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Indian Pediatr 2013;50:
759-763 |
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Clinical Profile and Outcome of Infantile
Onset Diabetes Mellitus in Southern India
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Poovazhagi Varadarajan, Thangavelu Sangaralingam, *Senthil
Senniappan, Suresh Jahnavi,
#Venkatesan Radha and
$Viswanathan
Mohan
From the Department of Pediatrics, Institute of Child Health and
Hospital for Children, Chennai, India; *Endocrinology, Great Ormond
Street Hospital for Children, London, UK; #Department
of Molecular Genetics, Madras Diabetes Research Foundation , and
$ Madras Diabetes Research Foundation, Chennai,
India.
Correspondence to: Dr Poovazhagi Varadarajan, 8/11 Manjolai Street,
Kalaimagal Nagar,
Ekkaduthangal, Chennai, Tamilnadu 600 032, India.
Email: [email protected]
PII: S097475591200932
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Objective: To study the etiology, clinical presentation and outcome
of infantile onset diabetes mellitus (IODM).
Design: Descriptive cohort study. Retrospective
study from 1999-2007 and prospective from 2008-2012.
Setting: The diabetic clinic at a Pediatric
tertiary care referral institute in Chennai.
Methods: All infants diagnosed to have diabetes
at less than one year of age were studied. Study variables were age at
onset, gender, mode of presentation, birth weight, initial blood
glucose, serum HbA1c, serum c–peptide levels, outcome at initial
presentation, insulin requirement, associated co-morbid conditions,
genetic analysis and outcome at the end of the study or until they were
followed up.
Results: 40 infants with infantile onset diabetes
were studied, constituting 8% of all children with onset of DM at less
than 12 years of age. 67.5% of these children presented with diabetic
keto acidosis (DKA), only 30% had a provisional diagnosis of DM or DKA
at first physician contact. 63% of IODM with onset less than 6 months
and 30% with onset more than 6 months were of low birth weight. Nearly
85% of the study group had low C-peptide levels. 84.5% of IODM with
onset less than 6 months and 55% of those with onset more than 6 months
were monogenic. Wolcott Rallison syndrome was the commonest type
encountered. Genetic diagnosis aided switching over from insulin to oral
sulphonylurea in 5 children with KCNJ11 and ABCC8
mutations. Missed diagnosis, recurrent admissions for metabolic
instability and developmental delay were common problems in IODM.
Mortality at 12.5 year follow up was 32.5%.
Conclusions: IODM with onset at less than 6
months is predominantly monogenic and low birth weight is more common.
55% of IODM were misdiagnosed at onset. Developmental delay is the
common co morbid condition in IODM. Genetic diagnosis aids change of
therapy to oral sulphonylurea.
Keywords: India, Infantile onset diabetes, Monogenic diabetes,
Neonatal diabetes.
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Infantile Onset Diabetes Mellitus (IODM) is an
uncommon form of diabetes. Diabetes Mellitus (DM) in the first 6 months
of life is usually monogenic and is referred to as neonatal diabetes,
and recent studies have suggested extending the screening for monogenic
diabetes into later part of infancy [1]. Hospital-based incidence has
been reported to be 1 in 125 type I DM patients [2]. Pediatric hospital
based studies reveal the incidence of IODM as high as 1 in 7 children
[3]. The reported incidence of neonatal diabetes mellitus varies from 1
in 89,000 to 1 in 4,00,000 live births [4-6]. Neonatal diabetes can be
either transient or permanent. Transient neonatal diabetes is usually
associated with abnormalities of chromosome 6 and KCNJ11 and ABCC8
[7]. Transient DM usually resolves before 18 months of age
but may reappear in early childhood [8]. Incidence of permanent neonatal
diabetes mellitus (PNDM) is 1 in 90,000 to 1in 2, 10,000 and these
infants present with persistent hyperglycemia which requires long term
insulin therapy [8]. This paper reports on 40 infants with IODM. To the
best of our knowledge this is the only study on IODM with a follow up
and genetic evaluation.
Methods
This descriptive study was conducted between January
2008 and April 2012 at the diabetic clinic of Institute of Child Health
and Hospital for Children, a major teaching hospital in Chennai, India.
