A novel case of neonatal diabetes as an isolated part of immune dysregulation, polyendocrinopathy, X‐linked (IPEX) syndrome

In this report, we present the first known case of intermediate developmental delay, epilepsy and permanent neonatal diabetes (DEND) syndrome caused by a Q52R mutation in the KCNJ11 gene who was successfully switched (at age 1.3 years) to sulphonylurea monotherapy, namely glibenclamide. The most recent evaluation, after 2 years, showed a glycated hemoglobin level of 6.0% (42 mmol/mol). This mutation is so severe that none of the previously reported four cases were able to switch from insulin to sulphonylurea monotherapy. The Q52R mutation seems to have a chance of positive response to glibenclamide administered every 3–6 h instead of the classical 8–12 h, in doses around or above 2.5 mg/kg/day.

BackgroundNeonatal diabetes along with congenital anomalies like duodenal atresia, tracheoesophageal fistula, intra uterine growth retardation, extrahepatic biliary obstruction and hypoplasia of pancreas is a very rare occurrence with evidence linking...

Background: A very rare disease, neonatal diabetes has historically been treated with subcutaneous insulin. A recent study showed efficacy of oral glyburide on a specific subset of newborns diagnosed with neonatal diabetes, and that it is safe to try even before genetic test results are available. Clinical Case: 1 day old male born at 41 weeks and 1 day was found to by hyperglycemic to the 300s. At that time, it was thought to be reactive hyperglycemia as he was in respiratory distress, had a pneumothorax, and his mother was GBS positive. He was started on an insulin drip, which was titrated to his blood glucose levels. At this time, serum insulin and C-peptide levels were found to be undetectable, confirming a diagnosis of neonatal diabetes (Insulin <1.0, n 2.0-19.6, C-peptide <0.10, n 0.8-3.85). Genetic testing was sent on genes commonly responsible for neonatal diabetes. On day of life 12 (DOL 12), he was started on diluted subcutaneous insulin Lispro. He was exquisitely sensitive to small amounts of insulin and was often hypoglycemic after even 0.1 units of diluted insulin (0.01u of commercial insulin Lispro). On DOL 14, as genetic testing results were still pending, he was started on oral glyburide. The drug was administered twice daily, but he remained hyperglycemic requiring advancement of the target dose to 0.5mg/kg/day. On DOL 22, Insulin and C-peptide levels were drawn after subcutaneous insulin had been discontinued for 48 hours. While not yet within normal limits, both values increased to detectable levels, demonstrating objective response the the glyburide therapy (Insulin 1.1, n 2.0-19.6, C-peptide 0.32, n 0.8-3.85). Ultimately, this dose of glyburide was too high for him, and he was discharged home on DOL 26 with 0.036mg/kg/day that will be titrated up as an outpatient as he continues to grow. Since discharge, his blood glucose levels have ranged between 100-200, with no values below 85. Interestingly, his first genetic testing results came back negative for all the mutations in the panel, including the most common mutations in neonatal diabetes that respond to sulfonylurea therapy, ABCC8 and KCNJ11. He is in the process of being enrolled in the a Neonatal Diabetes Registry where they will test for other genes implicated in neonatal diabetes. Conclusion: This is a case of neonatal diabetes with an unknown gene mutation showing efficacy of oral glyburide therapy.

Introduction: To date Neonatal Diabetes Mellitus (NDM) has not been reported in Singapore. Neonatal diabetes is a rare (1 in 100,00–300,000 live births) insulin-requiring form of diabetes with well defined subgroups, permanent neonatal diabetes (PND) and transient neonatal diabetes (TND), each accounting for approximately 50% of patients. Genotyping NDM identifies the exact unique molecular aetiology of very early onset insulin requiring diabetes and has the potential to dramatically alter the management of the patient, who would otherwise be insulin dependent for life. Method: We identified a child who presented at 3 and half months of age with diabetic ketoacidosis and determined the phenotypic and genotypic characteristics. Blood samples for molecular genetic analysis were sent to Royal Devon and Exeter Foundation Trust, UK. We determined her Continuous Glucose Monitoring profiles after initiation of sulphonylurea therapy. Results: The patient was diagnosed as a heterozygous for a missense mutation R201H, in the KCNJ11 gene. Results confirmed a diagnosis of permanent neonatal diabetes due to a mutation in the Kir6.2 subunit of the KATP channel. We initiated sulphonylurea therapy and subsequently ceased insulin treatment successfully. Currently 2 years old, this patient is no longer insulin dependent. Conclusion: This is the first case report of neonatal diabetes in Singapore. It describes the importance of correct identification of the case, and successful conversion of therapy from insulin to sulphonylureas with optimal blood glucose control. We emphasise the need for medical practitioners to consider molecular testing for all patients who present with diabetes below 6 months of age as this will facilitate accurate diagnosis and appropriate therapy.

