MON-232 Atypical Diabetes due to Hypomethylation at BWS ICR2 and the 6q24 loci: Potential Evidence for a Multifocal Hypomethylation Syndrome

Abstract Disclosure: S. Muneer: None. M. Dever: None. J. Adams: None. S.E. Pinney: None. Introduction: Imprinting disorders are rare diseases resulting from altered expression of imprinted genes that are regulated through DNA methylation. Two common imprinting disorders that involve glucose metabolism include Beckwith Weidemann Syndrome (BWS) and 6q24 Transient Neonatal Diabetes Mellitus (TNDM). BWS is an overgrowth syndrome that presents in infancy with macroglossia, hemihypertrophy, hyperinsulinism and concerns about embryonal tumors. BWS results from genetic and epigenetic alterations at chromosome 11p15.5 including changes in DNA methylation patterns at two imprinting control regions, ICR1 and ICR2. Although neonatal hyperinsulinism is common in BWS, there are rare case reports of diabetes. 6q24 TNDM often presents as diabetes in infants <12 months of age requiring insulin treatment. Typically, in 6q24 TNDM there is remission of hyperglycemia after a few months, sometimes followed by hypoglycemia, with diabetes re-presenting in adolescence. 6q24 TNDN has been attributed to overexpression PLAGL1 and HYMAI, due to paternal uniparental isodisomy of chromosome 6, duplication of 6q24 on the paternal allele or maternal 6q24 hypomethylation. Here we present a case of atypical diabetes in an adolescent with hypomethylation of two imprinted regions consistent with BWS and 6q24 TNDM. Clinical Case: 15-year-old female was referred to the CHOP Monogenic and Atypical Diabetes Clinic after presenting with several months of polyuria and polydipsia. She was found to have hyperglycemia without ketosis or acidosis, hgbA1C of 10.9%, glucose 267 mg/dL, insulin 19.5 uIU/mL, and c-peptide 3 ng/dL. Her BMI was at the 84th%ile for age. She was a term infant with a birthweight of 5 lbs 15 ounces and no known history of hypo- or hyperglycemia. Shortly after birth, her parents noted macroglossia and hemihypertrophy prompting an evaluation for BWS which revealed ICR2 hypomethylation. Family history was significant for GDM in her mother and T2DM in her mother and maternal grandmother. MODY genetic testing was negative, but testing for TNDM at 6q24 identified hypomethylation. With a multifocal imprinting disturbance, a whole exome sequence was recommended and is pending. For treatment, she was started on basal/bolus insulin based on the high presenting HgbA1C and metformin based on elevated insulin level. She currently has excellent glycemic control with CSII and AID pump therapy, metformin and GLP-1RA with her most recent HgbA1C of 6.6%. Conclusion: Atypical diabetes are rare forms of diabetes that affect 1-5% of children with diabetes and can be misdiagnosed as type 1 or 2 diabetes given the overlap of symptoms. Additional studies are required to understand the pathophysiology of multifocal imprinting disorders. Identifying the underlying molecular changes responsible for the development of diabetes will allow for personalized treatment plans to achieve optimal glucose control. Presentation: Monday, July 14, 2025