Neonatal diabetes mellitus: chromosomal analysis in transient and permanent cases

OBJECTIVES: To describe a large cohort of patients with transient neonatal diabetes mellitus (TNDM) and permanent neonatal diabetes mellitus (PNDM), and to investigate whether chromosome 6 analysis helps to distinguish TNDM from PNDM. STUDY DESIGN: Patients with TNDM (n = 29) (insulin therapy for <3 years) and 21 with PNDM were identified through a nationwide study. RESULTS: Although patients with PNDM were less likely to have had intrauterine growth restriction (36% vs 74% for TNDM, P <.006), were older at diagnosis (median: 27 vs 6 days, P <.01), and had higher initial insulin requirements (1.4 U/kg/day vs 0.6 U/kg/day, P <.006), no clinical features were reliable in distinguishing PNDM from TNDM on an individual case basis. Permanent insulin-dependent diabetes developed in 5 TNDM patients after 8 years of age, emphasizing the need for prolonged follow-up. Among the 19 TNDM patients tested, two had paternal isodisomy of chromosome 6, seven from 4 families had paternally-derived trisomy of the 6q region, and two had a methylation defect in the 6q24 region. No chromosome 6 anomalies were found in the 9 PNDM patients tested. CONCLUSION: When present, a chromosome 6 abnormality is strongly in favor of the "transient" form of the disease.     

Neonatal diabetes: a disease linked to multiple mechanisms]

Transient (TNDM) and Permanent (PNDM) Neonatal Diabetes Mellitus are rare conditions occurring in about 1: 300,000 live births. In TNDM growth retarded infants develop diabetes in the first few weeks of life only to go into remission in a few months with possible relapse to a permanent diabetes state usually around adolescence or as adults. We believe that pancreatic dysfunction in this condition is maintained throughout life with relapse initiated at times of metabolic stress such as puberty or pregnancy. In PNDM, insulin secretory failure occurs in the late fetal or early postnatal period. A number of conditions are associated with PNDM, some of which have been elucidated at the molecular levels. Among those, the very recently elucidated mutations in KCNJ11 and ABCC8 gene, encoding the Kir6.2 and SUR1 subunit of the pancreatic K(ATP) channel involved in regulation of insulin secretion accounts for one third to a half of the PNDM cases. Patients with TNDM are more likely to have intrauterine growth retardation and less likely to develop ketoacidosis than patients with PNDM. In TNDM, patients are younger at the diagnosis of diabetes and have lower initial insulin requirements. Considerable overlap occurs between the two groups, so that TNDM cannot be distinguished from PNDM based on clinical features. Very early onset diabetes mellitus seems to be unrelated to autoimmunity in most instances. Recurrent diabetes is common in patients with "transient" neonatal diabetes mellitus and, consequently, prolonged follow-up is imperative. Molecular analysis of chromosome 6 anomalies, the KCNJ11 and ABCC8 genes encoding Kir6.2 and SUR1 provide a tool to identify transient from permanent neonatal diabetes mellitus in the neonatal period. This analysis also has potentially important therapeutic consequences leading to transfer some patients, those with mutations in KCNJ11 and ABCC8 from insulin therapy to sulfonylureas. Realizing how difficult it is to take care of a child of this age with diabetes mellitus should prompt clinicians to transfer these children to specialized centers. Insulin therapy and high caloric intake are the basis of the treatment. Insulin pump may offer an interesting therapeutic tool in this age group in experienced hands.     

Neonatal diabetes with hyperchylomicronemia

Neonatal diabetes mellitus (NDM) is defined as hyperglycemia occurring in the first few weeks of life. It can be either transient (TNDM) or permanent (PNDM). A 25 days old newborn was brought to the hospital with restlessness, respiratory depression and cyanosis. He was born at term with a birth weight of 2,000 g. There was no consanguinity between his parents. His physical examination findings were as follows: Weight and height were under 3th percentile, he was hypoactive and dehydrated. Serum glucose level was 800 mg/dl; C-peptide was 0.41 ng/ml. Upon investigation for dyslipidemia in association with his neonatal diabetes, hyperchylomicronemia was found both in the patient and his father. Pancreatitis, anemia and cholestasis were also observed. Insulin treatment was started for his diabetes together with a special diet for dyslipidemia. At the end of 28 months of follow-up, dyslipidemia has resolved but the need for insulin therapy was still existing. However, TNDM was considered in differential diagnosis because he was small for gestational age (SGA) at birth and his symptoms had started at the 25th day of the neonatal period. Delayed recovery from insulin dependency brought out the possibility of PNDM. Furthermore, neonatal diabetes combined with hypechylomicronemia is a rare clinical picture. Reported cases of NDM with different clinical evaluation will help to better understanding of this disorder.     

