Randomized Clinical Trial of First-Line Genome Sequencing in Pediatric White Matter Disorders.

OBJECTIVE: Genome sequencing (GS) is promising for unsolved leukodystrophies, but its efficacy has not been prospectively studied. METHODS: A prospective time-delayed crossover design trial of GS to assess the efficacy of GS as a first-line diagnostic tool for genetic white matter disorders took place between December 1, 2015 and September 27, 2017. Patients were randomized to receive GS immediately with concurrent standard of care (SoC) testing, or to receive SoC testing for 4 months followed by GS. RESULTS: Thirty-four individuals were assessed at interim review. The genetic origin of 2 patient's leukoencephalopathy was resolved before randomization. Nine patients were stratified to the immediate intervention group and 23 patients to the delayed-GS arm. The efficacy of GS was significant relative to SoC in the immediate (5/9 [56%] vs 0/9 [0%]; Wild-Seber, p < 0.005) and delayed (control) arms (14/23 [61%] vs 5/23 [22%]; Wild-Seber, p < 0.005). The time to diagnosis was significantly shorter in the immediate-GS group (log-rank test, p = 0.04). The overall diagnostic efficacy of combined GS and SoC approaches was 26 of 34 (76.5%, 95% confidence interval = 58.8-89.3%) in <4 months, greater than historical norms of <50% over 5 years. Owing to loss of clinical equipoise, the trial design was altered to a single-arm observational study. INTERPRETATION: In this study, first-line GS provided earlier and greater diagnostic efficacy in white matter disorders. We provide an evidence-based diagnostic testing algorithm to enable appropriate clinical GS utilization in this population. ANN NEUROL 2020;88:264-273.

Asymptomatic Kawasaki Disease in a 3-Month-Old Infant.

Kawasaki disease (KD) is the leading cause of acquired heart disease in children in the United States. It is a systemic vasculitis characterized by diffuse inflammation of medium and small blood vessels. If untreated it can lead to myocardial infarction, ischemic heart disease, or sudden death. Early recognition and treatment decrease the incidence of coronary consequences, resulting in improved clinical outcomes. Incomplete KD is much less likely to fulfill major clinical diagnostic criteria. Infants <12 months of age are more likely to have an incomplete presentation, and children <6 months of age are more likely to develop cardiac complications. We present a case of a 3-month-old, previously healthy white boy who was noted to have a new transient cardiac murmur during a routine health assessment. He was completely asymptomatic, and physical examination was otherwise within normal limits. An echocardiogram was performed and showed abnormal dilation of several coronary arteries, consistent with the coronary ectasia associated with KD. Laboratory evaluation was significant for values suggestive of systemic inflammation. Based on these results, a presumed diagnosis of incomplete KD was made and treatment administered. Close surveillance was undertaken, and serial laboratory studies and imaging showed gradual resolution of inflammatory markers and cardiac ectasia. This unique case of incomplete KD without any of the physical signs normally associated with the disease emphasizes the spectrum of presentation and the possibility of missing a diagnosis of incomplete disease, reinforcing the need to remain vigilant.