Avery's Hypo and Hyperglycemia

87
Neonatal Hypoglycemia and

Hyperglycemia
DAVID WERNY, ALYSSA HUANG, JESSICA TENNEY, AND CATHERINE PIHOKER
KEY POINTS Neonatal Hypoglycemia

• Neonatal hypoglycemia requires diagnostic consideration and urgent Fetal to Neonatal Transition and Energy
management to prevent recurrent hypoglycemia and avoid neurologic
injury. Metabolism
• Neonatal metabolism in the first days of life reflects a transition from
the passive glucose consumption of the fetus to the active regulation of
Fetal glucose supply is dependent on maternal plasma levels and
glucose of the neonate. its diffusion across the placenta. There is no evidence for the exis-
• Diagnosing the cause of hypoglycemia requires an evaluation of the tence of fetal gluconeogenesis or a robust ability to adjust rapidly
hormonal and metabolic response to hypoglycemia. to maternal hypoglycemia.1–3 Once the placental link is inter-
• Patients with hyperinsulinemic hypoglycemia should be assessed for rupted, and glucose is no longer delivered continuously via the
diazoxide-responsiveness, and non-responsive patients should have an umbilical vein, the neonate must maintain normoglycemia and
evaluation to determine if the process is due to focal or diffuse disease. adequate cerebral glucose delivery despite minimal and sporadic
• Diabetes diagnosed before 6 months of age is very likely to have a enteral carbohydrate intake during the first 24 to 72 hours of
genetic cause. life. Glucose homeostasis is accomplished in a manner generally
• Patients with neonatal diabetes due to pathogenic variants in the KATP
similar to older children who are fasted: via secretion of the coun-
channel can be treated with oral sulfonylurea in place of insulin therapy.
ter-regulatory hormones—namely cortisol, glucagon, growth hor-
mone, and catecholamines—and their actions at target tissues, in
combination with the suppression of insulin secretion. In concert,
these hormonal changes regulate four different metabolic systems:
Introduction glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis (Fig.
87.1). The result is to facilitate normoglycemia until carbohydrate
Glucose is the primary metabolic fuel for the neonatal brain. intake and absorption occur on a more regular basis.
Maintenance of normal glucose levels in the serum and across In response to decreased delivery of glucose in the first few
the blood-brain barrier is essential for normal neurologic func- hours of life, glucagon and catecholamine levels rapidly increase,
tion and development. Hypoglycemia in the neonate, therefore, and insulin falls. This combination shifts metabolic activity from
requires thoughtful diagnostic evaluation and urgent treatment to anabolism to catabolism and induces enzymes necessary for glyco-
prevent injury to the central nervous system (CNS). The mecha- genolysis (glycogen phosphorylase) and gluconeogenesis (pyruvate
nisms underlying neonatal hypoglycemia are best understood as carboxylase and phosphoenolpyruvate carboxykinase [PEPCK]).3–5
inadequate hormonal and metabolic responses to hypoglycemia, Glycogenolysis plays the largest role in meeting glucose needs dur-
occurring in the context of the necessary shift from fetal to neo- ing the first 24 hours (approximately 50%) and causes a deple-
natal glucose metabolism in the first days of life. These pathways tion of glycogen stores from 50 mg/g of the liver at birth to
and pathologies are the focus of the initial portion of this chapter. <10 mg/g of the liver by 24 hours of life.2 Gluconeogenesis
In the latter portion of this chapter, we focus on hyperglycemia develops somewhat more slowly and is not fully active until 8 to
in neonates. Hyperglycemia most commonly occurs in the context 12 hours of life, providing only 20% to 30% of glucose needs in
of a physiologic stressor such as sepsis with cortisol and catechol- the first 24 hours.4,6
amine release. Intravenous glucose infusion and exogenous glu- Gluconeogenesis and lipolysis contribute to plasma glucose
cocorticoid administration can also cause hyperglycemia. Rarely levels after 8 to 12 hours of life, with their role increasing as gly-
genetic causes of hyperglycemia result in transient neonatal dia- cogen stores are depleted. Lipolysis produces glycerol, which can
betes mellitus (TNDM) or permanent neonatal diabetes mellitus enter the gluconeogenic pathways, and free fatty acids can be oxi-
(PNDM). dized directly by some organs, including the heart, kidney, and
1254
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CHAPTER 87 Neonatal Hypoglycemia and Hyperglycemia 1255
Glycogen
Galactose 6
7
Galactose-1-P UDP-glucose 4 3
9
8
UDP-galactose
Glucose-1-P
5 1
Glucose-6-P Glucose
Fructose Fructose-6-P
2
13 10 11
14
Fructose-1-P Fructose-1,6-DiP
12
Glyceraldehyde 3-P Dihydroxyacetone-P
1, 3-Diphosphoglycerate -Glycero-P Glycerol
Phosphoenolpyruvate
16 15
Alanine Pyruvate Oxaloacetate Triglycerides
Malate Citrate Free fatty acids

Lactate
Acetyl CoA
Fumarate -Ketoglutarate Ketone bodies
Succinate Glutamine
• Fig. 87.1 Key Metabolic Pathways of Intermediary Metabolism. 1, Glucose 6-phosphatase; 2, gluco-
kinase; 3, amylo-1,6-glucosidase; 4, phosphorylase; 5, phosphoglucomutase; 6, glycogen synthetase; 7,
galactokinase; 8, galactose-1-phosphate uridyl transferase; 9, uridine diphosphogalactose-4-epimerase;
10, phosphofructokinase; 11, fructose-1,6-diphosphatase; 12, fructose-1,6-diphosphate aldolase; 13,
fructokinase; 14, fructose-1-phosphate aldolase; 15, phosphoenolpyruvate carboxykinase; 16, pyruvate
carboxylase; UDP, uridine diphosphate. (Modified from Sperling MA, Menon RK. Differential diagnosis and
management of neonatal hypoglycemia. Pediatr Clin North Am. 2004;51:703–723.)
skeletal muscle, but long-chain fatty acids cannot cross the blood- The brain is the most metabolically active organ in the neonate,
brain barrier.7 Importantly, partial oxidation of fatty acids in the and its demand for glucose is proportional to brain weight.13,14
liver via ketogenesis produces ketones such as beta-hydroxybutyr- Glucose uptake and oxidation in the brain occurs via insulin-
ate (BOHB) and acetoacetate, which the brain can metabolize. independent facilitated diffusion through glucose transporter
However, ketogenesis is impaired in the first 8 to 12 hours of life, (GLUT) channels and is dependent on arterial blood glucose con-
coincident with the known transitional hypoglycemia of infancy centration. An in vivo study using rats (which are believed to have
discussed later.8,9 The importance of gluconeogenesis, lipolysis, GLUT channels with similar kinetics to humans) showed that the
and fatty acid metabolism is highlighted in breastfed infants as the consumption of glucose in the brain outpaces its replacement via
macronutrient profile of colostrum favors protein and fatty acids, diffusion at an arterial concentration of 36 mg/dL.15 At this point,
compared to the relative carbohydrate predominance of mature cerebral blood flow increases markedly to prevent severe CNS glu-
human milk.10 cose depletion and neurologic sequelae. The relatively large size
Glucagon continues to rise gradually over the first few days of of the neonatal brain and its high metabolic demand are associ-
life, concurrent with the known, gradual increase and stabilization ated with a two- to threefold higher (per weight) hepatic glucose
of glucose levels that normally occurs in infants by 48 to 72 hours production compared to adults. Conditions that interfere with
of life.11,12 hepatic glucose production, therefore, place the infant at risk for
1256 PA RT XV I I Endocrine Disorders
hypoglycemia, some of which are discussed briefly in this chapter, In those four neonates, three had no clinical signs at the time of
and others are discussed in Chapter 29. the abnormal recorded evoked potentials, and one was reported
In total, the combined counter-regulatory response and insu- to be drowsy. The challenge of defining a true threshold is under-
lin suppression are similar to the starvation response that occurs scored in these four infants, given that one of these was asymp-
in older children with two exceptions: (1) the additional com- tomatic with normally evoked potentials at a whole blood glucose
plication that maternal factors and immaturity of the counter- level of 1.9 mmol/L (34 mg/dL) on day 1 of life, while another
regulatory response can interfere with glucose homeostasis in the infant was symptomatic at 2.5 mmol/L (45 mg/dL).
neonatal period; and (2) the decrease in insulin production and
release of glycogen stores is less robust than in older children. Blood Glucose Monitoring
These latter factors may explain the “transitional hypoglycemia”
seen in normal infants during the first 24 hours of life. While symptomatic, prolonged hypoglycemia in neonates is a risk
factor for cerebral injury and poorer neurodevelopmental out-
comes, the lower limit of normoglycemia in asymptomatic infants
Transitional Neonatal Hypoglycemia has been difficult to elucidate.19,20 This is complicated by the pat-
Plasma glucose values in the first hours of life are frequently lower tern of transitional hypoglycemia mentioned above, during which
than accepted thresholds for normoglycemia in older children, plasma glucose values may drop to levels considered very low for
a phenomenon known as “transitional neonatal hypoglycemia.” older children. Maternal and neonatal conditions with a high risk
Serial measurements of glucose in the first days of life in healthy, for hypoglycemia are well-known, and it is a commonplace for
term appropriate for gestational age (AGA) infants demonstrate newborn nurseries to have screening protocols for these infants
average values in the 50s to low 60s (mg/dL).12,16 If normal is (Box 87.2). Such protocols commonly result in the treatment
defined as within two standard deviations from the mean, the of asymptomatic infants based on point-of-care (POC) glucose
lower limit of normal may be as low as the high 30s to low 40s in values, with the limited evidence available to define the optimal
the first few hours of life.16,17 In support of this, Lubchenco and threshold that minimizes overtreatment while still preventing
Bard showed that if feeding is delayed 3 to 6 hours from birth, neuroglycopenia and neurologic damage.
approximately 10% of healthy, term AGA infants will have glu- Multiple definitions of the ideal asymptomatic treatment
cose <30 mg/dL.12 threshold with regard to long-term neurologic outcomes have
A recent review of the data available on transitional hypo- been proposed: 47 mg/dL,21 45 mg/dL,22 40 mg/dL,23 and 30 mg/
glycemia shows that it is characterized by relative hyperinsulin- dL.24 It is unlikely that a single threshold exists, as the point at
ism as indicated by hypoketosis and preserved glycogen release
in response to glucagon.8,9 An additional factor may be the time
required for the enzymatic machinery of gluconeogenesis and gly- • BOX 87.1 Signs of Neonatal Hypoglycemia
cogenolysis to become active in response to the rise in glucagon
and catecholamine secretion after birth. Autonomic Neuroglycopenic
It is unknown whether the decline in glucose values or the rela- Sweating Hypotonia
tive hyperinsulinism seen with transitional hypoglycemia serves Pallor Lethargy
Tachycardia Coma
an adaptive function. The important diagnostic distinction is that
Tachypnea Seizure
this phase of hypoglycemia is transient. Just 2 of the 374 infants Tremor Weak suck
(0.5%) in the Lubchenco and Bard cohort had glucose <50 mg/dL “Jittery” Abnormal cry (weak, high pitched)
prior to feeding on day 3 or 4 of life.
Signs and Symptoms of Hypoglycemia

