Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease.

PURPOSE: We report a male child who presented at 15 months with perianal abscesses and proctitis, progressing to transmural pancolitis with colocutaneous fistulae, consistent with a Crohn disease-like illness. The age and severity of the presentation suggested an underlying immune defect; however, despite comprehensive clinical evaluation, we were unable to arrive at a definitive diagnosis, thereby restricting clinical management. METHODS: We sought to identify the causative mutation(s) through exome sequencing to provide the necessary additional information required for clinical management. RESULTS: After sequencing, we identified 16,124 variants. Subsequent analysis identified a novel, hemizygous missense mutation in the X-linked inhibitor of apoptosis gene, substituting a tyrosine for a highly conserved and functionally important cysteine. X-linked inhibitor of apoptosis was not previously associated with Crohn disease but has a central role in the proinflammatory response and bacterial sensing through the NOD signaling pathway. The mutation was confirmed by Sanger sequencing in a licensed clinical laboratory. Functional assays demonstrated an increased susceptibility to activation-induced cell death and defective responsiveness to NOD2 ligands, consistent with loss of normal X-linked inhibitor of apoptosis protein function in apoptosis and NOD2 signaling. CONCLUSIONS: Based on this medical history, genetic and functional data, the child was diagnosed as having an X-linked inhibitor of apoptosis deficiency. Based on this finding, an allogeneic hematopoietic progenitor cell transplant was performed to prevent the development of life-threatening hemophagocytic lymphohistiocytosis, in concordance with the recommended treatment for X-linked inhibitor of apoptosis deficiency. At >42 days posttransplant, the child was able to eat and drink, and there has been no recurrence of gastrointestinal disease, suggesting this mutation also drove the gastrointestinal disease. This report describes the identification of a novel cause of inflammatory bowel disease. Equally importantly, it demonstrates the power of exome sequencing to render a molecular diagnosis in an individual patient in the setting of a novel disease, after all standard diagnoses were exhausted, and illustrates how this technology can be used in a clinical setting.

An evaluation of the utility of routine laboratory monitoring of juvenile idiopathic arthritis (JIA) patients using non-steroidal anti-inflammatory drugs (NSAIDs): a retrospective review.

BACKGROUND: No consensus evidence-based guidelines for the routine laboratory monitoring of children with JIA receiving non-steroidal anti-inflammatory drugs (NSAIDs) exist. The purpose of this study is to evaluate the clinical utility of routine laboratory monitoring of hemoglobin, transaminases, blood urea nitrogen, serum creatinine, and urinalysis in patients with juvenile idiopathic arthritis (JIA) receiving NSAIDs. METHODS: The medical records of 91 children with JIA followed between 1996 and 2006 were retrospectively reviewed for laboratory results and clinically significant adverse effects attributed to NSAID use. Laboratory abnormalities were documented, with potential adverse clinical sequelae, including if NSAID use was discontinued. RESULTS: Abnormal laboratory results were recorded for 24 of 91 patients. Nearly all abnormalities were mild and not associated with adverse clinical sequelae. All patients but one continued to receive NSAID therapy after the abnormality was detected. CONCLUSIONS: Although detection of abnormal laboratory values occurred while on NSAIDs, these abnormalities did not correlate with adverse clinical signs and symptoms. The routine monitoring of laboratory tests in asymptomatic children treated with NSAIDs is of questionable utility.