Neonatal Diabetes Mellitus -- genetic aspects 2004

Transient (TNDM) and Permanent (PNDM) Neonatal Diabetes Mellitus are rare conditions occurring in 1:400,000-500,000 live births. In TNDM growth retarded infants develop diabetes in the first few weeks of life only to go into remission in a few months with possible relapse to a permanent diabetes state usually around adolescence or as adults. We believe that pancreatic dysfunction in this condition is maintained throughout life with relapse initiated at times of metabolic stress such as puberty or pregnancy. In PNDM, insulin secretory failure occurs in the late fetal or early post-natal period. A number of conditions are associated with PNDM, some of which have been elucidated at the molecular levels Among those, the very recently elucidated mutations in KCNJ11 gene, encoding the Kir6.2 subunit of the pancreatic KATP channel involved in regulation of insulin secretion accounts for one third to a half of the PNDM cases.     

Neonatal diabetes with hyperchylomicronemia

Neonatal diabetes mellitus (NDM) is defined as hyperglycemia occurring in the first few weeks of life. It can be either transient (TNDM) or permanent (PNDM). A 25 days old newborn was brought to the hospital with restlessness, respiratory depression and cyanosis. He was born at term with a birth weight of 2000 g. There was no consanguinity between his parents. His physical examination findings were as follows: Weight and height were under 3^th percentile, he was hypoactive and dehydrated. Serum glucose level was 800 mgJdl; C-peptide was 0.41 ngJml. Upon investigation for dyslipidemia in association with his neonatal diabetes, hyperchylomicronemia was found both in the patient and his father. Pancreatitis, anemia and cholestasis were also observed. Insulin treatment was started for his diabetes together with a special diet for dyslipidemia. At the end of 28 months of follow-up, dyslipidemia has resolved but the need for insulin therapy was still existing. However, TNDM was considered in differential diagnosis because he was small for gestational age(SGA) at birth and his symptoms had started at the 25^th day of the neonatal period. Delayed recovery from insulin dependency brought out the possibility of PNDM. Furthermore, neonatal diabetes combined with hypechylomicronemia is a rare clinical picture. Reported cases of NDM with different clinical evaluation will help to better understanding of this disorder.     

Relapsing 6q24‐related transient neonatal diabetes mellitus successfully treated with a dipeptidyl peptidase‐4 inhibitor: a case report

The most common form of transient neonatal diabetes mellitus (TNDM) is 6q24‐related TNDM. Patients are treated with insulin during the neonatal period until spontaneous remission. However, diabetes often recurs in adolescence, and there is no standard therapy for patients with a relapse. A paternal duplication at the 6q24 critical region spanning the pleiomorphic adenoma gene‐like 1 PLAGL1 gene was found in a Japanese patient with TNDM relapse. The patient was treated with a dipeptidyl peptidase‐4 (DPP4) inhibitor, alogliptin, at a dose of 25 mg per day. Immediately after treatment initiation, his hemoglobin A1c (HbA1c) levels dropped from 7.0–7.5% (52–58 mmol/mol) to 6.0–6.5% (41–47 mmol/mol) and remained stable for over a year. We reported the successful treatment of relapsed 6q24‐related TNDM with a DPP4 inhibitor. Although insulin has been the conventional treatment for such patients, treatments targeting the GLP1 pathway can be a useful alternative because these patients retain the β cell mass and responsiveness through G protein‐coupled pathways.     

ZFP57基因相关新生儿暂时性糖尿病双胎报告并文献复习

目的 探讨ZFP57基因变异所致新生儿暂时性糖尿病(TNDM)的临床及基因变异特征.方法 回顾分析2019年12月收治的一对ZFP 57基因变异所致TNDM双胎患儿的临床资料和基因测序结果.同时检索建库至2020年2月的中国知网数据库、万方数据库及PubMed数据库,复习相关文献.结果 双胎均为女性,生后24小时内出现...     