• BOX 87.2 aternal and Neonatal Conditions
M
Neonates with hypoglycemia may have no detectable symptoms That Increase the Risk of Neonatal
and may only be identified incidentally upon measurement of Hypoglycemia
blood glucose levels or in the monitoring of a high-risk infant.
When symptoms occur, they may be seen in a progression due to Maternal Conditions
initial counterregulatory hormone responses (such as adrenergic Diabetes (gestational or pre-gestational)
hormones as well as cortisol and growth hormone), which result Administration of drugs (β sympathomimetics [e.g., terbutaline, oral
in symptoms due primarily to the autonomic system (autonomic, hypoglycemic agents])
or “neurogenic” symptoms and signs). When deficient glucose Intrapartum dextrose infusion
Hypertension/preeclampsia
supply to the brain occurs, neurological dysfunction is detect-
able and may be considered the symptoms of “neuroglycopenia” Neonatal Conditions
(Box 87.1). However, these may be subtle and difficult to recog- Prematurity
nize clinically and may also be accompanied by other nonspecific Intrauterine growth restriction
symptoms such as apnea, cyanosis, temperature instability (espe- Hypoxia-ischemia
cially hypothermia), and bradycardia. Large/small for gestational age
It is difficult to define a consistent threshold in the neonate Sepsis
below which hypoglycemia produces the above symptoms, espe- Hypothermia
cially neuroglycopenia. One often-quoted study of 17 children Polycythemia
showed changes in auditory evoked potentials below a whole Presence of syndromic features (microphallus, midline defects, Beckwith-
Wiedemann syndrome)
blood glucose concentration of 47 mg/dL (2.6 mmol/L) but only
included four neonates with hypoglycemia (aged 1 to 3 days).18
which neurologic injury occurs is likely patient and situation- • BOX 87.3 omponents of Critical Sample and
C
dependent and related to the availability of ketones and other sub- Diagnostic Criteria for Hyperinsulinism
strates to the brain.
Based on Critical Sample at Time of
Recently, a prospective investigation into an appropriate glu-
cose treatment threshold for infants was performed with a cohort Hypoglycemia
of 404 infants of gestational age at least 35 weeks who were at Critical Sample Diagnostic Criteria for Hyperinsulinism
risk for hypoglycemia (infant of mother with diabetes, birth • Serum glucose • Insulin >2 uIU/mL)
<37 weeks gestational age, and birth weight <10th or >90th • Basic metabolic panel • β-hydroxybutyrate of <1.8 mmol/L
percentile).25 Infants also wore blinded continuous glucose moni- and venous blood gas • FFA <1.7 mmol/L
toring (CGM) systems to allow the investigators to evaluate for • Insulin • Glucagon stimulation test rise of
outcomes related to subclinical hypoglycemia missed on the inter- • C-peptide ≥30 mg/dL
mittent POC checks. Infants were treated to maintain a blood • Growth hormone • IGF-BP1 ≤110 ng/mL
glucose concentration of at least 47 mg/dL for at least the first • Cortisol
48 hours of life. Neurodevelopmental outcomes were then assessed • Free fatty acid
• Beta-hydroxybutyrate
at 2 years of age using the Bayley Scales of Infant Development
• Lactate
III and tests of executive and visual function. The authors found • IGFBP-1
no association between hypoglycemic episodes and neurosensory • Ammonia*
impairment and concluded that neonatal hypoglycemia was not • Acyl carnitine profile*
associated with the adverse neurologic outcomes when treatment • Serum amino acids*
was aimed at maintaining a blood concentration of 47 mg/dL in • Pyruvate*
these high-risk infants. A follow-up study with the same cohort • Urine organic acid*
of patients aimed to assess higher cognitive function at age 4.5 *
Not necessary to collect at time of hypoglycemia.
years. While once again, no neurosensory impairment was seen on
follow-up testing, an increased risk of poor executive and visual
motor performance was seen. Additionally, the risk was highest in
those with severe or recurrent hypoglycemia.26 reach the lab quickly because glucose in the plasma sample is lost
Recent Pediatric Endocrine Society (PES) guidelines make through glycolysis at a rate of 5% to 7%/h.29 Higher rates of loss
glucose threshold recommendations for infants that are at risk can occur with increased ambient temperature and in blood sam-
for hypoglycemia and without a known risk for permanent ples with high white blood cell counts.
hypoglycemic disorders such as hyperinsulinism, hypopituita-
rism, or an inborn error of metabolism. According to the PES, Normoinsulinemic Hypoglycemia
such infants should have a treatment threshold of 50 mg/dL in
the first 48 hours. Based on evidence that suggests average glu- Insulin’s role in maintaining normoglycemia is paramount.
cose values in normal infants older than 48 hours of age are no Insulin simultaneously lowers serum glucose concentration via
different than those of older children, the authors suggest that glucose uptake through insulin-sensitive glucose transporters and
these infants should demonstrate an ability to maintain glucose represses the effects of counterregulatory hormones, whose pri-
>60 mg/dL during a 6 to 8 hours fast prior to discharge.27 The mary function during hypoglycemia is to increase serum glucose
PES guidelines are designed to have high sensitivity to detect values. It is therefore relevant to divide a discussion of the causes
infants with a pathologic cause of persistent hypoglycemia and to of hypoglycemia into those that are associated with appropriate
detect these infants before they are discharged from the hospital. suppression of insulin during hypoglycemia (normoinsulinemic
The American Academy of Pediatrics (AAP) issued guidelines in hypoglycemia) and those that have inappropriate, elevated insulin
2011 with a focus on the first 24 hours of life, acknowledging that levels at the time of hypoglycemia (hyperinsulinemic hypoglyce-
transitional glucose levels in the first few hours of life can be as low mia) (Box 87.4).
as 30 mg/dL.28 The AAP guidelines recommend a target prefeed
glucose of 40 mg/dL in the first 4 hours of life and 45 mg/dL from
4 to 24 hours of life. The differences between the two guidelines Hypoglycemia in Premature and Small for
reflect the uncertainty regarding the significance of asymptomatic Gestational Age Infants
glucose levels <50 mg/dL in the first 48 hours of life, as well as the
different weighting of the risks and benefits of continued screen- Infants born premature or small for gestational age (SGA) are at
ing and longer hospital stays in the context of the clinical reality high risk for transient hypoglycemia due to immaturity of the
that most term infants in the United States are discharged home metabolic pathways described above, exacerbated by inadequate
between 24 and 48 hours of life. stores of glycogen and triglycerides. The doubling of average fetal
For diagnostic workup of hypoglycemia after 48 hours of age, weight from 1700 g at 32 weeks to 3400 g at birth is largely due to
we recommend a glucose threshold of 50 mg/dL for collection of the accrual of hepatic glycogen and adipose tissue fat stores, which
a “critical sample” to assess for the counterregulatory hormone then serve as an important reserve of substrates for energy metab-
response, insulin level, acidosis, and the presence of important olism in the first days of life. Hypoglycemia can also be caused
metabolic substrates such as BOHB, lactate, serum amino acids, by delayed maturation of enzymes necessary for gluconeogenesis.
and free fatty acids (Box 87.3). Most importantly, a plasma glu- Premature infants can have markedly reduced glucose-6-phospha-
cose level should be obtained simultaneously to allow for accurate tase activity relative to term infants that may persist for months
interpretation of the critical sample, as the POC test result may after birth.30 There is also a lack of glucose rise after administration
be artificially low. It’s important that the plasma glucose sample of gluconeogenic precursors, which suggests the impaired activity
• BOX 87.4 Causes of Neonatal Hypoglycemia the underlying cause of hypopituitarism, which may range from
severe midline malformations such as alobar holoprosencephaly
Hyperinsulinemic to more subtle abnormalities such as an isolated ectopic posterior
Transient: pituitary bright spot or a hypoplastic pituitary gland.
Infants of diabetic mothers Biochemical evaluation of hypopituitarism requires careful
Intrapartum dextrose infusion to mother consideration in the first months to a year of life. Conventional
Stress in peripartum/postnatal period: trauma, asphyxia, hypothermia stimulation tests used to diagnose GH deficiency in older children
Small for gestational age infants
have been used in infants, but normal responses are not well estab-
Permanent:
KATP channel defects
lished. The stimulation test believed to be safest for use in infants
Glutamate dehydrogenase (GLUD1)-activating mutation is the glucagon stimulation test, which causes a rapid rise, then
Short-chain 3-hydroxyacyl-coenzyme A dehydrogenase (HADH or rapid fall in glucose, placing the infant at risk for hypoglycemia.
SCHAD) mutation Therefore, this testing should only be done under close monitor-
Glucokinase (GCK) activating mutation ing, preferably in an ICU setting.32 As an alternative, taking into
HNF1A and HNF4A pathogenic variants account normal physiological processes in the perinatal period,
Uncoupling protein-2 (UCP2) pathogenic variants there is evidence that a single random GH measurement in the
Hexokinase-1 (HK1) pathogenic variants first week of life can adequately diagnose GH deficiency.33 Using a
Beckwith-Wiedemann syndrome (BWS) post-hoc defined threshold of 7 mcg/L, Binder et al. demonstrated
Postfundoplication (dumping syndrome)
a sensitivity and specificity of 100% and 98%, respectively, for the
Hyperinsulinism in congenital disorders of glycosylation
β-cell adenoma—MEN1
diagnosis of GH deficiency in the first week of life using a single
random GH measurement.33
Normoinsulinemic Similarly, optimal testing to diagnose adrenal insufficiency in
Transient: the neonatal period is a matter of debate. Glucagon stimulation
Developmental immaturity in adaptation to fasting: prematurity, SGA testing can be used to simultaneously assess for GH and ACTH
Increased metabolic expenditure: sepsis, erythroblastosis fetalis, deficiency but carries the risk of hypoglycemia mentioned above.
polycythemia The conventional ACTH stimulation test using Cortrosyn has
Maternal conditions: toxemia, administration of tocolytics (β been used in infants. However, the appropriate dose of 125 mcg,
sympathomimetics) 1 mcg, or 15 mcg/kg has not been well established, and endocri-
Permanent:
nologist preference varies. Importantly, infants with ACTH defi-
Hypopituitarism
Primary adrenal insufficiency
ciency will not develop classical salt-wasting with hyponatremia
Inborn errors of metabolism and hypokalemia due to intact aldosterone production and secre-
Glycogen storage disease tion, which is regulated not by the pituitary but by the renin-
Disorders of gluconeogenesis angiotensin system. Hyponatremia may occur but is less severe
Defects in fatty acid catabolism and ketogenesis relative to primary adrenal insufficiency and is likely due to
Organic acidurias reduced free water clearance, for which both cortisol and thyroid
Galactosemia hormone play a role.
Hereditary fructose intolerance An important consideration in patients with hypopituitarism is
that thyroid hormone should not be replaced until adrenal insuf-
ficiency has been either treated or ruled out, as thyroid hormone
replacement can precipitate an adrenal crisis if done in the context
of the enzymes of gluconeogenesis.31 For these reasons, SGA and of untreated adrenal insufficiency.
premature infants should be screened for asymptomatic hypogly-
cemia and supported with IV dextrose or nasogastric feeding until
their hypoglycemia resolves. It is important to note that hypogly- Isolated Adrenocorticotropic Hormone
cemia in these infants may be multifactorial, as hyperinsulinism Deficiency
may be a contributing factor as well (discussed later).
Isolated ACTH deficiency is very rare and is associated with patho-
genic variants in the genes responsible for the production and/or
Counterregulatory Hormone Deficiency modification of the proopiomelanocortin (POMC) precursor poly-
peptide. The TBX19 gene regulates transcription of the POMC/
Hypopituitarism ACTH gene in corticotrophs, and deficiency has been associated
Deficiencies of cortisol, growth hormone (GH), or their com- with adrenal insufficiency in infants.32 A low estriol level on the
bined deficiency in the neonatal period can cause hypoglyce- prenatal triple-marker screen may be a predictor of TBX19 patho-
mia. Often these two deficiencies occur together in the context genic variant and ACTH deficiency in general.33 Allelic pathogenic
of hypopituitarism with adrenocorticotropic hormone (ACTH) variants of the POMC gene itself affect all POMC peptides, includ-
hormone and GH deficiency. Infants with congenital hypopitu- ing α-melanocyte-stimulating hormone (α-MSH), resulting in red
itarism often have other signs of midline malformations such as hair and fair skin, in addition to ACTH deficiency, with severe
a midline cleft palate, nystagmus (observed in optic-nerve hypo- obesity developing within the first few months of life.34 Pathogenic
plasia; of note, however, is that nystagmus is usually not apparent variants in prohormone convertase 1/3 (PCSK1) result in impaired
until age 6 weeks, so it is not a distinguishing sign in the neonatal cleavage of ACTH from POMC, as well as several gut hormones.
period), seizures (holoprosencephaly), direct hyperbilirubinemia Deficiency results in severe congenital diarrhea and failure to thrive,
(thyroid hormone deficiency), or micropenis and undescended and a high risk of ACTH deficiency as well as panhypopituitarism,
testes in a male (gonadotropin deficiency). Brain MRI may reveal including central diabetes insipidus.35
Primary Adrenal Insufficiency hypogonadism, manifesting as delayed pubertal development

