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

Abstract

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.

Mapping Heterogeneity of Hepatocellular Carcinoma by Investigating Hepatocyte-Specific Genes/TFs/Pathways Across Cellular and Tumor Landscapes

“…Furthermore, HNF1A is involved in maintaining the stability and lineage commitment of hepatocytes, suppressing their plasticity and preventing lineage switching. Dysregulated expression of HNF1A in HCC may disrupt this regulatory function, leading to enhanced cellular plasticity and an increased propensity for transdifferentiation [51]. HCC cells with dysregulated HNF1A expression may exhibit greater exibility in adopting alternative cell fates, such as acquiring features of pancreatic β-cells, intestinal epithelial cells, or other cell types where HNF1A is involved.…”

Management of pregnancy in women with monogenic diabetes due to mutations in GCK, HNF1A and HNF4A genes

“…One centre reported that HNF4A mutations are the third most common cause of diazoxide-responsive CHI accounting for 18.6% of cases with identifiable genetic aetiology ( Flanagan et al, 2010 ). CHI generally develops within the first week of life with the majority presenting within the first two days of life ( Flanagan et al, 2010 ; Tung et al, 2018 ; McGlacken-Byrne et al, 2022 ). Inactivating HNF4A mutations associated with CHI tend to arise from the 7–9 isoforms expressed in the P2 promotor ( Kapoor et al, 2008 ).…”

Uncovering the candidate genes related to sheep body weight using multi-trait genome-wide association analysis

“…Increased expression levels of the DNM1L proteins may correlate with the degree of weight gain, and is closely related to the development of obesity (49)(50)(51)(52). HNF4A mutations are associated with a considerable increase in birth weight and macrosomia, and the gene acts in the intestine and kidney to promote white adipose tissue energy storage (53)(54)(55)(56). MKX is a potential regulator of brown adipose tissue development associated with obesity-related metabolic dysfunction in children (57).…”