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\begin{document}

\title{Case Report: Treatment of Hypoglycemia due to a Rare Pathogenic Variant
in \emph{AKT2} with Waxy Maize Heat-Modified Starch}



\author[1]{Madeline Parker}%
\author[1]{Daphne Yau}%
\affil[1]{University of Saskatchewan}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\sloppy


\textbf{Case Report: Treatment of Hypoglycemia due to a Rare Pathogenic
Variant in \emph{AKT2} with Waxy Maize Heat-Modified Starch}

\textbf{Madeline Parker\textsuperscript{1} \& Daphne
Yau\textsuperscript{1}}

\textsuperscript{1} Department of Pediatrics, University of
Saskatchewan, Saskatoon, Saskatchewan, Canada

\textbf{Corresponding author:}

Daphne Yau, MD MSc FRCPC

Pediatric Endocrinologist, Assistant Professor

University of Saskatchewan

Jim Pattison Children's Hospital

103 Hospital Drive

Saskatoon, SK

S7N 0W8

daphne.yau@usask.ca

(306) 655-2048 (tel), (306) 844-1536 (fax)



\textbf{Abstract}

\textbf{Introduction:} The serine-threonine kinase AKT2 is a critical
mediator of insulin's anabolic effects, particularly cellular glucose
uptake. The gain-of-function c.49G\textgreater{}A,
p.(Glu17Lys)\emph{AKT2} variant results in hypoketotic hypoglycemia with
suppressed insulin and free fatty acid levels due to constitutive
activation of the insulin signaling cascade. Although biochemical
similarities exist amongst the eight individuals identified to date, the
associated phenotype varies considerably. Treatment of these patients
remains challenging, consisting primarily of frequent feeds with
uncooked cornstarch.

\textbf{Case Presentation:} We describe a female with hemihypertrophy,
developmental delay, and dysmorphic features who presented to our center
with hypoglycemic seizures at age 6-months. Critical sample revealed
hypoketotic hypoglycemia, undetectable insulin, and suppressed free
fatty acids. Molecular testing confirmed a pathogenic
c.49G\textgreater{}A, p.(Glu17Lys) \emph{AKT2} mutation. Glycemic
control was initially difficult to establish, with recurrent
hypoglycemia despite high glucose infusion rates. Following in-hospital
administration of waxy maize heat-modified starch at age 4-years she
remained euglycemic overnight, despite a previous report showing no
benefit compared to uncooked cornstarch in an infant with the same
mutation.

\textbf{Conclusion:} Our report suggests waxy maize heat-modified starch
is a viable treatment option for patients with activating
c.49G\textgreater{}A \emph{AKT2} mutations and provides further evidence
of a broad phenotypic spectrum.

\textbf{Keywords:} hypoglycemia, AKT2, starch

\textbf{Key Clinical Message:} The gain-of-function
\emph{AKT2}c.49G\textgreater{}A variant causes hypoketotic hypoglycemia
with variable associated features. Due to lack of effective medications,
treatment is primarily supportive. This report suggests waxy maize heat
is a viable treatment option.



\textbf{Introduction}

Insulin's crucial role in energy metabolism is coordinated by a
post-receptor signaling cascade resulting in activation of Akt2, a
serine-threonine kinase. Expressed predominantly in insulin-sensitive
tissue, Akt2 promotes glucose uptake by regulating translocation of the
glucose transporter-4 (GLUT4) from cytoplasm to the cell
membrane.\textsuperscript{1} Further, Akt2 mediates insulin's metabolic
effects by suppressing gluconeogenesis\textsuperscript{1} and
lipolysis\textsuperscript{2}, and stimulating
lipogenesis.\textsuperscript{3}

A growing body of evidence supports the clinical relevance of AKT2.
Although rare, gain-of-function mutations in \emph{AKT2} have been
described in eight individuals with hypoketotic
hypoglycemia.\textsuperscript{4-8} Despite undetectable insulin levels,
their biochemical profiles closely resemble hyperinsulinemic
hypoglycemia due to constitutive activation of the insulin signaling
cascade. Additional reported features include accelerated linear growth,
hemihypertrophy, and polyhydramnios.\textsuperscript{4,6} Other features
have been variably reported including characteristic facies, acanthosis
nigricans, developmental delay and intellectual
disability.\textsuperscript{5,6}

Given the detrimental neurodevelopmental impact of hypoglycemia in
infancy and childhood, achieving euglycemia is critical. Management
consists of frequent carbohydrate-rich feedings, often including
uncooked cornstarch.\textsuperscript{5} However, with this approach,
euglycemia is achieved at the expense of excess weight gain and impaired
quality of life.\textsuperscript{7} Due to the anticipated lifelong
duration of treatment, alternate therapeutic approaches are needed. An
encouraging option is modified waxy maize heat modified starch (WMHMS)
which demonstrates improved tolerability and longer duration of action
than uncooked cornstarch.\textsuperscript{9}

We report a patient with an activating \emph{AKT2} mutation managed with
WMHMS, providing additional insight into the phenotypic spectrum.