Incidence of neonatal diabetes in Austria–calculation based on the Austrian Diabetes Register

Wiedemann B, Schober E, Waldhoer T, Koehle J, Flanagan SE, Mackay DJG, Steichen E, Meraner D, Zimmerhackl LB, Hattersley AT, Ellard S and Hofer S. Incidence of neonatal diabetes in Austria–calculation based on the Austrian Diabetes Register.
Background: Neonatal diabetes mellitus (NDM) is a rare monogenic form of diabetes which is diagnosed in the first 6 months of life. Several studies in the last few years provide information on genetic causes for NDM.
Objective: The aim of this study was to identify all patients with diabetes in the first 6 months of life through the Austrian Diabetes Register, which is available since 1989. A retrospective data analyses was performed to calculate the current incidence of NDM.
Subjects and Methods: Ten patients were registered with diabetes onset within the first 6 months of life in the Austrian Diabetes Register. Evaluation of detailed clinical data was performed by sending a questionnaire to all diabetes centers.
Results: Ten patients from nine different families with NDM were diagnosed in Austria from 1989 until September 2007. Seven patients (one male, six females) had transient NDM (TNDM), three (two males, one female) showed a permanent course [permanent neonatal diabetes mellitus (PNDM)]. One had immunodeficiency, polyendocrinopathy and enteropathy X-linked (IPEX) syndrome and another showed aplasia of the pancreas; no genetic etiology was found in the third case. In three out of seven patients with a transient course of NDM a genetic diagnosis was possible. Two female siblings had activating point mutations in the ABCC8 gene, although one patient had paternal uniparental isodisomy of chromosome 6q24. One patient's family did not consent to genetic testing.
Conclusions: The incidence of NDM in Austria is 1/160 949, with an incidence of 1/ 536 499 for PNDM and 1/229 928 for TNDM.     

Transient neonatal diabetes mellitus in a child with paternal uniparental disomy of chromosome 6

We report a male infant with transient neonatal diabetes mellitus (TNDM; MIM 601410), macroglossia, hypertelorism, umbilical hernia, inguinoscrotal hernia and onychomycosis. Diabetes mellitus was diagnosed 10 days after birth and resolved after 6.5 months of treatment. Genetic investigation indicated the presence of paternal uniparental disomy of chromosome 6 (UPD 6). The finding of paternal UPD 6 allows prediction of a transient, rather than permanent NDM, and no increased recurrence risk of TNDM in subsequent pregnancies. Therefore, finding of NDM should be a strong indicator for genetic testing.     

新生儿糖尿病13例分析

目的 总结分析13例新生儿糖尿病(NDM)的临床特点,为临床诊断和治疗提供参考.方法 对2004年7月至2009年9月广州市妇女儿童医疗中心诊治的13例NDM的临床表现、实验室检杳及临床转归进行回顾性分析总结.结果 13例患儿的平均出生体重为2.30 kg,诊断年龄中位数为2个月,均在生后3个月内起病,初诊血糖均值为22.2 mmol/L.9例因感染而诱发症状加重来诊,有5例有典型"三多一少"糖尿病症状,主要临床表现有体重不增甚至消瘦、烦渴、轻中度脱水,其中3例发生酮症酸中毒(DKA).1例同时伴有发育迟缓、癫痼,3例伴有高甘油三酯血症,1例伴有凝血功能异常,1例伴先天性心脏病(房间隔缺损).有1例胰岛素抗体(IAA)阳性,有6例糖化血红蛋白＞6%(7.2%～14%).所有患儿急性期均接受胰岛素治疗,胰岛素初始治疗剂量为0.56～1.00 U/(kg·d),最大治疗剂量为1.35 U/(kg·d),治疗24 h内血糖均明显下降,3例合并DKA患儿的酸中毒症状均在治疗48 h后缓解,血糖控制良好,急性期无一例死亡.随访至今(最短半年,最长6年)8例中4例符合暂时性NDM(TNDM);3例符合永久性NDM(PNDM);1例于2个月大时自行停用胰岛素治疗,3个月大时酮症酸中毒死亡.结论 NDM多无特异性临床表现,容易误诊误治,早期诊断和治疗预后良好,临床上确诊该病应注意与应激性高血糖、医源性或其他原因的高血糖症相鉴别;NDM可为暂时性和永久性,需密切动态观察.     

