A Case of Transient Neonatal Diabetes Mellitus Attributable to a Nonspecific Mutation in the ABCC8 Gene

Neonatal diabetes mellitus (NDM) is defined as hyperglycemia that persists for more than 2 weeks and requires insulin therapy. NDM principally occurs before 6 months of age. Transient NDM (TNDM) is a clinical form of NDM that persists for a median of 12 weeks and resolves completely by 18 months. However, it may relapse as type 2 DM during early adulthood. The major causes of TNDM are mutations in chromosome 6q24 or the KCNJ11 or ABCC8 genes; the latter encode the two subunits of the pancreatic adenosine triphosphate (ATP)-sensitive potassium channel (KATP-channel). This condition responds well to oral sulfonylurea therapy. Herein, we report a neonate who was small for gestational age and exhibited TNDM symptoms. Genetic analysis revealed a nonspecific mutation in ABCC8; he was successfully treated with oral sulfonylurea.

Transient Neonatal Diabetes Mellitus in SHORT Syndrome: A Case Report

SHORT syndrome is a rare autosomal dominant disorder characterized by multiple congenital defects and is historically defined by its acronym: short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay. Herein, we report a male infant with SHORT syndrome who presented with transient neonatal diabetes mellitus (TNDM) with insulin resistance. The proband was born at 38 weeks of gestation but displayed facial dysmorphic features. Intrauterine growth restriction (IUGR) was detected on a prenatal ultrasonography test. His birth weight was 1.8 kg (<3rd percentile), length 44 cm (<3rd percentile), and head circumference 31 cm (<3rd percentile). The patient's blood glucose level started to increase at 5 days of age (218–263 mg/dl) and remained high at 20 days of age (205–260 mg/dl). He was treated with subcutaneous insulin and the blood glucose level gradually stabilized. Blood glucose level was stabilized over time without insulin treatment at 6 weeks of age. Clinical exome sequencing showed a heterozygous pathogenic variant, NM_181523.3:c.1945C>T (p.Arg649Trp) in exon 15 of the phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) known as the causative gene for SHORT syndrome. Examination of the patient at 10 months of age revealed no hyperglycemic episode and glycated hemoglobin level was 5.2%. To the best of our knowledge, this is the first case of TNDM in SHORT syndrome due to a pathogenic variant of PIK3R1. We believe that our case can aid in expanding the phenotypes of SHORT syndrome.

Transient Neonatal Diabetes Mellitus and Seizure with an Unknown Etiology

Neonatal diabetes mellitus (NDM) is a monogenic form of diabetes, usually occurring in the first 6 months of life. Here, we present a newborn, which was admitted with epileptic seizure on the postnatal second day of life. Sepsis and meningitis were ruled out. Cranial imaging and electroencephalography revealed normal. She developed transient NDM on the follow-up and was diagnosed to carry an ABCC8 mutation. Although the neurological features are more common in patients with KCJN11 mutations, patients with ABCC8 mutations could also represent with subtle neurodevelopmental changes or even with epileptic seizures. The genetic testing and appropriate therapy is important in this patient group for predicting clinical course and possible additional features.

Phenotype of a transient neonatal diabetes point mutation (SUR1-R1183W) in mice

Background: The KATP channel plays a key role in glucose homeostasis by coupling metabolically generated changes in ATP to insulin secretion from pancreatic beta-cells. Gain-of-function mutations in either the pore-forming (Kir6.2) or regulatory (SUR1) subunit of this channel are a common cause of transient neonatal diabetes mellitus (TNDM), in which diabetes presents shortly after birth but remits within the first few years of life, only to return in later life. The reasons behind this time dependence are unclear. Methods: In an attempt to understand the mechanism behind diabetes remission and relapse, we generated mice expressing the common TNDM mutation SUR1-R1183W. We employed Cre/LoxP technology for both inducible and constitutive expression of SUR1-R1183W specifically in mouse beta-cells, followed by investigation of their phenotype using glucose tolerance tests and insulin secretion from isolated islets. Results: We found that the R1183W mutation impaired inhibition of KATP channels by ATP when heterologously expressed in human embryonic kidney cells. However, neither induced nor constitutive expression of SUR1-R1183W in mice resulted in changes in blood glucose homeostasis, compared to littermate controls. When challenged with a high fat diet, female mice expressing SUR1-R1183W showed increased weight gain, elevated blood glucose and impaired glycaemic control, but glucose-stimulated insulin secretion from pancreatic islets appeared unchanged. Conclusions: The mouse model of TNDM did not recapitulate the human phenotype. We discuss multiple potential reasons why this might be the case. Based on our findings, we recommend future TNDM mouse models employing a gain-of-function SUR1 mutation should be created using the minimally invasive CRISPR/Cas technology, which avoids many potential pitfalls associated with the Cre/LoxP system.

