TOLL-LIKE RECEPTOR 3 (TLR3) DYSFUNCTION IN A CHILD WITH VACTERL ASSOCIATION

Abstract

Introduction VACTERL association is an axial mesodermal dysplasia syndrome in which abnormalities are identified in 3 of 6 areas: vertebral, anal, cardiac, tracheo-esophageal, renal, and limb. Immunodeficiency has not been described in VACTERL. Here we present a case of an infant with VACTERL in whom TLR3 functional defects were observed. Case Description A 10-month-old, ex 34-week female with VACTERL association without tracheo-esophageal fistula (TEF) presented with multiple PCR-confirmed respiratory illnesses including: RSV, influenza B, rhinovirus/enterovirus, and Bordetella pertussis, requiring prolonged intubation. IgG, IgM, IgA, IgE, diphtheria/tetanus and pneumococcal titers, lymphocyte enumeration, and mitogen/antigen proliferation were normal. TLR function assay performed by ARUP labs revealed markedly decreased TLR3 function (decreased cytokine production in response to Poly (I:C)). TLR 1,2,4,5,6,7, and 8 responses were normal. Genetic testing to confirm the specific defect is pending. Discussion Toll-like receptors (TLR) play a critical role in innate immune responses. The typical presentation of TLR3 deficiency is increased susceptibility with severe sequelae to viral and bacterial pathogens. Tracheo-esophageal anomalies, which increase the risk of severe, recurrent respiratory infections are common in VACTERL; however, despite the absence of TEF, this patient presented with respiratory failure due to typical pathogens on multiple occasions. This case illustrates that a high index of suspicion for immunodeficiency is required when VACTERL patients present with respiratory compromise that cannot be accounted for by anatomic malformations alone. Early recognition and appropriate management of immunodeficiency may help prevent life-threatening complications and improve long-term prognosis.