ESPE Abstracts

Background: Dual-specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B) is a nutrient-sensing protein that suppresses the RAS–RAF–MEK pathway and is known to have a role in glucose uptake and glycolysis. The expression of DYRK1B increases during adipogenic differentiation suggesting an important role in adipogenesis. Mutations in DYRK1B have been described in three Iranian families and five Caucasian patients with Abdominal Obesity Metabolic Syndrome 3 (AOMS3). We report the youngest patient with phenotypic features of AOMS3 associated with a novel de-novo missense variant of the DYRK1B.

Case Presentation: A 13-years-old developmentally normal boy started to gain weight at the age of 4 years. He was a product of full-term uneventful pregnancy with a birth weight of 2.6kg, born to non-consanguineous parents. He had no significant neonatal history and in the family history his father had type 2 diabetes. He was tall (Height +2.39 SD, MPH: 180 cm) and obese (BMI +2.46 SD, mainly central) with marked acanthosis nigricans. He had a mild elevated blood pressure (147/90 mmHg) that was conservatively managed. He had an elevated HBA1c (6.1%), impaired fasting glucose (6.3 mmol/L), normal C peptide (6.81 ng/ml [0.70-11.20]) and insulin level (308 pmol/L [20-571]), negative type 1 diabetes antibody profile, elevated liver enzymes (ALT 191 IU/L [12-26], AST 65 IU/L [18-38], GTT 40 IU/L [6-15]) with normal thyroid function and lipid profile. On ultrasonographical examination, the liver was enlarged with marked fatty infiltration. His obesity was originally thought to be related to life style and he was managed with life-style modification. However, Targeted Exome Sequencing revealed a novel heterozygous missense variant c.1522C>T, (Pro508Serine) in the DYRK1B gene. Three in-silico prediction tools (cadd, sift, and mutation taster) suggest that this variant will have a deleterious effect on the encoded protein and thus is likely to be pathogenic. He was managed with metformin and dietary advise and had a stable glycemic profile but with minimal weight reduction.

Conclusion: This is the youngest patient with a novel variant in the DYRK1B gene associated with AOMS3. As mutations in DYRK1B gene are associated with early onset coronary artery disease, severe hypertension and frank type 2 diabetes in adults, the early identification of these patients will allow screening for the development of coronary artery disease and timely intervention in terms of management. Functional analysis of novel variants in DYRK1B will provide further insights into the molecular mechanisms of metabolic syndrome.