without elevation of gonadotropins. However, DAX-1 appears
Congenital Adrenal Hyperplasia to have a direct role in gonadal development, as there is also a
Cortisol deficiency in infants is most commonly due to pathol- component of primary hypogonadism.39,40 Further implicating its
ogy of the adrenal gland (primary adrenal insufficiency) caused role in gonadal development is the finding that DAX1 is the likely
by congenital adrenal hyperplasia (CAH). The most common critical gene for a duplication within Xp21 that causes sex-reversal
form of CAH, 21-hydroxylase deficiency (incidence 1/10,000 to with female external genitalia and variable presence of Mullerian
1/15,000 annually), results in ambiguous, virilized genitalia in an structures in 46 XY individuals.41–43 AHC is also seen as a part of
XX infant driven by overproduction of adrenal androgens synthe- Xp21 contiguous gene deletion syndrome, which occurs due to
sized from precursors upstream of the enzyme block. However, in the deletion of DAX1 and nearby genes encoding glycerol kinase
an XY infant, the presentation of CAH due to 21-hydroxylase is (GK) and dystrophin (DMD). Affected patients have severe devel-
more subtle and may present only with hyperpigmentation of the opmental delay and develop Duchenne’s muscular dystrophy in
skin, particularly of the scrotum. The classic presentation of hypo- addition to the primary adrenal insufficiency secondary to AHC.
natremia, hyperkalemia and severe dehydration due to the cortisol
and aldosterone deficiency of primary adrenal insufficiency often IMAGe Syndrome
do not develop until 7 to 10 days of life, so their absence in a IMAGe syndrome (intrauterine growth restriction, metaphyseal
newborn with hypoglycemia does not rule out CAH. Newborn dysplasia, congenital adrenal hypoplasia, and genital anomalies)
screening for the 21-hydroxylase deficiency form of CAH is now was first described in 1999 in 3 boys who presented with severe
widespread in the U.S., and thus a diagnosis is often suspected adrenal insufficiency shortly after birth.44 The affected infants also
early due to elevated 17-hydroxyprogesterone (17-OHP) levels had skeletal abnormalities, micropenis, and hypogonadotropic
on newborn bloodspot samples. Where hypoglycemia occurs in hypogonadism. Linkage analysis and sequencing in a 5-genera-
an infant, especially with any of the features mentioned above tion family identified a likely causative variant in the gene encod-
of salt wasting or ambiguous genitalia, confirmation of a normal ing cyclin-dependent kinase inhibitor 1 C (CDKN1C) located
17OHP should be sought. Treatment is with hydrocortisone and on chromosome 11p15 within an imprinted cluster of genes.45
fludrocortisone for glucocorticoid and mineralocorticoid replace- Affected patients in the pedigree had maternally transmitted
ment, respectively, along with sodium chloride supplementation pathogenic variants, suggesting that imprinting silences the pater-
due to the low salt content of breastmilk and most formulas. nal allele of CDKN1C. CDKN1C is believed to have a role in
More rare forms of CAH include 11-beta hydroxylase defi- inhibiting cell cycle progression, and gain-of-function variants
ciency (1/100,000 or 1/5000 in Jews of Moroccan ancestry),34 in CDKN1C are established as causative of IMAGe syndrome.
and the very rare 3-beta hydroxysteroid dehydrogenase (HSD) Interestingly, pathogenic variants in CDKN1C have also been
deficiency. Similar to 21-hydroxylase pathogenic variants, 46 XX associated with Beckwith-Wiedemann Syndrome (BWS) as well
infants with 11-beta hydroxylase deficiency resulting in hypogly- as Russel-Silver syndrome, demonstrating the importance of this
cemia will have ambiguous genitalia. They may also have hyper- gene in regulating growth.46
tension due to excessive production of deoxycorticosterone, a
potent mineralocorticoid located upstream of the 11-beta hydrox- Adrenocorticotropic Hormone Resistance
ylase enzyme block. 3-beta HSD deficiency results in undervir- Resistance to ACTH at the level of the adrenal gland causes a rare
ilized male genitalia due to deficient testosterone synthesis but form of primary adrenal insufficiency with retained aldosterone
may be associated with virilized female genitalia due to elevated secretion. ACTH is elevated, and cortisol is low. Hyperpigmentation
DHEA levels. Lipoid CAH is associated with pathogenic variants due to excessive production of α-MSH and stimulation of the mela-
in the STAR gene, which result in loss of function in the steroido- nocortin 1 receptor can be present at birth or develop over time.
genic acute regulatory protein (StAR), which impairs the transfer Almost 50% of cases are due to autosomal recessively inherited
of cholesterol into the mitochondria.35 This disrupts the neces- pathogenic variants in the melanocortin 2 receptor (MC2R, or
sary first step of steroid synthesis, the conversion of cholesterol ACTH receptor) and melanocortin 2 receptor accessory protein
to pregnenolone. These patients have cortisol deficiency, almost (MRAP) genes.37 Autosomal recessive pathogenic variants in nico-
always have aldosterone deficiency, and XY infants can have phe- tinamide nucleotide transhydrogenase (NNT) caused ACTH resis-
notypically female external genitalia due to impaired androgen tance in three consanguineous families, presumably due to increased
synthesis.36,37 oxidative stress in the adrenal zona fasiculata.37
X-linked Adrenal Hypoplasia Congenita Adrenal Hemorrhage
DAX-1 (dosage-sensitive sex reversal adrenal hypoplasia congeni- Adrenal hemorrhage is a rare occurrence in neonates and rarely
tal region of the X-chromosome; also known as NROB1) is a tran- results in adrenal insufficiency even when it is confirmed radio-
scription factor located on the short arm of the X-chromosome graphically, likely because adrenal hemorrhage occurs bilater-
(Xp21). It is expressed in adrenal, hypothalamic, pituitary, and ally in only 5% to 10% of cases.47 Maternal diabetes, high birth
hypothalamic tissues, but its gene targets are largely unknown.38 weight, fetal acidemia, and birth asphyxia are associated with
Pathogenic variants in DAX-1 result in underdevelopment or higher rates of adrenal hemorrhage. Additionally, neonatal adre-
agenesis of the adrenal gland with the potential to cause severe nal glands are larger than adult adrenal glands, increasing the risk
adrenal insufficiency in infancy, otherwise known as adrenal hypo- of hemorrhage.48
plasia congenita (AHC). Males are classically present in the first
weeks of life with vomiting, severe dehydration leading to vascular Inborn Errors of Metabolism
collapse, and often with hyperpigmentation. Some patients are
more mildly affected and present later in childhood with milder The neonatal inborn errors of metabolism are covered extensively
adrenal insufficiency. Patients later develop hypogonadotropic in Chapter 29, and the key pathways of metabolism are outlined
in Fig. 87.1. Hypoglycemia resulting from these conditions often further organ injury can be prevented by avoidance of dietary
requires fasting for at least 4 to 6 hours, and therefore they are less fructose and high-fructose corn syrup.
likely to present with hypoglycemia in infancy. However, a few
conditions can impact early fasting adaptation and, therefore, can Hyperinsulinemic Hypoglycemia
present with hypoglycemia in the neonatal period.
The next section will focus on infants with hypoglycemia due to
Glycogen Storage Diseases excessive insulin production. Hyperinsulinism may be caused by
Many glycogen storage diseases (GSDs) become clinically appar- transient or permanent disorders of insulin secretion, and single-
ent later in childhood. However, GSD type 1 can present in neo- gene defects predominate in the permanent forms of hyperinsu-
nates as it is associated with hypoglycemia after fasting for just 2 linism (Table 87.1). A key management distinction among infants
to 2.5 hours. GSD 1 results from impaired function of glucose- with hyperinsulinism is whether they can be managed with diazox-
6-phosphatase, the enzyme responsible for the final step of glyco- ide and, if not, whether they have a focal or diffuse abnormality
genolysis and gluconeogenesis in which glucose is produced from of pancreatic insulin regulation. Prior to discussing the causes and
glucose-6-phosphate (see Fig. 87.1). Patients have hepatomegaly management of hyperinsulinism, it is important to consider the
due to accumulation of fat, and untreated infants typically pres- physiology of insulin secretion from the pancreatic β-cell.
ent with elevated serum lactate, lipids, triglycerides, and uric acid.
Administering glucagon 2 to 4 hours after a carbohydrate meal is Mechanism of Insulin Secretion
helpful diagnostically as it causes a rise in lactate but no rise in
glucose. Treatment is with frequent feeding as well as more slowly Depolarization of the pancreatic β-cell leads to insulin secretion,
absorbed carbohydrates, such as uncooked cornstarch, to help and the most important regulator of membrane polarization in the
prolong fasting tolerance. pancreatic beta cell is the ATP-sensitive potassium channel (KATP
channel) (Fig. 87.2). The KATP channel is an octameric complex
Defects of Fatty Acid Catabolism and Ketogenesis of two different subunits: (1) four inward-rectifying potassium
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is channel subunits (Kir6.2 encoded by the KCNJ11 gene), and (2)
the most common disorder of fatty acid oxidation (1/17,000). four regulatory sulfonylurea receptor subunits that surround the
Newborn screening for MCAD deficiency is widespread, and channel and help regulate the open or closed conformation of the
infants are often detected based on screening. Defects arise from channel (SUR1 encoded by the ABCC8 gene). The channel is sen-
autosomal recessively inherited pathogenic variants in the ACADM sitive to the metabolic and energy state of the cell, as manifested
gene, and MCAD is responsible for the initial dehydrogenation of by the ATP/ADP ratio in the cellular cytoplasm. Glucose enters
acyl-CoAs with a chain length between 4 and 12 carbon atoms. the beta cell via an insulin-independent glucose channel (GLUT2
Patients with MCAD present with metabolic decompensation encoded by the SLCA2A gene). If glucose concentration is suf-
after periods of fasting or with illness, and acylcarnitine profile can ficiently high, it is phosphorylated by galactokinase to glucose-
show elevations in chain lengths of C6 to C10, with elevations of 6-phosphate, the first step of glycolysis and, therefore, the entry
C8 (octanoylcarnitine) being the most prominent. Hypoglycemia point for glucose in the metabolic pathways that produce ATP
is often a late finding, but lethargy, coma, and severe neurologic (see Fig. 87.1). The increased ATP/ADP ratio causes closure of the
injury can occur due to the additional lack of ketone bodies avail- KATP channel, resulting in membrane depolarization. In response
able to the brain. Children typically present between the ages of to depolarization, voltage-gated calcium channels open, and the
3 months and 3 years (average 18 months), but the presentation increase in intracellular calcium causes the fusion of the insulin-
can occur in the first few weeks of life.49 Uric acid, ammonia, and containing vesicles with the cellular membrane and subsequent
liver function tests are often abnormally elevated as well in the release of insulin extracellularly.
context of hepatic steatosis. The essential role that the KATP channel plays in regulating insu-
lin secretion is evidenced by the large number of pathogenic vari-
Galactosemia ants in either KCNJ11 and ABCC8 that cause either congenital
Galactosemia occurs due to pathogenic variants in one of three hyperinsulinism (decreasing channel presence in the membrane or
genes necessary to metabolize galactose to glucose: galactose favoring the closed conformation) or neonatal diabetes (favoring
1-phosphate uridyl transferase (GALT), galactokinase (GALK), the open channel conformation), both of which are discussed later
and uridine diphosphate (UDP) galactose 4-epimerase (GALE). in this chapter.
Hypoglycemia can be a clinical presentation of galactosemia, often
associated with other classic features such as hepatomegaly, jaun-
dice, failure to thrive, cataracts, and Escherichia coli sepsis.50,51
Diagnosis of Hyperinsulinism
Estimates of the incidence of congenital hyperinsulinism vary
Hereditary Fructose Intolerance widely depending on the study population but may be as high
Hereditary fructose intolerance (HFI) is due to pathogenic vari- as 1 in 2500 in regions with high rates of consanguinity.54 While
ants in the gene for aldolase B (ALDOB), responsible for metabo- hyperinsulinism is a common cause of neonatal hypoglycemia;
lizing fructose-1-phosphate into substrates for gluconeogenesis. the clinical features may be difficult to recognize and even missed
Vomiting, abdominal pain, acidosis, and hypoglycemia result after until detection in later life or adulthood. However, infants with
fructose or sucrose ingestion begins in infancy.52 The accumulation hyperinsulinism may have recognizable features of fetal hyperin-
of fructose-1-phosphate leads to liver and kidney dysfunction, the sulinemia, such as overgrowth and hypertrophic cardiomyopathy.
extent of which is proportional to the degree of fructose consump- The hypoglycemia is usually present early but can be initially dif-
tion. Hypoglycemia at least partially results from impaired gluco- ficult to distinguish from the transient neonatal hypoglycemia
neogenesis and glycogenolysis in the liver, resulting in impaired seen in the first few hours of life. Alternatively, hypoglycemia may
response to glucagon.53 Acute treatment is with IV dextrose, and be immediately apparent as more severe and recalcitrant to early
TABLE
87.1 Genetic Causes of Hyperinsulinemic Hypoglycemia
Inheritance Molecular Defect Chromosome Histology Clinical Features Treatment