The objective was to study the presentation and outcome of IODM. Data
collection was retrospective from 1999 to 2007 and prospective from 2008
to 2012. For the purpose of this study, children with onset of diabetes
at less than one year of age were considered as infantile onset and they
were sub classified as neonatal if the onset was less than 6 months of
age. (fasting C-peptide levels <0.5 pmol/mL was considered poor
pancreatic reserve). Data on infants treated as DKA where the
hyperglycemia persisted for <72 hours or infants who were treated as DKA
but died without confirmation by estimation of serum c-peptide levels or
serum insulin levels or HBA1 c at hospitalization were not included.
Study parameters included age at onset, gender, mode of presentation,
provisional diagnosis at admission, birth weight, initial blood glucose,
serum HbA1c, serum c–peptide levels, outcome at initial presentation,
insulin requirement, associated co-morbid conditions, genetic analysis
and outcome at the end of the study or until they were followed up.
Data were analyzed using Epi Info statistical
software and proportions were calculated. The study was undertaken after
the approval of the institutional ethical and scientific review board.
Informed consent was obtained from caregivers of all prospective
subjects.
Results
Over a period of 12.5 years from 1999 to 2012, 506
children aged less than 12 years were registered in our diabetic clinic
with diabetes Mellitus (DM), of whom 40 children (19 males) were IODM
i.e., diagnosed at age less than one year (7.9 % of the total clinic
diabetic population). Age at diagnosis ranged from 3 days to 12 months
(median 3.75 months). 27(67.5%) infants presented with diabetic keto
acidosis (DKA) at the onset. Only 13 infants were initially diagnosed to
have either diabetes or diabetic keto-acidosis. Revision of diagnosis
was made with blood glucose values in 22 infants while 5 infants were
screened for diabetes based on parental suspicion because the siblings
were known to have diabetes.
14 infants with IODM (30%) were born of
consanguineous marriage. 27.5% of the mothers reported previous
miscarriage or death of a sibling in infancy. Fever and polyuria were
the commonest presenting symptoms (Table I). Evaluation
for fever or hepatomegaly was a common mode of incidental diagnosis.
Candidiasis of the external genitalia was the primary reason for medical
attention in three infants. Sticky urine with flies and ants around the
urinated floor was the primary reason for parental suspicion of diabetes
in three infants.
TABLE I Clinical Presentation of Infantile Onset Diabetes
Initial presentation |
Number (%) |
Fever |
24(60%) |
Polyuria |
20(50%) |
Breathlessness |
18(45%) |
Vomiting |
18(45%) |
Altered sensorium |
16(40%) |
White genital patches |
4(1%) |
Poor feeding
|
3(0.75%) |
Irritability |
3(0.75%) |
Sticky urine
|
3(0.75%) |
Seizures
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2(0.5%) |
Birth weight of the infants ranged from 1.6 to 3.5 kg
(mean 2.39 ± 0.48) and 50% of the babies were low birth weight (<2.5
kg). Neonatal diabetes was encountered in 28 infants (70%). The initial
blood glucose ranged from 236 mg/dL to 950 mg/dL (mean 477 mg/dL). Among
the 25 infants who had C-peptide evaluation, 21(84%) had poor pancreatic
reserve while 3 were in the normal range. High C-peptide was seen in one
infant with Berardinelli Seip Congenital Lipodystrophy (BSCL). Mean
HbA1c at diagnosis was 9.4± 2.4%.
Among the children with neonatal diabetes (i.e.
onset <6 months of age), prevalence of low birth weight was higher than
those with onset above 6 months of age (P=0.04) (Table
II).
TABLE II Comparison Between Infants with Onset of Diabetes Before and After 6 Months of Age
Parameters |
Diabetes onset |
Diabetes onset
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|
<6 mo of age
|
between 6-12 mo
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|
(n=28 ) |
of age (n=12) |
M:F ratio |
1:1.2 |
1:1 |
Birth weight <2.5 kg |
63% |
30%* |
Mean initial blood glucose (mg/dL) |
478 |
477 |
Presentation as DKA |
60.7% |
75% |
Mean insulin dose |
1.19#
|
1.4#
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Mortality at presentation |
3.6% |
8.3% |
Overall mortality
|
21.42% |
41.6% |
Monogenic DM |
16/19= 84.2% |
5/9=55.5% |
*P=0.04; #units/kg/day. |
Among the 40 infants, 2 died at initial presentation,
5 were referred back to the referring institute after initial
stabilization and were not followed in our diabetic clinic. 33 infants
were followed up for variable duration ranging from 30 days to 12.5
years. During follow up, 4 (10%) infants (3 female) had complete
remission of DM (ability to maintain euglycemia without insulin). One
infant with ABCC8 mutation remitted at 6 months but was restarted
on insulin at 9.7 years of age due to persistent hyperglycemia.
