17q12 Deletion Syndrome. A Rare Association Between Diabetes and Renal/Urogenital Abnormalities

Abstract

Abstract Introduction: Maturity onset diabetes of the young type 5 (MODY 5) is an autosomal dominant, non-autoimmune form of diabetes mellitus caused by HNF1b gene mutations/deletions. Because of a high prevalence of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in MODY 5 patients, understanding the extra-pancreatic manifestations of MODY 5 can target genetic testing to provide an earlier diagnosis. Case Description: A 26-year-old male was referred for consultation after his primary care physician found an HbA1c of 11.4% and prescribed metformin 500mg/day. He reported weight loss during the previous weeks and a history of Attention Deficit Hyperactivity Disorder (ADHD). He denied urinary tract infections or renal disease. Family history included diabetes (24-year-old brother (also with ADHD) and both parents). His BMI was 17.07 kg/m2 and labs showed a normal lipid profile, including HDL-C 74 mg/dL; urine albumin 0.8 mg/dL; “inappropriately normal” insulin and c-peptide; and negative GAD65, IA-2, and ZNT8 antibodies. Glimepiride 1mg/day at breakfast was added, with referral to a geneticist to rule out MODY. A follow-up HbA1c was 7.1%; Januvia 100 mg/day was added. Glimepiride was later switched to glipizide 7.5 mg at breakfast and 2.5 mg at supper due to overnight hypoglycemia. Genetic testing revealed a male pathogenic 1.39 Mb deletion of 17q12 containing 20 genes, including HNF1b, consistent with MODY 5. Renal ultrasound showed mild hydronephrosis, increased echogenicity of both kidneys, and bilateral non-obstructing nephrolithiasis. Subsequently, his mother (previously diagnosed with diabetes, fatty liver disease, dyslipidemia, and multiple scattered non-obstructing calculi and cysts in both kidneys) was found to have the same genetic defect. His brother’s diabetes is currently well controlled with glargine 0.3 u/kg and aspart 0.05–0.15 u/kg/meal. Unlike the proband, he has obesity (BMI 30 kg/m2), dyslipidemia, and CKD (GFR 57 ml/min); further workup is pending at this time. Discussion: Because patients with MODY 5 are at high risk for CKD3-4/ESRD, MODY 5 should be considered in young adults with diabetes who have negative islet autoantibodies and extra-pancreatic manifestations including elevated liver enzymes, renal cysts and nephrolithiasis; ADHD and learning difficulties; and pancreatic and hepatic morphological abnormalities. HNF1b-targeted genetic testing should be considered in patients with this clinical presentation.