Sporadic Paternally inherited ABCC8/ 11p15 Focal Macrosomia, moderate to severe Poor response to diazoxide, local
KCNJ11 mutation with somatic hypoglycemia in first few days to resection for focal and near-total
loss of heterozygosity weeks of life pancreatectomy for diffuse form
AR ABCC8/KCNJ11 (inactivating) 11p15 Diffuse Macrosomia, onset in first few days Near-total pancreatectomy
to weeks of life, family history or
consanguinity may be present
AD ABCC8/KCNJ11 (dominant- 11p15 Diffuse Milder symptoms, may manifest in Usually responsive to
negative, inactivating) late infancy diazoxide (Pinney, 2008)
AD GLUD1 (activating) 10q23 Diffuse Modest hyperinsulinemia and Diazoxide, restriction of
hyperammonemia, onset usually leucine in diet
>6 months
AD GCK (activating) 7p13 Diffuse Modest hyperinsulinemia, onset May respond to diazoxide
usually >6 months
AR HADH 4q25 Diffuse Variable clinical presentation, Diazoxide
abnormal acylcarnitine profile
AD HNF4α or HNF1α 20q13 and Diffuse Possible Fanconi tubulopathy; may Diazoxide
12q24 have family history of MODY
AD UCP-2 11q13 Diffuse Diazoxide
AD HK1 10q22 Diffuse Variable severity and penetrance Diazoxide
AR PGM1 1q31 Congenital disorder of Galactose supplementation may
glycosylation; bifid uvula, benefit
hepatopathy, hypogonadotropic
hypogonadism, poor growth,
myopathy, dilated cardiomyopathy81
feeding. Confirming the diagnosis requires an index of suspicion than in hypoglycemia due to hyperinsulinism. While previous
on the part of the clinician, and a search for historical and physical data suggested an FFA cutoff of 0.5 mmol/L, recent data suggest
examination findings such as macrosomia and, potentially, signs that this cutoff misses many with true hyperinsulinism and that an
suggestive of an underlying syndrome known to be associated FFA cutoff of <1.7 mmol/L provides sensitivity to >85%. Other
with hyperinsulinism such as Beckwith-Wiedemann syndrome, biochemical data that are consistent with hyperinsulinism but
Kabuki syndrome, or Turner syndrome. In a state of excess glu- may not yield results in as timely a manner as is ideal for rapid
cose consumption, the normal physiologic rates of glucose supply clinical confirmation, include C-peptide levels ≥0.5 ng/mL and
are insufficient to maintain euglycemia, and thus a supraphysi- IGF-BP1 (an insulin-like growth factor binding protein that is
ologic glucose infusion rate (especially if >10 mg/kg/min) in the suppressed by insulin) levels ≤110 ng/mL.
hypoglycemic infant strongly suggests hyperinsulinism. Where Biochemical findings may be challenging to coordinate and
hypoglycemia is recognized and confirmed, the confirmatory collect in the setting of acute hypoglycemia. Therefore, a diag-
diagnosis of hyperinsulinism hinges on the critical detection of nostic challenge using a provocative fast performed under con-
inappropriate hyperinsulinemia, including measurable insulin, trolled conditions may be required.57 This should include the
and the metabolic markers of persistent insulin effect, including frequent sampling of plasma glucose, insulin, β-hydroxybutyrate,
suppressed free fatty acid (FFA) mobilization, hypoketosis (low and FFAs. At a point where the glucose falls below 2.8 mmol/L
beta-hydroxybutyrate, or BOHB) and an exaggerated glycemic (50 mg/dL), the test can conclude with a glucagon challenge to
response to glucagon (see Box 87.4).54,55 see the glycemic response to an IV or IM dose of glucagon (1 mg),
A 2016 retrospective review of infants with hypoglycemia followed by a collection of glucose levels every 10 minutes for
showed that some children with hyperinsulinism do not have 40 minutes. A rise of ≥30 mg/dL in plasma glucose is considered
detectable insulin at the time of hypoglycemia; of 28 subjects consistent with hyperinsulinism. This test has high specificity, and
with congenital hyperinsulinism, only 23 had detectable insulin while some patients with subsequently confirmed hyperinsulin-
(median value 6.7 uIU/mL). However, in those where ketosis was ism in the abovementioned study did not achieve a rise in glu-
measured, none had β-hydroxybutyrate levels >1.8 mmol/L.56 cose ≥30 mg/dL, its sensitivity is greater than relying solely on
Importantly, bedside β-hydroxybutyrate levels show a good corre- the detection of serum insulin levels at the time of hypoglyce-
lation with laboratory values, suggesting clinical utility in making mia. While the subsequent detection of urine ketones may pro-
a rapid diagnosis of hyperinsulinism. Similarly, infants without vide adjunctive data, ketonuria does not exclude hyperinsulinism,
hyperinsulinism have FFA levels on average three times higher and accurate diagnostic results are more likely to be achieved in a
• Fig. 87.2 Mechanisms of Insulin Secretion by the β-Cell of Pancreas. Glucose transported into the
β cell by the insulin-dependent glucose transporter, GLUT 2, undergoes phosphorylation by glucokinase
and subsequent metabolism, resulting in an increase in the intracellular ATP:ADP ratio. The increase in
the ATP:ADP ratio closes the KATP channel and initiates the cascade of events characterized by increase
in intracellular potassium concentration, membrane depolarization, calcium influx, and release of insulin
from storage granules. Leucine stimulates insulin secretion by allosterically activating glutamate dehy-
drogenase (GDH) and by increasing the oxidation of glutamate, thereby increasing the ATP:ADP ratio
and closure of the KATP channel. Pathogenic variants in the HADH gene, which codes for the mitochon-
drial enzyme L-3-hydroxyacyl-coenzyme A dehydrogenase that catalyzes the penultimate step in the fatty
acid β-oxidation pathway, are also associated with CHI. Pathogenic variants in HNF4α cause multiple
defects in glucose-stimulated insulin secretion. ×, inhibition; √, and stimulation. (Modified from Sperling
MA, Menon RK. Differential diagnosis and management of neonatal hypoglycemia, Pediatr Clin North Am.
2004;51:703–723.)
timely fashion at the bedside by blood sampling.58 These authors successfully be weaned off high delivered substrate support judi-
thus do not recommend routine reliance on urinary ketosis as a ciously over the first week or two of life.
replacement for the above protocol.
Perinatal Stress and Transient Hyperinsulinism
Hypoglycemia in Infants of Diabetic Mothers
While the well-described transitional hypoglycemia in normal
Transient hyperinsulinemic hypoglycemia is often associated with newborns typically resolves within the first hours to the first day
pregnancies affected by diabetes, including both gestational dia- of life, in stressed infants, a persistent form of hypoglycemia may
betes as well as permanent maternal diabetes. Infants are typically be seen.61 The mechanism, similar to transitional hypoglycemia in
macrosomic; despite high energy stores in the form of glycogen healthy newborns, appears to be related to persistent hyperinsulin-
and fat reserves secondary to fetal hyperinsulinemia, hypogly- ism, as ketogenesis and lipolysis remain suppressed. While some-
cemia may persist for several days after disconnection from the what unclear, it has been postulated that a lower glucose threshold
high maternal glucose supply. Hypoglycemia in infants of diabetic for insulin secretion persists, given that insulin is a key fetal growth
mothers typically resolves within the first days to the week of life. factor, and thus, its persistent secretion may confer a protective
Studies show that the severity of neonatal hypoglycemia in this effect on the small or stressed neonate.54 This may be seen in the
setting is impacted by late pregnancy maternal glycemia, with context of perinatal asphyxia, pre-eclampsia, or SGA and may
avoidance of maternal hyperglycemia reducing the severity of fetal require interventions with early frequent feeding, medical therapy
hyperinsulinemic hypoglycemia.59,60 Neonates may require high (including diazoxide directed at the hyperinsulinemia), or con-
rates of dextrose administration and/or frequent feedings, similar tinuous feeds to avoid the complications of hypoglycemia.27,62,63
to patients with permanent congenital hyperinsulinism, but may For SGA infants with hyperinsulinemic hypoglycemia, diazoxide
treatment is often required for as long as 6 months and has been

