Endocrine Abstracts

Background: HNF1β mutations are one of the commonly identified genetic causes of renal malformations, but one of the less common forms of MODY. HNF1β is involved in the development of kidneys, liver, pancreas, intestine and urogenital tract. Patients can present with distinctive but highly variable clinical features. The aim of this study is to evaluate the clinical, biochemical and radiological variability of HNF1β variants and the challenge of management on the basis of the insulin secretory response to glucose.

Methods: 11 HNF1β mutation positive subjects underwent phenotyping with a 2-h OGTT to determine their degree of glucose tolerance and insulin secretory response. Biochemical testing included magnesium, urate, faecal elastase (FE). Abdominal and pelvic ultrasound (US), Magnetic Resonance Imaging (MRI) of pancreas and liver were performed.

Results: Diabetes was present 9/11 patients. Diabetes was diagnosed at 29±16 years of age, BMI 23.4±2.5 kg/m², mean HbA1c was 67±15 mmol/mol. 5/9 on insulin (MDI) and 3/9 started on oral hypoglycaemic agents (OHAs-Metformin and Gliclazide MR) after OGTT and HNF1β mutation positive, with a significant reduction of insulin doses. 2/9 on OHAs required basal insulin after 10 years of diabetes diagnosis, 1/9 on OHA and 1/9 diet controlled. The insulin secretory response to glucose was variable but present in all the patients. Glucose (mmol/l), Insulin (mU/l) and C-Peptide (μg/l) mean at 0 min/120 min: 9.3(±4.8)/19.3(±8.3), 56.2(±65.8)/150.0(±77.3), 363.7(±219.5)/1364.6(±1031.7) respectively. 6/11 had mild asymptomatic hypomagnesaemia 0.64±0.09 mmol/l. 3/11 had hyperuricemia and 2 had early onset gout. 5/11 had deranged LFT’s. 3/11 had sub-clinical pancreas exocrine insufficiency (FE 52±40 μg/g). 7 patients have undergone for MRI demonstrating pancreas malformation in 4 subjects (atrophic pancreas, agenesis of the body and tail, partial pancreatic divisum), female genital tract abnormalities in 2 cases (uterus didelphys) and one patient with seminal vesical cysts as part of infertility investigation. 5/11 had renal cysts. 1 patient with CKD stage 3. 7 different mutations were identified; p.Gly83Ser (p.G83S) has been described as a novel mutation.

Conclusion: This case series highlights the spectrum of clinical manifestations of HNF1β variants. Genetic diagnosis enables the physician to screen for hypomagnesaemia, gout, pancreatic insufficiency and pancreatic/hepatic/genital malformations. The patients could benefit from insulin and/or OHA for treatment on the basis of insulin secretory response.