis for treatment decisons in XLT patients we intended to define the natural course of disease in XLT patients and assess the probability of severe disease related complications. A retrospective survey at centers treating primary immunodeficiency patients was carried out and data were collected for patients with a documented WASP gene mutation and a WAS disease severity score of 2 or less, implicating thrombocytopenia and mild eczema and minor infections only. Data from a total of 182 patients from 12 countries could be analyzed. Median age at last follow-up was 11.2 years (range 0.4–74.6). Overall probability of survival censored for SCT was favorable in this cohort with 95%, 86% and 78% at 20, 40 and 60 years of age respectively. We did however observe a high rate of severe disease related events such as potentially life threatening infection or bleeding, autoimmune disease or malignancy. Therefore the probability to be alive without a serious event was only 66%, 45% and 29% at 20, 40 and 60 years respectively. Out of all 182 patients 13 (7%) developed severe infectious events, 3 of which were fatal. Severe bleeding episodes occurred in 23/182 (13%), 4 of which were fatal. Autoimmune disease developed in 22/182 (12%) and 9/182 (5%) were diagnosed with malignancy, 6 of whom have died. Overall and event free survival probabilities were not significantly influenced by the type of mutation or the presence of WASProtein. Patients receiving any antibiotic prophylaxis or IVIG had no survival benefit compared to others. Splenectomy, which was performed in 39/182 patients (21%), posed a significant risk to experience a severe infectious event (p<0.0001) but offered no protection from bleeding (p=0.42). There was a trend towards less severe infectious episodes after splenectomy in patients with antibiotic prophylaxis (16% vs. 33%, p=0.21). This study presents the clinical course of the largest cohort of XLT patients studied so far. It demonstrates excellent long term survival but reveals high probabilities of severe disease related complications. Splenectomy as a significant risk factor for infectious complications was the only determinant of outcome that could be identified. These observations will aid in better decision making when considering treatment options for these patients.