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.     

Neonatal diabetes mellitus with pancreatic agenesis in an infant with homozygous IPF-1 Pro63fsX60 mutation

Permanent neonatal diabetes mellitus is a rare disorder known to be caused by activating mutations in KCNJ11 or ABCC8, inactivating mutations in INS, or very rarely in GCK or insulin promotor factor-1 (IPF-1) genes. We report a patient with permanent neonatal diabetes mellitus and severe exocrine pancreatic insufficiency. Ultrasound examination revealed pancreatic agenesis with a suggestion of a small amount of tissue in the head of the pancreas. Genetic testing revealed that the neonate had a homozygous Pro63fsX60 IPF-1 mutation. This is the second reported case of neonatal diabetes mellitus secondary to a homozygous mutation in the IPF-1 gene and supports the previously proposed biological role of IPF-1 in the pancreatic development in human.     

Pancreatic agenesis as cause for neonatal diabetes mellitus

BACKGROUND: Pancreatic agenesis is a rare cause of neonatal diabetes mellitus and the knowledge about the clinical features is sparse. A patient with pancreatic agenesis and double outlet right ventricle is reported. This association has not previously been reported. In addition a synopsis of the patients (n = 14) with pancreatic agenesis who have hitherto been described is given. METHOD: We studied one patient and obtained information on 13 additional patients with pancreatic agenesis by reviewing literature. RESULTS: Literature review: In one patient the pregnancy was terminated at 19 weeks. 31 % (4/13) of the infants died in the first week and 69 % (9/13) in the first six weeks of live, 17 % (2/12) were born preterm and 83 % (10/12) at term, 93 % (13/14) had severe intrauterine growth restriction, onset of diabetes was in 6 out of 10 infants during the first two days of live, ketonuria is rare and has been reported only once. 64 % (9/14) of the infants with pancreatic agenesis had additional malformations mainly of the biliary system (50 %) and/or the heart (36 %). 31 % (4/13) of the infants survived the neonatal period and developed normally. Failure to thrive was compensated by catch-up growth after replacement of pancreatic enzymes and surgical correction of the cardiac malformation. CONCLUSIONS: Pancreatic agenesis is a clinical entity characterized by severe intrauterine growth retardation, early onset of permanent neonatal diabetes mellitus without ketoacidosis, failure to thrive due to pancreatic exocrine dysfunction and associated malformations mainly of the biliary system or of the heart. Because of the high neonatal mortality, awareness of pancreatic agenesis as a possible cause of severe intrauterine growth restriction is important for the optimal treatment of diabetes mellitus, exocrine pancreatic insufficiency and the associated malformations.     

A rare case of acute lymphoblastic leukaemia with hemophilia A

Recent studies suggested a link between type 1 diabetes mellitus and pervasive developmental disorder. Moreover, permanent neonatal diabetes mellitus due to pancreatic agenesis can be associated with neurological deficit involving cerebellar functions, but no association with pervasive developmental disorder has been described so far. Clinical and neuropsychological evaluation of a child with pancreatic agenesis, mental retardation and pervasive developmental disorder is reported.     

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...     

A novel mutation in GATA6 causes pancreatic agenesis

Heterozygous mutations in GATA6 have been linked to pancreatic agenesis and cardiac malformations. The aim of this study was to describe a new mutation in GATA6 in an infant with pancreatic agenesis, associated with truncus arteriosus and absent gallbladder. Clinical data were obtained from chart review. Gene sequencing was performed on genomic DNA. The patient was a female infant diagnosed shortly after birth with a severe cardiac malformation, absent gallbladder, anomalous hepatic blood flow, unilateral hydronephrosis and hydroureter, neonatal diabetes, and pancreatic exocrine insufficiency. Despite prolonged intensive management care, she died at 3 months of age because of cardiac complications. Analysis of her genomic DNA revealed a novel missense mutation of GATA6. The novel mutation described in this case extends the list of GATA6 mutations causing pancreatic agenesis and cardiac malformations.     

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.     

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.     

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.     

The genetic basis of neonatal diabetes mellitus

Neonatal diabetes mellitus is a rare condition occurring within the first few months of life that can either be permanent or transient. Various genetic defects responsible for both permanent and transient neonatal diabetes have been identified. ATP-sensitive potassium (KATP) channels are key regulators of nutrient-induced insulin secretion in pancreatic beta cells. Activating mutations of the KATP channel, which prevent closure of the channel and thus inhibit insulin secretion, are now known to be the predominant cause of permanent neonatal diabetes. Transient neonatal diabetes may also be associated with activating mutations of the KATP channel. However, the majority of cases of transient neonatal diabetes have a mutation that maps to a locus on the long arm of chromosome 6, and mutations in two overlapping genes, ZAC and HYMA1, have been identified as the predominant cause of transient neonatal diabetes. These findings provide important insights into the molecular and genetic basis in the broad spectrum of diabetes mellitus.     

