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



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.


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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Serine/threonine-protein kinase


Branched-chain amino acids


Bannayan-Riley-Ruvalcaba syndrome


Birth weight


Beckwith-Wiedemann syndrome


Clinical-exome sequencing


Cowden syndrome


Free fatty acids


Growth hormone


Head circumference


Hyperinsulinemic hypoglycemia


Insulin-like growth factor binding protein 1/3


Insulin-like growth factor 1


Megalencephaly-capillary malformations syndrome


Autosomal dominant mental retardation-35


Megalencephaly-polymicrogyria-polydactyly-hydrocephalus Syndrome


Magnetic resonance imaging


Mammalian target of rapamycin


MTOR complex


MTOR inhibitor


Next-generation sequencing


PTEN hamartoma tumour syndrome


Phosphatidylinositol 3-kinase


Phosphatidylinositol (3,4,5)-trisphosphate


Phosphatase and tensin homolog


Whole-exome sequencing


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Corresponding author

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 (2021). https://doi.org/10.1007/s42000-021-00287-1

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  • PI3K/AKT/mTOR signaling pathway
  • Hypoglycemia
  • Macrocephaly
  • Overgrowth
  • Review