ESPE2021 Free Communications Diabetes (6 abstracts)
Clinical and genetic heterogeneity of HNF4A/HNF1A mutations in a multicentre paediatric cohort
Sinéad M. McGlacken-Byrne 1 , Jasmina Kallefullah Mohammad 1 , Niamh Conlon 2,3 , Diliara Gubaeva 4 , Julie Siersbæk 5 , Anders Jørgen Schou 5 , Huseyin Demibilek 6 , Antonia Dastamani 1 , Jayne Houghton 7 , Klaus Brusgaard 5 , Maria Melikyan 4 , Henrik Christesen 5 , Sarah E. Flanagan 8 , Nuala P. Murphy 2,3 & Pratik Shah 1
1Department of Paediatric Endocrinology, Great Ormond Street Hospital for Children, London, United Kingdom.;2Department of Paediatric Endocrinology, Children’s Health Ireland, Temple Street, Dublin, Ireland.;3School of Medicine, University College Dublin, Dublin, Ireland.;4Department of Paediatric Endocrinology, Endocrinology Research Centre, Moscow, Russian Federation.;5Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.;6Department of Pediatric Endocrinology, Hacettepe University, Faculty of Medicine, Ankara, Turkey.;7The Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom.;8Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, United Kingdom
Objective: The complex clinical phenotypes arising from HNF4A and HNF1A mutations are similar and include diazoxide-responsive CHI from infancy and maturity-onset diabetes of the young (MODY) from adolescence. We aimed to characterise the clinical and genetic aspects of a cohort of paediatric patients with HNF4A or HNF1A mutations.
Methods: Patients from five international centres over a 25-year period (1995-2020) with confirmed HNF4A/HNF1A mutations were included. Clinical and molecular genetic analysis data were obtained following case note review. Diazoxide responsiveness was defined as the ability to maintain normoglycaemia without intravenous glucose. Macrosomia was defined as a birth weight ≥ 90thcentile (≥1.3 SDS). Data are presented as median (interquartile range (IQR)) or mean (standard deviation (SD)).
Results: A total of 30 patients (70.0% female, n = 21) with a mean age of 8.0 years (SD 6.2) were included. Most developed hypoglycaemia within the first two days of life (median age 1 day, IQR 1-1.25). The mean birth weight was 3.8kg (SD 0.8), with most infants macrosomic (n = 19, 63.3%). Babies were born preterm (<37 weeks gestation) in 33.3% (n = 10) of cases. The mean glucose requirement at diagnosis was 13.1mg/kg/min (SD 4.7). Diazoxide was commenced in 25 patients (83.3%) at a median of 10.0 days of life (IQR 2.0-15.8) of which all responded. CHI resolved in nineteen patients (63.4%) following a median of 3.7 years (IQR 0.2-6.9). Nine (n = 9, 30%) had developmental delay. Two children were diagnosed with Fanconi syndrome (p.Arg63Trp, HNF4A). Four patients had hepatic or renal findings: deranged liver function tests (p.Gly292fs, HNF1A); hepatic enlargement (p.Arg311Cys, HNF4A); renal hypoplasia (p.Arg159Gln, HNF1A); liver cysts (p.Arg63Trp, HNF4A). Five patients (16.6%) developed MODY at a median of 11.0 years (IQR 9.0-13.9). A positive family history of diabetes mellitus was present in 22 (73.3%). Five parents were diagnosed with HNF4A/HNF1A MODY after their child’s diagnosis. De novo mutations in HNF4A were found in six unrelated patients; the remainder of mutations were inherited. Three different previously reported heterozygous HNF1A mutations were identified in four patients. Eighteen different heterozygous HNF4A mutations were identified in twenty six patients, including five novel mutations in seven patients (p.Val147fs; p.Met103Ile; p.Tyr300*; p.Gln349*; p.Gly60Val).
Conclusions: We expand on the natural history and the pancreatic and extra-pancreatic phenotypes of HNF4A/HNF1A mutations and illustrate the clinical and genetic heterogeneity of this condition.
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