Download A recessive mutations in INS gene in neonatal diabetes A Case

A recessive mutations in INS gene in neonatal diabetes
A Case Report
ABSTRACT
Neonatal diabetes mellitus (DM) is a persistent hyperglycemia occurring in the
first 4-6 weeks of life that lasts more than two weeks and requires insulin for
management. We report a case of a 23 days old boy with neonatal diabetes, due
to recessive inheritance INS promoter C-331 C>A mutation , accompanied by
diabetic ketoacidosis (DKA). The hyperglycemia and ketoacidosis resolved by
the 48th hour of treatment, consisting of IV insulin and rehydration.
Subsequently, insulin treatment was continued with neutral protamine hagedorn
(NPH) insulin. Neonatal DM due to genetic mutation may mimic sepsis and
should be kept in mind in all newborns who present with shortness of breath,
vomiting, and dehydration.
Key words: diabetes, neonatal, INS mutation, DKA.
Introduction
Neonatal diabetes mellitus (NDM) is monogenic diabetes representing 1-5% of
all cases of diabetes mellitus and can be divided in to Transient and permanent
neonatal diabetes mellitus (TNDM and PNDM) occurs in the first 4-6 weeks of
life. NDM is very rare conditions with an incidence of 1 in 300,000 to 500,000 live
births (1). Mutations in KCNJ11, ABCC8, and INS are the major causes of PND
(2). KCNJ11 and ABCC8 encode the subunits of the ATP sensitive potassium
channel (KATP) of the pancreatic β-cells and activating mutations of these
subunits impair insulin secretions (3). The insulin gene (INS) mutations are
associated with PND and other clinical conditions such as type 1b diabetes,
MODY, early onset type 2 diabetes, and TND (4). Here, we report a rare case of
a patient with PNDM due to recessive inheritance INS mutation accompanied by
diabetic ketoacidosis (DKA).
Case Report
A 23 days old baby boy was referred to king abdulaziz university hospital , with
3 days history of vomiting , shortness of breath and irritability , He is a
product of full term gestation , uncomplicated pregnancy , spontaneous vaginal
delivery SVD with low birth weight of 2.3 kg. He was well till three days prior
to presentation there was history of vomiting 2-3 times per day , milk content,
large to moderate in amount , non bilious, non bloody , non projectile , with no
history of diarrhea, constipation , Abdominal distention or jaundice. Associated
with history of Progressive Shortness of breath with no cyanosis, apnea, cough,
or sweating during feeding. Mother mentioned history of Irritability, crying all
night and increase in frequency of changing the dipper and becoming heavier, no
change of color or odor of the urine. He was on breast and formula feeding. No
consanguinity. There was family history of type 2 DM in grandmothers.(figure1)
On physical examination, the infant was irritable, severe respiratory distress in
form of grunting with flaring allae nasi , suprasternal , sub costal and
intercostals recession ,and kussmaul breathing, approximately 10% dehydration
with no dysmorphism .
His vital showed tachycardia (172 beats/min). His respiratory rate was 77
breaths/min, body temperature was 37.6°C (axillary), saturation 98% on room
air and blood pressure was 94/54 mmHg.
First-line laboratory analyses showed in table (1).
Tests
Results
Refrence
Serum glucose
48.2mmol/L
3.9 - 6.7
Serum sodium
122mmol/L
136 - 145
Serum cloride
5.9mmol/L
98 -107
Serum potassium
3.1mmol/L
3.5 - 5.1
Blood urea nitrogen
7.9mmol/L
2.5 - 6.4
Serum creatinine
89Umol/L
53 - 115
VVenous Blood Gas PH:7.023
7.34 -7.45
HCO3:4meq/L
18.5 - 24.5
PCO2:15mmHg
32 - 48
BE:-25
Blood Culture
insulin level
No growth
0.2mIU/l
3 - 17
C-Peptide
0.183nmol/l
0.37 - 1.47
Lactic acid
1.4
0.4 - 2
urine analysis
Specific gravity:1.028
Glucose:+4
Ketones:+3
urine culture
No growth
A diagnosis of DKA was made; case was referred to the PICU started on
intravenous insulin (0.1 IU/kg/hour) and a rehydration solution. Hyperglycemia
and ketoacidosis resolved by the 36th hour of treatment. Breastfeeding was
resumed with feedings at three intervals. Insulin treatment was continued with
subcutaneous neutral protamine hagedorn (NPH) (1 IU/kg/day) insulin.
