Facial Dysmorphic Features in a Patient With Nonketotic Hypoglycemia and a Pathogenic Variant in the AKT2 Gene

Abstract

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Treatment of hypoglycemia due to a rare pathogenic variant in AKT2 with waxy maize heat‐modified starch

“…Our patient initially required a markedly elevated GIR of 15 mg/kg/min in addition to intermittent dextrose boluses for breakthrough hypoglycemia. Although GIR is reported inconsistently, this exceeds the GIR of 3–5 mg/kg/min described in three previous cases 7,8 . Current management is nevertheless comparable to other cases, with a GIR of 4–5 mg/kg/min provided by intermittent nasogastric feeds including uncooked cornstarch during the day and a continuous feed overnight 7 .…”

“…Unfortunately, etiologic determination of our patient's developmental delay is confounded by MRI findings consistent with perinatal asphyxia secondary to shoulder dystocia. These abnormalities are unlikely the consequence of her activating AKT2 mutation, as normal brain MRIs have been documented in five individuals with the same mutation, four of whom have developmental delay or intellectual disability 4,5,7,8 . Nevertheless, hypoglycemia is likely contributory to her delay given her presentation with hypoglycemic seizures and initial challenges obtaining glycemic control.…”

“…9 Despite its purported benefits, WMHMS did not improve fasting blood glucose compared to uncooked cornstarch in a 6-month-old-male with an activating AKT2 mutation (Table 3). 8 However, this result should be interpreted cautiously as expression of pancreatic amylase is substantially reduced in infancy, impairing starch digestion. 18 Age-related differences in digestion could explain the contrasting improvement in fasting tolerance observed in our patient following WMHMS administration.…”

“…A growing body of evidence supports the clinical relevance of AKT2. Although rare, gain‐of‐function mutations in AKT2 have been described in eight individuals with hypoketotic hypoglycemia 4–8 . Despite undetectable insulin levels, their biochemical profiles closely resemble hyperinsulinemic hypoglycemia due to constitutive activation of the insulin signaling cascade.…”

Syndromic forms of congenital hyperinsulinism

“…The activating AKT2 p.Lys17Glu mutation (mosaic or germline) was identified in children with (asymmetric) overgrowth and severe recurrent hypoglycemia from infancy with a classical biochemical profile of hyperinsulinism (i.e., low serum levels of ketone and free fatty acids), but undetectable insulin (OMIM #240900) (39). Several other similar cases have been reported (40)(41)(42). AKT2 seems to be consistently associated with this metabolic phenotype.…”