BackgroundChildren with neonatal diabetes often present with diabetic ketoacidosis and hence are at risk of cerebral oedema and subsequent long‐term neurological deficits. These complications are difficult to identify because neurological features can also occur as a result of the specific genetic aetiology causing neonatal diabetes.Case reportsWe report two cases of neonatal diabetes where ketoacidosis‐related cerebral oedema was the major cause of their permanent neurological disability. Case 1 (male, 18 years, compound heterozygous ABCC8 mutation) and case 2 (female, 29 years, heterozygous KCNJ11 mutation) presented with severe diabetic ketoacidosis at 6 and 16 weeks of age. Both had reduced consciousness, seizures and required intensive care for cerebral oedema. They subsequently developed spastic tetraplegia. Neurological examination in adulthood confirmed spastic tetraplegia and severe disability. Case 1 is wheelchair‐bound and needs assistance for transfers, washing and dressing, whereas case 2 requires institutional care for all activities of daily living. Both cases have first‐degree relatives with the same mutation with diabetes, who did not have ketoacidosis at diagnosis and do not have neurological disability.DiscussionKetoacidosis‐related cerebral oedema at diagnosis in neonatal diabetes can cause long‐term severe neurological disability. This will give additional neurological features to those directly caused by the genetic aetiology of the neonatal diabetes. Our cases highlight the need for increased awareness of neonatal diabetes and earlier and better initial treatment of the severe hyperglycaemia and ketoacidosis often seen at diagnosis of these children.

We read with interest the observation by Khurana et al. (1) regarding the speculative treatment of their case of neonatal diabetes (ND) pending molecular genetic confirmation. The authors report the successful trial of a sulfonylurea in a baby diagnosed with diabetes on day 2 of life in whom an activating KCNJ11 mutation was subsequently identified. Khurana et al. suggest a controlled trial of sulfonylurea in patients with ND if genetic testing is not feasible. We would not agree with this suggested management plan for two reasons: Firstly, not all patients with ND will respond to treatment with a sulfonylurea, and secondly, the result of genetic testing for ND can be available …

Background: Neonatal diabetes mellitus (NDM) is a severe type of glucose metabolism disorder that appears in the first months of life and mostly presents with symptoms such as dehydration, inability to gain weight, and in extreme cases, ketoacidosis and coma. Strong evidence shows the benefits of early molecular tests that investigate variability in kATP channels such as KCNJ11, ABCC8, INS gene mutations, and 6q24 abnormalities. In the presence of these genomics changes, switching from Insulin treatment toward high-dose oral sulfonylurea can enhance the course of treatment, prognosis, and quality of life. Case Report: In this study, we report four cases of neonatal diabetes with different symptoms who were referred to Shahid Sadoughi Medical Center in Yazd, Iran. Conclusion: The diagnosis and treatment of NDM is a good model for implementing patient-centered and personalized medicine. For all patients with diabetes diagnosed before the 6th month of their age (even the 12th month), genetic testing should be considered.

