Article endocrinology

Neonatal Diabetes Mellitus:

The Impact of Molecular Diagnosis
Priti Pun, DO,* Robin
Clark, MD, Kim-Wah Abstract

Wan, PharmD, Ricardo Neonatal hyperglycemia has multiple causes, some of which are common (sepsis,
stress, phenytoin or glucocorticoid administration) and others of which are more rare,
Peverini, MD,* T. Allen
including transient neonatal diabetes and mutations of sulfonylurea receptors, which
Merritt, MD, MHA*
require molecular diagnosis. Many infants identified with the latter condition may
respond well to oral sulfonylurea medications. We describe an infant in whom
molecular diagnosis permitted such therapy as well as a new diagnosis for the mother,
Author Disclosure
who had been insulin-dependent for 17 years. In addition to aberrant expression of
Drs Pun, Clark, Wan, imprinted genes on chromosome 6q24 for transient neonatal diabetes, molecular
Peverini, and Merritt diagnosis offers a rationale for oral hypoglycemic agents (off-label use) that may
have disclosed no improve the lives of affected infants.
financial relationships
relevant to this Objectives After completing this article, readers should be able to:
article. This
1. List causes of neonatal diabetes mellitus.
commentary does
2. Describe the phenotypic features of permanent neonatal diabetes mellitus.
contain a discussion
3. Review the gene mutations associated with permanent neonatal diabetes mellitus.
of an unapproved/
investigative use of a
commercial Introduction
Neonatal diabetes mellitus is a rare disorder, occurring 1 in 400,000 births, that usually is
product/device.
associated with insufficient production of insulin. Approximately 50% of those identified
have the condition lifelong; in the remainder of affected infants, it may be transient but
later reappear. (1) The causes of neonatal diabetes differ from that of insulin-dependent
diabetes mellitus in childhood because of its highly variable course. Recent advances in
molecular diagnosis, including the discovery of an aberrant expression of imprinted genes
at chromosome 6q24, reports of paternal isodisomy of chromosome 6, and other molec-
ular gene mutations, present new diagnostic challenges that may offer alternative treat-
ments other than traditional insulin therapy. (2)(3)

Case Presentation
A term female infant is born via normal spontaneous vaginal delivery to a 17-year-old G2P1
Hispanic woman. Test results indicate that the mother is rubella-immune, hepatitis B surface
antigen-negative, and group B Streptococcus-negative and has B blood. The mother, in
whom diabetes was diagnosed at age 4 months, received prenatal care starting at 6 weeks
of pregnancy, folic acid supplementation, and insulin infusions via an insulin pump, with
an increase in her basal dose for adequate glycemic control. She had several urinary tract
infections during the pregnancy. The maternal grandfather has type 2 diabetes mellitus. The
mother had a previous spontaneous abortion occurring at 20 weeks gestation. She was
admitted 5 days before delivery for treatment of pyelonephritis with intravenous cefazolin.
Rupture of membranes occurred 20 hours before delivery. She received epidural anesthesia
with procaine and intravenous cefazolin during the delivery.
The infant, who weighs 2,670 g (3rd percentile for gestational age), is vigorous and has a
spontaneous cry. Apgar scores are 8 at 1 minute and 9 at 5 minutes. Initial blood glucose
measures 109 mg/dL (6.0 mmol/L). During hospitalization, the blood glucose appears to
elevate to 125 to 176 mg/dL (6.9 to 9.8 mmol/L) with the ingestion of formula, but measures

*Division of Neonatology, Loma Linda University School of Medicine.

Genetics, Loma Linda University School of Medicine.

NICU Pharmacy, Loma Linda University Childrens Hospital, Loma Linda, Calif.