\textbf{Clinical Presentation}

The proband is a 4-year-old female born large-for-gestational age at 38
weeks to healthy, non-consanguineous Caucasian parents. She was born via
spontaneous vaginal delivery complicated by a 3-minute shoulder dystocia
with Apgar scores of 4 at 1 minutes, 7 at 5 minutes and 8 at 10 minutes.
Birth weight was 4.14 kg (+2.6 SD), length 56cm (+3.68 SD), and head
circumference 36.5 cm (+2.7 SD). Pregnancy was remarkable only for a
thickened nuchal fold and bilateral choroid plexus cysts on prenatal
ultrasound. Amniocentesis was offered, but ultimately declined.

Shortly after birth, she developed mild hypoglycemia with a lowest
documented blood glucose of 2.6 mmol/L. Hypoglycemia was treated with a
10\% dextrose infusion for the first 24 hours of life, with a maximal
glucose infusion rate (GIR) of 4.2 mg/kg/minute. The presence of
bilateral proptosis, periorbital edema, subtle left facial hypertrophy,
and central hypotonia prompted evaluation for Beckwit-Wiedemann Syndrome
(BWS), which returned negative. Newborn metabolic screen was
unremarkable, and microarray demonstrated a normal, female result. The
hypoglycemia resolved spontaneously and was not investigated further.

At 6 months of age, she presented with a five-minute, generalised
tonic-clonic seizure. At presentation, her blood glucose was 1.9 mmol/L
and only transiently responsive to two 10\% dextrose boluses. A 10\%
dextrose infusion was started, and she was admitted to hospital for
further treatment and investigation. History was significant for several
1--2-minute episodes of `staring' and decreased responsiveness occurring
in the preceding two weeks. All episodes occurred in the morning,
following periods of fasting overnight. Examination again revealed
bilateral proptosis, periorbital edema, and central hypotonia (Figure
1). Auxology demonstrated weight 9.77 kg (+2.1 SD), length 78.3 cm (+5.1
SD), head circumference 46 cm (+2.6 SD).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 1:} The proband's facial features including bilateral
proptosis, periorbital edema, and subtle left facial hemihypertrophy.

During admission, a critical sample was drawn due to ongoing
hypoglycemia, which demonstrated hypoketotic hypoglycemia with a
laboratory glucose of 1.8 mmol/L and undetectable serum
beta-hydroxybutyrate. Cortisol was 207 nmol/L, considered inappropriate
in the context of hypoglycemia. To exclude adrenal insufficiency, a
standard dose ACTH stimulation test was performed and returned normal.
The insulin level, acylcarnitine profile, urine organic acids, and
plasma amino acids were not immediately available, as they are processed
at an outside laboratory (Table 1).

\textbf{Table 1: Critical sample at presentation}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
& Results & Reference Range\tabularnewline
\midrule
\endhead
Glucose & 1.8 mmol/L & 3.3-5.5 mmol/L\tabularnewline
Serum ketones & \textless{}0.1 mmol/L & 0.0-0.6 mmol/L\tabularnewline
Urine ketones & Negative & ------\tabularnewline
Serum insulin & \textless{}14.4 pmol/L & 43.0-194.0
pmol/L\tabularnewline
Cortisol & 207 nmol/L & 133.0-537.0 nmol/L\tabularnewline
Growth hormone & 6.09 ug/L & 0.00-8.00 ug/L\tabularnewline
Free fatty acids & 227.0 umol/L & 100.0-900.0 umol/L\tabularnewline
Acylcarnitine & Normal & -------\tabularnewline
Plasma amino acids & Normal & -------\tabularnewline
Urine organic acids & Normal & -------\tabularnewline
\bottomrule
\end{longtable}

A standard dose glucagon challenge was performed immediately following
critical sample collection, resulting in an increase in bedside
capillary glucose from 1.9 mmol/L to 4.4 mmol/L. This is in keeping with
hyperinsulinism, as an increment of at least 1.7 mmol/L suggests
suppression of hepatic glycogenolysis by excess
insulin.\textsuperscript{10} Given this glucagon response and
hypoketotic hypoglycemia, a presumptive diagnosis of congenital
hyperinsulinism was made. Although not initially available, the serum
free fatty acid level returned suppressed at 227 umol/L, further
supporting the initial diagnosis.

