LAUSR

Objective The phenotype mediated by HNF4A/HNF1A mutations is variable and includes diazoxide-responsive hyperinsulinaemic hypoglycaemia (HH) and maturity-onset diabetes of the young (MODY). Design We characterised an international multi-centre paediatric cohort of patients with HNF4A or HNF1A mutations presenting with HH over a 25-year period (1995-2020). Methods Clinical and genetic analysis data from five centres were obtained. Diazoxide-responsiveness was defined as the ability to maintain normoglycaemia without intravenous glucose. Macrosomia was defined as a birth weight ≥90th centile. SPSS v.27.1 was used for data analysis. Results A total of 34 patients (70.6% female, n=24) with a mean age of 7.1 years (SD 6.4) were included. A total of 21 different heterozygous HNF4A mutations were identified in 29 patients (four novel). Four different previously described heterozygous HNF1A mutations were detected in five patients. Most (97.1%, n=33) developed hypoglycaemia by day two of life. The mean birth weight was 3.8kg (SD 0.8), with most infants macrosomic (n=21, 61.8%). Diazoxide was commenced in 28 patients (82.3%); all responded. HH resolved in 20 patients (58.8%) following a median of 0.9 years (IQR 0.2-6.8). Nine patients (n=9, 26.5%) had developmental delay. Two patients developed Fanconi syndrome (p.Arg63Trp, HNF4A) and four had other renal or hepatic findings. Five (14.7%) developed MODY at a median of 11.0 years (IQR 9.0-13.9). Of patients with inherited mutations (n=25, 73.5%), a family history of diabetes was present in 22 (88.0%). Conclusions We build on knowledge of the natural history and pancreatic and extra-pancreatic phenotypes of HNF4A/HNF1A mutations, and illustrate the heterogeneity of this condition.