SAT-685 - A Novel DYRK1B Variant Associated with Abdominal Obesity Metabolic Syndrome 3 Features: A Case Report

Introduction

Although metabolic syndrome affects 20–30% of adults globally, a small subset arises from rare monogenic disorders. Abdominal obesity-metabolic syndrome 3 (AOMS3) is a rare autosomal dominant disorder associated with DYRK1B mutations and characterized by central obesity, severe insulin resistance, dyslipidemia, hypertension, and increased cardiovascular risk. We report a patient with features of AOMS3 and harboring a novel p.Arg344Cys variant.

Case Description

A 27-year-old woman with psoriatic arthritis and hypertension presented with weight gain and irregular menses since adolescence. Exam showed BMI 58.1 kg/m², marked central obesity, acanthosis nigricans of the neck, and stage 2 lipedema. Labs revealed severe insulin resistance (fasting insulin 62.8 μIU/mL, HbA1c 6.1%), elevated lipoprotein(a) (82.7 mg/dL), total cholesterol 206 mg/dL, LDL cholesterol 135 mg/dL, and HDL cholesterol 49 mg/dL. Thyroid dysfunction, hypercortisolism, and PCOS were excluded.

Genetic testing identified a heterozygous missense DYRK1B variant (p.Arg344Cys), substituting arginine for cysteine at codon 344. The clinical phenotype and genetic findings were consistent with AOMS3. Management included tirzepatide, metformin, rosuvastatin, and cardiology referral for cardiovascular risk assessment.

Discussion

AOMS3 is caused by heterozygous DYRK1B mutations on chromosome 19q13. DYRK1B mutations upregulate adipogenic factors and glucose-6-phosphatase, leading to insulin resistance and metabolic dysfunction. Literature review (2014 - 2026) identified pathogenic variants (p.His90Pro, p.Arg102Cys, p.Arg252His, p.Lys68Gln, and p.Pro508Ser) associated with AOMS3. The p.Arg344Cys variant has not been previously reported.

AOMS3 phenotype shows age-dependent progression, with central obesity and insulin resistance beginning in childhood, advancing to morbid obesity, dyslipidemia, type 2 diabetes, and then hypertension. AOMS3 should be suspected in early-onset severe obesity, premature cardiovascular events, metabolic syndrome with an autosomal dominant family history, and poor response to standard interventions. Secondary etiologies, including Cushing syndrome, hypothyroidism, medication-induced obesity, polygenic, and other monogenic obesity disorders, should be excluded. Confirmation requires genetic testing. Currently, no disease-modifying therapies are available for AOMS3. Management focuses on lifestyle modification, cardiovascular risk reduction, and pharmacological interventions, including metformin, GLP-1 receptor agonists, SGLT2 inhibitors, and lipid-lowering agents.

Conclusion

The DYRK1B p.Arg344Cys variant has not been previously reported and may represent a pathogenic variant associated with AOMS3. Further studies are warranted to determine the functional significance of this variant.

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