Initial stabilization was achieved with a bolus of 10\% dextrose
followed by continuous infusion. Despite GIR exceeding 15 mg/kg/min, she
experienced recurrent episodes of hypoglycemia requiring repeated
boluses of 10\% dextrose. The insulin level subsequently returned
undetectable, with no evidence of hemolysis or sample degradation
causing an artifactual reduction in measured insulin. Octreotide and
diazoxide were separately trialed given her persistent hypoglycemia and
biochemical profile otherwise suggestive of hyperinsulinism. She was
unable to tolerate a wean of intravenous dextrose or pauses in the
infusion exceeding 30 minutes, despite octreotide doses of up to 20
ug/kg/day or diazoxide of 15mg/kg/day. Both medications were eventually
discontinued, and she successfully transitioned to continuous
nasogastric feeds providing a GIR of 13 mg/kg/min before discharge home.

Given the severity and persistence of hypoglycemia, a comprehensive
panel for genes implicated in hypoglycemia, hyperinsulinemia, and ketone
metabolism was performed on peripheral blood leukocytes. This
demonstrated a pathogenic heterozygous variant in
\emph{AKT2,}c.49G\textgreater{}A, p.(Glu17Lys) previously reported in
other individuals with gain-of-function
\emph{AKT2}variants.\textsuperscript{4-8} To assess for possible
mosaicism, DNA from skin fibroblasts was subsequently analyzed and found
to be positive for the mutation.

Based on the glucose requirements reported in other
cases,\textsuperscript{7} feeds were changed to three times daily
followed by uncooked cornstarch at 1.5-2 g/kg to maintain euglycemia
between feeds, in addition to an overnight continuous feed which
provided an overall GIR of 4-5 mg/kg/min. More recently, a 4.3 g/kg dose
of WMHMS (1.5 packets of Glycosade?, Vitaflo USA, NJ) was trialed in
hospital with successful maintenance of overnight euglycemia without the
addition of a continuous feed (Figure 2).\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Figure 2: Overnight blood glucose following WMHMS
administration.}

Currently, at 4 years of age, the hypoglycemia is well-controlled on her
current regimen. She continues to exhibit central hypotonia, mild
ataxia, and moderate global developmental delay. Owing to these
features, a non-contrast brain MRI was performed which demonstrated
subtle white matter loss in the parietal region without evidence of
cystic change favoured to be sequelae of previous ischemic insult.
Investigations for metabolic causes of developmental delay returned
negative including serum ammonia, copper, ceruloplasmin, homocysteine,
amino acid and acylcarnitine profiles, as well as urine organic acids,
oligosaccharides, sialic acid, uric acid, mucopolysaccharide screen, and
creatine. In view of the constitutive insulin pathway activation, serial
abdominal ultrasounds have been performed for tumour surveillance which
have been unremarkable including liver and kidneys normal in size for
her age.

\textbf{Genetic Testing}

BWS testing was performed using methylation sensitive, multiplex
ligation-dependent probe amplification at the 11p15 locus and Sanger
sequencing of \emph{CDKN1C.}

The gene panel for hypoglycemia, hyperinsulinemia, and ketone metabolism
is a commercially available panel (Blueprint Genetics, Seattle, WA) and
included next-generation sequencing of the following genes: \emph{ABCC8,
ACAT1, ACSF3, AGL, AKT2, ALDOA, ALDOB, DIS3L2, ENO3, EPM2A, FBP1, G6PC,
GAA, GBE1, GCK, GLUD1, GPC3, GYG1, GYS1, GYS2, HADH, HMGCL, HMGCS2,
HNF1A, HNF4A, INSR, KCNJ11, KDM6A, KMT2D, LAMP2, LDHA, MPV17, NHLRC1,
NSD1, OXCT1, PC, PCK1, PDX1, PFKM, PGAM2, PGK1, PGM1, PHKA1, PHKA2,
PHKB, PHKG2, PIK3CA, PIK3R2, PRKAG2, PRKAG3, PTF1A, PYGL, PYGM, RBCK1,
SLC16A1, SLC2A2, SLC37A4} , and \emph{UCP2.}

\textbf{Discussion}

In this case report, we describe a young female with hypoketotic
hypoglycemia and dysmorphic features secondary to an
activating\emph{AKT2} mutation.

