Pediatric Hepatocyte Nuclear Factor 1B (HNF1B) Disease: Diabetes and Endocrine Manifestations.

Context: Mutations in hepatocyte nuclear factor 1B (HNF1B) are rare but they are known to cause structural renal disease and diabetes mellitus. There is limited data on pediatric HNF1B disease. Objective: To analyze the clinical characteristics of HNF1B-related disease in a cohort of children identified at a single pediatric tertiary medical center, with a specific focus on endocrine-related disease. Methods: Subjects with HNF1B genetic variants were identified from the Children's Hospital of Philadelphia Atypical Diabetes Registry between 2013 and 2022. Results: Of the 11 pediatric subjects with HNF1B mutations or deletions, 7 (64%) initially presented with diabetes, sometimes referred to as MODY5, while 4 (36%) were diagnosed based on family history or a genetic evaluation of renal disease. Only one patient presented with diabetic ketoacidosis, and three presented with diabetic ketosis. Of the four children with HNF1B mutations identified by familial mutation analysis or based on renal disease, two developed diabetes during the course of the study. Abnormalities in fasting lipid profiles were common: 10 with triglycerides >90 mg/dL, 5 with LDL-C >110 mg/dL, 5 with HDL-C <45, and 7/11 with non-HDL cholesterol >120 mg/dL. Over half of the subjects had hyperparathyroidism with PTH (>65 pg/mL) and a calcium concentration >9 mg/dL. Conclusion: This case series represents one of the largest pediatric HNF1B-related disease cohorts at a single center. The majority of patients with diabetes presented with clinical features distinct from Type 1 or Type 2 diabetes. Pediatricians should consider genetic testing for HNF1B mutations when children are diagnosed with diabetes and have renal abnormalities, hyperlipidemia, and hyperparathyroidism.