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.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Branched-chain amino acids
Free fatty acids
Insulin-like growth factor binding protein 1/3
Insulin-like growth factor 1
Megalencephaly-capillary malformations syndrome
Autosomal dominant mental retardation-35
Magnetic resonance imaging
Mammalian target of rapamycin
PTEN hamartoma tumour syndrome
Phosphatase and tensin homolog
Jansen LA, Mirzaa GM, Ishak GE, O’Roak BJ, Hiatt JB, Roden WH, Gunter SA, Christian SL, Collins S, Adams C et al (2015) PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia. Brain 138(Pt 6):1613–1628
Keppler-Noreuil KM, Sapp JC, Lindhurst MJ, Parker VE, Blumhorst C, Darling T, Tosi LL, Huson SM, Whitehouse RW, Jakkula E et al (2014) Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum. Am J Med Genet A 164A(7):1713–1733
Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7(8):606–619
Sun XJ, Rothenberg P, Kahn CR, Backer JM, Araki E, Wilden PA, Cahill DA, Goldstein BJ, White MF (1991) Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature 352(6330):73–77
Hay N (2011) AKT isoforms and glucose homeostasis - the leptin connection. Trends Endocrinol Metab 22(2):66–73
Terauchi Y, Tsuji Y, Satoh S, Minoura H, Murakami K, Okuno A, Inukai K, Asano T, Kaburagi Y, Ueki K et al (1999) Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 alpha subunit of phosphoinositide 3-kinase. Nat Genet 21(2):230–235
Thauvin-Robinet C, Auclair M, Duplomb L, Caron-Debarle M, Avila M, St-Onge J, Le Merrer M, Le Luyer B, Héron D, Mathieu-Dramard M et al (2013) PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy. Am J Hum Genet 93(1):141–149
Deau M-C, Heurtier L, Frange P, Suarez F, Bole-Feysot C, Nitschke P, Cavazzana M, Picard C, Durandy A, Fischer A, Kracker S (2015) A human immunodeficiency caused by mutations in the PIK3R1 gene. J Clin Invest 125(4):1764–1765
Stocker H, Andjelkovic M, Oldham S, Laffargue M, Wymann MP, Hemmings BA, Hafen E (2002) Living with lethal PIP3 levels: viability of flies lacking PTEN restored by a PH domain mutation in Akt/PKB. Science 295(5562):2088–2091
Tong Z, Fan Y, Zhang W, Xu J, Cheng J, Ding M, Deng H (2009) Pancreas-specific PTEN deficiency causes partial resistance to diabetes and elevated hepatic AKT signaling. Cell Res 19(6):710–719
Shang L, Henderson LB, Cho MT, Petrey DS, Fong CT, Haude KM, Shur N, Lundberg J, Hauser N, Carmichael J et al (2016) De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism. Neurogenetics 17(1):43–49
Keppler-Noreuil KM, Parker VE, Darling TN, Martinez-Agosto JA (2016) Somatic overgrowth disorders of the PI3K/AKT/mTOR pathway & therapeutic strategies. Med Genet C Semin Med Genet 172(4):402–421
Rivière JB, Mirzaa GM, O’Roak BJ, Beddaoui M, Alcantara D, Conway RL, St-Onge J, Schwartzentruber JA, Gripp KW, Nikkel SM et al (2012) De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet 44(8):934–940
Mirzaa G, Parry DA, Fry AE, Giamanco KA, Schwartzentruber J, Vanstone M, Logan CV, Roberts N, Johnson CA, Singh S et al (2014) De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. Nat Genet 46(5):510–515
Hussain K, Challis B, Rocha N, Payne F, Minic M, Thompson A, Daly A, Scott C, Harris J, Smillie BJ et al (2011) An activating mutation of AKT2 and human hypoglycemia. Science 334(6055):474
Leiter SM, Parker VER, Welters A, Knox R, Rocha N, Clark G, Payne F, Lotta L, Harris J, Guerrero-Fernández J et al (2017) Hypoinsulinaemic, hypoketotic hypoglycaemia due to mosaic genetic activation of PI3-kinase. Eur J Endocrinol 177(2):175–186
Maiorana A, Dionisi-Vici C (2017) Hyperinsulinemic hypoglycemia: clinical, molecular and therapeutical novelties. J Inherit Metab Dis 40(4):531–542
Tenorio J, Mansilla A, Valencia M, Martínez-Glez V, Romanelli V, Arias P, Castrejón N, Poletta F, Guillén-Navarro E, Gordo G et al (2014) A new overgrowth syndrome is due to mutations in RNF125. Hum Mutat 35(12):1436–1441
Matsuo T, Ihara K, Ochiai M, Kinjo T, Yoshikawa Y, Kojima-Ishii K, Noda M, Mizumoto H, Misaki M, Minagawa K et al (2013) Hyperinsulinemic hypoglycemia of infancy in Sotos syndrome. Am J Med Genet A 161A(1):34–37
Mirzaa G, Timms AE, Conti V, Boyle EA, Girisha KM, Martin B, Kircher M, Olds C, Juusola J, Collins S et al (2016) PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution. JCI Insight 1(9):e87623
Granados A, Eng C, Diaz A (2013) Brothers with germline PTEN mutations and persistent hypoglycemia, macrocephaly, developmental delay, short stature, and coagulopathy. J Pediatr Endocrinol Metab 26(1–2):137–141
Ozsu E, Sen A, Ceylaner S (2018) A case of Riley Ruvalcaba syndrome with a novel PTEN mutation accompanied by diffuse testicular microlithiasis and precocious puberty. J Pediatr Endocrinol Metab 31(1):95–99
