ESPE Abstracts (2022) 95 RFC8.1

1La Paz University Hospital, Madrid, Spain; 2Institute of Medical & Molecular Genetics (INGEMM), IdiPAZ, La Paz University Hospital and CIBERER (U753), ISCIII, Madrid, Spain; 3Príncipe de Asturias Hospital, Madrid, Spain; 4Puerta de Hierro Hospital, Madrid, Spain; 5Ramón y Cajal Hospital, Madrid, Spain

Background and Aims: HNF4A-MODY clinical expression is broad, ranging from hypoglycemic hyperinsulinism in the neonatal period and early childhood to hyperglycemia and diabetes, as insulin secretion progressively decreases in adult patients. The main objective was to clinically and molecularly characterize patients with glycemic alterations, negative autoimmunity and confirmed molecular diagnosis of HNF4A-MODY.

Materials and Methods: Cross-sectional study of 121 patients with suspected monogenic diabetes analyzed by targeted NGS with a custom panel including up to 482 genes implicated in or associated with dysglycemia. Variants were classified according to ACMG criteria and prioritized using criteria of confidence and quality, coverage (20x/pb >95%), allele frequency (AF) in control population <1% (gnomAD controls), impact ("missense", "nonsense", "frameshift", "splicing effect") and in silico prediction of pathogenicity (CADD V1.4, score >20).

Results: Predicted deleterious HNF4A variants were detected in 9/121 (7.4%). They presented 9 different variants (1xfs + 8 missense; 4 previously described and 5 novel), all in functional domains of HNF4A, classified as pathogenic/probably pathogenic in 3 cases, or as VUS in the remaining 6. 4/10 presented hypoglycemia at diagnosis, two were 1-month-old infants with neonatal hyperinsulinism and hypoketotic hypoglycemias who responded adequately to diazoxide. The other two were 6 and 18 years old, respectively, the last one with an atypical presentation with recurrent hypoglycemia. Her 72h fasting test was normal with no endogenous hyperinsulinism, no response to the glucagon test, and a basal C-peptide of 1.1 ng/ml with normal OGTT. Among those who presented hyperglycemia as a reason for consultation (6/10), 3 were between 14 and 15 years old and the remaining 3 were > 30 years old at molecular diagnosis. 3/6 were treated with sc insulin (0.7-1IU/kg/day), 2 patients with metformin (one of them associated with Glimepiride), and one patient (15 years old) was only on dietary treatment and exercise. The median HbA1C among patients with hyperglycemia was: 6.2% RIC (5.7-7.2%).

Conclusions: HNF4A-MODY has different clinical expressions, depending among other factors on age of diagnosis, being in general more frequent as hypoglycemia in younger patients. The molecular diagnosis will allow to optimize/personalize treatment, given the known good response to treatment with sulfonylureas in patients with HNF4A-MODY (only 1/10 was treated with metformin and sulfonylurea before molecular diagnostics). Neonates with hypoglycemic hyperinsulinism had a good response to treatment with diazoxide; the molecular diagnosis of these patients confirms the need for a continuous follow-up to early detection of diabetes in adulthood.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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