Transient Neonatal Diabetes Research Articles

Transient neonatal diabetes in extremely low-birth-weight baby treated with long-acting insulin (Glargine)

Neonatal diabetes mellitus (NDM) is not uncommon amongst extreme preterm or extremely low-birth-weight (ELBW) neonates. The treatment for NDM to achieve normoglycemia is not without challenges because of lack of one ideal strategy for appropriate treatment. The management of NDM begins with insulin, but it is very difficult to adjust the doses and route of administration because of the dilemma of frequently developing hypoglycaemia and then hyperglycaemia again after stopping insulin. We report here an ELBW baby initially treated with regular insulin and then glargine, long-acting insulin, was administered subcutaneously as once daily dose with successful control of hyperglycaemia. Previously, two cases have been reported where glargine was used to control NDM. The possibility of recommendation for successful treatment with subcutaneous long-acting insulin to treat NDM amongst ELBW neonates is discussed.

Chromosome 6q24-related diabetes mellitus.

.Chromosome 6q24-related diabetes mellitus is the most common cause of transient neonatal diabetes (TNDM), accounting for approximately two-thirds of all TNDM cases. Patients with 6q24-TNDM develop insulin-requiring diabetes soon after birth, followed by the gradual improvement and eventual remission of the disorder by 18 mo of age. The most important clinical feature of affected patients is a small-for-gestational age (SGA) birth weight, which reflects the lack of insulin in utero. It is believed that 6q24-TNDM is caused by the overexpression of the paternal allele of the imprinted locus in chromosome 6q24, which contains only two expressed genes, PLAGL1 and HYMAI. Identified mechanisms include: (1) duplication of the paternal allele, (2) paternal uniparental disomy, and (3) hypomethylation of the maternal allele. Many patients with TNDM relapse after puberty. Relapsed 6q24-related diabetes is no longer transient and typically occurs in non-obese patients who are autoantibody negative. Thus, these patients possess features indistinguishable from those of maturity-onset diabetes of the young (MODY). Conversely, it has been shown that not all patients with 6q24-related diabetes have a history of TNDM. 6q24-related diabetes should therefore be considered as one of the differential diagnoses for patients with MODY-like diabetes, especially when they are SGA at birth.

Neonatal Diabetes: the importance of genetic testing

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.

Neonatal Diabetes: Nurse Navigator Role

Neonatal Diabetes: Nurse Navigator Role

Fanconi syndrome and neonatal diabetes: phenotypic heterogeneity in patients with GLUT2 defects.

Fanconi-Bickel syndrome, caused by mutations in SLC2A2 encoding the glucose transporter 2 (GLUT2), is characterized by generalized proximal renal tubular dysfunction manifesting in late infancy. We describe phenotypic heterogeneity of Fanconi-Bickel syndrome in three siblings, including early and atypical presentation with transient neonatal diabetes mellitus in one. The second-born of a non-consanguineous couple, evaluated for polyuria and growth retardation, had rickets, hepatomegaly and proximal tubular dysfunction from 4 to 6 months of age. A male sibling, who expired at 4 months, also had hepatomegaly and growth retardation. The third sibling had polyuria, glucosuria and mild proteinuria on day 3 of life. Hyperglycemia was detected 2 weeks later, which required therapy with insulin for 3 months. Mild metabolic acidosis was present at 2 weeks; hypercalciuria, phosphaturia and aminoaciduria were seen at 6 months. Sanger sequencing showed a homozygous missense mutation in SLC2A2 (exon 7, c.952G > A), causing glycine to arginine substitution; both parents were heterozygous carriers. Patients with SLC2A2 mutations may present either with isolated neonatal diabetes or with hepatomegaly and the renal Fanconi syndrome. Fanconi-Bickel syndrome shows phenotypic heterogeneity and may manifest early with subtle or atypical features, mandating a high index of suspicion.

A tissue-specific promoter derived from a SINE retrotransposon drives biallelic expression of PLAGL1 in human lymphocytes.

The imprinted gene PLAGL1 is an important regulator of apoptosis and cell cycle arrest. Loss of its expression has been implicated in tumorigenesis in a range of different cancers, and overexpression during fetal development causes transient neonatal diabetes mellitus (TNDM). PLAGL1 lies within an imprinted region of chromosome 6q24, and monoallelic expression from the major, differentially methylated promoter (P1) occurs in most human tissues. However, in peripheral blood leukocytes, the active promoter (P2) is non-imprinted and drives biallelic transcription. We report here a novel PLAGL1 promoter (P5) derived from the insertion of a primate-specific, MIR3 SINE retrotransposon. P5 is highly utilized in lymphocytes, particularly in T cells, and like P2, directs biallelic transcription. Our results show that it is important to consider P5 in relation to PLAGL1 function in T cells when investigating the dysregulation of this gene.

