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Hypoglycemia due to PI3K/AKT/mTOR signaling pathway defects: two novel cases and review of the literature

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Abstract

Introduction

The PI3K/AKT/mTOR signaling pathway is important for the regulation of multiple biological processes, including cellular growth and glucose metabolism. Defects of the PI3K/AKT/mTOR signaling pathway are not usually considered among the genetic causes of recurrent hypoglycemia in childhood. However, accumulating evidence links hypoglycemia with defects of this pathway.

Case reports and review

We describe here two cases of macrocephaly and hypoglycemia bearing genetic defects in genes involved in the PI3K/AKT/mTOR pathway. The first patient was diagnosed with a PTEN hamartoma tumour syndrome (PTHS) due to the de novo germline missense mutation c.[492 + 1G > A] of the PTEN gene. The second patient presented the autosomal dominant mental retardation-35 (MDR35) due to the heterozygous missense mutation c.592G > A in the PPP2R5D gene. A review of the literature on hypoglycemia and PI3K/AKT/mTOR signaling pathway defects, with a special focus on the metabolic characterization of hypoglycemia, is included.

Conclusions

PI3K/AKT/mTOR pathway defects should be included in the differential diagnosis of patients with hypoglycemia and macrocephaly. Clinical suspicion and molecular confirmation are important, not just for an accurate genetic counselling but also for defining the follow-up management, including cancer surveillance. The biochemical profile of hypoglycemia varies among patients. While most patients are characterized by low plasmatic insulin levels, hyperinsulinemia has also been observed. Large patient cohorts are needed to gain a comprehensive profile of the biochemical patterns of hypoglycemia in such defects and eventually guide targeted therapeutic interventions.

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Abbreviations

AKT:

Serine/threonine-protein kinase

BCAA:

Branched-chain amino acids

BRRS:

Bannayan-Riley-Ruvalcaba syndrome

BW:

Birth weight

BWS:

Beckwith-Wiedemann syndrome

CES:

Clinical-exome sequencing

CS:

Cowden syndrome

FFA:

Free fatty acids

GH:

Growth hormone

HC:

Head circumference

HH:

Hyperinsulinemic hypoglycemia

IGFBP-1/3:

Insulin-like growth factor binding protein 1/3

IGF-1:

Insulin-like growth factor 1

MCAP:

Megalencephaly-capillary malformations syndrome

MDR35:

Autosomal dominant mental retardation-35

MPPH:

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus Syndrome

MRI:

Magnetic resonance imaging

mTOR:

Mammalian target of rapamycin

mTORC:

MTOR complex

mTORi:

MTOR inhibitor

NGS:

Next-generation sequencing

PHTS:

PTEN hamartoma tumour syndrome

PI3K:

Phosphatidylinositol 3-kinase

PIP3:

Phosphatidylinositol (3,4,5)-trisphosphate

PTEN:

Phosphatase and tensin homolog

WES:

Whole-exome sequencing

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Author notes

  1. Maines E. and Franceschi R. contributed equally to the work.

Authors and Affiliations

  1. Division of Pediatrics, S. Chiara General Hospital, Largo Medaglie d’oro, 9, 38122, Trento, Italy

    Evelina Maines, Roberto Franceschi & Massimo Soffiati

  2. Division of Metabolism and Research Unit of Metabolic Biochemistry, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    Diego Martinelli

  3. Division of Medical Genetics, S. Chiara General Hospital, Trento, Italy

    Fiorenza Soli

  4. Molecular Genetics Laboratory, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    Francesca Romana Lepri

  5. CIBIO - Centre for Integrative Biology, Università Degli Studi Di Trento, Italy & Dulbecco Telethon Institute, Trento, Italy

    Giovanni Piccoli

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Correspondence to Evelina Maines.

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Ethics approval and consent to participate

The latest revision of the Helsinki Declaration as well as the Oviedo Declaration was the basis for the ethical conduct of the study. The study protocol was designed and conducted to ensure adherence to the principles and procedures of good clinical practice and to comply with the Italian laws. Written informed consent for the publication of the clinical details and clinical images was obtained from the parents of patient 2. Written informed consent for the publication of the clinical details was obtained from the parents of patient 1. A copy of the consent forms is available for review from the Editor of this journal.

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Key points

• PI3K/AKT/mTOR signaling pathway defects were first linked to hypoglycemia in 2011. Up to now, variants in seven genes of the PI3K/AKT/mTOR pathway have been associated with hypoglycemia: AKT2, AKT3, PIK3CA, PIK3R2, PPP2R5D, CCND2 and PTEN.

• Reports of recurrent hypoglycemias in patients with defects in this pathway are increasing. Nevertheless, defects of the PI3K/AKT/mTOR signaling pathway are not usually considered in the differential diagnosis and targeted hypoglycemia gene panels rarely include PI3K/AKT/mTOR genes. Moreover, detailed data on the biochemical profile of hypoglycemia in these defects are limited.

• Our paper highlights the need to consider PI3K/AKT/mTOR pathway defects in the differential diagnosis of hypoglycemia in children with overgrowth, particularly macrocephaly. A review of the literature on hypoglycemia and PI3K/AKT/mTOR signaling pathway defects, with a special focus on the metabolic characterization of hypoglycemia, is included.

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Maines, E., Franceschi, R., Martinelli, D. et al. Hypoglycemia due to PI3K/AKT/mTOR signaling pathway defects: two novel cases and review of the literature. Hormones 20, 623–640 (2021). https://doi.org/10.1007/s42000-021-00287-1

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