الفهرس 
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Abstract
Type 1 diabetes mellitus (T1DM) is the most common cause of diabetes mellitus (DM) in children, accounting for over 95% of cases. Amongst patients diagnosed with early-onset DM especially those diagnosed before the age of 12 months, there is an increasing recognition of diabetes caused by single gene mutations [also known as monogenic diabetes of infancy or neonatal diabetes mellitus (NDM)].
About 50% of NDM patients are due to ATP-sensitive potassium (KATP) channel mutations, which can be transferred from insulin to oral sulphonylurea (SU) therapy leading to a paradigm shift in their management. Therefore, molecular testing to confirm the genetic cause of DM is essential to improve their clinical care.
The aim of this study was to classify patients diagnosed with early-onset DM at Alexandria University Children’s Hospital (AUCH) into T1DM, and monogenic DM categories, and to detect differences in molecular characteristics of NDM patients at our center in comparison to other countries.
This retrospective/prospective observational study was conducted on 62 patients diagnosed with early-onset DM (age of onset <2 years) at AUCH from January 2000 to November 2020. The patients were divided into 3 groups according to the age of onset of DM: group 1 included 12 patients diagnosed ≤6 months, group 2 included 27 patients diagnosed >6-12 months, while 23 patients >12-24 months at onset were assigned as group 3. Molecular testing was done in patients diagnosed with DM ≤6 months and those with negative pancreatic autoantibodies.
The age range at enrollment in the current study was 1.40–17.82 years, with a median of 4.10 years. The ratio between males to females was almost 1:1. Patients came mainly from urban areas in Alexandria, in addition to 4 other governorates including
El-behira, Sohag, Kafr El-Sheikh, and Matrouh.
Twenty one percent of the patients (13/62) were born to consanguineous parents. Almost a third of the patients diagnosed with DM at age of onset ≤6 months had positive consanguinity; however, no significant difference was detected in comparison to other groups. Twenty two percent of the patients had diabetic parents. A quarter of the patients (3/12) diagnosed with DM at age of onset before 6 months had a diabetic sibling.
The median of maternal age at delivery was 27 years and the median of GA of the patients was 39 weeks. Patients diagnosed ≤6 months of age had birth weights significantly lower than groups 2 and 3 (p1=0.018*, and p2=0.001* respectively). The probability of having a monogenic cause of DM was higher in patients who were born small for gestational age (SGA), as 5 out of 6 patients with SGA had a confirmed genetic diagnosis.
The majority of patients were exclusively breast-fed (71%). It was noticed that patients diagnosed before 6 months of age had earlier age of introduction of solid food than the other groups, with a median of 5 months (IQR 4.5–6 months).
The majority of patients were diagnosed initially with DKA (85.5%). Almost three quarters of the patients (46/62) were diagnosed with cerebral edema complicating DKA and improved on receiving mannitol or hypertonic saline, and 5 patients (8.1%) had convulsions at diagnosis.
The weight Z-score at onset in our cohort was significantly lower in patients diagnosed ≤6 months of age compared to the other age at onset groups (median -2.26 vs
-0.46 vs -0.76 SD, p=0.009*). At follow up, the least weight Z-score was observed in group 1 ranging between -5.78 and 0.91 SD (median -0.89 SD), with a statistically significant difference in comparison to other groups (p=0.022*). Patients in group 1 were shorter compared to groups 2 and 3 (median -1.99 SD), with a statistically significant difference of p=0.001* (p1=0.006*, p2<0.001*).
Neurological manifestations were the most frequently reported extra-pancreatic features (13/62, 21%), with epilepsy being the most common in 14.5% of the patients. Other neurological features reported in our cohort included developmental delay, hypertonia, muscle weakness, squint, and facial palsy. The second most common extra-pancreatic feature was short stature in 8 out of 62 patients (12.9%); 6 of whom were diagnosed with DM at age below 6 months (50% of group 1) with a statistically significant difference in comparison to other groups (p<0.001*). Six patients (9.7%) had lower limb deep vein thrombosis at initial presentation with DKA, and three patients (4.8%) had umbilical hernia.
Twenty four patients (38.7%) had T1DM, whereas 11 patients (17.7%) had genetically confirmed monogenic cause of DM. We identified 4 novel and 7 known mutations causing monogenic DM in the current study. More than 60% (7 out of 11) of patients with a genetic diagnosis were diagnosed with DM at or below 6 months of age. The most common monogenic causes of DM were EIF2AK3 mutations (n=3), followed by KCNJ11 (n=2), and ABCC8 (n=2). Other mutations included SLC19A2 (n=1), INS (n=1), GCK (n=1), and TNFAIP3 (n=1).
Wolcott-Rallison syndrome caused by EIF2AK3 gene mutation was the most common cause of NDM accounting for 42.9% of patients diagnosed at age ≤6 months. Two of the identified EIF2AK3 mutations in the present study were known, while a homozygous novel missense mutation was identified in one patient. The three patients with WRS were all born to consanguineous parents; who were confirmed to be heterozygous carriers for the EIF2AK3 mutation.