reported to last as long as 22 months.64 L-3-Hydroxyacyl-Coenzyme A Dehydrogenase Gene
Pathogenic Variants
L-3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD; encoded
Genetic Causes of Hyperinsulinemic by the HADH gene) is a mitochondrial enzyme responsible for
Hypoglycemia the β-oxidation of fatty acids. Patients with autosomal recessive
pathogenic variants can have a presentation similar to those with
Pathogenic Variants in the KATP Channel Genes KCNJ11 hyperinsulinemia-hyperammonemia syndrome.71 This is due to
and ABCC8 HADH’s additional role as a direct inhibitor of GDH activity
Pathogenic variants in the KCNJ11 and ABCC8 genes located via protein-protein interaction.72 These patients share the same
on chromosome 11p15.1 are the most common cause of per- hypoglycemic sensitivity to protein-loading as patients with
manent hyperinsulinism, accounting for about 40% to 50% of hyperinsulinemia-hyperammonemia; however, they do not have
cases in neonates, the majority of which affect ABCC8.65,66 Most hyperammonemia and do not have an increased risk for a seizure
commonly, this is due to pathogenic variants that prevent chan- disorder. Affected patients can be identified by the presence of
nel formation, trafficking to the cell membrane, or insensitivity to elevated serum 3-hydroxybutyryl-carnitine and elevated urine
the cellular ATP/ADP ratio. In the absence of a functional KATP, 3-hydroxyglutaric acid.73
channel the β-cell is permanently depolarized, leading to insulin
secretion. Because diazoxide activity requires a functional channel Glucokinase Pathogenic Variants
present in the cell membrane, patients with KCNJ11 or ABCC8 Glucokinase (GCK) catalyzes the reaction of glucose to glucose-
pathogenic variants typically do not respond to diazoxide therapy. 6-phosphate and serves as the “glucose sensor” of the pancreatic
However, some autosomal dominant mutations in KCNJ11 and beta cell. Dominant, activating pathogenic variants lower the
ABCC8 are responsive to diazoxide.67 glucose threshold for insulin secretion, causing hypoglycemia.
The mechanism of inheritance of the pathogenic variant affect- Activating GCK pathogenic variants are usually de novo and not
ing KATP channel function correlates strongly with the extent of inherited from either parent; therefore family history is typically
pancreatic involvement. Patients with autosomal recessively inher- negative. Affected infants can be large for gestational age and have
ited (biallelic) pathogenic variants will have diffuse involvement severe hypoglycemia in the neonatal period, but there is a wide
of the pancreas, whereas patients with one paternally inherited spectrum of severity of presentation and hypoglycemia. Diazoxide
pathogenic variant will have a focal disease. The focal lesion arises therapy is effective in some cases, but pancreatectomy is required
from a somatic loss of the maternal allele in a sub-population for some patients.74
of pancreatic cells, leading to focal unopposed expression of
the mutated paternal allele, as well as unbalanced expression of Hepatocyte Nuclear Factor-4-Alpha and Hepatocyte
imprinted genes that contribute to cellular hyperplasia.66,68 Rarely, Nuclear Factor-1-Alpha Pathogenic Variants
dominant-negative single allele pathogenic variants can result in HNF4A (hepatocyte nuclear factor-4-alpha) and HNF1A (hepa-
diffuse disease. As described later in this section, the extent of pan- tocyte nuclear factor-1-alpha) are transcription factors expressed in
creatic involvement directly impacts treatment. Patients with the hepatocytes, beta cells, intestinal epithelial cells, and renal tubular
focal histological subtype can be cured by targeted surgical resec- cells and are traditionally associated with mature onset diabetes of
tion, whereas those with the diffuse disease may require near-total youth (MODY) type 1 and 3, respectively. Transcriptional regu-
pancreatectomy for definitive therapy. lation targets of HNF4A and HNF1A include each other, glu-
cose transporter 2 (GLUT2), and possibly Kir6.2, but the exact
Activating Variant of the Glutamate Dehydrogenase 1 cause of hyperinsulinism in infants is unclear.75 Interestingly,
Gene: Hyperinsulinemia-Hyperammonemia Syndrome some patients with neonatal hyperinsulinism due to HNF4A
After pathogenic variants in KCNJ11 and ABCC8, pathogenic and HNF1A develop diabetes years later in adolescence or young
variants in glutamate dehydrogenase 1 (GLUD1) are the second adulthood, consistent with MODY 1 and 3.76 Diazoxide is an
most common cause of genetic hyperinsulinism. Glutamate effective therapy for patients with hypoglycemia secondary to
dehydrogenase is an enzyme thought to localize to the mito- HNF4A and HNF1A pathogenic variants. HNF4A hyperinsulin-
chondrial matrix protein that converts GDP to GTP, which in ism has also been described in combination with renal Fanconi
turn regulates amino acid and ammonia metabolism. Autosomal tubulopathy and hepatomegaly due to increased glycogen stores.75
dominant gain-of-function pathogenic variants increases the
GTP/GDP ratio in the beta cell, leading to the closure of the Beckwith-Wiedemann Syndrome
KATP channel and subsequent depolarization and insulin secre- Patients with BWS have characteristic features, including mac-
tion. Presentation is typically between 4 and 12 months of age, rosomia, macroglossia, hemihypertrophy, ear pits, umbilical
but infants can present in the first few days of life with hypo- hernia, and a high risk for embryonal tumors. BWS results from
glycemia.69 Leucine is an allosteric activator of GDH, causing epigenetic or genomic abnormalities in the imprinted 11p15.5
hypoglycemia to worsen 30 to 90 minutes after a protein-rich region or heterozygous maternally inherited pathogenic vari-
meal. In addition to hyperinsulinemic hypoglycemia, patients ants at CDKN1C. The majority (85%) of patients with BWS
also have elevated serum ammonia levels (hyperinsulinemia- do not have a family history of the disorder. Children conceived
hyperammonemia syndrome), although this is believed to have by assisted reproductive technologies may be at increased risk for
no clinical consequence and does not require therapy.2 The BWS and other imprinted disorders. Up to 50% of patients have
hypoglycemia is diazoxide-responsive, and carbohydrate-loading hyperinsulinemic hypoglycemia with a wide spectrum of sever-
is encouraged prior to protein-rich meals to prevent hypoglyce- ity, most of which resolves in the first few days of life.77,78 The
mia. Patients may also develop generalized seizures, including cause of hyperinsulinism in BWS is variable and may depend on
absence epilepsy.70 the patient’s specific genetic abnormality, which rarely includes
pathogenic variants in either KCNJ11 or ABCC8.78 Patients with to possibly be causative.83 FOXA2 regulates the expression of
BWS may respond to diazoxide; however, some patients require ABCC8, KCNJ11, and HADH, as well as several regulators of
partial pancreatectomy. pituitary gland development, such as SHH, Gli2, and NKX2-2.
The patient responded to diazoxide, suggesting that at least partial
Other Genetic Causes of Hyperinsulinism function of Sur1 and Kir6.2 was present.
Pathogenic variants in uncoupling protein 2 (UCP2) have been
shown in a few individuals who presented with diazoxide-sensitive
hyperinsulinemic hypoglycemia in infancy.79 UCP2 has subse-
Postfundoplication Hypoglycemia
quently been shown to regulate mitochondrial, and cellular oxi- Neonates undergoing fundoplication for gastric reflux or other rea-
dation and decreased UCP2 activity is thought to increase the sons are at risk for postprandial hypoglycemia related to dumping
oxidation of glucose, thereby increasing the intracellular ATP/ syndrome. Often this hypoglycemia goes undetected—prompting
ADP ratio and increasing insulin secretion. There are some con- the need for better surveillance, including the use of continuous
flicting data regarding the role of UCP2 in hyperinsulinism, with glucose monitoring.84 Approximately 25% of neonates develop
a large-scale sequencing study not supporting the role of UCP2 dumping syndrome after fundoplasty, most of which is identi-
in causing hyperinsulinism. However, in another study of a fied in the first postoperative week.85,86 Hypoglycemia occurs 1
large cohort of diazoxide-responsive patients, 5 out of 211 were to 3 hours after a meal due to an exaggerated insulin response to
found to have one of 4 UCP pathogenic variants. The mecha- early postmeal hyperglycemia, which is often detectable as well.
nism of hypoglycemia in patients with UCP2 pathogenic variants Treatment is with gradual gastric feeds, and sometimes continu-
appears to be due to an exaggerated insulin response to glucose ous feeds are required. Uncooked cornstarch, pectin, octreotide,
rather than persistent hyperinsulinism. With the cooperation of and acarbose have been attempted with varying degrees of suc-
a 4-generation pedigree of autosomal dominantly inherited con- cess.85 More recently, GLP-1 levels were found to be high in
genital hyperinsulinism, investigators identified a new single gene children with dumping syndrome, which led to GLP-1 receptor
cause of hyperinsulinism: hexokinase 1 (HK1).80 Family members antagonists being studied as a potential treatment for postprandial
were varyingly affected, but all who were treated with diazoxide hypoglycemia from dumping syndrome.85,87
responded well.
Autosomal recessive pathogenic variants in phosphoglu-
comutase 1 (PGM1) cause a syndrome of abnormal protein Differentiation Between Focal Adenomatous and
N-glycosylation associated with multifactorial hypoglycemia.81 Diffuse Pancreatic Hyperplasia
Patients demonstrate defects in glycogen breakdown as well as
postprandial hyperinsulinemia, both of which have been associ- Patients with hyperinsulinism who are not responsive to diazoxide
ated with hypoglycemia in infancy.54 Other congenital disorders of therapy should receive specialized imaging to evaluate for a focal
glycosylation have been associated with hyperinsulinism, includ- pancreatic lesion that can be cured surgically. Positron emission
ing CDG1a (phosphomannomutase 2 deficiency) and CDG1b tomography (PET) imaging with 18F-fluoro-L-DOPA exploits
(mannosephosphate isomerase deficiency).82 the fact that pancreatic β-cells take up the radiolabeled L-DOPA
Recently an infant was diagnosed with a combination of con- (Fig. 87.3). Simultaneous PET and MRI, therefore, provide
genital hyperinsulinism and hypopituitarism. A variant of uncer- visualization of the hyperactive β-cells within the pancreas and
tain significance (VUS) identified in the FOXA2 gene was thought allows the differentiation of focal and generalized hyperactivity
A B
• Fig. 87.3 (A) Frozen sections obtained from three pancreatic sites during surgery for a focal form of
hyperinsulinism in the head. Specimens taken from the tail and body show islets of Langerhans at rest
with little cytoplasm, leading to crowded nuclei, whereas the focal form aspect from the head is that of
multilobular involvement with local signs of β-cell hyperactivity: abundant cytoplasm and large, abnormal
nuclei (toluidine blue stain; original magnifications ×200 and ×100). (B) Frozen sections obtained from
three pancreatic sites during surgery for diffuse form of hyperinsulinism. On each biopsy, there is one islet
showing hyperfunctional signs with abundant cytoplasm and irregular nuclei more than four times the
size of the acinar nuclei nearby taken as internal control. The disease involves the whole pancreas and, in
consequence, can be called diffuse, which does not mean that all islets are involved in the same manner
(toluidine blue stain; original magnification ×200). (From Delonlay P, Simon A, Galmiche-Rolland L, et al.
Neonatal hyperinsulinism: clinicopathologic correlation. Hum Pathol. 2007;38:387–399.)
(see Fig. 87.3). This distinction is critical as it is far preferable is effective but not sustainable as a long-term treatment strategy
to perform a curative focal resection rather than a “near-total” due to the need either for IV infusion or continuous delivery via
pancreatectomy which has a more variable outcome ranging from a subcutaneous catheter. Continuous subcutaneous delivery sys-
continued hyperinsulinism to diabetes.88 tems have been described, but they are limited by crystallization of
In all, approximately half of patients requiring surgery will the glucagon and obstruction of the tubing.94 Sirolimus, a known
have a focal lesion.65 Such imaging is often successful in identify- cause of transplant-related diabetes, has also been used experimen-
ing the appropriate surgical management in those patients with tally with some success.95
hyperinsulinism refractory to medical management.89 Nutritional factors should also be considered by increasing the
carbohydrate content of feeds or by altering the length and fre-
quency of feeding breaks. Continuous dextrose (D20W) delivered
Management of Hyperinsulinemic enterally is sometimes required to maintain normoglycemia over-
Hypoglycemia night.96 Families should be taught how to use a glucometer and
to be vigilant for signs and symptoms of hypoglycemia. Parental
The goal of treatment is to minimize hypoglycemia frequency education on the administration of glucagon is necessary prior to
and duration to prevent impaired neurologic development. discharge.
First-line treatment is with diazoxide, which opens the beta-cell Patients that require pancreatectomy have a high risk for future
ATP-dependent potassium channel, limiting depolarization and development of insulin-dependent diabetes and neurobehavioral
thereby decreasing insulin secretion. Common side effects of problems.88 Lord et al. recently reported the outcomes for 121 chil-
diazoxide include hypertrichosis and fluid retention, sometimes dren with congenital hyperinsulinism treated with pancreatectomy,
requiring diuretic use. finding that 36% developed diabetes during long-term follow-up,
Pulmonary hypertension has also been described in a small and 20% of these patients developed diabetes in the immediate
number of patients receiving diazoxide.90 A retrospective cohort postoperative period. The risk of diabetes was associated with the
study was able to estimate the risk for pulmonary hypertension to percentage of pancreatectomy: 93% of those with diabetes had a
be 7% (13 out of 177 patients), the majority of which were symp- 95% pancreatectomy or greater, while those without diabetes had
tomatic.91 The onset of pulmonary hypertension was most com- a median 65% pancreatectomy. Also, 48% had neurobehavioral
monly within 2 weeks of starting therapy but could occur at any concerns, including 21% of patients with psychiatric or behavioral
time while on treatment with diazoxide. Pulmonary hypertension concerns, 18% with speech delay, and 16% with a learning dis-
resolved in 10 out of the 13 patients identified but persisted for ability, using parent-reported questionnaires. Quantitative measures
as long as 12 months after discontinuation of diazoxide. Risk fac- of adaptive behavior were abnormal in 27% of patients. The find-
tors for the development of pulmonary hypertension included the ing that these neurodevelopmental outcomes were similar for the
presence of congenital heart disease and higher volumes of fluid focal and diffuse groups suggests that a shared exposure to recurrent
given prior to the start of diazoxide. The authors proposed a best hypoglycemia in the neonatal period may be causative.
practice guideline that recommends obtaining an echocardiogram
prior to starting diazoxide and 1 to 2 weeks following initiation Neonatal Hyperglycemia
of therapy.
As mentioned above, not all hyperinsulinism patients will Insulin is a critical mediator of fetal growth, and therefore infants
respond to diazoxide (particularly those with KATP channel patho- with hyperglycemia due to persistent insulin deficiency are almost
genic variants), and second-line therapies include subcutaneous universally born small for gestational age and have a history of
octreotide and glucagon infusion (Table 87.2). Octreotide is intrauterine growth restriction. It is thought that the autoimmune
known to result in tachyphylaxis, causing diminishing efficacy process leading to beta-cell destruction takes at least 6 months
of the medication. There is also a possible association with nec- to manifest itself, and therefore autoimmune-mediated Type 1
rotizing enterocolitis, which requires special consideration in the Diabetes does not occur earlier than 6 months of age, with the
neonatal population.92,93 Lanreotide, a long-acting form of soma- notable exception of IPEX-related diabetes.97 Persistent hyper-
tostatin administered as a once a month injection, has been suc- glycemia that meets the criteria for diabetes (>125 mg/dL fast-
cessful in treating hyperinsulinism as well.92,93 Glucagon infusion ing or >200 mg/dL) in an infant <6 months of age suggests a
TABLE
87.2 Drugs Used in the Management of Neonatal Hyperinsulinism
Drug Dose/Route Mechanism of Action Adverse Effects