Introduction : we present 2 cases of neonatal diabetes. Mutations in ABCC8 and KCNJ11 genes encoding for the pancreatic KATP channel can lead to transient neonatal diabetes (TNDM) as well as permanent neonatal diabetes (PNDM). KATP channel mutations causing TNDM typically result in diabetes being diagnosed before 6 months of age. Majority of neonatal diabetes patients with KATP channel mutations can be managed with sulphonylureas. Methods : sequence analysis of the ABCC8, KCNJ11, INS and EIF2AK3 genes. Results : case 1: a 9-day old male who presented with jaundice for 3 days and fever for a day. On presentation, baby was febrile, lethargic, with no primitive reflexes. A diagnosis of bilirubin encephalopathy and sepsis was made. On presentation, serum bilirubin was 902 micromil/dl and dropped to 70micromil/dl after 48hours of intensive phototherapy and IV rehydration. On day 3 of admission, infant was noticed to be severely dehydrated although his diapers were soaked with urine. Investigations showed: Random blood sugar 33.1, glucosuria 3+, ketonuria 2+, and enterobacter sepsis. He was managed with insulin infusions and IV antibiotics. By 4th week, baby no longer required insulin, was tolerating full feeds and temperature had settled. Blood sugars have remained within normal range. Sequence analysis of the ABCC8, KCNJ11, INS and EIF2AK3 genes did not identify a pathogenic mutation. Case 2: a 16 week old baby bought to the ER on account of severe weight loss despite good appetite. Random blood sugar on presentation was 33.3mmol/l . Baby was was managed for DKA and discharged home on human premix insulin 30/70 after 2 months of hospital stay. Genetic testing revealed a mutation in the KCNJ11 gene. Baby was switched to glibenclamide, and blood sugars have remained stable. Conclusion : a diagnosis of diabetes before 6 months of age warrants genetic testing to guide treatment decisions.

The most common monogenic cause of neonatal diabetes is mutation in KCNJ11, which encodes a potassium channel in pancreatic beta cells. Some mutations in this gene, including Q52R, have been described in association with neurological deficits, but never with hepatic involvement. We report the second case of neonatal diabetes in a patient with a KCNJ11/Q52R mutation. This patient's clinical course did not include obvious neurological deficits despite the presence of prematurity, but did include transient hyperbilirubinemia, and recurrent hypoglycemia. The phenotypic spectrum of KCNJ11 mutations is variable and is likely influenced by additional genetic and environmental factors.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Babies Are Sweet, but Should Not be This Sweet: A Case of Neonatal Diabetes

IntroductionDuring the last few decades, an increase in the incidence of type 1 diabetes (DT1) in children was reported in most parts of the word.AimsStudy the epidemiologic and clinical particularity...

Neonatal diabetes mellitus (NDM) is defined as hyperglycemia and impaired insulin secretion with onset within 6months of birth. While rare, NDM presents complex challenges regarding the management of glycemic control. The availability of continuous subcutaneous insulin infusion pumps (CSII) in combination with continuous glucose monitoring systems (CGM) provides an opportunity to monitor glucose levels more closely and deliver insulin more safely. We report four cases of young infants with NDM successfully treated with CSII and CGM. Moreover, in two cases with Kir 6.2 mutation, we describe the use of CSII in switching therapy from insulin to sulfonylurea treatment. Insulin pump requirement for the 4 neonatal diabetes cases was the same regardless of disease pathogenesis and c-peptide levels. No dilution of insulin was needed. The use of an integrated CGM system helped in a more precise control of BG levels with the possibility of several modifications of insulin basal rates. Moreover, as showed in the first two case-reports, when the treatment was switched from insulin to glibenclamide, according to identification of Kir 6.2 mutation and diagnosis of NPDM, the CSII therapy demonstrated to be helpful in allowing gradual insulin suspension and progressive introduction of sulfonylurea. During the neonatal period, the use of CSII therapy is safe, more physiological, accurate and easier for the insulin administration management. Furthermore, CSII therapy is safe during the switch of therapy from insulin to glibenclamide for infants with permanent neonatal diabetes mellitus.

Background: Wolcott–Rallison Syndrome (WRS) is a rare autosomal recessive disorder characterized by permanent neonatal diabetes mellitus, skeletal dysplasia, hepatic dysfunction, and other systemic associations. Clinical Description: A 3-month-old infant with a history of fever and poor oral intake presented with severe dehydration, acidosis and 3+ urine ketones and was diagnosed to have sepsis and diabetic ketoacidosis (DKA). He also developed acute kidney injury (AKI) with blood urea 118 mg/dL and serum creatinine 1.5 mg/dL. Management: The child was ventilated, stabilized, and managed for DKA with fluids and insulin as per guidelines. AKI was managed with peritoneal dialysis. Genetic analysis revealed homozygous mutation in eukaryotic translation initiation factor 2-alpha kinase 3 gene consistent with the diagnosis of WRS. A close follow-up was kept with regular screening for other associated manifestations. Central hypothyroidism was detected first followed by skeletal dysplasia and chronic kidney disease. Growth retardation and developmental delay are also present. Conclusion: Neonatal diabetes cases need an early genetic work up and watchful follow-up for the manifestation of other possible associated features.

Two neonatal diabetes cases with different mutations and treatments