Identification of Plagl1/Zac1 binding sites and target genes establishes its role in the regulation of extracellular matrix genes and the imprinted gene network.

PLAGL1/ZAC1 undergoes parental genomic imprinting, is paternally expressed, and is a member of the imprinted gene network (IGN). It encodes a zinc finger transcription factor with anti-proliferative activity and is a candidate tumor suppressor gene on 6q24 whose expression is frequently lost in various neoplasms. Conversely, gain of PLAGL1 function is responsible for transient neonatal diabetes mellitus, a rare genetic disease that results from defective pancreas development. In the present work, we showed that Plagl1 up-regulation was not associated with DNA damage-induced cell cycle arrest. It was rather associated with physiological cell cycle exit that occurred with contact inhibition, growth factor withdrawal, or cell differentiation. To gain insights into Plagl1 mechanism of action, we identified Plagl1 target genes by combining chromatin immunoprecipitation and genome-wide transcriptomics in transfected cell lines. Plagl1-elicited gene regulation correlated with multiple binding to the proximal promoter region through a GC-rich motif. Plagl1 target genes included numerous genes involved in signaling, cell adhesion, and extracellular matrix composition, including collagens. Plagl1 targets also included 22% of the 409 genes that make up the IGN. Altogether, this work identified Plagl1 as a transcription factor that coordinated the regulation of a subset of IGN genes and controlled extracellular matrix composition.

Maternal fertility problems and risk for transient neonatal diabetes mellitus.

The study of imprinting disorders in the context of infertility and its treatment is important, as studies have indicated an increased risk. In this study, we evaluated the risk of transient neonatal diabetes mellitus (TNDM), defined here as diabetes mellitus presenting within the first six weeks of life, in children born to women with fertility problems. This nationwide register-based cohort study comprised all 2,107,837 children born in Denmark between 1977 and 2010. Of these, 121,044 (5.7%) children were born to women with fertility problems. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between maternal fertility status and the risk for TNDM. A total of 103 children developed TNDM during the follow-up period. Children born to women with fertility problems had an elevated risk for TNDM, after adjustment for birth year, maternal age at birth and parental history of diabetes, although this was not statistically significant (HR = 1.49; 95% CI 0.73-3.03). The risk of children born in the period 1994-2010 (a period with more comprehensive information on maternal fertility problems and with more invasive fertility treatment procedures) was increased almost twofold (HR = 1.92; 95% CI 0.92-4.00) but was still not statistically significant. Our results indicate that children born to women with fertility problems, particularly after 1993, may be at an elevated risk for TNDM. As the increased risks were not statistically significant, however, the finding may be due to chance.

Transient neonatal diabetes mellitus and activating mutation in the KCNJ11 gene in two siblings

Transient neonatal diabetes mellitus is a rare disease usually associated with chromosome 6 abnormalities. Mutations of the genes encoding the potassium channel are rarely associated with these transitional forms. Herein, we report the clinical features of two siblings with a heterozygous mutation C679 G>A in the KCNJ11 gene.

Epidemiology, clinical characteristics, and genetic etiology of neonatal diabetes in Japan.

Neonatal diabetes mellitus (NDM) is a rare but potentially devastating metabolic disorder, with a reported incidence of one per 300000-500000 births generally, and hyperglycemia develops within the first 6months of life. NDM is classified into two categories clinically. One is transient NDM (TNDM), in which insulin secretion is spontaneously recovered by several months of age, but sometimes recurs later, and the other is permanent NDM (PNDM), requiring lifelong medication. Recent molecular analysis of NDM identified at least 12 genetic abnormalities: chromosome 6q24, KCNJ11, ABCC8, INS, FOXP3, GCK, IPF1, PTF1A, EIF2AK3, GLUT2, HNF1β, and GLIS3. Of these, imprinting defects on chromosome 6q24 and the KCNJ11 mutation have been recognized as the major causes of TNDM and PNDM, respectively, in Caucasian subjects. Although the pathogenesis and epidemiology of NDM in Japan seem to be clinically distinct, they are still unclear. In this review, we summarize the epidemiology, clinical characteristics, and genetic etiology in Japanese patients with NDM compared with the data on Caucasian patients.

Transient Neonatal Diabetes Mellitus: A Challenge and Opportunity for Specialized Nursing Care.