Genetic testing result confirmed the diagnosis of recessively inherited neonatal
diabetes due to homozygous mutation in gene INS located at promoter with DNA
description c-331 C>A.
During the follow-up, glucose levels were 5.2 mmol/l, His most recent HbA1c
4.2%. Currently, the patient is 2 months old on NPH regiment.
Discussion
NDM is a rare entity & can be presented with non specific sepsis –like
symptoms including grunting, shortness of breath, tachypnia, lethargy,
irritability & jaundice.
ND cases include transient (TND) and permanent (PND) forms of
diabetes, which display differing insulin dependency and molecular
mechanism of disease pathogenesis (5).
Intrauterine growth restriction has been reported in PNDM associated
with recessive INS mutations (6). Our case had homozygous INS
promoter mutation (C-331 C>A), and his birth weight was on the 3rd
centile (2.3Kg) with high possibility to be PNDM.
The most common causes of PNDM are mutations in the genes encoding for the
two subunits of ATP-sensitive potassium channel (KATP) of the pancreatic beta
cell, KCNJ11 and ABCC8, accounting for about 50 and 10% of all cases,
respectively. However, heterozygous, dominant mutations in the insulin gene
(INS) are also frequently found in patients with PNDM, representing about 15–
20% of all cases [2,7].
Most patients with PNDM have activating mutation in KCNJ11 or
ABCC8, the gene encoding the potassium ATP-sensitive channel subunits
Kir 6.2 and SUR1 (8,9), or heterozygous mutations in priproinsulin INS
gene(2,10). In contrast abnormality in chromosome 6p24 are the most
common cause of TNDM (11), followed by mutations in KCNJ11 and
ABCC8 gene (12).
Despite these advances, the etiology of neonatal diabetes is still not known
in 30% of patient with PNDM(13), suggesting other genetic (syndromatic)
causes such as Woclott-Rallison syndrome(AR),immune dysregulation,
polyendocrinopathy ,enteropathy, X-linked (IPEX) syndrome (x-linked
R),phosphoribosyl-ATP pyrophosphate hyperactivity (X-linked),&
glucokinase deficiency (MODY2)(14).
In recessive mutations diabetes occur as result of decrease insulin
biosynthesis through distinct mechanisms, including gene deletion, lack of
translation initiation signal, and altered mRNA stability because of
disruption of polydenylation signal(6). A subset of recessive mutations
caused abnormal INS transcription, inclouding the deletion of C1 and E1
cis regulatory element, or three different single base-pair substitution in a
CC dinucleotide sequence located between E1 & A1 element(6). As in our
patient with mutation in C-331 C>A.
Patient with recessive INS were diagnosed earlier (median 1 week vs. 10
weeks) and have lower birth weight (-3.2 SD score vs. -2 SD score)
compared to those with dominant INS mutations (6).
Insulin therapy is crucial in TNDM and some cases of PNDM to obtain
satisfactory weight gain and growth in those infants .on the other hand
PNDM due to mutation in KCNJ11 or ABCC8 usually respond to
sulfanyleurea (6,14,15).
In conclusion, recessive mutations in INS is a rare cause of neonatal
diabetes and should be suspected in every patient presented with picture
of neonatal sepsis.
References
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Figure 1: Squares represent male family member, and circles represent
female member. Solid squares represent persons with diabetes carrying the mutation
.