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. 2023 Nov 16;18(1):360.
doi: 10.1186/s13023-023-02954-5.

An expanded clinical spectrum of hypoinsulinaemic hypoketotic hypoglycaemia

Alena Welters #  1 , Sarah M Leiter #  2 , Nadine Bachmann  3 , Carsten Bergmann  3 , Henrike Hoermann  1 , Eckhard Korsch  4 , Thomas Meissner  1 , Felicity Payne  5 , Rachel Williams  5 , Khalid Hussain  6 , Robert K Semple #  2   7   8 , Sebastian Kummer #  9
Affiliations

An expanded clinical spectrum of hypoinsulinaemic hypoketotic hypoglycaemia

Alena Welters et al. Orphanet J Rare Dis. .

Abstract

Background: Hypoketotic hypoglycaemia with suppressed plasma fatty acids and detectable insulin suggests congenital hyperinsulinism (CHI). Severe hypoketotic hypoglycaemia mimicking hyperinsulinism but without detectable insulin has recently been described in syndromic individuals with mosaic genetic activation of post-receptor insulin signalling. We set out to expand understanding of this entity focusing on metabolic phenotypes.

Methods: Metabolic profiling, candidate gene and exome sequencing were performed in six infants with hypoketotic, hypoinsulinaemic hypoglycaemia, with or without syndromic features. Additional signalling studies were carried out in dermal fibroblasts from two individuals.

Results: Two infants had no syndromic features. One was mistakenly diagnosed with CHI. One had mild features of megalencephaly-capillary malformation-polymicrogyria (MCAP) syndrome, one had non-specific macrosomia, and two had complex syndromes. All required intensive treatment to maintain euglycaemia, with CHI-directed therapies being ineffective. Pathogenic PIK3CA variants were found in two individuals - de novo germline c.323G>A (p.Arg108His) in one non-syndromic infant and postzygotic mosaic c.2740G>A (p.Gly914Arg) in the infant with MCAP. No causal variants were proven in the other individuals despite extensive investigation, although rare variants in mTORC components were identified in one. No increased PI3K signalling in fibroblasts of two individuals was seen.

Conclusions: We expand the spectrum of PI3K-related hypoinsulinaemic hypoketotic hypoglycaemia. We demonstrate that pathogenic germline variants activating post-insulin-receptor signalling may cause non-syndromic hypoinsulinaemic hypoketotic hypoglycaemia closely resembling CHI. This distinct biochemical footprint should be sought and differentiated from CHI in infantile hypoglycaemia. To facilitate adoption of this differential diagnosis, we propose the term "pseudohyperinsulinism".

Keywords: Hypoinsulinemic hypoglycaemia; Insulin signalling; PI3K; Pseudohyperinsulinism.

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Conflict of interest statement

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

References

    1. Galcheva S, Demirbilek H, Al-Khawaga S, Hussain K. The genetic and molecular mechanisms of congenital hyperinsulinism. Front Endocrinol (Lausanne) 2019;10:111. doi: 10.3389/fendo.2019.00111. - DOI - PMC - PubMed
    1. Huang X, Liu G, Guo J, Su Z. The PI3K/AKT pathway in obesity and type 2 Diabetes. Int J Biol Sci. 2018;14(11):1483–96. doi: 10.7150/ijbs.27173. - DOI - PMC - PubMed
    1. Hussain K, Challis B, Rocha N, Payne F, Minic M, Thompson A, et al. An activating mutation of AKT2 and human hypoglycemia. Science. 2011;334(6055):474. doi: 10.1126/science.1210878. - DOI - PMC - PubMed
    1. Leiter SM, Parker VER, Welters A, Knox R, Rocha N, Clark G, et al. Hypoinsulinaemic, hypoketotic hypoglycaemia due to mosaic genetic activation of PI3-kinase. Eur J Endocrinol. 2017;177(2):175–86. doi: 10.1530/EJE-17-0132. - DOI - PMC - PubMed
    1. Nellist M, Schot R, Hoogeveen-Westerveld M, Neuteboom RF, van der Louw EJ, Lequin MH, et al. Germline activating AKT3 mutation associated with megalencephaly, polymicrogyria, Epilepsy and hypoglycemia. Mol Genet Metab. 2015;114(3):467–73. doi: 10.1016/j.ymgme.2014.11.018. - DOI - PubMed

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