A CASE OF RECURRENT ASPIRATION PNEUMONIA AND PERSISTENT EOSINOPHILIA

Abstract

Introduction Homozygous or compound heterozygous loss-of-function (LOF) mutations in CARMIL2 are associated with combined immunodeficiency disorder with a variable phenotypic presentation in 10 families (21 patients). Clinical manifestations include recurrent skin and lung infections, dermatitis, chronic diarrhea, esophagitis, and failure-to-thrive. Here we describe a case of immune deficiency associated with an apparently homozygous, novel variant c.1942delC (p.His648ThrfsX20) in the CARMIL2 gene (RLTPR). Case Description The patient presented with recurrent pneumonias from 6-29 months of age, 11 requiring hospitalization. Pneumonias and bronchiectasis were attributed to aspiration of liquids, confirmed on barium swallow. Whole exome sequencing identified an apparently homozygous pathogenic variant (c.1954delC, resulting in frameshift p.H648TfsX20) in CARMIL2 gene. Immune evaluation was significant for poor antibody response to 12 of 14 pneumococcal serotypes, absent lymphocyte proliferation to antigens (candida and tetanus) with reduced lymphocyte proliferation to mitogens (PHA and Con A), an excess of CD19+B cells (2769 cells/mcL), low-level EBV viremia (5806 copies), and persistent eosinophilia (1.82-6.18x10³/µL). Total immunoglobulin levels (IgG, IgM, IgA, IgE) and CD8+T-suppressor cell-, CD4+T-helper cell-, and CD56+NK cell-counts were within normal range. Discussion Here we report a case of combined immune deficiency with associated findings of aspiration, recurrent pneumonias, eosinophilia, and B-cell lymphocytosis with EBV viremia in a child with an apparently homozygous novel variant in the CARMIL2 gene. This case report provides further evidence that homozygous LOF mutations in CARMIL2 are associated with a combined immune defect with varied phenotypic features. Identification of this mutation may have prognostic value and will guide genetic counseling.