Vy Hong-Diep Kim

Hematopoietic stem cell transplantation in patients with gain-of-function signal transducer and activator of transcription 1 mutations

Background: Gain‐of‐function (GOF) mutations in signal transducer and activator of transcription 1 (STAT1) cause susceptibility to a range of infections, autoimmunity, immune dysregulation, and combined immunodeficiency. Disease manifestations can be mild or severe and life‐threatening. Hematopoietic stem cell transplantation (HSCT) has been used in some patients with more severe symptoms to treat and cure the disorder. However, the outcome of HSCT for this disorder is not well established. Objective: We sought to aggregate the worldwide experience of HSCT in patients with GOF‐STAT1 mutations and to assess outcomes, including donor engraftment, overall survival, graft‐versus‐host disease, and transplant‐related complications. Methods: Data were collected from an international cohort of 15 patients with GOF‐STAT1 mutations who had undergone HSCT using a variety of conditioning regimens and donor sources. Retrospective data collection allowed the outcome of transplantation to be assessed. In vitro functional testing was performed to confirm that each of the identified STAT1 variants was in fact a GOF mutation. Results: Primary donor engraftment in this cohort of 15 patients with GOF‐STAT1 mutations was 74%, and overall survival was only 40%. Secondary graft failure was common (50%), and posttransplantation event‐free survival was poor (10% by 100 days). A subset of patients had hemophagocytic lymphohistiocytosis before transplant, contributing to their poor outcomes. Conclusion: Our data indicate that HSCT for patients with GOF‐STAT1 mutations is curative but has significant risk of secondary graft failure and death.

Novel Combined Immune Deficiency and Radiation Sensitivity Blended Phenotype in an Adult with Biallelic Variations in ZAP70 and RNF168

With the advent of high-throughput genomic sequencing techniques, novel genetic etiologies are being uncovered for previously unexplained Mendelian phenotypes, and the underlying genetic architecture of disease is being unraveled. Although most of these “mendelizing” disease traits represent phenotypes caused by single-gene defects, a percentage of patients have blended phenotypes caused by pathogenic variants in multiple genes. We describe an adult patient with susceptibility to bacterial, herpesviral, and fungal infections. Immunologic defects included CD8+ T cell lymphopenia, decreased T cell proliferative responses to mitogens, hypogammaglobulinemia, and radiation sensitivity. Whole-exome sequencing revealed compound heterozygous variants in ZAP70. Biallelic mutations in ZAP70 are known to produce a spectrum of immune deficiency that includes the T cell abnormalities observed in this patient. Analyses for variants in genes associated with radiation sensitivity identified the presence of a homozygous RNF168 variant of unknown significance. RNF168 deficiency causes radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties syndrome and may account for the radiation sensitivity. Thus, the patient was found to have a novel blended phenotype associated with multilocus genomic variation: i.e., separate and distinct genetic defects. These findings further illustrate the clinical utility of applying genomic testing in patients with primary immunodeficiency diseases.

Adenosine deaminase deficiency: current treatments and emerging therapeutics

ABSTRACT Introduction: Adenosine deaminase (ADA) deficiency is a systemic metabolic disorder characterized by severe immune and non-immune abnormalities and is often fatal in infancy. ADA deficiency can be treated by allogeneic hematopoietic stem cell transplantation (HSCT), ADA enzyme replacement therapy (ERT) or ex vivo gene therapy (GT). Areas covered: This article discusses the different treatment options currently available for ADA deficiency, remaining challenges and expected developments. Expert opinion: Experts in ADA deficiency should manage this complex disease, as a patient’s individual factors often determine treatment course. Unconditioned HSCT from an HLA identical sibling is the preferred option. ERT can provide short-term benefits for patients without such donors, or until other definitive treatments are established. Commercial gamma-retrovirus GT, currently available only in Italy, or investigational lentivirus GT have, to date, been shown to be safe, although long-term follow up is needed to determine their continued effectiveness. Therefore, GT should be considered for patients without an appropriate HSCT donor and when families are able to travel to Italy or participate in research protocols. Additional studies into the pathogenesis of ADA deficiency and the effects of the different treatment modalities will assist in determining the ideal management for individual patients.