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Genetic and clinical heterogeneity of permanent neonatal diabetes mellitus: a single tertiary centre experience

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Abstract

Aims

Neonatal diabetes mellitus (NDM) is a rare disease where diabetes presents during the first six months of life. There are two types of this disorder: permanent neonatal diabetes (PNDM) and transient neonatal diabetes mellitus (TNDM). PNDM occurs due to mutations in genes involved in either beta-cell survival, insulin regulation, and secretion. This study aims to define the genetic aetiology and clinical phenotypes of PNDM in a large Egyptian cohort from a single centre.

Methods

Patients with PNDM who were diagnosed, treated, or referred for follow-up between January 2002 and January 2021 were identified and clinically phenotyped. All patients were tested for mutations in EIF2AK3, KCNJ11, ABCC8, INS, FOXP3, GATA4, GATA6, GCK, GLIS3, HNF1B, IER3IP1, PDX1, PTF1A, NEUROD1, NEUROG3, NKX2-2, RFX6, SLC2A2, SLC19A2, STAT3, WFS1, ZFP57 using targeted next-generation sequencing (NGS) panel. INSR gene mutation was tested in one patient who showed clinical features of insulin resistance.

Results

Twenty-nine patients from twenty-six families were diagnosed with PNDM. Pathogenic variants were identified in 17/29 patients (59%). EIF2AK3, INS, and KATP channel mutations were the commonest causes with frequency of 17%, 17%, and 14%, respectively. Patients with ABBC8 and KCNJ11 mutations were successfully shifted to sulfonylureas (SU). Paired data of glycosylated haemoglobin before and after SU transfer showed improved glycaemic control; 9.6% versus 7.1%, P = 0.041.

Conclusions

PNDM is a heterogenous disease with variable genotypes and clinical phenotypes among Egyptian patients. EIF2AK3, INS, ABCC8, and KCNJ11 mutations were the commonest causes of PNDM in the study cohort. All patients with KATP channel mutations were effectively treated with glyburide, reflecting the fact that genetic testing for patients with NDM is not only important for diagnosis but also for treatment plan and prognosis.

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Data availability

All patients’ data are available in Table 2. Any additional materials are available from the corresponding author on reasonable request.

Code availability

The clinical data were analysed using the Statistical Package of Social Science (SPSS) programme for Windows (Standard version 21).

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Acknowledgements

We are grateful to all the families that participated in this study. Genetic testing performed at the University of Exeter Medical School was funded through a Wellcome Trust Senior Investigator Award (098395/Z/12/Z).

Funding

Genetic testing performed at the University of Exeter Medical School was funded through a Wellcome Trust Senior Investigator Award (098395/Z/12/Z). EDF is a Diabetes UK RD Lawrence fellow. SEF has a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (105636/Z/14/Z).

Author information

Authors and Affiliations

  1. Pediatric Endocrinology and Diabetes Unit, Department of Pediatrics, Mansoura Faculty of Medicine, Mansoura University, Mansoura University Children’s Hospital, Gomhoria Street, Mansoura, Dakhlia, 35516, Egypt

    Wafaa Laimon, Magdy El-Ziny, Amany El-Hawary, Ashraf Elsharkawy, Nanees Abdel-Badie Salem, Hadil Mohamed Aboelenin & Mohammad Hosny Awad

  2. Institute of Biomedical and Clinical Science, University of Exeter, Exeter, UK

    Sarah E. Flanagan & Elisa De Franco

Authors
  1. Wafaa Laimon
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  2. Magdy El-Ziny
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  5. Nanees Abdel-Badie Salem
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  6. Hadil Mohamed Aboelenin
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  8. Sarah E. Flanagan
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  9. Elisa De Franco
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Contributions

W.L. initiated the main study idea. W.L., M.E., A.E., A.E., N.S., H.A., and M.A. contributed to the study design. W.L. collected patients’ samples, collected, and analysed the data. S.E.F. and E.D.F. analysed the genetic data. W.L. wrote the first draft of the manuscript. M.E., A.E., A.E., N.S., H.A., S.E.F., E.D.F., and M.A. revised and edited the manuscript. All the authors approved the final submitted manuscript.

Corresponding author

Correspondence to Wafaa Laimon.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This report has been approved by institutional review board and was in accordance with the 1964 Helsinki declaration and its later amendments.

Consent to participate

Informed written consents to publish the cases have been obtained from the patients’ parents.

Consent for publication

Patients signed informed consent regarding publishing their data. Parents of patient 14.1 signed informed consent for publication of Supplementary Fig. 1 and Supplementary Fig. 2.

Additional information

Managed by Massimo Porta.

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Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 24 KB)

It shows acanthosis nigricans at neck, axilla and groin, prominent nipple, hypertrichosis and clitromegaly

Supplementary file2 (TIF 31212 KB)

592_2021_1788_MOESM3_ESM.tif

A: It shows prominent infraorbital creases, low set ears, thick lips, and acanthosis nigricans. B: It shows umbilical hernia and abdominal distension

Supplementary file3 (TIF 17586 KB)

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Laimon, W., El-Ziny, M., El-Hawary, A. et al. Genetic and clinical heterogeneity of permanent neonatal diabetes mellitus: a single tertiary centre experience. Acta Diabetol 58, 1689–1700 (2021). https://doi.org/10.1007/s00592-021-01788-6

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  • DOI: https://doi.org/10.1007/s00592-021-01788-6

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