ESPE Abstracts (2023) 97 P1-478

1Yerevan State Medical University, Yerevan, Armenia. 2Muratsan University Hospital, Yerevan, Armenia. 3Institute of Pediatric Endocrinology, Moscow, Russian Federation. 4Alder Hey Children’s Hospital, Liverpool, United Kingdom. 5Research Centre for Medical Genetics, Moscow, Russian Federation

Background: Congenital hyperinsulinism (CHI) is a heterogeneous group of disorders, characterized by hypoglycemia due to inappropriate insulin secretion. Despite huge progress in understanding the pathophysiology of CHI, its etiology remains unknown in about 30% of cases.

Aim: To perform whole-exome sequencing in patients with CHI.

Results: A total of 314 patients with congenital hyperinsulinism underwent genetic testing using NGS panel (GLUD1, HNF1A, GCK, ABCC8, HNF4A, INSR, KCNJ11, SLC16A1, HADH, KDM6A, KMT2D). Additional tests for syndromic CHI forms included chromosome 11 methylation analysis (n=28), karyotype (n=9), transferrin isoelectric focusing (n=13) and Chromosome microarray (n=5). Pathogenic variants were found in 187 (59.5%) cases: KCNJ11/ABCC8 (n=138); GLUD1 (n=18), GCK (n=6), HNF4A (n=6), HADH (n=2), INSR (n=2), HNF1A (n=1), SLC16A1 (n=1), Beckwith-Wiedemann syndrome (n=8), Kabuki (n=3), Turner (n=2). 94.6% of the cases with negative genetics were diazoxide (Dzx) responsive. Whole exome sequencing was performed in 17 patients with either Dzx unresponsive CHI (n=4) or those having unusual clinical phenotype (n=13). Mutations in various genes were found in 3/4 and 6/13 patients with Dzx-unresponsive and Dzx-responsive CHI resp (Table 1). Some of these genes are well-known to cause CHI whereas others are not clearly established. Two patients with medically resistant CHI required subtotal pancreatectomy and conservative treatment after the surgery (somatostatin analogues, Dzx, insulin receptor antibody).

Table 1. Clinical characteristics of patients and genetic results of the whole-exome sequencing.
Case Gene Variant Inheritance Age at onset Phenotype
1* CACNA1D p.Phe767del Denovo 1 d Profound developmental delay, muscle hypotonia, subclinical hyperaldosteronism, congenital glaucoma
2* NOTCH2** p.S2427T, heteroz Denovo 8 m UR
3* ABCC5** c.129G>A: p.P43P, heteroz Denovo 3 y UR
4 EIF2S3 с.671Т>G, heteroz Maternal 21 m Obesity, dysmorphism, mental delay
5 EP300 c.3163C>T, p.R1055X. heteroz Denovo 1 d IUGR, short stature, facial dysmorphism,
6 CREBBP c.4270C>T, p.Pro1424Ser, heteroz ND 3 w Developmental delay, facial dysmorphism, epilepsy, cerebral palsy, corpus collosum hypoplasia
7 KCNH6 c.1136G>A, p.Arg379Gln, heteroz ND 3 d Facial hemi hyperplasia, flat nasal bridge.
8 MAFA** p.Hiz208del, heteroz Denovo 3 m Muscle hypotonia, cerebral palsy
9 DNAJC3 p.Arg393Ter/p.Arg346Ter ND 6 m hypothyroidism, short stature, dysmorphic features
*Dzx unresponsive **genes not previously described in CHI d- days, m – months, w – weeks, y – years, UR - unremarkable

Conclusions:Whole exome sequencing is helpful to diagnose rare syndromic forms of CHI. Studies on bigger cohorts will allow to estimate significance of the candidate genes and to modify CHI gene panel.

Volume 97

61st Annual ESPE (ESPE 2023)

The Hague, Netherlands
21 Sep 2023 - 23 Sep 2023

European Society for Paediatric Endocrinology 

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