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92 to 124 mg/dL (5.1 to 6.9 mmol/L) with the ingestion of
human milk. The mother has adequate production of milk,
and mother and child are discharged from the hospital
45 hours after delivery. Because of her history of diabetes
mellitus, the mother is instructed by her pediatrician to
check the infants blood glucose daily to monitor stability,
using her own glucometer. At home, the infant breastfeeds
well every 2 to 3 hours and has approximately six wet
diapers daily. The daily blood glucose measurements are
approximately 120 mg/dL (6.7 mmol/L) until 8 days of
age, when a measurement reads 318 mg/dL (17.6 mmol/
L). Her pediatrician instructs the mother to bring the
infant to the emergency department, where the infants
blood glucose measures 351 mg/dL (19.5 mmol/L) and the
infant is admitted to the neonatal intensive care unit.
On admission, physical examination of the small-for-
gestational age infant reveals a weight of 2,640 g (30-g
decrease from birthweight), decreased subcutaneous tissue,
normal vital signs (temperature of 36.8C, heart rate of
137 beats/min, respiratory rate of 43 breaths/min, mean
blood pressure of 52 mm Hg), comfortable breathing in
room air, no cardiac murmur, and no dysmorphic features.
A sepsis evaluation is completed and antibiotics discon-
tinued on return of negative cultures at 72 hours. Initial
laboratory evaluation reveals glycosuria (70 mg/dL
[3.9 mmol/L]); normal C-peptide, cortisol, and thyroid-
stimulating hormone; hemoglobin A1C of 3.4% (normal,
7%); and decreased serum insulin of 1.1 mcIU/mL
(7.6 pmol/L). Findings on abdominal ultrasonography,
electroencephalography, cranial ultrasonography, and
echocardiography are normal. Ketonuria is not present.
Blood glucose concentrations are difficult to control, rang-
ing from 89 to 379 mg/dL (4.9 to 21.0 mmol/L) while
the infant receives insulin infusions varying from 0.01 to
0.08 units/kg per hour. The recommendation from an
endocrinology consultation is a regimen of a long-acting
insulin (detemir 0.5 units subcutaneous every 12 hours)
and a short-acting insulin (glulisine as needed for blood
glucose 300 mg/dL [16.7 mmol/L]). Blood glucose values
on this treatment regimen range from less than 40 mg/dL
(2.2 mmol/L) to more than 500 mg/dL (27.8 mmol/L).
Humalog insulin is administered every 3 hours to improve
serum glucose control. Treatment with an oral sulfonylurea
(glyburide) beginning on day 31 of hospitalization ulti-
mately improves control of the fluctuating blood glucose
values. The infant is discharged from the hospital at 34 days
of age with oral sulfonylurea therapy.
Differential Diagnosis
Hyperglycemia in the neonatal period has several causes,
including high rates of glucose infusion during paren-
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endocrinology neonatal diabetes mellitus
teral nutrition therapy or an early manifestation of a stress
response to a critical illness, especially bacteremia or
injury. Hyperglycemia also can be seen with glucocorti-
coid therapy and following phenytoin administration
(suppression of insulin release/insulin sensitivity). (4)
Neonatal diabetes mellitus, a rare cause of hyperglycemia
(described in 1 in 300,000 to 500,000 cases), is defined
as persistent hyperglycemia occurring in the first 6 post-
natal months. (5) Most infants in this category are small
for gestational age and can present with signs of dehy-
dration, weight loss, and glucosuria with or without
ketonuria in addition to hyperglycemia.
Neonatal diabetes mellitus can be categorized accord-
ing to syndromic and nonsyndromic causes of hypergly-
cemia. Syndromic causes of permanent diabetes mellitus
(PNDM) include: (2)
Promoter transcription factor 1 (PTF1A)-related in
which mutations in the PTF1A gene cause variable
degrees of pancreatic agenesis. This syndrome can
be associated with cerebellar agenesis and severe
neurologic dysfunction.
Immune dysregulation, polyendocrinopathy, and
enteropathy X-linked (IPEX) syndrome in which
affected individuals develop systemwide autoim-
munity in the first year after birth. Inheritance is
X-linked, and most affected males have the com-
monly observed triad of watery diarrhea, eczema-
tous dermatitis, and insulin-dependent diabetes
mellitus.
Wolcott-Rallison syndrome, which involves
infantile-onset diabetes mellitus, exocrine pancre-
atic dysfunction, epiphyseal dysplasia, develop-
mental delay, acute liver failure, osteopenia, and
hypothyroidism.
A syndrome of neonatal diabetes with congenital
hypothyroidism that involves neonatal diabetes,
congenital hypothyroidism, congenital glaucoma,
hepatic fibrosis, and polycystic kidneys.
Our patient did not have a phenotype or other diag-
nostic features consistent with syndromic hyperglycemia,
and we documented normal newborn screening results
with normal thyroid function. Although she was small for
gestational age, syndromic hyperglycemia was excluded
early in our evaluation.
Among the nonsyndromic causes of hyperglycemia,
transient neonatal diabetes mellitus (TNDM) comprises
50% to 60% of cases of neonatal diabetes. This entity
begins in the first 6 postnatal weeks in a term infant and
subsequently improves by 24 months in the majority of
cases (93%). Affected infants typically develop diabetes in
