*Facial features = exophthalmos, periorbital puffiness, proptosis, low-set ears, tented mouth, flat nasal bridge.
**The older male proband is designated A and the younger B.
Despite variable clinical features, our patient’s presentation overlaps considerably with previous reports, including growth parameters reflective of excess insulin action. The near universal presence of hemi-hypertrophy is suggestive of mosaicism, which would account for variability amongst other features including acanthosis nigricans, hypotonia, and facial dysmorphisms. Two previously published cases ofAKT2 mutation were found to be mosaic for the variant7 and notably two siblings inherited the variant from their unaffected father who was found to carry the variant at low level of mosaicism in his sperm.5 Mosaicism was not detected in our patient’s peripheral blood leukocytes or skin fibroblasts, although it cannot be excluded at other tissues.
The variable occurrence of developmental delay is also notable, as this outcome is potentially preventable. 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.4,5,7,8Nevertheless, hypoglycemia is likely contributory to her delay given her presentation with hypoglycemic seizures and initial challenges obtaining glycemic control. Previous studies of children with congenital hyperinsulinism suggest development is adversely impacted by both hypoglycemic duration and severity, emphasizing the need for prompt recognition and treatment.15
At present, the mainstay of treatment is nutritional support with frequent, carbohydrate-rich feeds. 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 While this approach provides glycemic control, previously described limitations include obesity secondary to excess caloric intake.7
The metabolic and quality of life implications of frequent feeding make anti-hypoglycemic agents an attractive therapeutic option. Consistent with previous reports,5,7 diazoxide and octreotide were ineffective in our patient as these agents target upstream insulin release, as opposed to downstream signaling.13 Due to its action on this pathway, sirolimus was trialed in a sibling pair with activating AKT2 mutations. The frequency of hypoglycemic episodes and carbohydrate need were reduced, however overnight fasting was extended only up to four hours.5 Although no serious adverse effects occurred, use of sirolimus in congenital hyperinsulinism and PIK3CA-related overgrowth spectrum has been associated with severe infectious and hematologic complications, including sepsis and anemia requiring blood transfusion.16,17 Sirolimus was only modestly effective in children with congenital hyperinsulinism, further highlighting the need for novel therapeutic approaches.17
An enticing option is WMHMS, which is approved for children >2 years with glycogen storage disease (GSD) in Canada. WMHMS is a slow-release carbohydrate, shown to provide improved glycemic control with less gastrointestinal discomfort than uncooked cornstarch.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 AKT2mutation.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. Unfortunately, overnight hypoglycemia necessitated WMHMS discontinuation after three nights at home. Given otherwise unchanged daytime feeds, a conceivable explanation is increased energy expenditure at home, where activity is unrestricted. The family remains willing to use WMHMS and an increased dose of 5.8 g/kg was recommended, though it has yet to be attempted by the family.