A new variant of a known mutation in two siblings with permanent neonatal diabetes mellitus

Permanent neonatal diabetes mellitus is a rare disorder usually presenting within the first few weeks or months of life. This disorder is genetically heterogeneous and has been associated with mutations in various genes. The genetic cause remains mostly unknown although several genes have been linked to this disorder. Mutations in KCNJ11, ABCC8, or INS are the cause of permanent neonatal diabetes mellitus in about 50%-60% of the patients. With genetic studies, we hope to increase our knowledge of neonatal diabetes, whereby new treatment models can become possible. Here, we defined a new variant of a known mutation, INS Exon 1-3 homozygous deletion, in two siblings diagnosed with permanent neonatal diabetes mellitus.     

Congenital hyperinsulinism in an infant caused by a macroscopic insulin-producing lesion

Congenital hyperinsulinism is the most common cause of persistent neonatal hypoglycemia. Severe congenital hyperinsulinism is most often due to inactivating mutations in either the ABCC8 or KCNJ11 genes, which encode the SUR1 and Kir6.2 proteins, respectively--the two components of the ATP-sensitive K+ (KATP) channel; neonatal hypoglycemia due to macroscopic insulin-producing pancreatic lesions or adenomas are extremely rare. KATP channel hyperinsulinism is classified as diffuse or focal, the latter being associated with paternally-derived mutations of ABCC8 or KCNJ11 and somatic loss of heterozygosity of the maternal alleles. KATP channelopathies usually produce microscopic intra-pancreatic lesions and are typically unresponsive to drug therapy, requiring > 95% pancreatectomy for diffuse disease and occasionally more limited pancreatic resection for focal disease; macroscopic pancreatic lesions and adenomas are focally excised. We describe a 1 month-old infant with severe congenital hyperinsulinism who had a macroscopic insulin-producing pancreatic lesion successfully treated with focal lesion enucleation.     

KCNJ11 activating mutations cause both transient and permanent neonatal diabetes mellitus in Cypriot patients

Heterozygous mutations of the KCNJ11 gene encoding the Kir6.2 subunit of the ATP-sensitive potassium channel (K(ATP) channel) of the pancreatic β-cell cause diabetes in about 30-60% of all permanent neonatal diabetes mellitus cases diagnosed before 6 months of age. The K(ATP) channel plays an essential role in the regulation of the electrical status of the membrane through which the secretion of insulin is activated. Transient neonatal diabetes mellitus due to KCNJ11 mutations is less frequent than abnormalities affecting the imprinted region of chromosome 6q24. We studied the genetic basis of two Cypriot patients who developed diabetes before 6 months of age. They both carried mutations of the KCNJ11 gene. The R201H mutation was identified in a patient who developed hyperglycemia and ketoacidosis at the age of 40 d and was successfully transferred to sulphonylureas which activate the channel through an ATP independent route. The R50Q mutation was identified in a child diagnosed at day 45 after birth with remission of his diabetes at 9 months of age. The same defect was identified both in his asymptomatic mother and the recently diagnosed 'type 2' diabetic maternal grandmother. The remission-relapse mechanism in cases of transient neonatal diabetes is not known. Nevertheless, it is possible that the residue of the mutation within the Kir6.2 molecule is associated with the sensitivity to ATP reflecting to the severity of the diabetic phenotype.     

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.     

Microcephaly,epilepsy, and neonatal diabetes due to compound heterozygous mutations in IER3IP1: insights into the natural history of a rare disorder

Neonatal diabetes mellitus is known to have over 20 different monogenic causes. A syndrome of permanent neonatal diabetes along with primary microcephaly with simplified gyral pattern associated with severe infantile epileptic encephalopathy was recently described in two independent reports in which disease‐causing homozygous mutations were identified in the immediate early response‐3 interacting protein‐1 (IER3IP1) gene. We report here an affected male born to a non‐consanguineous couple who was noted to have insulin‐requiring permanent neonatal diabetes, microcephaly, and generalized seizures. He was also found to have cortical blindness, severe developmental delay and numerous dysmorphic features. He experienced a slow improvement but not abrogation of seizure frequency and severity on numerous anti‐epileptic agents. His clinical course was further complicated by recurrent respiratory tract infections and he died at 8 years of age. Whole exome sequencing was performed on DNA from the proband and parents. He was found to be a compound heterozygote with two different mutations in IER3IP1: p.Val21Gly (V21G) and a novel frameshift mutation p.Phe27fsSer*25. IER3IP1 is a highly conserved protein with marked expression in the cerebral cortex and in beta cells. This is the first reported case of compound heterozygous mutations within IER3IP1 resulting in neonatal diabetes. The triad of microcephaly, generalized seizures, and permanent neonatal diabetes should prompt screening for mutations in IER3IP1. As mutations in genes such as NEUROD1 and PTF1A could cause a similar phenotype, next‐generation sequencing approaches—such as exome sequencing reported here—may be an efficient means of uncovering a diagnosis in future cases.     

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.     

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.     

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.