*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.