Following genetic analysis, she was successfully switched over to oral
sulphonylurea at 10 years. The second child remitted at 5 months of
therapy and is off insulin for 17 months with a HbA1c of 5.4 and has
normal growth and development. The third child with ABCC8
mutation remitted at 4.5 months of age and is off insulin for 5.5 years
with HbA1c of 6.4%. The fourth child remitted at 4 months of therapy and
is off insulin for 14 months and tested negative for ABCC8, KCNJ11
and INS.
TABLE III Syndromic Forms and Genetic Mutations of IODM
Types
|
Predominant clinical features |
Onset <6mo |
Onset >6 mo
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Wolcott Rallison syndrome |
Developmental delay, short stature, elevated liver enzymes,
hepatic failure, skeletal dysplasia |
5 |
4 |
Berardinelli Seip congenital lipodystrophy |
Insulin resistance, failure to thrive, hepato- splenomegaly,
lack of subcutaneous fat, coarse facies,
hypertriglyceridemia |
|
1 |
Fanconi Bickel syndrome |
Round facies, hepatomegaly, rickets |
1 |
|
Other Genetic mutations |
ABCC8 |
5 |
|
|
KCNJ11 |
2 |
|
|
GCK |
1 |
|
|
INS1 |
1
|
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Based on the clinical features and genetic reports
[9], the classification arrived in 21 infants is shown in Table
III. Amongst the remaining 19 infants, one had pancreatic hypoplasia,
seven were negative for KCNJ11, ABCC8 and INS and eleven infants
did not undergo genetic evaluation. Five IODM’s with mutation in
KCNJ11 and ABCC8 were switched over to sulphonylurea (glibenclamide)
successfully (Table IV). All are developmentally normal.
TABLE IV Transfer of Infants from Insulin to Oral Sulphonylurea Therapy (Glibenclamide)
No |
Genetic mutation |
Age at diagnosis |
Age at switch |
Glibenclamide dose |
HbA1c before
|
HbA1c after |
Current age
|
|
|
of DM (months) |
over (months) |
at switch over |
switch over |
switch over |
(months) |
1 |
ABCC8 |
4 |
120 |
0.75 mg/kg/day |
9.8 |
7.6% |
122 |
2 |
KCNJ11 |
2.73 |
22 |
1 mg/kg/day |
7.97% |
5.1% |
46 |
3 |
KCNJ11 |
2.83 |
5 |
1 mg/kg/day |
7.2% |
6.9% |
15 |
4 |
ABCC8 |
1.27 |
7.5 |
1.2 mg/kg/day |
7.3% |
5.9% |
14 |
5 |
ABCC8 |
2.6 |
4 |
1.75 mg/kg/day |
14.6% |
6.8% |
10 |
WRS was the commonest form of syndromic diabetes in
this study group. Of the 9 infants with features suggestive of WRS, 4
were genetically confirmed to have EIF2AK3 mutation. Four
children with WRS had an episode of hepatic failure and recovered. Two
of the 9 infants had radiological features suggestive of WRS and
associated hypothyroidism was encountered in 5 children. Among the four
children with EIF2AK3 mutation, one died at 3 years of age.
The common co-morbid conditions were
hepatosplenomegaly (35%) and developmental delay (51.5%). Less common
co-morbid features included short stature, squint, microcephaly, optic
atrophy and failure to thrive. Recurrent hospitalization after the
initial diagnosis was encountered in all but 7 of the infants followed
up at our centre. The reasons for hospitalization were hypoglycemic
episodes, DKA and hyperglycemia with intercurrent infections and hepatic
failure. Recurrent DKA was a major issue in three infants due to poor
compliance with therapy. During follow up, hypoglycemic episodes were
encountered in most of the children. Over the period of 12.5 years, 13
out of the 40 infantile onset diabetic children died. Causes of death
were DKA with cerebral edema, sepsis, acute respiratory distress
syndrome, disseminated intravascular coagulation, hypoglycemia,
refractory cardiac failure, septic shock and renal failure.
Discussion
The incidence of IODM among all children with
diabetes mellitus (<12 years) seen at our centre is 1 out of 13. No
gender preponderance was noted in contrast to the existing literature
with female preponderance [1, 2]. It is clinically difficult to
differentiate between Transient neonatal diabetes mellitus and Permanent
diabetics mellitus. PNDM could be nonsyndromic, syndromic or rarely due
to pancreatic hypoplasia. Both non syndromic and syndromic PNDM may be
due to mutation as previously described [10].
