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

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    URI
    https://rde.dspace-express.com/handle/11287/622428
    Author
    McGlacken-Byrne, S. M.
    Mohammad, J. K.
    Conlon, N.
    Gubaeva, D.
    Siersbæk, J.
    Schou, A. J.
    Demirbilek, H.
    Dastamani, A.
    Houghton, J. A. L.
    Brusgaard, K.
    Melikyan, M.
    Christesen, H.
    Flanagan, S. E.
    Murphy, N. P.
    Shah, P.
    Date
    2022-02-22
    Journal
    European journal of endocrinology
    Type
    Journal Article
    Publisher
    BioScientifica
    DOI
    10.1530/eje-21-0897
    Rights
    © European Society of Endocrinology 2022
    Metadata
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    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 multicentre paediatric cohort of patients with HNF4Aor HNF1Amutations 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 (s.d. 6.4) were included. A total of 21 different heterozygous HNF4Amutations were identified in 29 patients (four novels). Four different 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 kg (s.d. 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 (interquartile range (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 the knowledge of the natural history and pancreatic and extra-pancreatic phenotypes of HNF4A/HNF1Amutations and illustrate the heterogeneity of this condition.
    Citation
    Eur J Endocrinol. 2022 Feb 22;186(4):417-427. doi: 10.1530/EJE-21-0897.
    Publisher URL
    https://eje.bioscientifica.com/doi/10.1530/EJE-21-0897
    Note
    This article is freely available online. Click on the 'Additional Link' above to access the full-text via the publisher's site.
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    • 2022 Eastern publications
    • Diabetes and endocrinology
    • Genetics and genomics

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