RECURRENT LUNG INFECTIONS IN A HETEROZYGOUS CARRIER OF NOVEL NSMCE3 MUTATION.

Abstract

<h3>Introduction</h3> Several biallelic missense mutations in NSMCE3 lead to chromosome breakage syndrome (LICS), which presents with early-onset lung disease, pneumonia, B- and T- cell dysfunction and resultant death in early childhood. The protein product of NSMCE3 helps bridge and stabilize the SMC5/6 complex, which plays a crucial role in DNA double-strand break repair and is thought to help suppress viral infections. <h3>Case Description</h3> A 5-year-old male with atopic dermatitis and reactive airway disease presented for evaluation of recurrent sinopulmonary infections. In one year, he had three episodes of acute otitis media and five viral upper respiratory infections, complicated by multiple bacterial pneumonias. Initial immunologic workup showed low CD8+ T-cells that subsequently normalized. He also had marginally-low IgM, but showed intact humoral response to HiB vaccine and Pneumovax. Three years later, he experienced two more episodes of bacterial pneumonia, one requiring two rounds of antibiotics for clinical improvement. Genetic testing (Invitae Primary Immunodeficiency Panel) showed a heterozygous variant of uncertain significance, a deletion-insertion mutation of the NSMCE3 gene (nucleotides 41 and 42 are deleted and two cytosines inserted, which changes glutamine to proline at the 14th amino acid position in the protein product). <h3>Discussion</h3> In most cases, heterozygous carriers can compensate for a defective allele. Our patient has a missense mutation in one NSMCE3 allele, which may affect the protein product's conformation. Since this protein functions in DNA repair and known mutations have been associated with pneumonia and viral infections, we hypothesize that his reduced level of normal protein may underlie his recurrent pneumonias.