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Literature review current through: Jan 2019. | This topic last updated: Jan 31, 2019.
INTRODUCTION
Neonatal diabetes mellitus (DM) is characterized by the onset of persistent hyperglycemia within the
first six months of life due to impaired insulin function and is frequently caused by a mutation in a
single gene affecting pancreatic beta cell function.
The presentation, clinical manifestations, diagnosis, and evaluation for neonatal DM will be reviewed
here. An overview of causes and management of neonatal hyperglycemia is discussed separately.
(See "Neonatal hyperglycemia".)
TERMINOLOGY
The terminology describing DM in the first year of life is somewhat confusing. Neonatal DM is the
commonly used term to describe monogenic forms of DM that present during infancy. Although
some patients present within the neonatal time period of the first 30 days of life, infants most often
present within the first six months of life, and occasionally present up to 12 months of life [1-3]. In
contrast, polygenic autoimmune type 1 diabetes is unlikely to present within the first six months of
life (see "Epidemiology, presentation, and diagnosis of type 1 diabetes mellitus in children and
adolescents", section on 'Age and gender' and "Epidemiology, presentation, and diagnosis of type 1
diabetes mellitus in children and adolescents", section on 'Infants'). Therefore, the term neonatal DM,
which is most commonly used in the literature and clinically, will be the term used throughout this
topic and refers to patients up to one year of life who present with monogenic DM.
EPIDEMIOLOGY
DM is a rare cause of neonatal and infantile hyperglycemia with reported incidence ranging from 1 in
90,000 to 160,000 live births [4,5]. Most infants who present with DM in the first six months of life will
have a monogenic cause referred to as neonatal DM [1]. (See 'Terminology' above.)
PATHOGENESIS
Mutations that cause neonatal DM are a result of impaired insulin function due to one of the following
mechanisms [1]:
● Abnormal beta cell function affecting insulin production and secretion – KCNJ11, ABCC8, INS,
GCK, SLC2A2, SLC19A2, RFX6 [6-15]
The relative frequency of different genetic causes was determined in a large case series of 1020
patients diagnosed with neonatal DM before six months of age [2]. Comprehensive genetic testing
identified causal mutation in more than 80 percent of cases. Mutations in KCNJ11 and ABCC8, which
encode for subunits of the ATP-sensitive potassium channel (KATP) in the pancreatic beta cell, were
the most common (n = 390) found in 46 percent of infants with neonatal diabetes from
nonconsanguineous families and 12 percent of identified consanguineous families. Mutations in the
gene that encodes insulin (INS) had similar rates of 10 percent in patients from nonconsanguineous
and consanguineous families (n = 110). In consanguineous families, the most common genetic cause
was a homozygous mutation in EIF2AK3 gene causing Wolcott-Rallison syndrome (OMIM#226980, n
= 24 percent) (n = 76).
Although neonatal DM may also occur in preterm infants (gestational age <37 weeks), it is more
challenging to make a diagnosis in this group of patients. In a second case series, 146 of 750 infants
with diabetes diagnosed before six months of age were born preterm [30]. A genetic etiology was
identified in 97/146 (66 percent) preterm infants compared with 501/604 (83 percent) term infants
[30]. KCNJ11 gene mutations were less common in preterm infants.
Phenotypic expression — Gene mutations that cause neonatal DM are expressed as one of the
following clinical subtypes [2,3]:
● Diabetes mellitus responsive to oral sulfonylurea (mutations of KCNJ11 or ABCC8, which encode
subunits of the KATP channel) – 40 percent of cases
● Permanent isolated diabetes mellitus that require lifelong insulin therapy (mutations of INS) – 10
percent of cases
● Syndromic diabetes mellitus with extra-pancreatic features (eg, Wolcott-Rallison syndrome due
to mutations of EIF2AK3 mutations) – 10 percent
Transient neonatal DM — Twenty percent of patients will present with transient neonatal DM that
resolves in infancy (usually by 13 to 18 weeks of age) but may recur later in life [1-3,31]. In the
previously mentioned large case series, 20 percent of the cohort had a genetic diagnosis of transient
neonatal DM [2]. The underlying genetic defects included:
● Overexpression of the imprinted region of chromosome 6q24, which include the genes PLAGL,
HYMAI, and ZPF57 [32-36]. The overexpression of this region has been attributed to either a
mutation in the zinc finger transcription factor ZPF57 leading to hypomethylation of the
imprinted loci, or due to the duplication of 6q24 from either paternal uniparental disomy or an
unbalanced duplication of the paternal chromosome 6 [34-36]. Of note, patients may develop
hypoglycemia in later infancy or childhood after the initial hyperglycemic phase [31].
