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.     

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.     

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.     

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.     

大鼠胎仔十二指肠闭锁与肝脏胰腺在发育中的关系

目的 制作阿霉素诱导大白鼠胎仔出现先天性十二指肠闭锁的动物模型，并探讨十二指肠闭锁与伴发的胰腺、肝脏发育不良的关系。方法 Wister孕鼠10只，分为实验组7只，对照组3只，分别于妊娠第6－9d腹腔注射阿霉素1.75mg/kg或等体积的生理盐水，妊娠20d剖宫取胎仔，对十二指肠、肝脏及胰腺做解剖、电镜及光镜观察。结果 阿霉素组获取胎仔67只，十二指肠闭锁35只，占52.2%(35/67)，其中腔内闭锁1只，占2.9%(1/35)；十二指肠闭锁近远端由纤维带或胰腺组织充填者27只，占77.1%(27/35)，闭锁近远端分别为游离盲端者7只，占20.0%(7/35)。肝脏畸形22只，占32.8%(22/67)，其中21只同时存在十二指肠闭锁畸形。大体形态改变表现为部分肝分叶的缺失，尾状叶缺失14例，占63.6%(14/22)，5只尾状叶及乳突叶同时缺失，占22.7%（5／22），3例尾状叶、乳突叶也肝右叶均缺失，占13.6%(3/22)。镜下观察见部分肝小叶呈发育不良改变。胰腺异常36只，占53.7%(36/67)，其中34例同时存在十二指肠闭锁畸形。大体形态改变主要表现在胰腺体积变小，23只胰颈、体、尾部均缺如，占63.9%(23/36)，13只胰体、尾部缺如，占36.1%(13/36)。组织学观察显示部分胰腺腺泡发育不良。结论 阿霉素诱导大白鼠胎仔出现先天性十二指肠闭锁是一种可靠的模型制作方法，其十二指肠、肝脏和胰腺三者在发育过程中是相互影响的。     

Urinary tract abnormalities in association with oesophageal atresia: frequency,significance, and influence on management

Urinary tract abnormalities occur in about 24% of infants with oesophageal atresia. It is important in the neonatal period to recognise those that may cause renal damage if untreated so that the long-term complications of renal disease, e. g., reflux-associated nephropathy, can be prevented. Our current practice is to obtain a renal ultrasound and micturating cystourethrogram during the first admission. If the infant has not been observed to pass urine, then renal ultrasound should be performed before repair of the oesophageal atresia, because there is inadequate functioning renal tissue for long-term survival in 3% of oesophageal atresia patients. The absence of Potter's syndrome in infants with both oesophageal atresia and bilateral renal agenesis means that these patients often cannot be identified pre-operatively on clinical grounds alone. Offprint requests to: Spencer W. Beasley     

Intestinal atresia: management problems in a developing country

Over a 13-year period, 24 children with intestinal atresia were managed at the Jos University Teaching Hospital, Jos, Nigeria. Intestinal atresia ranks as the second most common cause of neonatal intestinal obstruction (after anorectal malformation) in our hospital. Five children had duodenal obstruction (two atresia, two duodenal webs, one annular pancreas), 17 had jejunoileal atresia, and two had colonic atresia. Fourteen were boys, and 10 were girls (M:F: 1.17:1). The median age at presentation to the surgeon was 6 days (range: 1 day-12 years). The most common presenting features were bilious vomiting and abdominal distension. Six patients did not pass meconium within the first 24 h of birth. The median weight at presentation was 2.6 kg (range: 1.1 kg-5.0 kg). Seven patients (four with jejunoileal atresia and three with duodenal obstruction) had associated congenital anomalies. Diagnostic investigation was plain abdominal x-ray, showing double-bubble gas shadows in duodenal atresia and varying degrees of air-fluid levels in jejunoileal and colonic atresias. An upper gastrointestinal series was done in three patients and a barium enema in one. Retrocolic duodenojejunostomy was done for all patients with duodenal atresia and annular pancreas, duodenotomy and web excision for those with duodenal webs, and resection with end-to-end anastomosis for those with jejunoileal atresia. One child with atresia involving the whole ileum and the colon had a jejunorectal anastomosis, while the other child with colonic atresia had caecostomy followed later by ileorectal anastomosis. Ten neonates died, giving a mortality rate of 41.7%. Mortality from intestinal atresia is still high in our environment, due mainly to lack of neonatal intensive care facilities.     

