Combined immunodeficiency and hypoglycemia associated with mutations in hypoxia upregulated 1.

To the Editor: Immunodeficiencies featuring congenital neutropenia have varying presentations, including life-threatening bacterial infections. These conditions can be caused by defects in more than 10 genes. Most genes operate in the endolysosomal system, and their perturbed action induces unfolded protein response and altered mitochondrial function. The resulting cell stress drives neutrophils to apoptosis. We evaluated a 45-year-old woman showing symptoms of combined immunodeficiency and disturbed glucose metabolism since birth (for detailed case description, see this article’s Online Repository at www.jacionline.org). She was born small for gestational age and her subsequent growth was poor. Her appearance was slightly dysmorphic, featuring oval face, pectus carinatum, and broad long bone metaphyses. During childhood, she experienced episodes of stress-induced hypoglycemia. From infancy to adulthood, she suffered from numerous septic infections of the respiratory tract, skin, and mucous membranes. At age 4 years, she had severe septic herpetic gingivostomatitis, after which herpetic stomatitis recurred monthly for several years. In adulthood, she contracted herpetic encephalitis followed by recurring condylomatous warts in her thighs and genital area. G-CSF and intravenous immunoglobulin treatment were initiated in her 20s, which led to the normalization of her absolute neutrophil count and significantly decreased the rate of bacterial infections. An immunodysregulatory component was evident, as the patient developed hidradenitis suppurativa in her teens and relapsing Takayasu arteritis as an adult. Currently, the patient receives G-CSF, immunoglobulin replacement therapy, rituximab, and oral prednisolone (5 mg/d). Detailed immunological workup is presented in Tables E1-E3 in this article’s Online Repository at www.jacionline.org. The patient showed broad abnormalities in the myeloid lineage. She had microcytic anemia, fluctuating thrombocytopenia, and constant granulocytopenia (see Table E1 in this article’s Online Repository at www.jacionline.org). Neutrophils showed poor chemotaxis and increased activation. Bone marrow biopsies showed inconstant myeloid maturation arrest that resolved on G-GSF treatment (data not shown). In addition, antigen presentation and adaptive immunity were affected. Both plasmacytoid and monocytoid dendritic cells were reduced in peripheral blood, and the expression of costimulatory CD86 molecule was low in both monocytoid dendritic cells and monocytes. These together with a low PHA stimulation response suggested impaired antigen presentation. In the T-cell compartment, the proportions of CD4 and CD8 T cells were within normal range, with naive CCR7CD45RA cells dominating the repertoire. The Bcell count was very low, and B-cell development skewed toward mature B cells with reduced switched memory B cells. Despite normal immunoglobulin levels, responses to polysaccharide antigens were completely absent. It is unlikely that the observed changes are due to the patient’s