Clinical and genetic heterogeneity of HNF4A/HNF1A mutations in a multicentre paediatric cohort with hyperinsulinaemic hypoglycaemia

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 multicentre paediatric cohor t 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 obtai ned. Diazoxide responsiveness was defined as the ability to maintain normoglycaemia without intravenous gluc ose. 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 (s.d. 6.4) were included. A total of 21 different heterozygous HNF4A mutations were identified in 29 patients (four novels). Four diff erent previously described heterozygous HNF1A mutations were detected in five patients. Most (97.1%, n = 33) developed hypoglycaemia by day 2 of life. The mean birth weight was 3.8 k g (s.d. 0.8), with most infants macrosomic (n = 21, 61.8%). Diazoxide was commenced in 28 patients (82.3%); all res ponded. HH resolved in 20 patients (58.8%) following a median of 0.9 years (interquartile range (IQR): 0.2-6.8). Nin e 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 pa tients with inherited mutations (n = 25, 73.5%), a family history of diabetes was present in 22 (88.0%). Conclusions: We build on the knowledge of the natural history and pancreati c and extra-pancreatic phenotypes of HNF4A/HNF1A mutations and illustrate the heterogeneity of this condition.