Unusual case of neonatal diabetes mellitus due to congenital pancreas agenesis

Congenital absence of the pancreas is an extremely rare condition. We participated in the care of a patient with an unusual presentation of neonatal diabetes attributable to agenesis of the pancreas. Additional clinical features of the patient included cardiac septal defects, gall bladder agenesis and duodenal malrotation. Appropriate institution of insulin, exocrine pancreatic supplements and surgical repair of the cardiac and intestinal anomalies resulted in the infant's survival. Of the reported cases of congenital pancreas agenesis, two cases have been ascribed to mutations in the insulin promoter factor-1(Ipf-1) gene. Deletion of the Ipf-1-homolog pdx-1 in mice results in the failure of pancreas to develop. Analysis of both exons of the Ipf-1 coding sequence from the presented patient's genomic DNA, however, did not identify a mutation. These results suggest that a congenital or genetic perturbation occurred in this infant most likely before the appearance of dorsal pancreatic bud in the 3 mm long embryonic stage, around the embryonic day 25 in human development, before the onset of Ipf-1 expression.     

Glyburide ameliorates motor coordination and glucose homeostasis in a child with diabetes associated with the KCNJ11/S225T,del226‐232 mutation

Gain‐of‐function mutations of KCNJ11 can cause permanent neonatal diabetes mellitus, but only rarely after 6 months of age. Specific uncommon mutations KCNJ11give rise to a syndrome defined as developmental delay, epilepsy, and neonatal diabetes (DEND), or – more frequently – to a milder sub‐type lacking epilepsy, denoted as intermediate‐DEND (iDEND). Our aim was to consider a possible monogenic etiology in a 12‐yr‐old boy with early onset diabetes and mild neurological features. We studied a subject diagnosed with diabetes at 21 months of age, and negative to type 1 diabetes autoantibodies testing. He had learning difficulties during primary school, and a single episode of seizures at the age of 10 yr. We performed direct DNA sequencing of the KCNJ11 gene with subsequent functional study of mutated channels in COSm6 cells. The patient's clinical response to oral glyburide (Glyb) was assessed. Motor coordination was evaluated before and after 6 and 12 months of Glyb therapy. Sequencing of the KCNJ11 gene detected the novel, spontaneous mutation S225T, combined with deletion of amino acids 226–232. In vitro studies revealed that the mutation results in a K_ATP channel with reduced sensitivity to the inhibitory action of ATP. Glyb improved diabetes control (hemoglobin A1c on insulin: 52 mmol/mol/6.9%; on Glyb: 36 mmol/mol/5.4%) and also performance on motor coordination tests that were impaired before the switch of therapy. We conclude that KCNJ11/S225T, del226‐232 mutation caused a mild iDEND form in our patient. KCNJ11 should be considered as the etiology of diabetes even beyond the neonatal period if present in combination with negative autoantibody testing and even mild neurological symptoms.     

Hepatobiliary scintigraphy and the string test in the evaluation of neonatal cholestasis

We evaluated [99mTc]diisopropylphenyl-carbamoylmethylimidodiacetic acid ([99mTc]DISIDA) cholescintigraphy with measurement of duodenal fluid radioactivity collected by the string test in patients with neonatal cholestasis. Twenty-six infants with prolonged jaundice and acholic stools were studied prospectively. Twelve patients had neonatal hepatitis, 12 biliary atresia, and one each Alagille syndrome and alpha 1-antitrypsin deficiency liver disease. All infants except the biliary atresia patients and four of the neonatal hepatitis patients revealed bowel activity on scan 6 h after tracer administration. At 24 h, three of these latter patients with neonatal hepatitis and two of the patients with biliary atresia revealed bowel activity. String radioactive counts for neonatal hepatitis ranged from 99,574 to 967,205 cpm (374,504 +/- 232,210 cpm; mean +/- SD) and for biliary atresia from 8,342 to 370,346 cpm (117,149 +/- 98,698 cpm; mean +/- SD). While neither test alone was capable of correctly differentiating among all patients, those patients with biliary atresia had either a negative hepatobiliary scan at 24 h or string radioactive count below 197,007 cpm. Disparity between the hepatobiliary scan and the string radioactive counts mandates further diagnostic investigation. These data suggest that simultaneous administration of the string test with hepatobiliary scintigraphy is advantageous in the evaluation of infants with cholestatic jaundice.     

