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Autosomal dominant hyper-IgE syndrome (AD-HIES), characterised by eczema, increased susceptibility to skin and lung infections, elevated IgE and skeletal abnormalities is associated with heterozygous STAT3 mutations. The autosomal recessive variant (AR-HIES) has similar immunological findings but mainly lacks extraimmune manifestations. Several AR-HIES patients have recently been shown to harbour mutations in the gene for dedicator of cytokinesis 8 (DOCK8). Here, we present the long-term outcome of a girl having received a hematopoietic stem cell graft for an at that time genetically undefined combined immunodeficiency associated with severe eczema, multiple food allergies, excessively elevated serum IgE levels and eosinophilia. She was recently found to carry a homozygous nonsense mutation in the DOCK8 gene. HSCT resulted in complete immunological correction, even though mixed donor chimerism occurred. Clinically, the outcome was characterised by disappearance of skin manifestations and severe infections, improvement of pulmonary function and constant decline of IgE levels. Outcome in untransplanted DOCK8 deficient patients is poor because of frequent life-threatening infections, CNS bleeding and infarction, and increased susceptibility to malignancy. This argues for early curative therapeutic approaches, supported by this report of successful long-term outcome after HSCT.

X-linked thrombocytopenia (XLT) is a mild form of the Wiskott-Aldrich syndrome (WAS) caused by mutations in the WAS gene. A recent retrospective study of the clinical outcome and molecular basis of a large cohort of XLT patients demonstrated that although overall survival is excellent, event free survival is severely affected with conservative treatment. To answer the question whether hematopoietic stem cell transplantation (HSCT) offers a viable alternative therapeutic option in XLT, we retrospectively investigated the outcome of HSCT in a cohort of 24 XLT patients who received HSCT between 1990 and 2011 at 14 transplant centers in the United States, Italy, Germany, Canada, and Japan. The engraftment rate was 100% and the overall survival rate was 83.3%. Of the four non-survivors, 2 underwent splenectomy prior to HSCT and died of sepsis, and two of aspergillus infections associated with severe GVHD. In all but one patient, pretransplant complications were resolved by HSCT. Our data indicate that HSCT following myeloablative conditioning is curative and associated with acceptable risks as a treatment option for XLT.

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.

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