● Mutations of either KCNJ11 or ABCC8 that encode subunits of the KATP channel, which are
discussed below.
● Case reports of patients with mutations of INS, which encodes preproinsulin [37-39].
KATP channels are also found in the brain. Severe cases of KCNJ11 mutations may also present with
developmental delay and epilepsy along with DM [44]. This combination of findings is referred to as
DEND (developmental delay, epilepsy, neonatal diabetes) syndrome. It is thought that early diagnosis
and treatment may improve neurologic outcome.
In addition, approximately 10 percent of patients with KCNJ11 mutations causing neonatal DM are
not responsive to treatment with sulfonylureas and must be treated with insulin [43]
Syndromic neonatal DM — DM is a clinical feature of many different syndromes that present
during infancy caused by mutations in at least 17 genes [2]. Syndromic causes of neonatal DM
account for approximately 10 percent of cases due to impairment of insulin function through a range
of pathogenetic mechanisms including abnormal pancreatic development, beta cell destruction, and
impaired beta cell function and severe insulin resistance syndromes.
Other more rare syndromes that present with neonatal DM include [1,4]:
CLINICAL FEATURES
Presentation — Due to the genetic heterogeneity underlying neonatal DM, the clinical presentation of
affected infants varies from incidentally identified asymptomatic hyperglycemia to severe
dehydration and diabetic ketoacidosis (DKA) [1,2,4].
● Small for gestational age – Frequently neonatal DM presents prenatally with intrauterine growth
restriction due to a deficiency of functional insulin, which is an in utero growth factor. Catch-up
growth is observed when there is subsequent appropriate postnatal treatment.
● Poor postnatal growth (ie, failure to thrive) for infants who do not receive appropriate therapy.
● Diabetic ketoacidosis (DKA) – Infants with neonatal DM are at risk for dehydration and
electrolyte abnormalities due to urinary losses and acidosis due to ketogenesis. However, the
signs and symptoms of DKA in infants are nonspecific and include irritability, lethargy, tachypnea,
and evidence of hypovolemia (eg, sunken eyes and fontanels). The frequency of DKA at
presentation varies and is dependent on the specific underlying genetic disorder. DKA is reported
to occur in approximately 30 percent of patients with mutations of INS (isolated diabetes
mellitus requiring insulin) and ranges from 30 to 75 percent for those with mutations of either
KCNJ11 or ABCC8 (DM responsive to sulfonylurea) [4,6]. Patients with transient DM due to
overexpression of 6q24 typically do not present with DKA [4]. (See "Clinical features and
diagnosis of diabetic ketoacidosis in children and adolescents", section on 'Signs and
symptoms'.)
● Malabsorptive diarrhea – In some cases, pancreatic exocrine function may also be impaired
(sometimes due to pancreatic aplasia/hypoplasia) resulting in malabsorptive diarrhea [26,46,47].
● Hypothyroidism – GLIS3 [23] (see "Clinical features and detection of congenital hypothyroidism",
section on 'Thyroid dysgenesis').
● Cardiac abnormalities – GATA4, GATA6 [24,49] (see "Isolated atrial septal defects (ASDs) in
children: Classification, clinical features, and diagnosis", section on 'Genetic disorders').
● Polycystic kidney disease – HNF-1 beta [27] (see "Renal hypodysplasia", section on 'HNF1b-
related disease (renal cysts and diabetes syndrome)').
• KCNJ11 mutations can be associated with severe developmental delay, epilepsy, muscle
weakness, and dysmorphic features [6]. These findings are also known as the DEND
(developmental delay, epilepsy, neonatal diabetes) syndrome [51]. (See 'Neonatal DM
responsive to sulfonylurea' above.)
DIAGNOSIS
Making a diagnosis of neonatal DM in infants <6 months of age is challenging. A clinical diagnosis of
DM is made for infants who have persistent insulin-dependent hyperglycemia beyond three days with
blood glucose levels >200 mg/dL and in whom alternative causes for elevated blood glucose levels
have been excluded. For neonates and infants with DM, neonatal DM due to a monogenic etiology is
confirmed when genetic testing identifies a causative gene mutation. (See 'Genetic testing' below and
'Terminology' above.)