the first week after birth and have severe intrauterine
NeoReviews Vol.11 No.6 June 2010 e307
endocrinology neonatal diabetes mellitus
growth restriction, dehydration, and hyperglycemia
without ketoacidosis. (6) Paternal uniparental disomy of
chromosome 6, unbalanced duplication of 6q24 on the
paternal allele, and 6q24 methylation defect are three
mechanisms known to cause TNDM in 90% of cases.
(3)(7) Although cases resolve within 1 year, a small
number of patients have recurrent diabetes in adoles-
cence and adulthood. Further research to delineate
whether these recurrences are due to insulin deficiency or
insulin resistance is required.
Molecular Diagnosis
Excluding syndromic causes, PNDM can be due to gene
mutations affecting the adenosine triphosphate (ATP)-
sensitive potassium channel. Of the five gene muta-
tions identified, mutations in KCNJ11 have been attrib-
uted to 30% of PNDM cases. (1) In addition, mutations
in ABCC8 (19%), INS (20%), and GCK (4%) are associ-
ated with development of PNDM. (2) The mode of
inheritance for KCNJ11 mutation is autosomal domi-
nant. (8) KCNJ11 codes for proteins (Kir6.2) that form
components of the pancreatic beta cell potassium ATP
channel. (8)(9) In a normally functioning beta cell,
following uptake of glucose, the increase in the intracel-
lular ATP/adenosine diphosphate (ADP) ratio results in
closure of the potassium ATP channels. This causes
depolarization of the cell membrane and opening of
voltage-dependent calcium channels. The influx of cal-
cium is the mechanism that triggers insulin release.
Among individuals who have KCNJ11 and ABCC8
gene mutations, the potassium channels fail to close,
and the influx of calcium does not occur. The defects
associated with GCK mutations indirectly affect the
ATP-sensitive potassium channels by altering the
intracellular ADP/ATP ratio. These events result in fail-
ure of glucose-stimulated insulin secretion (directly in
KCJ11 and ABCC8 mutations, indirectly in GCK
mutations).
The phenotype of the disease largely depends on the
severity of the mutation and the expression of the gene.
Marked hyperglycemia, normal C peptide values, and
low birthweight (at or below the 3rd percentile) are
common phenotypic features of most cases of PNDM.
(5) Differences in the expression of the mutation in
KCNJ11 in the central nervous system and skeletal mus-
cle show the marked variation in the phenotype. Several
cases of neonatal diabetes associated with neurologic
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abnormalities have been reported. The most severe is
described as developmental delay, epilepsy, neonatal di-
abetes (DEND) syndrome. (5)
The incidence of PNDM due to defects in KCNJ11
continues to increase. An extensive review of the litera-
ture indicates approximately 96 cases reported toward of
the end of 2009. Importantly, most cases of TNDM and
PNDM cannot be differentiated clinically and require
molecular diagnosis. When persistent neonatal hypergly-
cemia occurs without an underlying cause or without an
identifiable syndrome, genetic analysis is required to
identify the precise molecular defect that will aid in
determining the clinical prognosis, guide treatment, and
provide for genetic counseling. Quality of life may be
substantially improved if the infants condition can be
managed on oral medication.
Treatment initially involves control of hyperglycemia
with use of a continuous insulin infusion. However, if
genetic screening reveals the presence of mutations in
KCNJ11 or ABCC8, an alternative therapeutic strategy
with oral sulfonylureas can be employed. Use of oral
sulfonylureas for treatment of neonatal hyperglycemia
due to defects in KCNJ11 is believed to be due to the
effects of the drug on closure of the potassium-sensitive
ATP channels on the beta cell. (5) This stimulates the
cascade of events leading to insulin release from the beta
cell. Studies have shown that sulfonylurea treatment
provides improved glycemic control, as demonstrated by
lower blood glucose concentrations and reduced hemo-
globin A1C measurements when compared with insulin
treatment. (5) A caveat to this is that sulfonylurea therapy
has been shown to be beneficial in most, but not all cases.
Current research provides insufficient evidence as to why
sulfonylurea therapy is not as effective in about 20% of
infants. (7) Importantly, further evaluation of this treat-
ment modality is required because the safety of pro-
longed use of sulfonylurea therapy in children has not
been established.
Having eliminated the other causes of hyperglycemia,
molecular diagnosis was undertaken for our infant, which
revealed a defect in KCNJ11. Although the infants
serum glucose could be lowered successfully with continuous
insulin infusion during the initial 24 hours after admis-
sion, the use of subcutaneous short- and longer-acting insu-
lin resulted in wide variations in serum glucose values
(Fig. 1), with a short interval of lispro insulin therapy prior
to receipt of the genetic diagnosis. Glucose values after
initiation of treatment with an oral sulfonylurea (gly-
buride) and subsequent dose adjustment to avoid low blood
values (discharge dose of glyburide 0.5 mg orally every
12 hours) is documented in Figure 2. Blood glucose values
 endocrinology neonatal diabetes mellitus