AKT2 is a serine/threonine kinase in the insulin signalling pathway.
Insulin activates a transmembrane tyrosine kinase receptor, which
phosphorylates insulin receptor substrate (IRS) proteins, leading to
activation of phosphadtidylinositol-3-kinase
(PI3K).\textsuperscript{11}PI3K in turn generates phosphatidylinositol
(3,4,5)-trisphosphate which activates AKT.\textsuperscript{12} Several
AKT isoforms exist, of which AKT2 has been shown to mediate the
metabolic actions of insulin.\textsuperscript{1} The \emph{AKT2}
c.49G\textgreater{}A variant has been reported as \emph{de novo} in
patients with a similar clinical picture as our patient (Table 2). This
gain of function \emph{AKT2}variant leads to independent, constitutive
activation of the insulin pathway in target tissues including liver,
adipose, and skeletal muscle.\textsuperscript{7} Consequently, the
biochemical profile resembles hyperinsulinism with suppressed free fatty
acids and ketones.\textsuperscript{13} However, insulin levels are
undetectable due to negative feedback from the constitutively active
signaling cascade.\textsuperscript{14}

\textbf{Table 2: Summary of the clinical features of individuals with
c.49G\textgreater{}A} \emph{AKT2} \textbf{mutations}\selectlanguage{english}
\begin{longtable}[]{@{}llllllllll@{}}
\toprule
\begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Clinical features}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
Our patient\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
Hussain, et al\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
Hussain, et al\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
Hussain, et al\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
Garg, et al\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
Arya, et al\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
Dushar, et al**\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
Dushar, et al**\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
Ochoa Molina, et al\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Sex\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
F\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
M\textsubscript{A}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
M\textsubscript{B}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
F\textsubscript{c}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
M\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
F\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
M\textsubscript{A}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
M\textsubscript{B}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
M\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Acanthosis nigricans\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{A}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Developmental Delay\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{A}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{B}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Dysmorphic features*\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{B}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{A}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{B}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Hemihypertrophy\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{A}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{C}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{A}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{B}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Hypoinsulinemic hypoglycemia\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{A}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{B}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{C}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{A}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{B}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Hypoglycemic seizures\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{A}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{C}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{A}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{B}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Hypotonia\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{B}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{A}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{B}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Macrosomia\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{A}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{B}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{C}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{A}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{B}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Polyhydramnios in utero\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{B}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
X\textsubscript{B}\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

*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
of\emph{AKT2} mutation were found to be mosaic for the
variant\textsuperscript{7} 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.\textsuperscript{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 \emph{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.\textsuperscript{4,5,7,8}Nevertheless, 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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{7} While this
approach provides glycemic control, previously described limitations
include obesity secondary to excess caloric intake.\textsuperscript{7}

The metabolic and quality of life implications of frequent feeding make
anti-hypoglycemic agents an attractive therapeutic option. Consistent
with previous reports,\textsuperscript{5,7} diazoxide and octreotide
were ineffective in our patient as these agents target upstream insulin
release, as opposed to downstream signaling.\textsuperscript{13} Due to
its action on this pathway, sirolimus was trialed in a sibling pair with
activating \emph{AKT2} mutations. The frequency of hypoglycemic episodes
and carbohydrate need were reduced, however overnight fasting was
extended only up to four hours.\textsuperscript{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.\textsuperscript{16,17} Sirolimus was only
modestly effective in children with congenital hyperinsulinism, further
highlighting the need for novel therapeutic
approaches.\textsuperscript{17}

An enticing option is WMHMS, which is approved for children
\textgreater{}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.\textsuperscript{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
\emph{AKT2}mutation.\textsuperscript{8} However, this result should be
interpreted cautiously as expression of pancreatic amylase is
substantially reduced in infancy, impairing starch
digestion.\textsuperscript{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.

\textbf{Conclusion}

We describe the ninth individual presenting with hypoketotic
hypoglycemic secondary to an activating \emph{AKT2} mutation causing
autonomous activation of the downstream insulin signaling cascade. Our
patient's dysmorphic features, developmental delay, and hemihypertrophy
provide additional evidence of a broad phenotypic spectrum. Due to the
anticipated lifelong duration of treatment, safe and tolerable options
are needed. Our initial success with WMHMS indicates it is a promising
option, although additional research is needed to establish dosing.

\textbf{Author Contributions}

MP reviewed the literature, authored the manuscript, and briefly
participated in the patient's clinical care. DY provides longitudinal
clinical care for the patient and was responsible for conceptualization.
DY contributed to literature and manuscript review, in addition to
editing.

\textbf{Acknowledgements}

The authors would like to thank Drs. Sara Ames, Marisa Chard, Mark
Inman, and Munier Nour for their contributions to an earlier version of
this work.

\textbf{Funding Information}

The authors received no financial support for this case report.

\textbf{Conflict of Interest Statement}

The authors declare no conflicts of interest.

\textbf{Consent}

In accordance with journal policy, written informed consent was obtained
from the patient's parents to publish this report.

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\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

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\end{figure}\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
\end{figure}

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