McDermott JH, Hickson N, Banerjee I, Murray PG, Ram D, Metcalfe K, Clayton-Smith J, Douzgou S (2018) Hypoglycaemia represents a clinically significant manifestation of PIK3CA- and CCND2-associated segmental overgrowth. Clin Genet 93(3):687–692
Nellist M, Schot R, Hoogeveen-Westerveld M, van der Neuteboom RF, Louw EJ, Lequin MH, Bindels-de Heus K, de Sibbles BJ, Coo R, Brooks A et al (2015) Germline activating AKT3 mutation associated with megalencephaly, polymicrogyria, epilepsy and hypoglycemia. Mol Genet Metab 114(3):467–473
Liu J, Ding G, Zou K, Jiang Z, Zhang J, Lu Y, Pignata A, Venner E, Liu P, Liu Z et al (2020) Genome sequencing analysis of a family with a child displaying severe abdominal distention and recurrent hypoglycemia. Mol Genet Genomic Med 8(3):e1130
Arya VB, Flanagan SE, Schober E, Rami-Merhar B, Ellard S, Hussain K (2014) Activating AKT2 mutation: hypoinsulinemic hypoketotic hypoglycemia. J Clin Endocrinol Metab 99(2):391–394
Stutterd C, McGillivray G, Stark Z, Messazos B, Cameron F, White S, Melbourne Genomics Health Alliance, Mirzaa G, Leventer R (2018) Polymicrogyria in association with hypoglycemia points to mutation in the mTOR pathway. Eur J Med Genet 61(12):738–740
Şıklar Z, Çetin T, Çakar N, Berberoğlu M (2020) The effectiveness of Sirolimus treatment in two rare disorders with nonketotic hypoinsulinemic hypoglycemia: The role of mTOR pathway. J Clin Res Pediatr Endocrinol. https://doi.org/10.4274/jcrpe.galenos.2020.2019.0084
Deciphering Developmental Disorders Study (2015) Large-scale discovery of novel genetic causes of developmental disorders. Nature 519:223–228
Chen HJ, Romigh T, Sesock K, Eng C (2017) Characterization of cryptic splicing in germline PTEN intronic variants in Cowden syndrome. Version 2. Hum Mutat 38(10):1372–1377
Eng C (2001) PTEN hamartoma tumor syndrome. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle: University of Washington, Seattle; 1993–2020
Ponzi E, Maiorana A, Lepri FR, Mucciolo M, Semeraro M, Taurisano R, Olivieri G, Novelli A, Dionisi-Vici C (2018) Persistent hypoglycemia in children: targeted gene panel improves the diagnosis of hypoglycemia due to inborn errors of metabolism. J Pediatr 202(272–278):e4
Esposito A, Viale G, Curigliano G (2019) Safety, tolerability, and management of toxic effects of phosphatidylinositol 3-kinase inhibitor treatment in patients with cancer: a review. JAMA Oncol. https://doi.org/10.1001/jamaoncol.2019.0034
Wieman HL, Wofford JA, Rathmell JC (2007) Cytokine stimulation promotes glucose uptake via phosphatidylinositol-3 kinase/Akt regulation of Glut1 activity and trafficking. Mol Biol Cell 18:1437–1446
Macheda ML, Rogers S, Best JD (2005) Molecular and cellular regulation of glucose transporter (GLUT) proteins in cancer. J Cell Physiol 202:654–662
Buerkle A, Weber WA (2008) Imaging of tumor glucose utilization with positron emission tomography. Cancer Metastasis Rev 27(4):545–554
Jiang WJ, Peng YC, Yang KM (2018) Cellular signaling pathways regulating beta-cell proliferation as a promising therapeutic target in the treatment of diabetes. Exp Ther Med 16(4):3275–3285
Davis S, Ware MA, Zeiger J, Deardorff MA, Grand K, Grimberg A, Hsu S, Kelsey M, Majidi S, Matthew RP et al (2020) Growth hormone deficiency in megalencephaly-capillary malformation syndrome: an association with activating mutations in PIK3CA. Am J Med Genet A 182(1):162–168
Cholley F, Trivin C, Sainte-Rose C, Souberbielle JC, Cinalli G, Brauner R (2001) Disorders of growth and puberty in children with non-tumoral hydrocephalus. J Pediatr Endocrinol Metab 14(3):319–327
Demirbilek H, Hussain K (2017) Congenital hyperinsulinism: diagnosis and treatment update. J Clin Res Pediatr Endocrinol 9(Suppl 2):69–87
Minute M, Patti G, Tornese G, Faleschini E, Zuiani C, Ventura A (2015) Sirolimus therapy in congenital hyperinsulinism: a successful experience beyond infancy. Pediatrics 136(5):e1373–e1376
Güemes M, Shah P, Roženková K, Gilbert C, Morgan K, Hussain K (2016) Severe hyperinsulinaemic hypoglycaemia in Beckwith-Wiedemann syndrome due to uniparental disomy. Horm Res Paediatr 85(5):353–357
Kamien B, Ronan A, Poke G, Sinnerbrink I, Baynam G, Ward M, Gibson WT, Dudding-Byth T, Scott RJ (2018) A clinical review of generalized overgrowth syndromes in the era of massively parallel sequencing. Mol Syndromol 9(2):70–82
Smpokou P, Fox VL, Tan WH (2015) PTEN hamartoma tumour syndrome: early tumour development in children. Arch Dis Child 100(1):34–37
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.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
• 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.
About this article
Cite this article
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
- PI3K/AKT/mTOR signaling pathway