Recurrent rhinovirus infections in a child with inherited MDA5 deficiency

Lamborn, Ian T.; Jing, Huie; Zhang, Yu; Drutman, Scott B.; Abbott, Jordan K.; Munir, Shirin; Bade, Sangeeta; Murdock, Heardley M.; Santos, Celia P.; Brock, Linda G.; Masutani, Evan; Fordjour, Emmanuel Y.; McElwee, Joshua J.; Hughes, Jason D.; Nichols, Dave P.; Belkadi, Aziz; Oler, Andrew J.; Happel, Corinne S.; Matthews, Helen F.; Abel, Laurent; Collins, Peter L.; Subbarao, Kanta; Gelfand, Erwin W.; Ciancanelli, Michael J.; Casanova, Jean-Laurent; Su, Helen C.

At birth (37 wk), she was found to have intrauterine growth retardation. Infection screening during routine prenatal care had indicated past maternal infection with HSV-1, Toxoplasma, and CMV. At 40 d of age, she had an upper respiratory infection that was PCR-positive for both HRV/ enterovirus and influenza B virus. She developed respiratory failure, which required mechanical ventilation including extra-corporeal membrane oxygenation. Tracheal aspirates grew out Haemophilus influenzae, Streptococcus viridans, Acinetobacter spp., enterococcus, Escherichia coli, and other coliform bacteria. Subsequently, she had more than 15 hospital admissions for respiratory distress precipitated by viral respiratory infections. Multiplex PCR revealed two episodes of influenza A; three prolonged intervals of repeated HRV/ enterovirus recovery; four episodes of coronaviruses (OC43, NL63, HKU1); two episodes of adenovirus; and one each of RSV and human parainfluenza virus type 4. Wedge lung biopsy histology, performed when she was 6 mo of age, revealed adequate alveolar architecture with evidence of chronic small airways disease (mucous stasis and collection of foamy alveolar macrophages), but without evidence of active bronchiolitis, pneumonitis, or other inflammatory processes. She continues to require supplemental oxygen, and had ground glass opacities but no bronchiectasis on chest computed tomography. She has been hospitalized on multiple occasions for coliform urinary tract infection and acute gastroenteritis with dehydration, but without detectable viral pathogens. She had an abscess near her G-tube insertion site that grew out Klebsiella pneumoniae and Enterobacter cloacae. Although she initially had low serum immunoglobulin levels and decreased lymphocyte counts (affecting T, NK, and B cell subsets), these all normalized between 3 to 4 yr old. Replacement immunoglobulins were discontinued and she has since responded with functional antibodies to tetanus, diphtheria, and Haemophilus influenzae vaccines. She has no history of opportunistic or chronic systemic virus infection including EBV or CMV despite serological evidence of past exposure. Additionally, when 2 yr of age, she developed new-onset type 1 diabetes mellitus with detectable GAD65 autoantibodies. She has short stature, low weight, hypotonia, weakness, and delays in motor and language development. Brain MRI has shown low periventricular white matter volume with ventriculomegaly, and structural abnormalities of hippocampus, olfactory bulbs, septum pellucidum, and corpus callosum. High-resolution chromosomal microarray analysis identified a 4-kb deletion on chromosome 2 that included the TM4SF20 gene. This copy number variant has been associated with language delay, white matter hyperintensities, and varied developmental abnormalities in South Asian populations (Wiszniewski et al., 2013) . Several regions of absence of heterozygosity totaling 45 MB on five separate chromosomes were also identified. She also had de novo or rare autosomal recessive variants that were identified in genes highly expressed in the brain (Table S2 ). The convergence of these multiple genetic problems in our patient illustrate how two or more distinct monogenic diseases can occur in a significant proportion of the population examined by WES (Yang et al., 2013 (Yang et al., , 2014 Retterer et al., 2016) .