阿霉素诱导十二指肠闭锁的实验研究

目的 制作阿霉素诱导大白鼠胎仔出现先天性十二指肠闭锁的模型。方法 Ｗｉｓｔａｒ孕鼠１０只,于妊娠第６至第９天腹腔注射阿霉素１．７５ｍｇ／ｋｇ,妊娠２０天剖宫取胎仔,做解剖、电镜及光镜观察。结果 用药组获胎仔３２只,十二指肠闭锁２６例（８１．３％）,其中腔内闭锁１５．４％,闭锁近远端由纤维或胰腺相连者占４６．２％,近远端游离者为３８．５％,十二指肠闭锁畸形均伴有胰腺发育异常,９例胰颈、胰体及胰尾缺如     

Lack of correlation between infection with reovirus 3 and extrahepatic biliary atresia or neonatal hepatitis

Infection with reovirus 3 (Reo-3) has been suggested as the cause of extrahepatic biliary atresia and idiopathic neonatal hepatitis, but confirmation has been lacking. Therefore we have searched for a specific anti-Reo-3 antibody response in the sera of patients with biliary atresia or neonatal hepatitis and for Reo-3 antigens in their hepatobiliary tissues. Sera from 23 infants with extrahepatic biliary atresia, 12 with neonatal hepatitis, 30 age-matched control patients with other liver diseases, and 55 control patients without liver disease were tested by an enzyme-linked immunosorbent assay for total (IgA, IgG, and IgM) anti-Reo-3 antibodies; sera of infants younger than 6 months of age were tested also for IgM anti-Reo-3 antibodies alone. There was no difference between either total or IgM anti-Reo-3 antibody levels in infants with extrahepatic biliary atresia or neonatal hepatitis and levels in control infants. Reo-3 antigens were not detected in the hepatobiliary tissues of 19 infants (18 with biliary atresia, one with neonatal hepatitis) by an immunoperoxidase method that readily demonstrated Reo-3 in control infected HEp-G2 cells. Our data do not support a relationship between neonatal liver diseases and infection with Reo-3.     

Usefulness of magnetic resonance cholangiopancreatography in biliary structures in infants: a four-case report

In this paper, we report the usefulness of magnetic resonance cholangiopancreatography (MRCP) in excluding biliary atresia (BA) as the cause of neonatal cholestasis. MRCP with a 1.5-T magnetic resonance (MR) imaging unit was performed on four jaundiced neonates and infants aged from 38 days to 106 days. The diagnosis of BA (n=2) was confirmed with surgery, liver biopsy and surgical cholangiography. Diagnosis of neonatal hepatitis (NH, n=2) was confirmed with clinical follow-up until jaundice resolved, while one of them was diagnosed with surgical cholangiography. In all discoloured acholic stools, increased direct bilirubin (4.4–11.3 mg/dl) with positive lipoprotein X prompted technetium ^99mTc disofenin scanning, which showed no excretion. Computed tomography (CT) showed a gallbladder in one with hepatitis but no intrahepatic bile duct in two with BA. The Kasai operation was performed in two patients with BA. In two patients with BA, neither the common bile duct nor the common hepatic ducts were visible at MRCP. In two patients with NH, MRCP clearly depicted both the common hepatic and the common bile ducts. MRCP was accurate in excluding BA as the cause of neonatal cholestasis, while ^99mTc disofenin cholescintigraphic findings were false-positive in two patients with non-obstructive cholestasis. We conclude that MRCP can be used to depict the major biliary structures of neonates and small infants and to exclude BA as the cause of neonatal cholestasis by allowing visualisation of the biliary tract.     

Intestinal absorption of calcium and magnesium in hepatobiliary disease in infancy

The intestinal absorption of calcium and magnesium was measured by metabolic balance studies in 6 normal infants, 13 infants with biliary atresia, 5 infants with successfully repaired biliary atresia, 7 infants with neonatal hepatitis, and 2 infants with choledochal cyst. The absorption of both elements was impaired in these disorders. The malabsorption of these elements was most marked in biliary atresia. In successfully repaired biliary atresia the absorption was increased to the normal levels. In neonatal hepatitis the degree of the malabsorption was variable in individual cases. In choledochal cyst the reduction of the absorption was less marked than in biliary atresia and neonatal hepatitis. In biliary atresia parenteral vitamin D increased moderately the absorption of both elements, though oral vitamin D had little effect. In infants with biliary atresia receiving a milk containing medium-chain triglycerides the absorption was moderately raised. There was a clear relation between the absorption of calcium and that of magnesium: the per cent. absorption of magnesium was almost the same as that of calcium in most cases. The serum calcium level determined during the studies was within the normal ranges in hepatobiliary diseases. The serum magnesium level was, however, found to be generally reduced in these conditions. It was greatly reduced in the patients with biliary atresia.     

Phenobarbital-enhanced hepatobiliary scintigraphy in the diagnosis of biliary atresia: two decades of experience at a tertiary center

Background

Hepatobiliary scintigraphy is highly sensitive for diagnosing biliary atresia; however, its specificity has varied in the literature from 35% to 97%.

Objective

The purpose of this study was to re-evaluate the accuracy of phenobarbital-enhanced hepatobiliary scintigraphy in differentiating biliary atresia from other causes of neonatal cholestasis.