No evidence for additional imprinting defects in Silver-Russell syndrome patients with maternal uniparental disomy 7 or 11p15 epimutation

Silver-Russell syndrome (SRS) is mainly characterised by intrauterine and postnatal growth retardation (IUGR and PNGR), asymmetry, clinodactyly V and craniofacial abnormalities. More than 35% of patients carry a hypomethylation of the telomeric imprinting centre region 1 (ICR1) in 11p15; single patients show a maternal duplication of 11p15. An additional 7-10% of patients with SRS have maternal uniparental disomy of chromosome 7 (mUPD7). Another disorder caused by epigenetic defects is transient neonatal diabetes mellitus (TNDM) which is associated with loss of methylation (LOM) in 6q24. After detecting methylation loss at multiple imprinted loci in patients with TNDM, Mackay et al. recently proposed the existence of a maternal hypomethylation syndrome presenting as TNDM. They therefore concluded that patients with other disorders associated with LOM at one (maternally) methylated locus might also carry LOM at multiple loci. Similar observations have also been reported in Beckwith-Wiedemann syndrome (BWS): nearly 25% of patients displayed abnormal methylation patterns of ICRs additional to those in 11p15. To show whether general hypomethylation is a common phenomenon in imprinting disorders we carried out methylation analyses for the imprinted regions 14q32, 6q24 and the centromeric imprinting region ICR2 on 11p15 for 10 patients with SRS carrying mUPD7 and 22 patients with LOM at the telomeric imprinting region ICR1. We showed that further epigenetic defects did not occur in the groups of SRS with LOM of ICR1 or mUPD7, and that these subentities do not belong to the diseases with a general hypomethylation defect, such as TNDM and BWS.     

Transient neonatal diabetes with two novel mutations in the KCNJ11 gene and response to sulfonylurea treatment in a preterm infant

Neonatal diabetes mellitus (NDM) is a rare condition that can be either transient or permanent. K(ATP) channel (Kir6.2 or SUR1) mutation, chromosome 6 abnormalities, insulin, or glucokinase gene mutations can lead to isolated NDM. Cases caused by Kir6.2 mutation usually result in permanent NDM (PNDM) rather than transient NDM (TNDM). The majority of patients with the Kir6.2 or SUR1 mutation can be successfully managed with a sulfonylurea agent, without the need for insulin. We report a preterm male with NDM having two novel missense mutations, E322A and D352H, in the KCNJ11 gene. At 2 months of age, successful transition from insulin to glibenclamide (glyburide) therapy of the patient was managed. At 5 months of age, his diabetes went in to remission.     

Transient neonatal diabetes mellitus in an infant with paternal uniparental disomy of chromosome 6 including heterodisomy for 6q24

We describe a female infant who developed transient neonatal diabetes mellitus (TNDM) (MIM 601410). At birth she presented with growth retardation and macroglossia. Diabetes was diagnosed on the fourth day of life and it resolved after two months of insulin therapy. Genetic testing revealed the presence of paternal uniparental disomy of chromosome 6 (UPD6) including heterodisomy of 6q24. This is the first documented case of uniparental heterodisomy for chromosome 6.     

Neonatal diabetes mellitus and KCNJ11 gene mutation: report of a family case

Neonatal diabetes mellitus (NDM) is characterized by hyperglycemia within the first month of life and insulin dependence for at least two weeks. There are two types of NDM, transient (TNDM) and permanent (PNDM), which are genetically different. We report the case of two brothers who developed hyperglycemia without ketosis on the 18th day and 2 h of life, respectively. Thyroid function tests, abdominal ultrasound and karyotype where normal and there were no pancreatic antibodies. The first one required insulin therapy for the first 92 days of life and the second for 5 months. The mother developed gestational diabetes during both pregnancies and she was later diagnosed diabetes mellitus (without antibodies). They were studied for mutations in KCNJ11 gene (principally related to the permanent form). The three of them showed the E229K mutation (frequently associated with the transient form). A genetic study is essential in NDM to achieve the most accurate prognosis possible.     

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 300 000–500 000 births generally, and hyperglycemia develops within the first 6 months 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.     