DIAGNOSTIC EVALUATION
For infants with persistent hyperglycemia, the following diagnostic evaluation is performed to exclude
other causes of neonatal hyperglycemia and to differentiate monogenic neonatal DM from polygenic
autoimmune type 1 DM. Further genetic testing is performed for infants with a clinical diagnosis of
neonatal DM to determine the causative gene mutation.
● Review of history:
• Are there any medications associated with elevated blood glucose levels (eg,
corticosteroids, beta-adrenergic agents)? If so, consider discontinuation if possible.
• Is there any history of diarrhea or loose fatty stools suggesting pancreatic exocrine
functional impairment? If so, consider obtaining fecal elastase measurement. (See
"Approach to chronic diarrhea in neonates and young infants (<6 months)", section on 'Stool
testing' and "Exocrine pancreatic insufficiency", section on 'Fecal elastase-1'.)
● If the patient is on parenteral nutrition, review the rate of glucose infusion. If it is greater than 8
mg/kg per minute, decrease the glucose infusion rate initially to a rate of 6 mg/kg per min if
possible and evaluate the subsequent blood glucose level to see if it remains persistently
elevated. (See "Neonatal hyperglycemia", section on 'Reduction of glucose infusion rate'.)
● Laboratory evaluation:
• Obtain blood cultures to rule out sepsis. (See 'Differential diagnosis' below.)
• HbA1C is not recommended to diagnose DM in infants <6 months of age because neonates
have a high concentration of fetal hemoglobin (HgbF) and therefore a lower concentration of
hemoglobin A (HgbA) [52]. An elevated HbA1C >6.5 percent in an infant <6 months would
still be consistent with a diagnosis of diabetes, but a normal HbA1C would not be reassuring
if there is clinical suspicion of neonatal diabetes.
Genetic testing — Once the diagnosis of DM has been established in an infant less than 12 months of
age, targeted genetic testing to confirm and identify a monogenic etiology is recommended as this
can guide treatment recommendations. Genetic testing is cost-effective because management of a
high proportion of patients is improved with identification of the underlying defect (eg, patients
responsive to oral sulfonylurea therapy). We suggest using screening panels from commercial
laboratories that include 15 to 20 candidate genes for neonatal DM, as a cost-effective approach for
neonatal DM genetic testing. As bioinformatics support for whole exome sequencing and whole
genome sequencing becomes more readily available and more cost-effective, this testing approach
will supersede candidate gene testing for neonatal DM. The United States National Center for
Biotechnology Information (NCBI) genetic registry lists test services in the United States and other
select countries.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis for neonatal hyperglycemia is broad and is discussed separately. (See
"Neonatal hyperglycemia", section on 'Causes'.)
For persistent hyperglycemia, DM is a diagnosis of exclusion. The most common causes of neonatal
hyperglycemia are differentiated from DM as follows (see 'Diagnostic evaluation' above):
MANAGEMENT
Insulin therapy
In our practice, we use CSII to administer insulin along with continuous glucose monitoring because
an insulin pump can reliably deliver small doses of insulin (although dilution of the insulin may be
needed due to the small size of the infant). CSII is started using basal insulin at a dose bet 0.1 to 0.3
units per kg per day depending on the most recent intravenous needs and then titrated based on
glucose control with a targeted range of 100 to 200 mg/dL. Correction insulin for preprandial glucose
levels over 250 mg/dL may be needed [3,54-58]. Initially, neonates and young infants may not need
additional bolus insulin for meals. As the infant grows and eating patterns change this need for
prandial insulin may evolve.
Alternatively, multiple daily injections based on preprandial glucose levels can be used with a similar
target glucose level of 100 to 200 mg/dL. When using multiple daily dosing, we prefer the use of
rapid-acting analog insulins (insulin lispro, aspart, or glulisine) given three to four times per day
before a feed. A starting dose of 0.1 to 0.15 units per kg per dose is used when the pre-prandial
glucose level is over 200 to 250 mg/dL. Alternatively, long-acting insulins such as glargine may be
used at a dose of 0.2 to 0.4 unit/kg per day divided in one to two injections per day [3,53,54]. However,
intermediate-acting insulins such as NPH should not be used as they have been associated with an
increased risk for erratic control and hypoglycemia.
For these patients, the transition from insulin to sulfonylurea treatment is conducted in an inpatient
setting supervised by a clinician with expertise in managing infants with diabetes in order to avoid
hypoglycemia because the insulin requirement can decrease rapidly once sulfonylurea treatment has
been initiated. The effectiveness of sulfonylurea treatment is related to the specific mutation [43,59].