Diazoxide 5-15 mg/kg/day in three Binds to SUR1 subunit, opens KATP channel Fluid retention, hypertrichosis, rarely
divided doses orally eosinophilia, leukopenia, hypotension
Chlorothiazide (in conjunction with 10-20 mg/kg/day in two Synergistic response to diazoxide Hyponatremia, hypokalemia
diazoxide to decrease fluid retention) divided doses orally
Octreotide 5–25 μg/kg/day 6–8 hourly Inhibits insulin secretion by binding to Anorexia, nausea, abdominal pain,
SC injection or IV infusion somatostatin receptors and inducing diarrhea, tachyphylaxis
hyperpolarization of β-cells, direct inhibition Risk of NEC in young infants, thus
of voltage-dependent calcium channels lower doses are recommended
Glucagon 1–20 μg/kg/h, SC or IV Increases glycogenolysis and Nausea, vomiting, paradoxical insulin
infusion gluconeogenesis secretion at high dose
monogenic cause strongly, and genetic testing is positive in at least chromosome 6q24. Within this imprinted region are two genes,
80% of cases.98 About 50% of infants with diabetes in the first PLAGL1 and HYMAI, that share a promoter. This promoter is
few months of life will have a resolution by 1 to 2 years of age differentially methylated depending on the parent of allelic ori-
(transient neonatal diabetes, or TNDM), but a significant portion gin. In the normal situation, only the paternally inherited allele
of these patients will have relapse of diabetes later in childhood or is expressed, while the maternally inherited allele is methylated
adolescence.99,100 Family history of early adulthood onset diabetes and not expressed. Situations that lead to a relative increase in the
mellitus, perhaps reported as or assumed initially to be T1DM or expression of PLAGL1 and HYMAI cause TNDM. These include
T2DM, or MODY, can suggest an inherited abnormality of insu- paternal uniparental disomy, duplication of the 6q24 on the pater-
lin secretion, but positive family history is not present in 70% of nal allele, hypomethylation of the maternal allele producing inap-
molecularly confirmed cases.98 Elucidation of the specific genetic propriate PLAGL1 and HYMAI expression from the maternal
etiology has immediate implications for treatment, as those with allele, or multilocus imprinting disturbance (MLID) caused by
pathogenic variants in the KCNJ11 or ABCC8 components of biallelic pathogenic variants in ZFP57. The mechanism by which
the KATP channel are best treated with oral sulfonylurea rather overexpression of PLAGL1 and HYMAI leads to TNDM is not
than insulin. fully understood. A second, nonimprinted promoter also controls
PLAGL1 expression, which has led to the hypothesis that the
postnatal remission of TNDM is due to a switch over to this non-
Transient Stress-Related Hyperglycemia imprinted promoter postnatally. This form of TNDM resolves at
Most commonly, neonatal hyperglycemia is transient and caused a median age of 3 months, but about half of patients will have
by physiologic stress such as sepsis or other acute illness, particu- a return of diabetes during adolescence. Management is with
larly in infants receiving continuous intravenous dextrose infu- subcutaneous insulin therapy until remission. Associated clinical
sions (Box 87.5).101 Cortisol and catecholamines secreted during features include intrauterine growth retardation (IUGR), macro-
acute illness increase gluconeogenesis, glycogen breakdown, and glossia (44%), and umbilical hernia (21%), while other reported
insulin resistance, all of which increase plasma glucose concentra- findings have included facial dysmorphism (18%), cardiac and
tion. The hyperglycemia will improve as the neonate’s overall clini- renal anomalies (9%), and hand anomalies (8%).102,103
cal status improves and as glucose infusion rates are minimized to Interestingly, reports have shown that a subset of patients with
the lowest necessary amount. Insulin infusions may be necessary TNDM due to 6q24 abnormalities develops hyperinsulinemic
to control hyperglycemia in the short term. hypoglycemia after the resolution of neonatal diabetes.104 These
patients have reportedly responded to diazoxide therapy and,
Neonatal Diabetes Mellitus at follow-up, have still required treatment with diazoxide 1 to
4 years later.
Neonatal diabetes mellitus (NDM) is a genetically heterogeneous
disease with over 20 known genetic subtypes. Different types of Transient Neonatal Diabetes Mellitus due to KATP
NDM vary widely in their prognosis, from mild self-resolving Pathogenic Variants
hyperglycemia to permanent forms associated with severe neuro- About 25% of patients with TNDM have normal methylation at
developmental features. Some types of NDM respond to sulfonyl- 6q24. Most of these 6q24 normal TNDM patients have heterozy-
ureas, while others do not. Thus, early referral for genetic testing gous activating pathogenic variants in either KCNJ11 or ABCC8,
should be made as soon as a clinical diagnosis of NDM is made. It the two components of the KATP channel, as described previously.
is important to recognize that the absence of a family history does Activating pathogenic variants in these same genes can also cause
not exclude a genetic cause, as most NDM-causing pathogenic PNDM; see below. Although some studies have suggested that
variants arise spontaneously.98 TNDM-causing pathogenic variants are functionally less severe
than PNDM-causing pathogenic variants, some pathogenic vari-
Transient Neonatal diabetes Mellitus due to Chromosome ants in KCNJ11 have been reported in both PNDM and TNDM
6q24 Anomalies patients, so an absolute genotype-phenotype correlation may not
The majority (70%) of patients with transient neonatal diabetes exist.105,106 Compared with 6q24-associated TNDM, infants with
mellitus (TNDM) have an abnormality of the imprinted region of KATP-associated TNDM have higher birth weight, later diagnosis,
later remission, and earlier relapse of hyperglycemia.107 No sig-
nificant clinical differences have been noted between KCNJ11
and ABCC8-related TNDM, both of which respond favorably to
• BOX 87.5 ifferential Diagnoses of Neonatal
D sulfonylureas.
Hyperglycemia
Additional Genetic Causes of Transient Neonatal
Common Causes Diabetes Mellitus
Excessive intravenous glucose infusion
Impaired glucose homeostasis in preterm/sick/SGA infants
Several different biallelic pathogenic variants within the pro-
Sepsis moter of the insulin gene (INS) have been reported in TNDM
Stress patients.108 Pathogenic variants within the promoter of the INS
Corticosteroids gene can also cause PNDM. Genotype-phenotype correlations
are limited as several of these variants have been reported in both
Rare Causes TNDM and PNDM. For example, the INS promoter variant(c.-
Transient neonatal diabetes 331C>G) has been reported to cause TNDM in some individuals
Permanent neonatal diabetes and PNDM in others, even within the same family. The reason for
this variability is unknown.
Homozygous pathogenic variants in the gene SLC2A2, encod- is often the initial presentation, making early genetic diagnosis
ing the GLUT2 transporter, which transports glucose into the helpful as it can guide management and necessary screening. For
beta cell, have been reported in 4 unrelated patients with TNDM; example, patients with biallelic pathogenic variants in EIF2AK3
parents were first cousins in 3 of these patients.107,109 Three of the have Wolcott-Rallison syndrome, which usually presents with
patients presented with apparently isolated diabetes, but even- neonatal diabetes, while other features (skeletal dysplasia, develop-
tually, all four demonstrated findings associated with Fanconi- mental delays, and liver dysfunction) may not manifest until later.
Bickel syndrome (FBS). Biallelic pathogenic variants in SLC2A2 A quarter of NDM patients whose parents are consanguineous
are known to cause FBS, whose features include renal Fanconi have Wolcott-Rallison syndrome, making it the most common
syndrome, poor growth, hepatomegaly, and impaired utilization cause of PNDM among this group of patients. The remaining
of glucose and galactose.110 However, over 95% of patients with syndromic causes of neonatal diabetes are listed in Table 87.3.
biallelic SLC2A2 pathogenic variants present with symptoms of Because of the considerable number of genetic causes of neona-
FBS without evidence of neonatal diabetes, but the reason for this tal diabetes, sequencing multiple genes in parallel is typically the
variable expressivity is unknown. most efficient diagnostic approach.
Nonsyndromic Causes of Permanent Neonatal
Diabetes Mellitus TABLE
Infants with neonatal diabetes without evidence of remission in 87.3 Syndromic Causes of Neonatal Diabetes
the first year or two of life are classified as having PNDM. The
most common cause of PNDM is heterozygous, activating patho- Gene Syndrome Reference
genic variants in the potassium channel subunit genes KCNJ11 EIF2AK3 Wolcott-Rallison syndrome 122,123
and ABCC8 (more commonly KCNJ11), accounting for almost
half of all patients with PNDM.111,112 These pathogenic variants FOXP3 IPEX syndrome: severe diarrhea, type 1 DM, 124,125
decrease the potassium channel’s sensitivity to the cellular ATP dermatitis, X-linked
concentration, keeping the channel inappropriately open and GATA4 Neonatal and childhood onset DM, may 126
inhibiting insulin secretion. 20% of individuals with PNDM have pancreatic hypoplasia, cardiac
due to KCNJ11 pathogenic variants will also have developmental malformations, and neurocognitive defects
delay, epilepsy, and neonatal diabetes (DEND) syndrome.113 There GATA6 Pancreatic agenesis, ± congenital heart 127
are clear genotype-phenotype correlations within the KCNJ11 defects
gene, with some pathogenic variants being associated with DEND
syndrome and others with only PNDM. Patients with PNDM GLIS3 NDM with congenital hypothyroidism 128,129
due to pathogenic variants in KCNJ11 and ABCC8 typically HNF1B Renal cysts and diabetes (RCAD), neonatal 130
respond well to sulfonylureas.114 Interestingly, some neurologic diabetes (NDM)
features of DEND have also been reported to respond to sulfo-
IER3IP1 NDM with microcephaly, lissencephaly, and 131,132
nylureas, highlighting the importance of the potassium channel
epileptic encephalopathy
in neuronal cells.115
Pathogenic variants within the INS are also a common cause MNX1 NDM with neurologic features, Currarino 133,134
of PNDM, found in approximately 10% of patients with PNDM. syndrome (sacral agenesis, imperforate
INS gene pathogenic variants can be homozygous (more common anus)
among offspring of consanguineous relationships) or heterozy- NEUROD1 NDM with cerebellar hypoplasia, 135
gous, but in both cases, the pathogenic variants lead to inadequate sensorineural hearing loss, visual impairment
production of insulin protein.98,108,116
NEUROG3 NDM with congenital malabsorptive diarrhea 136,137
Rarer genetic causes of nonsyndromic PNDM include biallelic
inactivating pathogenic variants in glucokinase (GCK), and the NKX2-2 NDM with developmental delays, hypotonia, 134
transcription factor PDX1.117,118 GCK serves as the “glucose sen- short stature and hearing loss
sor” of the beta cell, converting glucose into glucose 6-phosphate. PTF1A NDM with pancreatic and cerebellar 138
PDX1 is a transcription factor necessary for the formation of the agenesis
pancreas in utero. Heterozygous pathogenic variants in GCK are a
relatively common cause of MODY, accounting for 20% to 50% RFX6 NDM with pancreatic hypoplasia, intestinal 139,140
of MODY patients. Therefore, GCK should be strongly consid- atresia, gall bladder hypoplasia (Mitchell-
Riley syndrome)
ered in patients with PNDM who have a positive family history
of MODY, mild fasting hyperglycemia, or gestational diabetes in SLC19A2 NDM with deafness and thiamine-responsive 141
a nonobese mother. Some patients with homozygous pathogenic megaloblastic anemia (Rogers syndrome)
variants of PDX1 have pancreatic agenesis, producing exocrine SLC2A2 NDM with renal dysfunction (Fanconi Bickel 142
insufficiency in addition to PNDM, while in others, a pancreatic syndrome)
exocrine function is intact.118
WFS1 Wolfram syndrome, DIDMOAD, low frequency 143
Syndromic Causes of Neonatal Diabetes Mellitus sensorineural hearing loss, optic atrophy
In addition to the genes described above, there are multiple other PAX6 Neonatal diabetes with brain malformations, 144
known genetic causes of NDM, which are typically considered microcephaly, and microphthalmia
“syndromic” because they are often associated with other non- LRBA Common variable immunodeficiency with 145
endocrine features. Although some syndromic forms of NDM autoimmunity
present with other features (e.g., congenital heart defects), diabetes
Management of Neonatal Hyperglycemia Suggested Readings