Identification of infants with ABCC8/KCNJ11
mutation provides an opportunity to switch over from insulin injections
to oral sulphonylurea therapy [ 5-7,11-15]. Insulin alone may not be
able to reverse the neurological impairment in infantile onset diabetes.
But oral sulphonylurea therapy can improve both the glycemic control and
neurological status in some of these patients [16]. Rarely type1 DM with
onset in infancy has been reported as also the KCNJ11 mutation
beyond 6 months in infancy [17,18].
The prevalence of monogenic diabetes varies from 63%
to 78.5% in infants under 6 months and 6.6% to 12.5% in infants between
7-12 months. [19,20].The prevalence was correspondingly 84% and 55% in
this study. The increased incidence in infants between 7- 12 months is
probably due to the increased occurrence of Wolcott Rallison syndrome
and this could probably be explained by the higher incidence of
consanguinity.
DKA as the initial presentation was encountered in
67.5% in comparison to 83% in an earlier study from Chennai [3]. Missed
diagnosis is common in infantile onset DM (67.5%). Classical symptoms of
diabetes were not the presenting complaint in most of the cases.
Incidental hyperglycemia was the diagnostic clue in 17 infants. Initial
diagnosis in the study group included acute CNS infection, septic shock,
urinary tract infection, renal tubular acidosis, bronchopneumonia,
bronchiolitis, diarrheal dehydration, metabolic encephalopathy, and
hepatomegaly for evaluation. Fever, vomiting and lethargy are common
manifestations of IODM [21]. Evaluation of these infants should include
family history of consanguinity, examination for dysmorphic features,
auto-antibodies for type 1 DM followed by genetic studies. It is
essential to evaluate for monogenic diabetes in all antibody negative
infants with diabetes mellitus.
Among the 40 infants, mortality at initial diagnosis
was 5%. Need for hospitalization exists for most of the diabetic infants
during follow up for severe metabolic derangements or intercurrent
infection. Children with WRS have hepatomegaly, elevated liver enzymes,
short stature, skeletal deformities, and developmental delay with or
without hypothyroidism [22]. Hypoglycemic episodes and hepatic failure
are common in WRS. Mortality is reported to be high in WRS [1,3,22].
Infantile onset BSCL is very rare and the infant in this study had
hepatosplenomegaly, generalized lack of subcutaneous fat, hirsutism,
dyslipidaemia, and dysmorphic facies and died of a rapid fatal course.
Insulin requirement at stabilization for infants
ranged from 0.35 to 3 units/kg/day. Intermediate acting insulin is
preferred as this prevents hypoglycemia associated with short acting
insulin. Use of continuous subcutaneous insulin infusion may be an ideal
option to deliver smaller doses of insulin [23]. Dispensing less than
one unit of insulin posed difficulty in IODM. Developmental delay and
seizures were the common co-morbid conditions. Syndromic associations
like Wolcott Rallison syndrome, DEND syndrome [24], consequences of the
hypoglycemia and cerebral edema in DKA could explain the high incidence
of developmental delay and seizures in IODM. None of the children
followed up showed retinopathy or nephropathy. Mortality in IODM over
12.5 year period was 32.5%. A pediatric report of one year follow up of
IODM have shown a mortality of 16.6% from Chennai [3]. The limitations
of this study include lack of genetic diagnosis in some the infants due
to various reasons and being a retrospective study at a referral centre,
not all subjects were followed up to the end of the study period.
Acknowledgments: Molecular genetic laboratory at
Royal Devan and Exeter NHS foundation trust for performing a part of the
genetic work up free of cost.
Contributors: VP: designed the study and was
involved in the data collection; VP, ST, SS and MV: were involved in the
study design and data analysis; JS and RV: were involved in the genetic
evaluation. All the authors were involved in manuscript preparation.
Funding: A part of the genetic investigations for
children in this study group was done by the Indian Council of Medical
Research through the project "Genetic Analysis of Maturity Onset
diabetes of young (MODY) and Neonatal diabetes in India".
Competing interest: None stated.
What Is Already Known?
• Indian literature describes few case
reports of neonatal diabetes and its outcome.
What This Study Adds?
• Diagnosis is often missed in infantile
onset diabetes mellitus.
• Among the IODM with onset at age <6 months,
85% is monogenic.
• Developmental delay is more common in
infantile onset diabetec melletus and mortality is 32.5%.
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