Differences between Transient Neonatal Diabetes Mellitus Subtypes can Guide Diagnosis and Therapy

Objective: Transient neonatal diabetes mellitus (TNDM) is caused by activating mutations in ABCC8 and KCNJ11 genes (KATP/TNDM) or by chromosome 6q24 abnormalities (6q24/TNDM). We wanted to assess whether these different genetic aetiologies result in distinct clinical features. Design: Retrospective analysis of the Italian data set of patients with TNDM. Methods: Clinical features and treatment of 22 KATP/ TNDM patients and 12 6q24/TNDM patients were compared. Results: Fourteen KATP/TNDM probands had a carrier parent with abnormal glucose values, four patients with 6q24 showed macroglossia and/or umbilical hernia. Median age at diabetes onset and birth weight were lower in patients with 6q24 (1 week; -2.27 SD) than those with KATP mutations (4.0 weeks; -1.04 SD) (p=0.009 and p=0.007, respectively). Median time to remission was longer in KATP/TNDM than 6q24/TNDM (21.5 vs 12 weeks) (p=0.002). Two KATP/TNDM patients entered diabetes remission without pharmacological therapy. A proband with the ABCC8/L225P variant previously associated with permanent neonatal diabetes entered 7-year long remission after 1 year of sulfonylurea therapy. Seven diabetic individuals with KATP mutations were successfully treated with sulfonylurea monotherapy; four cases with relapsing 6q24/TNDM were treated with insulin, metformin or combination therapy. Conclusions: If TNDM is suspected, KATP genes should be analyzed first with the exception of patients with macroglossia and/or umbilical hernia. Remission of diabetes without pharmacological therapy should not preclude genetic analysis. Early treatment with sulfonylurea may induce long-lasting remission of diabetes in patients with KATP mutations associated with PNDM. Adult patients carrying KATP/TNDM mutations respond favourably to sulfonylurea monotherapy.

Longitudinal Glycaemic Profiles during Remission in 6q24-Related Transient Neonatal Diabetes Mellitus

<b><i>Introduction:</i></b> Transient neonatal diabetes mellitus (TNDM) is a rare condition that is characterized by the presence of diabetes mellitus during the first 6 months of life and remission by 18 months of age. It usually relapses at a median age of 14 years. Hyperinsulinaemic hypoglycaemia is a relatively common complication during remission. Although β-cell function is reported to be impaired at relapse, the clinical course of glycaemic profiles during remission in patients with TNDM remains largely unknown. <b><i>Case Presentation:</i></b> Longitudinal glycaemic profiles were investigated annually from remission (185 days) to relapse (14.5 years) in a patient with TNDM due to paternal 6q24 duplication using the oral glucose tolerance test (glucose intake: 1.75 g/kg to a maximum of 75 g). The patient’s β-cell function and insulin sensitivity were assessed by calculating the insulinogenic index, homeostasis model assessment of β-cell function (HOMA-β), homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index, and Matsuda index. Early insulin response to glucose intake was impaired throughout remission, whereas fasting insulin and β-cell function by HOMA-β gradually increased in the first few years since remission, followed by a gradual decline in function. In contrast, HOMA-IR fluctuated and peaked at 6.5 years of age. <b><i>Conclusion:</i></b> This is the first report of annual longitudinal glycaemic profiles in a patient with 6q24-related TNDM during remission. We identified fluctuations in β-cell function and insulin resistance during remission.

Severe Dental Disease as a Presenting Sign of Relapsed 6q24-Related Transient Neonatal Diabetes Mellitus

Transient neonatal diabetes mellitus (TNDM) is a rare form of diabetes that presents in infancy and is characterized by intrauterine growth restriction and hyperglycemia without ketones on urinalysis. Patients are treated with insulin until remission, usually within the first year. Relapse to a permanent state may occur later in life, with a mean age of 14 years. The most common cause of TNDM is a chromosome 6q24 mutation that affects pancreatic β-cell function. Reports of relapse have been limited. We describe a case of an adolescent female with TNDM due to 6q24 hypomethylation who relapsed at 15 years of age with severe dental disease as the presenting sign.