Summary Background Genetic disorders and congenital anomalies are the leading causes of infant mortality. Diagnosis of most genetic diseases in neonatal and paediatric intensive care units (NICU and PICU) is not sufficiently timely to guide acute clinical management. We used rapid whole-genome sequencing (STATseq) in a level 4 NICU and PICU to assess the rate and types of molecular diagnoses, and the prevalence, types, and effect of diagnoses that are likely to change medical management in critically ill infants. Methods We did a retrospective comparison of STATseq and standard genetic testing in a case series from the NICU and PICU of a large children's hospital between Nov 11, 2011, and Oct 1, 2014. The participants were families with an infant younger than 4 months with an acute illness of suspected genetic cause. The intervention was STATseq of trios (both parents and their affected infant). The main measures were the diagnostic rate, time to diagnosis, and rate of change in management after standard genetic testing and STATseq. Findings 20 (57%) of 35 infants were diagnosed with a genetic disease by use of STATseq and three (9%) of 32 by use of standard genetic testing (p=0·0002). Median time to genome analysis was 5 days (range 3–153) and median time to STATseq report was 23 days (5–912). 13 (65%) of 20 STATseq diagnoses were associated with de-novo mutations. Acute clinical usefulness was noted in 13 (65%) of 20 infants with a STATseq diagnosis, four (20%) had diagnoses with strongly favourable effects on management, and six (30%) were started on palliative care. 120-day mortality was 57% (12 of 21) in infants with a genetic diagnosis. Interpretation In selected acutely ill infants, STATseq had a high rate of diagnosis of genetic disorders. Most diagnoses altered the management of infants in the NICU or PICU. The very high infant mortality rate indicates a substantial need for rapid genomic diagnoses to be allied with a novel framework for precision medicine for infants in NICU and PICU who are diagnosed with genetic diseases to improve outcomes. Funding Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, and National Center for Advancing Translational Sciences.

BackgroundInsulinoma is a rare diagnosis in the general population with estimates of 1 in 250,000 people per year. Reports of these pancreatic islet cell tumors are even more unusual in children and adolescents. Chronic hypoglycemia due to an insulinoma often presents with neuroglycopenic symptoms that can easily be overlooked, especially in adolescents where nonspecific complaints are common. This may result in delayed diagnosis with prolonged periods of untreated hypoglycemia and associated complications. The rarity of pediatric insulinoma, vagueness of presenting symptoms, and challenge of tumor localization make insulinoma a true diagnostic quandary for clinicians.Case PresentationIn this report, we present a 15-year-old female who visited her primary care provider complaining of intermittent episodes of altered mental status including fatigue, irritability, and poor concentration. Her outpatient management included routine laboratory studies, drug screening, electroencephalogram (EEG), valproic acid initiation, CT scan of the abdomen, and endoscopic ultrasound with documentation of hypoglycemia, but otherwise inconclusive results. The patient was admitted to a tertiary children’s hospital with severe refractory hypoglycemia 8 months after the initial evaluation. A serum critical sample was obtained and magnetic resonance imaging (MRI) of the abdomen performed which confirmed the presence of a pancreatic mass ultimately identified as an insulinoma. She went on to have surgical resection of her tumor resulting in complete resolution of her hypoglycemia and associated symptoms.ConclusionWithin this report we demonstrate the importance of being vigilant for fasting hypoglycemia secondary to insulinoma even when the patient presents with nonspecific symptoms such as fatigue, irritability, or problems with concentration. If these neuroglycopenic complaints are unnoticed or misdiagnosed, patients with a potentially curable disease are put at risk of neurologic injury, or even death, due to untreated severe hypoglycemia.

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This laboratory-based algorithm resulted in reduced laboratory utilization, and aligned our practice to recommendations of the Pediatric Endocrine Society. Similar algorithms could be created for other dynamic tests to reduce unnecessary laboratory utilization.