on discharge ranged from 50 to

183 mg/dL (2.8 to 10.2 mmol/L).
The maximum glyburide dose re-
quired by this infant (0.7 mg/kg per
day) was within the reported range
of drug doses used to treat children
who have neonatal diabetes (0.05
to 1.5 mg/kg per day) and compar-
able to the doses used by others
(0.85 mg/kg per day) in manage-
ment of the disease in a child who had
nonKATP channel genetic mutation-
associated neonatal diabetes melli-
tus. (10)(11)
Neonatologists and a geneticist
who evaluated the infant also per-
formed similar molecular diagnos-
tic testing on the mother and con-
firmed that she manifested the same
sulfonylurea receptor disorder. The Figure 1. Serum glucose concentrations after admission and after the initiation of
mother was transitioned from insu- detemir and glulisine insulin therapy following a short interval of continuous insulin
lin pump therapy to oral sulfonyl- infusion. On day 24, when the molecular diagnosis of sulfonylurea receptor deficiency was
urea (glyburide) therapy, which made, the infant was transitioned to lispro insulin and glyburide orally. Glucose values are
should improve her quality of life sub- represented with diamonds over time, with the upper and lower limits. Glucose values
stantially. were difficult to maintain on insulin therapy in concert with breastfeeding, as illustrated.
The transition from insulin to oral sulfonylurea therapy begins on day 24.
Conclusion
This case demonstrates the impor-
tance of reviewing the origins of
maternal diseases known to com-
plicate pregnancy and influence the
newborn. Although rare and esti-
mated to occur in 1 in 300,000 to 1
in 500,000 live births, familial
PNDM has been documented early
in the newborn period. Thus, a
molecular basis of neonatal hy-
perglycemia should be sought to
provide for therapies that can be
administered orally, thereby avoid-
ing the long-term complications
associated with prolonged insulin
therapy. In addition, questions re-
garding the safety of sulfonylurea
use in children and the long-term
outcomes of infants and children
treated with sulfonylureas remain
to be identified, and off label
use of these medications will con- Figure 2. Serum glucose concentrations (diamonds) achieved over days 26 to 28 on
tinue. Long-term neurodevelop- varying doses of oral glyburide. Bars indicate glyburide therapy as mg/kg infant body
mental follow-up of this infant and weight.