Transient neonatal diabetes mellitus (TNDM) is a rare disorder, with a reported incidence of approximately 1 in 450,000 live births. It is characterized by insulin-requiring hyperglycemia in the neonatal period. The disease improves by early childhood, but the patient may relapse in later life. Diagnosis is made after genetic testing following presentation with hyperglycemia not conforming to Type 1 or Type 2 diabetes. Management is based on insulin and possible sulfonylurea administration. Three genetically distinct subtypes of TNDM are recognized. Type 1 TNDM is due to overexpression of genes at the 6q24 locus, whereas the 11p15 locus is involved in Type 2 and 3 TNDM. In this article the clinical presentation, management, and genetics of TNDM are discussed, particularly emphasizing the role of the neonatal nurse.

Sulfonylurea treatment in an infant with transient neonatal diabetes mellitus caused by an adenosine triphosphate binding cassette subfamily C member 8 gene mutation.

.Neonatal diabetes mellitus (NDM) is an insulin-requiring monogenic form of diabetes that generally presents before six months of age. The following two types of NDM are known: transient NDM (TNDM) and permanent NDM (PNDM). Here we report on an infant with TNDM caused by a mutation (p.Gly832Cys) of the gene for the ATP binding cassette subfamily C member 8 (ABCC8). The patient exhibited hyperglycemia (600 mg/dL) at five weeks of age and insulin treatment was initiated. As genetic analysis identified a missense mutation within ABCC8, the insulin was replaced by glibenclamide at five months of age. Thereafter, the insulin was successfully withdrawn and his glycemic condition was well controlled at a dose of 0.0375 mg/kg/d. Since the patient’s blood glucose was under control and serum C-peptide levels were measurable, glibenclamide was stopped at 1 yr, 10 mo of age. The lack of DM relapsed to date confirms the TNDM diagnosis. In conclusion, when insulin is replaced with a sulfonylurea-class medication (SU) in NDM patients, serum C-peptide levels should be closely monitored and fine adjustment of SU dose is recommended.

A Novel Approach to the Management of Neonatal Diabetes Using Sensor-Augmented Insulin Pump Therapy With Threshold Suspend Technology at Diagnosis.

Neonatal diabetes mellitus (NDM) is a rare genetic condition with an incidence of 1 in 100,000 (1) that presents before 1 year of age (2). There are two main clinical forms of NDM: permanent NDM (PNDM), which requires lifelong treatment with insulin, and transient NDM (TNDM), which may spontaneously remit and sometimes recurs in the second to third decade of life. In most cases, TNDM and PNDM cannot be distinguished clinically at the time of diagnosis, and genetic analysis needs to be performed. The genetic origin for >90% of TNDM cases has been established. In TNDM, 68% of the cases have abnormalities in an imprinted region on chromosome 6q24; 10% have KCNJ11 gene mutations; and 13% have an ABCC8 gene mutation (3). Multiple genes involved in pancreatic development, β-cell apoptosis, or dysfunction cause PNDM (4). The most common mutations are in the KATP channel genes KCNJ11 (30%) and ABCC8 (11%) or the insulin (INS) gene (13%) (3). Insulin is acutely required in most infants to establish metabolic control in NDM (5). Early initiation of sulfonylurea treatment is also recommended (6) as a treatment option in selected cases of NDM caused by ABCC8 and KCNJ11 mutations, and, in responsive cases, sulfonylurea therapy provides better long-term metabolic control (7,8) and could even improve neurodevelopmental outcomes (9). The MiniMed 530G (Medtronic, Inc., Northridge, CA) is a first-generation artificial pancreas system approved by the U.S. Food and Drug Administration (FDA) on 26 September 2013 for the management of diabetes in people ≥16 years of age. The system includes an external glucose sensor and insulin pump, transmitter, glucose meter, and therapy management software. Sensor signals are transmitted to the MiniMed 530G insulin pump and converted into glucose values every 5 minutes. Fingerstick blood glucose testing is still required for both …

Depressor Anguli Oris in IVF Twins.

