ESPE Abstracts

Introduction: Neonatal Diabetes Mellitus (NDM) is characterised by severe hyperglycaemia, usually diagnosed in the first 6 months of life. Genetic diagnosis helps distinguishing between its different causes and between transient (TNDM) and permanent (PNDM) forms, with repercussions on the therapeutic approach and follow-up.

Aim: Clinical and molecular characterisation of a series of NMD cases under endocrinological follow-up between 2014-2022.

Material and Methods: Descriptive, cross-sectional, multicentre study of 9 NDM cases genetically confirmed by targeted NGS panel. Detected variants were classified according to ACMG criteria and prioritised using confidence and quality criteria, coverage (20x bp >95%), allele frequency <1% (gnomAD controls, V2.1.1), impact ("missense", "nonsense", "frameshift", "splicing effect") and in silico prediction of pathogenicity (CADD V1.6, score > 20).

Results: 3/9 presented with Martinez-Frias Syndrome (MFS) caused by the homozygous RFX6 p.(Arg181Trp) founder pathogenic variant, product of consanguineous parents. All presented PNDM, IUGR, polyhydramnios, intestinal atresia and malrotation, vesicular agenesis, pancreatic hypoplasia, bile duct dilatation and cholestasis. The single survivor received a multivisceral transplant at age 20 months. 2/9 presented pathogenic variants in ABCC8: p.(Arg1379Ser) in an infant born at 33 weeks with BW 1490g, with persistent hyperglycaemias at two weeks of life, and p.(Ile1268Phe)(Ala1264Val) in compound heterozygosity in the second one. 2/9 presented likely pathogenic heterozygous variants in KCNJ11: p.(Trp68Cys), in a 57-day-old infant with hyperglycaemia, 849mg/dL, and ketonemia (up to 4.6 mmol/L), history of prematurity and IUGR, who was treated with continuous insulin perfusion (currently on sulphonylureas). The second case, a girl born to a mother with pregestational DM, presented the p.(Arg50Gln) with glycaemia of 153mg/dL at 3 days of life. 1/9 had NDM due to paternal uniparental disomy of chromosome 6 (preterm newborn, 31+6 weeks + IUGR), and finally, 1/9 presented NDM associated with a complete heterozygous HNF1B deletion with prenatal diagnosis of bilateral cystic renal dysplasia and persistent hypomagnesaemia.

Conclusions: Channelopathies, associated with mutations in ABCC8, coding for the SUR1 subunit of the K+ channel, and KCNJ11, coding for the Kir6.2 subunit, represent the most frequent molecular bases of NDM in our cohort. In consanguineous families with an association of PNDM and bilio-hepato-pancreatic malformations, MFS must be considered. Multivisceral transplantation is the only treatment capable of changing the fatal course of MFS. We report the fourth case of PNDM associated with a HNF1B variant, so its analysis should be included in NGS panels and assessment of the genitourinary tract and magnesaemia performed.