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Clinical and genetic characteristics of patients with congenital hyperinsulinism in 21 non-consanguineous families from Serbia

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Abstract

Persistent hypoglycaemia in newborns and infants is most commonly caused by congenital hyperinsulinism (CHI). Most CHI studies report outcomes in children from both consanguineous and non-consanguineous families which can affect the phenotype-genotype analysis. The aim of this study was to analyze characteristics of patients with CHI in 21 non-consanguineous families from Serbia. This retrospective cohort study included a total of 21 patients with CHI treated in the Mother and Child Healthcare Institute of Serbia during the past 20 years. The prevalence of macrosomia at birth was very low in our cohort (4.8%). Median age at presentation was 6 days, with seizures as the presenting symptom in 76% of patients. Only four patients (19%) were diazoxide unresponsive, and eventually underwent pancreatectomy. Genetic testing was performed in 15 patients and genetic diagnosis was confirmed in 60%, with all patients being heterozygous for detected mutations. The ABCC8 gene mutations were detected in 55.6%, GLUD1 in three patients (33.3%) with HIHA syndrome and one patient had HNF4A gene mutation and unusual prolonged hyperglycaemia lasting 6 days after diazoxide cessation. Neurodevelopmental deficits persisted in 33% of patients.

Conclusion: This is the first study regarding CHI patients in Serbia. It suggests that in countries with low consanguinity rate, majority of CHI patients are diazoxide responsive. The most common mutations were heterozygous ABCC8, followed by GLUD1 and HNF4A mutations, suggesting the potential benefit of population-tailored genetic analysis approach, targeting the mutations causing CHI via dominant inheritance model in regions with low consanguinity rates.

What is Known:

• Persistent hypoglycaemia during infancy and early childhood is most commonly caused by congenital hyperinsulinism (CHI).

• Consanguinity is a very important factor regarding the genetics and phenotype of CHI, increasing the risk of autosomal recessive genetic disorders, including the severe, diazoxide-unresponsive forms caused by recessive inactivating mutations in ABCC8 and KCNJ11.

What is New:

• Results of the present study which included CHI patients from 21 non-consanguineous families suggest that in countries with low consanguinity rates, majority of CHI patients can be diazoxide responsive, with most common mutations being heterozygous ABCC8, followed by GLUD1 and HNF4A mutations.

• Unusually prolonged hyperglycaemic reaction to diazoxide treatment in a patient with HNF4A mutation was also described in the present study.

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Data availability

Anonymized data can be provided by the authors upon request.

Code availability

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Abbreviations

18F-DOPA-PET:

18F-fluoro-dihydroxyphenylalanine positron emission tomography

ABCC8:

ATP-binding cassette subfamily C member 8

CHI:

Congenital hyperinsulinism

GLUD1:

Glutamate dehydrogenase 1

HNF4A:

Hepatocyte nuclear factor 4 alpha

HIHA:

Hyperinsulinism-hyperammonemia syndrome

KCNJ11:

Potassium inwardly rectifying channel subfamily J member 11

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Acknowledgements

We would like to express our deepest thanks to Professor Dr. Sarah Flanagan and other members of the Exeter Molecular Genetics Laboratory team for providing genetic testing for CHI.

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Authors and Affiliations

  1. Institute for Children’s Diseases, Clinical Centre of Montenegro, Podgorica, Montenegro

    Maja Raicevic

  2. Department of Pediatric Endocrinology, Mother and Child Health Care Institute of Serbia “Dr Vukan Cupic”, Radoja Dakica 8, Belgrade, 11070, Serbia

    Maja Raicevic, Tatjana Milenkovic, Sladjana Todorovic, Katarina Mitrovic & Rade Vukovic

  3. Department of Pediatrics, Division of Endocrinology, Sidra Medicine, Doha, Qatar

    Khalid Hussain

  4. Department of Metabolism and Clinical Genetics, Mother and Child Health Care Institute of Serbia “Dr Vukan Cupic”, Belgrade, Serbia

    Maja Djordjevic & Adrijan Sarajlija

  5. School of Medicine, University of Belgrade, Belgrade, Serbia

    Maja Djordjevic, Jelena Martic, Adrijan Sarajlija & Rade Vukovic

  6. Department of Neonatology, Mother and Child Health Care Institute of Serbia “Dr Vukan Cupic”, Belgrade, Serbia

    Jelena Martic

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  1. Maja Raicevic
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Contributions

MR and RV designed the research study. MR gathered the data, conducted statistical analyses and wrote the first draft of the manuscript. All authors contributed to the study design, revised and approved the final version of the manuscript.

Corresponding author

Correspondence to Rade Vukovic.

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Ethics approval

The study was approved by the Hospital Ethics Committee and conducted in accordance with the Declaration of Helsinki.

Consent to participate

Having in mind the retrospective design and data anonymization in the present study, the need for consent to participate was waived by the Hospital Ethics Committee.

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Having in mind the retrospective design and data anonymization in the present study, the need for consent to participate was waived by the Hospital Ethics Committee.

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The authors declare no competing interests.

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Communicated by Peter de Winter

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Raicevic, M., Milenkovic, T., Hussain, K. et al. Clinical and genetic characteristics of patients with congenital hyperinsulinism in 21 non-consanguineous families from Serbia. Eur J Pediatr 180, 2815–2821 (2021). https://doi.org/10.1007/s00431-021-04051-w

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  • DOI: https://doi.org/10.1007/s00431-021-04051-w

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