Delaying conception has increased the demand on assisted reproduction. Currently, more than 1% of children are conceived through assisted reproductive technologies (ART) worldwide and this number is likely to continue increasing (1). Like any other medical intervention ART is associated with both short-term and long-term complications. IVF pregnancies may be at increased risk for multiple pregnancies, preterm birth, low birth weight, congenital anomalies, and perinatal mortality. It has long been known that the rate of congenital malformations is somewhat increased among infants born after in vitro fertilization (IVF). Risks of neural tube defects, orofacial clefts, cardiac defects, alimentary tract atresia, and hypospadias were increased. Possible association between IVF and the occurrence of imprinting anomalies, which can cause rare conditions such as Angelman syndrome, Beckwith-Wiedemann syndrome, PraderWilli syndrome, russell-silver syndrome, UPD 14 syndrome, pseudohypoparathyroidism 1b, transient neonatal diabetes mellitus, and maternal hypomethylation syndrome (2, 3). In our cases, premature twins were born by ceserean section to a 38-year-old gravida 2, para 2 female. The mother had uncomplicated antenatal course. Infants were born after IVF (double embryo transfer). A prenatal ultrasound and NST were normal. At birth there were no problems. Apgar score was 9 at 1 and 5 minutes. During a routine physical examination, asymmetric crying face was noticed in both of twins; the right corner of the mouth drew right and downward, while the left corner did not move. Their extra-ocular movements were intact with perfect closure of the eyes. They were presumed to have asymmetric crying facies (ACF) secondary to hypoplasia of depressor anguli oris. Their echocardiogram and cranial MRI investigations was normal. Their chromosome and FISH analysis were normal. ACF is a minor anomaly, which presents with drooping of the corner of the mouth on the unaffected side when cying or grimacing and seen in 0.5% 1% of newborns. It is caused by either agenesis or hypoplasia of the depressor anguli oris muscle. ACF has been associated with other congenital anomalies in 20% to 70% of cases. Most anomalies are found in the head/neck and cardiovascular systems but they can also involve the skeletal, genitourinary, and gastrointestinal systems. In particular, ACF has been associated with the 22q11 deletion syndrome (4, 5). In summary, we report IVF twins with ACF. They were first IVF cases with ACF in the literature. We conclude that the general risk for a congenital malformation after IVF and some rare malformation syndromes are over represented among infants born after IVF and a multidisciplinary team should follow these patients, with screening for complications and appropriate management.

Approach to the patients with transient neonatal diabetes mellitus

Transient neonatal diabetes mellitus is a kind of rare special types of diabetes. It should be distinguished from type 1 diabetes. Genetic analysis can be used to define the subtype of neonatal diabetes mellitus, which helps us to select the most appropriate treatment and to predict the disease recurrence. Sulfonylureas is able to improve insulin secretion in most patients with transient neonatal diabetes mellitus and provide effective glycemic control. A case of transient neonatal diabetes mellitus is reported in order to call attention to the diagnosis and treatment of this disease. (Chin J Endocrinol Metab, 2016, 32: 510-513) Key words: Transient neonatal diabetes mellitus; Gene; Sulfonylureas

Scanning and analysis of the KATP channel mutations in 12 cases of infancy onset type 1 diabetes mellitus

Objective To screen the mutation of KATP channel mutations in Chinese pedigrees with infantile onset type 1 diabetes mellitus(T1DM) and neonatal diabetes mellitus. Methods A cohort of 12 children of infant onset T1DM and neonatal diabetes mellitus admitted into Beijing Children's Hospital between March 2004 and June 2013 were selected.PCR amplification and direct sequencing were used to analyze the 39 exons of ABCC8 gene and one exon of KCNJ11.And the mutational sites of the parents of the probands was sequenced in order to identify the inheritance. Results Analysis revealed ABCC8 mutation in 25%(3/12 cases) of the patients, a case of transient neonatal diabetes(TNDM), a case of permanent neonatal diabetes mellitus(PNDM) and a case of infant onset T1DM.All positive patients showed a known heterozygosis mutation in the ABCC8 gene(R1182Q, c.3545G>A, D209E, c.627C>G, E208K c. 622G>A). The residue R1182Q, which was located at a position involved in joining transmembrane domain 2 to nucleotide binding domain 2, the mutations E208K and D209E were located in the intracellular region that links the transmembrane domain with the gatekeeper module.All the three mutations were located throughout the cytoplasm part of SUR1 protein.The TNDM successfully transferred from insulin to oral sulfonylureas therapy. Conclusions There is a complex genetic pathogenesis in neonatal and infant-onset diabetes.The KATP channel activating mutations is one of the main causes of neonatal diabetes mellitus and may cause T1DM in infants in China.Oral Glibenclamide therapy seems highly effective for some patients with the KATP channel activating mutations. Key words: KATP channel; Infancy onset type 1 diabetes mellitus; Neonatal diabetes mellitus; Glibenclamide

Genome-wide DNA methylation analysis of transient neonatal diabetes type 1 patients with mutations in ZFP57.

