ESPE Abstracts

Background: In contrast to hypoglycaemia due to congenital hyperinsulinism, there are patients with a similar metabolic profile of hypoketotic hypoglycaemia, but low insulin levels and relatively low glucose requirements to maintain euglycaemia. So far, four patients with activating mutations in the insulin signal-transducing kinase AKT2 have been described, each also showing a syndromic phenotype including hemihypertrophy.

Objective and hypotheses: We present a 3.5 year-old girl with similar metabolic and syndromic features, but no AKT2 mutation, suggesting a possible mutation in another gene of the same pathway.

Method: Exome sequencing was undertaken in the proband and parents and analysed to look for either de novo or compound heterozygous pathogenic mutations.

Results: A mosaic mutation (p.Glu726Lys) in PIK3CA, encoding the p110 catalytic subunit of phosphatidylinositol 3-kinase, was detected in lymphocyte, hair bulb, fibroblast, and cheek swab DNA from the patient but neither parent. Mosaic mutations in this gene are known to cause segmental overgrowth disorders such as the Megalencephaly-Capillary malformation (MCAP) syndrome, which have not been described to be associated with hypoglycaemia so far. Typical features of this syndrome (e.g. Macrocephaly, Epilepsy, Capillary malformations, Focal or segmental body overgrowth) were found in our patient on review. Although glucose requirements to maintain euglycaemia in our patient is relatively low (2.4mg/kg/min), fasting tolerance is very short (~2.5–3 h, aged 3 years). Increased basal levels of signalling downstream from phosphatidylinositol 3-kinase (PI3K) were detected in serum starved dermal fibroblasts from the patient. We suggest that liver affection in somatic mosaicism of PIK3CA mutation leads to suppressed hepatic gluconeogenesis, driven by constitutive, ligand-independent activation of the insulin receptor pathway explaining the hypoglycaemic phenotype in this patient.

Conclusion: Here, we present a patient that extends the spectrum of MCAP syndrome to include markedly reduced fasting tolerance and recurrent hypoketotic hypoglycaemia with low insulin levels.

Funding: RKS is supported by The Wellcome Trust (Senior Research Fellowship in Clinical Science 098498/Z/12/Z.