LAUSR

Abstract 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 deficiency.