For neonatal DM due to mutations in ABCC8 or KCNJ11, the relative to doses of sulfonylurea used are
much higher compared with doses used to treat patients with type 2 diabetes (0.2 mg/kg per day).
Since the KATP channels are also found in the brain, treatment with sulfonylurea drugs can effectively
treat neurological symptoms associated with DEND (developmental delay, epilepsy, neonatal
diabetes) syndrome that are associated with mutations in KCNJ11, and there is some evidence that
earlier initiation of treatment improved outcomes [44,59]. Since the treatment approach in neonatal
DM is altered based on the genetic mutation, it is important to obtain expedited genetic testing as
soon as the diagnosis of neonatal DM is made.
After establishing euglycemia with insulin therapy and in the absence of pancreatic
hypoplasia/aplasia, consanguinity, or syndromic features, an empiric trial of sulfonylurea is
suggested while awaiting the results of genetic testing in consultation with a pediatric
endocrinologist [3,42].
Pancreatic enzyme and nutrient supplementation — If the infant has pancreatic exocrine deficiency,
pancreatic enzyme replacement similar to that used in patients with cystic fibrosis is required to
maximize enteral calorie absorption. In addition, nutrient repletion including fat soluble vitamins may
be required. (See "Cystic fibrosis: Assessment and management of pancreatic insufficiency", section
on 'Pancreatic enzyme replacement therapy' and "Cystic fibrosis: Nutritional issues", section on
'Nutrient deficits and goals'.)
● Neonatal diabetes mellitus (DM) is the commonly used term to describe monogenic forms of DM
that typically present within the first 12 months of life. Although some patients present within the
neonatal time period of the first 30 days of life, infants most often present with neonatal DM
within the first six months of life, occasionally up to 12 months of life, and very rarely after 12
months of age. (See 'Terminology' above.)
● Neonatal DM is caused by one of more than 20 identified genetic mutations (See 'Overview of
gene mutations' above.)
● Neonatal DM is expressed as one of several clinical subtypes depending on the specific gene
mutation and including transient DM, DM responsive to oral sulfonylurea, permanent DM
requiring lifelong insulin therapy, and syndromic neonatal DM. (See 'Phenotypic expression'
above.)
● Infants with neonatal DM can present with incidentally noted hyperglycemia or symptomatically
with clinical findings of dehydration, low birth weight, failure to thrive, glucosuria, ketoacidosis,
and osmotic diuresis. (See 'Presentation' above.)
● A clinical diagnosis of neonatal DM is made for infants who have persistent insulin-dependent
hyperglycemia beyond three days with blood glucose levels >200 mg/dL and in whom alternative
causes for elevated blood glucose levels have been excluded. The diagnosis is confirmed when
genetic testing identifies a causative gene mutation. (See 'Diagnosis' above and 'Genetic testing'
above.)
● The diagnostic evaluation for neonatal DM focuses on exclusion of other causes of neonatal
hyperglycemia including distinguishing monogenic neonatal DM from polygenic autoimmune
type 1 DM. Further genetic testing is performed for infants with a clinical diagnosis of neonatal
DM to determine the causative gene mutation. (See 'Diagnostic evaluation' above.)
● The differential diagnosis of neonatal DM is broad and includes sepsis, hyperglycemia due to
excessive glucose intravenous infusion, and hyperglycemic medications as well as type 1 DM.
(See 'Differential diagnosis' above.)
● For infants with persistent hyperglycemia including those with neonatal DM, management is
initially directed towards correction of fluid and electrolyte abnormalities and reduction of
hyperglycemia by the administration of a continuous infusion of intravenous insulin. After the
infant is stable and has started oral feedings, subcutaneous insulin therapy can be started either
through multiple daily injections or as a continuous subcutaneous insulin infusion using an
insulin pump. (See 'Management' above.)
● For patients with neonatal DM due to mutations in KCNJ11 or ABCC8, treatment with
sulfonylurea drugs (glyburide [glibenclamide]) may effectively treat hyperglycemia and reduce or
eliminate the need for insulin treatment. (See 'Sulfonylurea therapy' above.)
● Infants with pancreatic exocrine deficiency may require pancreatic enzyme and nutrient
supplementation similar to that used in patients with cystic fibrosis to ensure adequate growth.
(See "Cystic fibrosis: Assessment and management of pancreatic insufficiency", section on
'Pancreatic enzyme replacement therapy' and "Cystic fibrosis: Nutritional issues", section on
'Nutrient deficits and goals'.)
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