BackgroundTransient neonatal diabetes mellitus 1 (TNDM1) is a rare imprinting disorder characterized by intrautering growth retardation and diabetes mellitus usually presenting within the first six weeks of life and resolves by the age of 18 months. However, patients have an increased risk of developing diabetes mellitus type 2 later in life. Transient neonatal diabetes mellitus 1 is caused by overexpression of the maternally imprinted genes PLAGL1 and HYMAI on chromosome 6q24. One of the mechanisms leading to overexpression of the locus is hypomethylation of the maternal allele of PLAGL1 and HYMAI. A subset of patients with maternal hypomethylation at PLAGL1 have hypomethylation at additional imprinted loci throughout the genome, including GRB10, ZIM2 (PEG3), MEST (PEG1), KCNQ1OT1 and NESPAS (GNAS-AS1). About half of the TNDM1 patients carry mutations in ZFP57, a transcription factor involved in establishment and maintenance of methylation of imprinted loci. Our objective was to investigate whether additional regions are aberrantly methylated in ZFP57 mutation carriers.MethodsGenome-wide DNA methylation analysis was performed on four individuals with homozygous or compound heterozygous ZFP57 mutations, three relatives with heterozygous ZFP57 mutations and five controls. Methylation status of selected regions showing aberrant methylation in the patients was verified using bisulfite-sequencing.ResultsWe found large variability among the patients concerning the number and identity of the differentially methylated regions, but more than 60 regions were aberrantly methylated in two or more patients and a novel region within PPP1R13L was found to be hypomethylated in all the patients. The hypomethylated regions in common between the patients are enriched for the ZFP57 DNA binding motif.ConclusionsWe have expanded the epimutational spectrum of TNDM1 associated with ZFP57 mutations and found one novel region within PPP1R13L which is hypomethylated in all TNDM1 patients included in this study. Functional studies of the locus might provide further insight into the etiology of the disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-016-0292-4) contains supplementary material, which is available to authorized users.

Chromosome 6q24 methylation defects are uncommon in childhood-onset non-autoimmune diabetes mellitus patients born appropriate- or large-for-gestational age.

Methylation defects in the imprinting locus at chromosome 6q24 result in transient neonatal diabetes and small-for-gestational age (SGA) births (1). These phenotypes are primarily ascribed to the overexpression of PLAGL1, a paternally expressed gene on 6q24 that regulates cell cycle and apoptosis (2). Paternal uniparental disomy involving 6q24, as well as copy-number gains of paternal PLAGL1 alleles and epimutations in maternal alleles, have been identified as the causes of hypomethylation at the differentially methylated region (DMR) of PLAGL1 (3, 4). Recently, Yorifuji et al. reported the identification of 6q24 uniparental disomy in three patients with childhood-onset non-autoimmune diabetes mellitus (5). The three patients were identified through methylation-specific PCR analysis of the PLAGL1 DMR of 113 patients clinically suspected of having maturity-onset diabetes of the young (MODY). These results expanded the phenotypic consequences of 6q24 methylation defects to include MODY-like manifestations without a history of neonatal diabetes. However, the frequency of 6q24 methylation defects among patients with childhood-onset non-autoimmune diabetes remained unknown.

A case of transient neonatal diabetes due to a novel mutation in ABCC8.

Neonatal diabetes mellitus (NDM), characterized by hyperglycemia and the need for insulin treatment within the first 6 mo of life, is a rare monogenic form of diabetes with an estimated incidence of 1 in 90,000 neonates (1). Approximately half of NDM cases are transient and resolve at a median age of 3 mo (transient NMD: TNDM), while the remaining cases develop into a permanent form of diabetes (permanent NDM: PNDM; MIM # 606176). Adult onset non-autoimmune diabetes occurs in a significant number of patients with TNDM (2). Most cases of TNDM (approximately 70%) are caused by abnormalities in chromosome 6q24, including paternal duplications, paternal uniparental isodisomy, and loss of methylation. In a few patients, activating mutations in the genes, which encode the two subunits of the β-cell ATP-sensitive potassium channel, i.e. ABCC8 and KCNJ11, have been reported to be associated with TNDM. Interestingly, recent studies have shown that familial analysis of TNMD with ABCC8 mutations revealed that their family members with adult onset non-autoimmune diabetes also have the same mutations (3). Here, we present a Japanese case with TNDM harboring a novel p.Glu350Asp mutation in ABCC8. Familial analysis revealed that his non-symptomatic sister and mother, other family members with adult-onset diabetes without neonatal episodes of hyperglycemia, also possessed the same mutation.

The evolving phenotype of transient neonatal diabetes 1: findings from the international register

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