NeoReviews Vol.11 No.6 June 2010 e309

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endocrinology neonatal diabetes mellitus

follow-up electroencephalography in addition to close
monitoring of glucose are underway.
American Board of Pediatrics Neonatal-Perinatal
Medicine Content Specification
Know the causes, including genetic and
autogenic disorders, of neonatal
hyperglycemia, including transient diabetes
mellitus.
References
1. De Leon D, Stanley C. Permanent neonatal diabetes mellitus.
Gene Reviews. 2008:124
2. #601410: Diabetes mellitus, transient neonatal 1. Online Men-
delian Inheritance in Man (OMIM). 2008. Accessed March 2010 at:
http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id601410
3. Temple IK, James RS, Crolla JA, et al. An imprinted gene(s) for
diabetes? Nat Genet. 1995;9:110 112
4. Al-Rubeaan K, Ryan EA. Phenytoin induced insulin sensitivity.
Diabetes Med. 1991;10:968 970
5. Bryan J, Bryan L. Neonatal diabetes mellitus. Endocrine Rev.
2008;29:265291
6. Polak M. Neonatal diabetes mellitus: insights for more common
forms of diabetes [editorial]. J Clin Endocrinol Metab. 2007;92:
3774 3776
7. Polak M, Sheild J. Neonatal and very early onset diabetes
mellitus. Semin Neonatol. 2004;9:59 65
8. Sagen J, Raeder H, Hathout E, et al. Permanent neonatal
diabetes due to mutations in KCNJ11 encoding Kir6.2. Diabetes.
2004;53:27132718
9. Gloyn A, Phil D, Bruining G, et al. Activating mutations in the
gene encoding the ATP-sensitive potassium-channel subunit
Kir6.2 and permanent neonatal diabetes. N Engl J Med. 2004;350:
1838 1849
10. Thrkkahraman D, Bircan I, Tribble ND, et al. Permanent
neonatal diabetes mellitus caused by a novel homozygous (T168A)
glucokinase (GCK) mutation: initial response to oral sulphonylurea
therapy. J Pediatr. 2008;153:122126
11. Loomba-Albrecht LA, Glaser NS, Styne D, Bremer AA. An
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NeoReviews Quiz
6. Neonatal diabetes mellitus is defined as persistent hyperglycemia occurring in the first 6 months after birth,
usually associated with insufficient production of insulin. Of the following, most cases of neonatal diabetes
mellitus represent:
A. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.
B. Promoter transcription factor 1A-related syndrome.
C. Syndrome of neonatal diabetes with congenital hypothyroidism.
D. Transient neonatal diabetes with aberrant genes on chromosome 6q24.
E. Wolcott-Rallison syndrome.

7. Neonatal diabetes mellitus can be transient, recurrent, or permanent. Permanent diabetes mellitus can result
from gene mutations affecting the adenosine triphosphate-sensitive potassium channel. Of the following,
most cases of permanent diabetes mellitus are attributed to mutations involving the gene:
A. ABCC8.
B. GCK.
C. INS.
D. KCNJ11.
E. PTF1A.

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 Neonatal Diabetes Mellitus: The Impact of Molecular Diagnosis
Priti Pun, Robin Clark, Kim-Wah Wan, Ricardo Peverini and T. Allen Merritt
NeoReviews 2010;11;e306
DOI: 10.1542/neo.11-6-e306

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 Neonatal Diabetes Mellitus: The Impact of Molecular Diagnosis
Priti Pun, Robin Clark, Kim-Wah Wan, Ricardo Peverini and T. Allen Merritt
NeoReviews 2010;11;e306
DOI: 10.1542/neo.11-6-e306

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://neoreviews.aappublications.org/content/11/6/e306

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