Permanent Neonatal Diabetes Mellitus (PNDM) is a very rare form of insulin secretory failure that presents within the late fetal or early post natal period. Unlike its transient form, the permanent form of this condition does not go into remission, and remains as a chronic case of Insulin Dependent Diabetes Mellitus (IDDM). The condition is almost always associated with intrauterine growth retardation. However, this growth retardation is corrected with insulin supplementation, implying that it is an effect of low fetal insulin levels, rather than the cause of neonatal diabetes. Other clinical features of PNDM include failure to thrive, fever, thirst, frequent urination, dehydration, hyperglycemia, and acidosis with or without ketonuria. PNDM has a reported incidence of 1 in 400,000 neonates.
Patients with PNDM need to be on exogenous insulin administration throughout their life. Some patients may also respond to oral sulfonylurea treatment.
Many genes have been implicated in the pathogenesis of PNDM. Most important of these are the GCK (Glucokinase), KCNJ11 (Potassium Channel, Inwardly Rectifying, Subfamily J, Member 11), and the ABCC8 (ATP-Binding Cassette, Subfamily C, Member 8) genes. Complete deficiency of the Glucokinase enzyme due to homozygous mutations in the GCK gene results in the severe PNDM, while a heterozygous condition leads to the milder, Maturity Onset Diabetes of the Young. The KCNJ11 and ABCC8 genes, both code for subunits of the pancreatic potassium ATP channel, which is involved in the regulation of insulin secretion. About a third to half of the cases of PNDM seem to have mutations in one of these genes. Interestingly, patients with mutations in these two genes seem to respond better to treatment with sulfonylurea.
Bappal et al. (1999) estimated the prevalence and incidence rates of permanent neonatal insulin dependant diabetes mellitus (PNIDDM) and described its profile in Oman by studying all children (five children) diagnosed with this condition between 1991 and 1995. They were also investigated by viral serology for TORCH and Coxackie virus, presence of islet cells antibodies by indirect immunofluorescence technique on human pancreatic sections, plasma C-peptide concentration by radioimmunoassay, and glycated hemoglobin. HLA typing of all the children was also undertaken. The treatment plan was the same in all the children with a combination of intermediate and short acting human insulin once or twice a day according to the patient's needs. The prevalence and incidence rates (which included the prevalence of insulin dependant diabetes mellitus among the children of under five years) were estimated by using the final results of the general census of population which was published yearly by the Ministry of Health. The mean incidence of PNIDDM during the study period was found to be 2.2/100,000 live births/year which was the highest reported in the world, and the prevalence of IDDM in children under five years by the end of 1995 was 2.0 per 100,000 with 8.8% of all the cases of IDDM in this age group being those with PNIDDM. All children in this study had consanguineous parents, and the prevalences of IDDM and NIDDM were high among their siblings, parents and relatives. Two siblings' father and paternal aunt had IDDM, and NIDDM was found in their grandfather and granduncle, while one mother had gestational diabetes, Hashimoto's thyroiditis was found in another mother and a third mother had vitiligo. The mean age of onset was 15.4 days (6 to 20 days), the mean duration of symptoms before diagnosis was 4.4 days (2 to 8 days), and the presenting symptoms were diarrhea and dehydration in all children, while four out of the five children had fever, polyuria, tachypnea, or lethargy and poor feeding. All children were born with intrauterine growth retardation as their mean birth weights was 1.86 kg (1.5 kg to 2.3 kg), and they were of low weight at the time of diagnosis (mean of 1.94 kg). Initial investigations revealed mean blood glucose of 34.4mmol which did not correlate with either the age of onset or the duration of symptoms, and mean pH of 7.17 (80% had pH less than 7.2) which correlated significantly with the blood glucose. They also had significantly high triglycerides with a mean of 19.06, and mild to moderate ketonuria in four children. Other investigations revealed hyponatremia (sodium did not correlate with blood glucose level), hyperkalemia (potassium did not correlate with blood pH), prerenal uremia in 80% of the children (urea did not correlate with creatinine), and negative viral serology (IgG and IgM classes). No islet cells antibodies were detected in any of the children. During the course of the illness, three infants were admitted five times in the first year for symptomatic hypoglycemia, and three other patients had three episodes of ketoacidosis. There was no evidence of partial or complete remission in any of the children, and the initial C-peptide on presentation was less than 0.199 pmol/l during hyperglycemia and the level continued to be low in serial measurements, reflecting absence of endogenous insulin secretion. HLA typing of the patients revealed HLA DR3 and/or DR4 in 80% of the children which were common HLA loci associated with IDDM. One child developed autoimmune hypothyroidism with the presence of thyroid antibodies and biochemical hypothyroidism, while another child died at the age of 2.5 years after aggressive hepatitis and liver failure following transfusion.
Soliman et al. (1999) corrected the incidence rate of PNIDDM in the Sultanate of Oman during the study period from January 1989 to December 1994 to be 1.788 +/- 0.82 per 100,000 live births per year. They added that at the end of December 1994 the prevalence rate was 2.4 per 100,000 children below the age of 5 years. They constituted 41.6% of all cases of IDDM in this age group. Diarrhea, fever, lethargy, poor feeding and failure to thrive were the most common presenting symptoms. Despite marked growth retardation at birth, there was a significant improvement of growth after initiating insulin therapy. Four of the five patients had normal developmental milestones, one had mild developmental delay following a severe and prolonged attack of hypoglycemia. None of the patients had exocrine pancreatic deficiency.
Deeb et al. (2016) found 25 cases of Neonatal Diabetes Mellitus in Abu Dhabi between the years 1985-2013, giving an incidence rate of 1:29,241 live births. Of these, 23 patients had Permanent Neonatal Diabetes Mellitus (PNDM, incidence rate 1:31,900). The authors noted that the incidence of PNDM was among the highest in the world. Genetic analysis of the PNDM patients revealed recessive EIF2AK3 mutations (in 9 patients), homozygous INS mutations (in 6), deletion of the PTF1A enhancer (in 2), a heterozygous KCNJ11 mutation (in 1) and a novel ABCC8 variant (in 1). The genetic cause could not be determined in 4 PNDM patients. The study highlighted the finding that the etiology of PNDM in Abu Dhabi is different from Europe and USA, but similar to Northwest Saudi Arabia and Turkey. It also emphasized the importance of genetic testing, as the identification of the KCNJ11 mutation allowed the patient to switch from insulin treatment to oral sulphonylurea and the detection of the EIF2AK3 mutation allowed two heterozygous parents to have a healthy child through preimplantation genetic diagnosis.
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