Management of hyperglycemia in the neonatal period is dictated Adamkin DH. Neonatal hypoglycemia. Curr Opin Pediatr. 2016;28:
by the clinical scenario and the results of genetic testing. Transient 150–155.
hyperglycemia is best managed by treating the underlying cause De Leon DD, Thornton PS, Stanley CA, Sperling MA. Hypoglycemia
(e.g., sepsis). In addition to close monitoring of glucose, exog- in the Newborn and Infant. Pediatric Endocrinology. Philadelphia:
Elsevier; 2014.
enous glucose administration can be decreased to approximately Lemelman MR, Letourneau L, Greeley SA. Neonatal diabetes mellitus:
3 mg/kg/min. If necessary, insulin treatment can commence, start- an update on diagnosis and management. Clin Perinatol. 2018;45:
ing with a low-dose insulin infusion (e.g., 0.03 units/kg/h). 41–59.
Treatment of neonatal diabetes requires insulin, at least until Menon RK, Sperling MA. Carbohydrate metabolism. Semin Perinatol.
a genetic diagnosis is made. For those with a genetic aberration at 1988;12:157–162.
6q24, insulin requirements usually drop quite quickly, and treat- Rubio-Cabezas O, Hattersley AT, Njolstad PR, et al. Pediatric
ment is often discontinued by 12 weeks of age.119 Hyperglycemia International Society for Adolescent Diabetes. 2014. ISPAD Clinical
may recur with intercurrent illness and then recurs in over half of Practice Consensus Guidelines. The diagnosis and management of
children, generally at the time of puberty. monogenic diabetes in children and adolescents. Pediatr Diabetes.
Infants with an identified pathogenic variant in KCNJ11 or 2014;15(Suppl 20):47–64.
Stanley CA. Perspective on the genetics and diagnosis of congenital
ABCC8 can be treated with sulfonylureas. Generally, it is best to hyperinsulinism disorders. J Clin Endocrinol Metab. 2016;101:
gradually decrease insulin dosing as sulfonylurea treatment is initi- 815–826.
ated. Sulfonylurea dosing tends to be higher than typically used in Stanley CA, Rozance PJ, Thornton PS, et al. Re-evaluating “transitional
adults. While over 90% of those with a KCNJ11 or ABCC8 patho- neonatal hypoglycemia”: mechanism and implications for manage-
genic variant can successfully transition from insulin to sulfonylurea ment. J Pediatr. 2015;166:1520.
and maintain near normal glycemic control, the factors associated Stanley CA, Anday EK, Baker L, Delivoria-Papadopolous M. Metabolic
with sulfonylurea failure are the specific genetic variant and longer fuel and hormone responses to fasting in newborn infants. Pediatrics.
duration of diabetes.120 Treatment with sulfonylureas is not only 1979;64:613–619.
effective in achieving euglycemia but also has led to improvements Thornton PS, Stanley CA, De Leon DD, et al. Pediatric Endocrine
Society. Recommendations from the Pediatric Endocrine Society for
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evaluation and management of persistent hypoglycemia in neonates,
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Acknowledgments
We would like to thank the authors of the 9th edition of this References
chapter—Vandana Jain, Ming Chen, and Ram K. Menon—
whose work was the starting point for our chapter. The complete reference list is available at Elsevier eBooks+.

