ObjectiveTo describe perinatal stress induced hyperinsulinism (PSIHI), determine the prevalence of neurodevelopmental differences, and identify risk factors for poor developmental prognosis.MethodsSubjects with a history of hyperinsulinism (HI) and perinatal stress and in whom resolution of the HI was demonstrated were included. Medical record review, caregiver interview, and three validated developmental assessments were completed.ResultsOf the 107 subjects (75% male), 36% were born between 32 and 37 weeks. Median age of hypoglycemia presentation was 0 days. Median age at HI diagnosis was 12 days (IQR 13.5). Median length of time for initiation of definitive treatment was 14 days (IQR 14).Caregiver interviews were completed for 53 of 79 eligible subjects. Developmental concerns were reported by 51%. Neurodevelopmental assessments were completed by caregivers of 37 of the 53 enrolled subjects. The proportion of subjects scoring >1 SD and >2 SD away from the mean in the direction of concern on the major composite scores was significantly greater than in the general population (40.5% vs. 15.8%, P ≤ 0.0001 and 18.9% vs. 2.2%, P ≤ 0.0001, respectively).Male sex, small for gestational age status (SGA), and treatment with continuous feeds were associated with assessment scores >1 SD from the mean (P < 0.05). SGA and preeclampsia were associated with assessment scores >2 SD from the mean (P < 0.05).ConclusionWhile the majority of infants presented with hypoglycemia in the first day of life, diagnosis and treatment occurred 12–14 days later. Children with PSIHI are at high risk of neurodevelopmental deficits and are more likely to perform below average on developmental assessment.

Tyrosinemia type I (TT1) is an inborn error of tyrosine metabolism with features including liver dysfunction, cirrhosis, and hepatocellular carcinoma; renal dysfunction that may lead to failure to thrive and bone disease; and porphyric crises. Once fatal in most infantile-onset cases, pre-symptomatic diagnosis through newborn screening (NBS) protocols, dietary management, and pharmacotherapy with nitisinone have improved outcomes. Succinylacetone provides a sensitive and specific marker for the detection of TT1 but is not universally utilized in screening protocols for the disease. Here, we report an infant transferred to our facility for evaluation and management of hyperinsulinism who subsequently developed acute-onset liver, respiratory, and renal failure around one month of life. She was found to have TT1 caused by novel pathogenic variant in fumarylacetoacetate hydrolase (c.1014 delC, p.Cys 338 Ter). Her NBS, which utilized tyrosine as a primary marker, had been reported as normal, with a tyrosine level of 151 µmol/L (reference: <280 µmol/L). Retrospective analysis of dried blood spot samples via tandem mass spectrometry showed detectable succinylacetone ranging 4.65–10.34 µmol/L. To our knowledge, this is the first patient with TT1 whose initial presenting symptom was hyperinsulinemic hypoglycemia. The case highlights the importance of maintaining a high suspicion for metabolic disease in critically ill children, despite normal NBS. We also use the case to advocate for NBS for TT1 using succinylacetone quantitation.

BACKGROUND: Hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in neonates, infants and children. Persistent hypoglycemia due to HI in the neonatal period and infancy has detrimental effects on the developing brain, leading to permanent brain damage. As such, neonatal hypoglycemia due to HI may be one of the most readily preventable causes of neurodevelopmental impairment. While monogenic forms of HI are rare with an estimated incidence in the US of 1:50,000 live births, perinatal stress-induced HI (PSIHI) is common and affects up to 50% of at-risk neonates, with an estimated incidence of 1:12,000 live births. There is a paucity of high quality evidence investigating neurodevelopmental outcomes in PSIHI. Methods: Subjects with HI and history of perinatal stress diagnosed between 2013 - 2018 and with demonstrated cure by fasting test by 2 years were included. Exclusion criteria included patients born prior to 32 wks gestation, congenital or syndromic HI and other diagnoses known to impact development. Medical records were reviewed and families were interviewed and asked to complete questionnaires for three validated neurodevelopmental assessments: ABAS-3, BRIEF-P, and CBCL (1.5–5). Results: Medical records of 98 eligible subjects were reviewed to date (74% males), 37% were born between 32–37 wks (mean gestational age 37.2 wks). Mean birth weight was 2.53kg. Median age of hypoglycemia presentation was 0 days, as 67% of subjects presented on day of life 0. Median age at HI diagnosis was 12 days, and the median length of time from first episode of hypoglycemia to definitive treatment was 14 days. Mean maximum glucose infusion rate was 12 mg/kg/min. 81% of subjects were successfully treated with diazoxide. Median time to demonstrated resolution of disease was 210 days. Parent interviews were completed for 33 subjects to date. Developmental concerns were reported by 52% of parents, and 41% reported pediatrician concerns. A diagnosis of speech delay was reported by 45% of parents, and 24% reported concerns for a learning disability. Behavioral concerns were reported by 45%, with 21% reporting diagnoses or specific concerns for ADHD and 12% reported diagnoses or strong concerns for autism. Neurodevelopmental assessments were completed in 15 subjects to date. The proportion of study subjects who scored more than 1 SD and 2 SDs outside the normal range on any of the major assessment scales was 33% and 6%, respectively (vs 15.8% and 2.2% in the general population for any individual scale). Conclusion: Children with PSIHI are predominantly male and most are born at term. While the majority of infants presented with hypoglycemia in the first day of life, diagnosis occurred most often 12 days later, with definitive treatment achieved after two weeks of life. Patients with PSIHI are at high risk of neurodevelopmental deficits, and are more likely to perform below average on developmental testing.

The diagnosis and management of central diabetes insipidus in critically ill children is not standardized. Our objective was to characterize differences between Pediatric Critical Care Medicine (PCCM) and Pediatric Endocrinology (PE) clinicians in the diagnosis and management of new-onset CDI in the pediatric intensive care unit. We also sought to characterize knowledge gaps among general pediatrics (GP) residents. This is a scenario-based survey to assess patterns of diagnosis and management of new-onset CDI that was distributed to PCCM, PE, and GP clinicians who work in a quaternary care urban children's hospital. Of 275 PCCM, PE, and GP clinicians surveyed, 158 (57%) responded. More PCCM than PE clinicians relied on serum sodium levels (96 vs. 75%, p <0.01) and more PE than PCCM clinicians relied on serum osmolality (91 vs. 40%, p < .001) for diagnosis. Fewer PCCM than PE clinicians favored restricting IV fluids to two-thirds maintenance rate (4 vs. 37%, p <0.001). More PCCM than PE clinicians favored a starting dose of 0.5 milli-units/kg/h for IV vasopressin infusion (76 vs. 53%, p = 0.048). More PCCM clinicians than PE clinicians favored titrating the IV vasopressin infusion every 20 minutes (24 vs. 2%, p = 0.02), whereas more PE clinicians than PCCM clinicians favored titration every 60 minutes (38 vs. 14%, p = 0.03). GP residents earlier in training had greater self-reported gaps in knowledge. We observed substantial variability in the diagnosis and management of new-onset CDI in critically ill children among PCCM, PE, and GP clinicians. There is a need for greater standardization in care of these patients.