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: 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.     

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.     

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.     

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.     

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.     

Successful sulfonylurea treatment of an insulin‐naïve neonate with diabetes mellitus due to a KCNJ11 mutation

Wambach JA, Marshall BA, Koster JC, White NH, Nichols CG. Successful sulfonylurea treatment of an insulin‐naïve neonate with diabetes mellitus due to a KCNJ11 mutation. Activating mutations in the K_ATP‐channel cause neonatal diabetes mellitus (NDM), and patients have been safely transitioned from insulin to sulfonylureas. We report a male infant with permanent NDM (PNDM), born to a PNDM mother. Blood glucose began to rise on day of life (DOL) 2, and sulfonylurea (glyburide) therapy was initiated on DOL 5. Glucose was subsequently well controlled and normal at 3 months. A K_ATP mutation (R201H; KCNJ11) was detected in the infant, the mother, and 6‐yr‐old sister with PNDM; both were also subsequently transitioned off insulin onto glyburide. To our knowledge, this is the youngest NDM patient to receive oral glyburide and, importantly, the only one deliberately initiated on sulfonylureas. Strikingly, the current dose (0.017 mg/kg/d) is below the reported therapeutic range and approximately 75‐fold lower than doses required by the affected sister and mother. Pancreatic insulin disappears in an animal model of K_ATP‐induced NDM, unless glycemia is well controlled, thus, a dramatically lower glyburide requirement in the infant may reflect preserved insulin content because of early sulfonylurea intervention. Safe and effective initiation of glyburide in an insulin‐naïve neonatal patient with K_ATP‐dependent PNDM argues for early detection and sulfonylurea intervention.     

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.     

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.     

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.     

新生儿糖尿病研究进展

新生儿糖尿病是一组异质性单基因遗传病,常被误诊为1型糖尿病.永久性新生儿糖尿病与免疫无关,主要与KCNJ 11、ABCC8和胰岛素基因等基因突变有关;多以酮症酸中毒起病,伴宫内发育迟缓、脱水.基因检测有助于疾病分型,并可根据不同致病基因进行靶向治疗.对于ATP敏感的K+通道基因突变的永久性新生儿糖尿病患儿可口服磺脲类降...     

Neonatal diabetes mellitus due to pancreas agenesis: a new case report and review of the literature

Neonatal diabetes mellitus (NDM) is a rare condition (1:400 000 neonates) defined as hyperglycemia occurring in the first months of life, lasting more than 2 wk and requiring insulin for management. We here report on a 33-month-old girl with pancreatic agenesis, an extremely rare cause of permanent neonatal diabetes mellitus (PNDM). Timely diagnosis and adequate treatment of both endocrine and exocrine insufficiency may permit survival and normal development.     

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.     

Neonatal diabetes mellitus because of pancreatic agenesis with dysmorphic features and recurrent bacterial infections

Abstract:  Pancreatic agenesis is a rare cause of neonatal diabetes mellitus (NDM). It can be associated with malformations of the heart, the biliary tract, and the cerebellum. We report an infant with NDM because of pancreatic agenesis, intra-uterine growth retardation, dysmorphic features, and recurrent bacterial infections. He was born to healthy consanguineous parents. With adequate replacement of insulin and pancreatic enzymes, his blood glucose levels were controlled and his weight slowly increased. However, he continued to develop recurrent serious bacterial infections and died at the age of 11 months with sepsis and respiratory failure. Analysis of the PTF1A and PDX1 genes, which have been associated with congenital agenesis of the pancreas, did not reveal any mutation. Genetic abnormalities of chromosome 6 associated with transient neonatal diabetes as well as mutations in the KCNJ11 and ABCC8 genes encoding the pancreatic potassium channel were also excluded as a cause of the NDM in this patient. The association of permanent neonatal diabetes because of pancreatic agenesis, dysmorphism, and non-specific immunodeficiency is previously undescribed and may represent a new possibly autosomal recessive syndrome.     

AV59M KCNJ11 gene mutation leading to intermediate DEND syndrome in a Chinese child

Heterozygous activating mutations in the KCNJ11 gene can cause permanent and transient neonatal diabetes. In the present study, we sequenced the KCNJ11 gene in a Chinese boy diagnosed with permanent neonatal diabetes mellitus (PNDM) and also in his parents. A heterozygous 175G > A (V59M) mutation was identified in the patient, while no KCNJ11 gene mutations were found in his parents, indicating that this mutation is de novo. The patient with the V59M mutation successfully switched from insulin injections to oral glibenclamide; 2 years of follow-up revealed that the patient had intermediate developmental delay, epilepsy and neonatal diabetes (DEND) syndrome. This is the first patient who is reported to have iDEND syndrome due to KCNJ11 V59M mutation in China.     

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.     

Different faces of non-autoimmune diabetes of infancy

The aim of this report is to describe four cases of non-autoimmune diabetes that presented in infancy. Three had transient neonatal diabetes mellitus (TNDM) with diabetic ketoacidosis at onset, followed by complete remission after several months of insulin treatment. While the fourth case was initially diagnosed as TNDM, she had renal, hepatic and pancreatic dysplasia. These cases illustrate that diabetes in infants can be difficult to diagnose and that patients with TNDM can have a recurrence of diabetes several years later.     

Permanent neonatal diabetes with arthrogryposis multiplex congenita and neurogenic bladder – a new syndrome?

Abstract: Neonatal diabetes mellitus is a rare (1/400 000 newborns) but potentially devastating condition, which may be transient or permanent; typical symptoms occur within the first 4 wk of life. The transient form is a developmental insulin production disorder that resolves postnatally. Fifty to 60% of cases can be seen as transient form. Cases that require lifelong insulin therapy can be described as permanent condition. This fraction of cases is less common than the transient form. There are no clinical features that can predict whether a neonate with diabetes mellitus but no other dysmorphology will eventually have permanent neonatal diabetes mellitus (PNDM) or transient neonatal diabetes mellitus. Some metabolic or genetic defects such as complete deficiency of glucokinase or heterozygous activating mutations of KCNJ11, encoding Kir6.2, were found in patients with PNDM. A preterm female infant with a gestational age of 36 wk was admitted to the neonatal intensive care unit in the first hours of life due to prematurity and intra‐uterine growth retardation. She was diagnosed as having arthrogryposis multiplex congenita on the first day. Hyperglycemia was detected on the third day of life, and she required insulin treatment. The patient is now 6 yr old with PNDM, arthrogryposis multiplex, neurogenic bladder, immune deficiency, constipation, and ichthyosis. Is this a new form of neonatal diabetes mellitus?