Avery's Hypo and Hyperglycemia

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Neonatal Hypoglycemia and

KEY POINTS Neonatal Hypoglycemia

Glyceraldehyde 3-P Dihydroxyacetone-P

1, 3-Diphosphoglycerate -Glycero-P Glycerol

Malate Citrate Free fatty acids

Signs and Symptoms of Hypoglycemia

Primary Adrenal Insufficiency hypogonadism, manifesting as delayed pubertal development

Inheritance Molecular Defect Chromosome Histology Clinical Features Treatment

treatment is often required for as long as 6 months and has been

Drug Dose/Route Mechanism of Action Adverse Effects

Management of Neonatal Hyperglycemia Suggested Readings

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Avery's Hypo and Hyperglycemia

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Avery's Hypo and Hyperglycemia

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87

Neonatal Hypoglycemia and

KEY POINTS Neonatal Hypoglycemia

Glyceraldehyde 3-P Dihydroxyacetone-P

1, 3-Diphosphoglycerate -Glycero-P Glycerol

Malate Citrate Free fatty acids

Signs and Symptoms of Hypoglycemia

Primary Adrenal Insufficiency hypogonadism, manifesting as delayed pubertal development

Inheritance Molecular Defect Chromosome Histology Clinical Features Treatment

treatment is often required for as long as 6 months and has been

Drug Dose/Route Mechanism of Action Adverse Effects

Management of Neonatal Hyperglycemia Suggested Readings

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1, 3-Diphosphoglycerate -Glycero-P Glycerol