Materials and methods

We retrospectively reviewed all hepatobiliary scans of infants with cholestasis at our institution from December 1990 to May 2011. Per our routine protocol the scans were obtained after pretreatment with phenobarbital (5 mg/kg/day for 5 days) to achieve a serum level of ≥15 mcg/ml. Normal hepatic uptake with no biliary excretion by 24 h was considered consistent with biliary atresia.

Results

One hundred eighty-six infants with 210 hepatobiliary scans composed the study group. Forty-three (23%) infants had the final diagnosis of biliary atresia. Hepatobiliary scintigraphy was 100% sensitive, 93% specific and 94.6% accurate in diagnosing biliary atresia. Of the 186, 39/111 (35.1%) term and 2/68 (2.9%) preterm infants had biliary atresia; two of seven children with unknown gestational age also had biliary atresia. Other diagnoses included neonatal hepatitis, total parenteral nutrition cholestasis, Alagille syndrome, cystic fibrosis, choledochal cyst, hypothyroidism, alpha-1 antitrypsin deficiency and persistent cholestasis of unknown etiology.

Conclusion

Phenobarbital-enhanced hepatobiliary scintigraphy is highly accurate in differentiating biliary atresia from other causes of neonatal cholestasis. Biliary atresia is rare in premature infants.     

Neonatal Intestinal Obstruction in a Developing Tropical Country: Patterns, Problems, and Prognosis

The experience with 211 cases of neonatal intestinal obstruction in Lagos, Nigeria, is described in an attempt to define the pattern in a developing country. Some of the major differences from the established pattern in the West include absence of meconium ileus and the relatively low prevalence of duodenal atresia which accounted for 8 per cent of bowel obstruction. Jejuno-ileal atresia and Hirschprung's disease constituted 21 and 14 per cent, respectively. Imperforate anus, as in the West, was the commonest, occurring in 38 per cent. Although neonatal intestinal obstruction was seen throughout the year a peak involving all the major types appeared in the second quarter. This may indicate an aetiological relationship with malaria. Delay in presentation, shortage of personnel, and inadequate facilities were the major problems associated with management of neonatal intestinal obstruction. The overall surgical mortality was 35 per cent; respiratory failure, metabolic disturbances, and malabsorption being the major causes of death.     

Mutant neurogenin‐3 in a Turkish boy with congenital malabsorptive diarrhea

Congenital diarrheal disorders are caused by disruption in nutrient digestion, absorption, or transport, enterocyte development and functioning, or enteroendocrine functioning. Many additional rare forms of congenital diarrhea are expected to be linked to genes associated with appropriate intestinal fluid and electrolyte balance. Neurogenin‐3 mutation, a very rare form of congenital diarrhea, disrupts enteroendocrine cell differentiation and is characterized by malabsorption and the absence of pancreatic islet cells. Diabetes mellitus is typically associated with malabsorptive diarrhea at early onset or at later presentation in neurogenin‐3 mutation. Here, we describe the case of an infant with homozygous neurogenin‐3 mutation who had severe malabsorptive diarrhea and episodes of hyperchloremic metabolic acidosis after birth. Remarkably, cholestyramine was effective at reducing stool volume and frequency and improved the consistency of the stools; diabetes was not present in this patient.     

Recent developments in diagnostics and treatment of neonatal cholestasis

Neonatal cholestasis is characterized by conjugated hyperbilirubinemia in the newborn and young infant and is a sign common to over 100 hepatobiliary and/or metabolic disorders. A timely evaluation for its etiology is critical in order to quickly identify treatable causes such as biliary atresia, many of which benefit from early therapy. An expanding group of molecularly defined disorders involving bile formation, canalicular transporters, tight junction proteins and inborn errors of metabolism are being continuously discovered because of advances in genetic testing and bioinformatics. The advent of next generation sequencing has transformed our ability to test for multiple genes and whole exome or whole genome sequencing within days to weeks, enabling rapid and affordable molecular diagnosis for disorders that cannot be directly diagnosed from standard blood tests or liver biopsy. Thus, our diagnostic algorithms for neonatal cholestasis are undergoing transformation, moving genetic sequencing to earlier in the evaluation pathway once biliary atresia, “red flag” disorders and treatable disorders are excluded. Current therapies focus on promoting bile flow, reducing pruritus, ensuring optimal nutrition, and monitoring for complications, without addressing the underlying cause of cholestasis in most instances. Our improved understanding of bile formation and the enterohepatic circulation of bile acids has led to emerging therapies for cholestasis which require appropriate pediatric clinical trials. Despite these advances, the cause and optimal therapy for biliary atresia remain elusive. The goals of this review are to outline the etiologies, diagnostic pathways and current and emerging management strategies for neonatal cholestasis.