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Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts.

ADA-deficient patients commonly suffer from long-term complications, emphasizing the need for improved management and for multi-disciplinary follow-up.

(ADA) is a ubiquitous enzyme important for the degradation and salvage of adenosine (Ado) and deoxyAdo (dAdo). Autosomal-recessive defects that severely disrupt the function of ADA lead to accumulation of purine metabolites, which are toxic for rapidly proliferating cells, such as lymphocytes. 1 Most ADA-deficient patients present in the first year of life with profound T-and B-cell defects, leading to severe combined immunodeficiency (SCID). In addition, ADA-deficient patients frequently suffer from liver, lungs, bone, and other tissues abnormalities. 1 Management of ADA deficiency includes supportive care with antimicrobials such as trimethoprim/ sulfamethoxazole (TMP-SMZ) and immunoglobulins. Enzyme replacement therapy (ERT) with polyethylene-glycol-conjugated ADA can improve purine homeostasis and may serve as a ''bridge'' until patients undergo allogeneic hematopoietic stem cell transplantation (HSCT) or gene therapy (GT). HSCT using healthy HLA-matched or mismatched family-related or unrelated donors can correct the immune and some of the systemic abnormalities. 2 Myelodysplasia has previously been reported among ADA-deficient patients; however, because most patients were after unsuccessful HSCT or GT, the role of the metabolic abnormality was not clear. 3 Here, we tested the hypothesis that ADA deficiency could be directly associated with myeloid abnormalities and neutropenia. We analyzed data from all 20 patients diagnosed at our center

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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.

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