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.

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.

Background MIRAGE syndrome is a rare multisystem disorder characterized by myelodysplasia, infection, growth restriction, adrenal hypoplasia, genital phenotypes, and enteropathy. The syndrome is associated with mutations in Sterile Alpha Motif Domain Containing 9 ( SAMD9) gene, encoding an endosome fusion facilitator protein with additional function in growth factor signaling. To date, there are no reported cases of MIRAGE syndrome associated with severe insulin resistance in infancy. Clinical Case The patient was a premature female infant born at 30 6/7 weeks gestation with a history of IUGR and brain abnormalities. Her hospital course was complicated by respiratory failure, impaired immune function, chronic diarrhea due to pancreatic exocrine deficiency, anemia, and primary adrenal insufficiency. Whole exome sequencing revealed a novel, de novo missense mutation in SAMD9 (R1293Q), confirming the clinical diagnosis of MIRAGE syndrome. At 5 months of age, she developed severe hyperglycemia with insulin resistance (insulin 303 µIU/mL, normal < 13 µIU/mL, and C-peptide 18.2 ng/mL, normal < 2.2 ng/mL). Markers of insulin receptor defects were normal, including adiponectin, IGFBP-1, and SHBG, and no mutations were identified in INSR by whole exome sequencing. The patient had no episodes of diabetic ketosis or metabolic acidosis, and had no lipodystrophy or acanthosis nigricans on exam. Initially, an insulin infusion of 0.1-0.2 U/kg/hr was sufficient to maintain euglycemia. By age 6 months, persistent hyperglycemia led to a rapid increase of the insulin infusion to 18 U/kg/hr over the course of 3 days. On day 2 of insulin up titration, glucophage was started at 15 mg/kg/day. After 72 hours of escalating insulin doses and 48 hours of glucophage, both her hyperglycemia and insulin resistance rapidly improved, with insulin requirements decreasing to < 0.5 U/kg/hr over the next 2 days to maintain glucose in the 100-200 mg/dL range. In the following months, her insulin requirement varied greatly. While fasting, no insulin was needed to maintain euglycemia. However, while on parental nutrition or enteral feeds, insulin infusion requirement varied at 0.03 U/kg/hr - 0.5 U/kg/hr. At 8 months, she transitioned to subcutaneous insulin while enteral feeds were optimized and condensed. Subcutaneous insulin doses were gradually increased to 20-24 U/kg/day in an effort to maintain blood glucose <200 mg/dl. Unfortunately, at 9 months of age, the patient expired from sepsis. Conclusion This is the first case of severe insulin resistance presenting as a manifestation of MIRAGE syndrome due to a missense mutation in SAMD9 . This patient had improvement in glycemic control after treatment with glucophage and insulin. SAMD9 mutations should be considered in patients with multiple endocrinopathies including adrenal hypoplasia, severe insulin resistance, and pancreatic exocrine d...

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