Increasing prevalence of type 2 diabetes in adolescents

OBJECTIVE: The rising prevalence of obesity in childhood and adolescence in North America has been paralleled by the emergence of type 2 diabetes in the adolescent age group. We have examined trends in the prevalence of type 2 diabetes in adolescents attending a diabetes clinic in Auckland, New Zealand. METHODS: Surveys of the prevalence of type 2 diabetes in attendees at the adolescent diabetes clinic at the Auckland Diabetes Centre were undertaken in 1996 and 2002. The proportion of type 2 diabetes in incident cases of diabetes diagnosed between these years was also calculated. RESULTS: The prevalence of type 2 diabetes was 1.8% (2/110) in 1996, and 11.0% (18/163) in 2002 (P = 0.008). Type 2 diabetes accounted for 12.5% (6/48) of incident cases of diabetes in the years 1997-1999, and 35.7% (10/28) of cases in the years 2000-2001, indicating a sharp rise in the incidence (P = 0.017) between the two periods. At diagnosis the mean age of the type 2 diabetes subjects was 15 years and the mean body mass index 34.6 kg/m2. Risk factors for cardiovascular disease were common in the subjects with type 2 diabetes: 85% had dyslipidaemia, 58% had increased albumin excretion rates and 28% had systolic hypertension. CONCLUSIONS: Obesity-related type 2 diabetes now accounts for a substantial proportion of newly recognized diabetes in the adolescent age group - and this proportion is escalating rapidly. Adverse cardiovascular risk factors are prevalent in this population. Public health measures to curtail the rise of obesity in childhood and adolescence are required urgently.     

Treatment of adolescents with type 2 diabetes

BACKGROUND: A worldwide increased incidence of adolescents with type 2 diabetes mellitus is evident. Only few substances are available for treatment of adolescents with type 2 diabetes. We report on our experience of treatment in the diabetes centre in Leipzig, Germany. PATIENTS AND METHODS: At the moment we care for three patients with type 2 diabetes (two girls and one boy) age 16 - 17 years. We retrospectively analyzed the patients records for symptoms at onset, BMI, HbA1c and treatment for a maximum of 4 years. RESULTS: None of the adolescents had typical symptoms at onset. All had first or second degree relatives with type 2 diabetes. Diagnosis was made using oral glucose tolerance test. BMI at onset was 26 kg/m (2) (90.-97 percent) to 35.2 kg/m (2) (>99.5 percent). Fasting and stimulated insulin and c-peptide levels were elevated in all cases. An elevated HbA1c level was found in one patient. Two patients had further metabolic symptoms like hypertriglyceridemia or hyperurikemia. We started with metformin after dietary instructions in all cases. One girl is on insulin at the moment and the boy stopped metformin after weight reduction of 24.5 kg. CONCLUSIONS: In Germany type 2 diabetes is diagnosed more frequently at an early age. Adolescents with type 2 diabetes should be treated in a centre for pediatric diabetology. Treatment should consist of an individualized care for all aspects of type 2 diabetes.     

Three-year prevalence and incidence of diabetes among American Indian youth in Montana and Wyoming, 1999 to 2001

OBJECTIVES: To estimate the prevalence and incidence of type 2 diabetes among American Indian youth. STUDY DESIGN: Medical records were reviewed annually for all patients with diabetes who were <20 years of age at 6 Indian Health Service facilities in Montana and Wyoming. All cases < or =5 years of age or weight per age < or =10th percentile at diagnosis or with islet cell antibodies were considered as probable type 1. Among the remaining cases, probable type 2 diabetes was defined when a child had one or more of the following characteristics: weight per age > or =95th percentile or acanthosis nigricans at diagnosis, elevated C-peptide or insulin, family history of type 2 diabetes; treatment with oral agents with or without insulin or no hypoglycemic therapy after 1 year of follow-up. RESULTS: From 1999 to 2001, 53% of prevalent cases and 70% of incident cases were categorized as probable type 2 diabetes. The average annual prevalence of probable type 1 and type 2 diabetes was 0.7 and 1.3 per 1000. The average annual incidence rates for probable type 1, and type 2 diabetes were 5.8, 23.3 per 100,000. CONCLUSIONS: The incidence of probable type 2 diabetes was approximately 4 times higher than type 1 diabetes among American Indian youth in Montana and Wyoming     

Growth in a Series of Diabetic Children on Identical Treatment with "Free" Diet and Insulin 1944–1960: A Contribution to the Aetiology of Diabetic Dwarfism

An account is given of growth in a series of 195 cases of juvenile diabetes treated on a standard regimen ("free" diet + insulin) and collected during the period 1944–1960. Scrutiny of the series shows that growth was as a rule normal. Undersized children usually had small parents. A few cases of retarded growth may however be explained by excessive feeding with relative insulin deficiency. Two cases showing the classical picture of diabetes dwarfism with hepatomegaly and infantile mentality are described. Both were inadequately controlled, owing to ignorance on the part of the parents. These cases support the view that the condition is caused by relative insulin deficiency. The theory is further borne out by the improvement that took place in one of these children when she was finally brought under adequate control.