A 5-year-old female presented at age 2 with recurrent respiratory and ear infections, aphthous ulcers, and severe neutropenia (absolute neutrophil count [ANC] = 400 cells/mcl). Immunological testing at age 4 showed neutropenia, normal T cell, B cell, and natural killer (NK) cell numbers, normal immunoglobulin G/A/M, normal total hemolytic complement, protective tetanus titer, and 3/23 protective pneumococcal titers. The ANC exceeded 1,000 cells/mcl during infections. Bone marrow biopsy demonstrated normal trilineage hematopoiesis, suggesting a neutrophil egress problem.
Genetic testing of immunodeficiency genes revealed two variants of uncertain significance in trans in the gene encoding the neutrophil-selective chemokine receptor CXCR2: c.191T>G and c.865C>T. Both variants are in CXCR2 transmembrane regions and have a gnomAD prevalence of <0.01%.
AlphaMissense in silico prediction scores are 0.86 for c.191T>G and 0.852 for c.865C>T, indicating they are likely deleterious. Each parent was heterozygous for one mutation. c.865C>T has been reported previously in a patient with CXCR2 deficiency and chronic neutropenia.
Functional testing of cells transfected separately with plasmids encoding each variant showed that while each CXCR2 protein was expressed intracellularly, neither variant was expressed on the cell surface, explaining the lack of signaling upon CXCR2 agonist stimulation. Primary patient neutrophils also lacked surface CXCR2 and did not respond in vitro to the CXCR2-selective agonist CXCL2.
To our knowledge, this patient is the 7th identified with severe selective neutropenia, recurrent infections, and complete CXCR2 deficiency caused by biallelic loss-of-function mutations in CXCR2. Neutropenia despite normal neutrophil development is also found in Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome, an inborn error of immunity caused by hyperfunctional mutations in the panleukocyte chemokine receptor CXCR4. Neutrophil distribution is normally a balance of CXCR4-mediated retention in bone marrow and CXCR2-mediated egress from bone marrow. Unlike CXCR2-deficient patients, WHIM patients typically also have severe lymphopenia, may have hypogammaglobulinemia and warts, and do not present with mucositis. Dysmorphic neutrophils are often found in WHIM patient bone marrow but not in CXCR2-deficient marrow.
This case illustrates the crucial value of genetic testing for developing a complete mechanism-based taxonomy of severe congenital neutropenia and other congenital conditions.
