Characterization of novel PNLIP variants in congenital pancreatic lipase deficiency.

BACKGROUND/OBJECTIVES: Studies of a rare homozygous missense mutation identified in two brothers diagnosed with congenital pancreatic lipase deficiency (CPLD) provided the first definitive evidence linking CPLD with missense mutations in the gene of PNLIP. Herein, we investigated the molecular basis for the loss-of-function in the three novel PNLIP variants (c.305G > A, p.(W102∗); c.562C > T, p.(R188C); and c.1257G > A, p.(W419∗)) associated with CPLD. METHODS: We characterized three novel PNLIP variants in transfected cells by assessing their secretion, intracellular distribution, and markers of endoplasmic reticulum (ER) stress. RESULTS: All three variants had secretion defects. Notably, the p.R188C and p.W419∗ variants induced misfolding of PNLIP and accumulated as detergent-insoluble aggregates resulting in elevated BiP at both protein and mRNA levels indicating increased ER stress. CONCLUSIONS: All three novel PNLIP variants cause a loss-of-function through impaired secretion. Additionally, the p.R188C and p.W419∗ variants may induce proteotoxicity through misfolding and potentially increase the risk for pancreatic acinar cell injury.

Mutations and variants of ONECUT1 in diabetes.

Genes involved in distinct diabetes types suggest shared disease mechanisms. Here we show that One Cut Homeobox 1 (ONECUT1) mutations cause monogenic recessive syndromic diabetes in two unrelated patients, characterized by intrauterine growth retardation, pancreas hypoplasia and gallbladder agenesis/hypoplasia, and early-onset diabetes in heterozygous relatives. Heterozygous carriers of rare coding variants of ONECUT1 define a distinctive subgroup of diabetic patients with early-onset, nonautoimmune diabetes, who respond well to diabetes treatment. In addition, common regulatory ONECUT1 variants are associated with multifactorial type 2 diabetes. Directed differentiation of human pluripotent stem cells revealed that loss of ONECUT1 impairs pancreatic progenitor formation and a subsequent endocrine program. Loss of ONECUT1 altered transcription factor binding and enhancer activity and NKX2.2/NKX6.1 expression in pancreatic progenitor cells. Collectively, we demonstrate that ONECUT1 controls a transcriptional and epigenetic machinery regulating endocrine development, involved in a spectrum of diabetes, encompassing monogenic (recessive and dominant) as well as multifactorial inheritance. Our findings highlight the broad contribution of ONECUT1 in diabetes pathogenesis, marking an important step toward precision diabetes medicine.

Rare Extracardiac Anomalies Presented with Right Heterotaxy Syndrome in a Newborn Baby: A Case Report.

BACKGROUND Heterotaxy is a syndrome of abnormal arrangement of the internal thoracic-abdominal structures across the left-right axis of the body. It is a primary disorder with 2 main settings - bilateral left sidedness (polysplenia syndrome) or right sidedness (asplenia syndrome) - although some overlapping or uncertainties may occur. Patients with right heterotaxy typically present with asplenia, complex heart disease, and other thoracoabdominal organ situs abnormalities. CASE REPORT We present a unique case of congenital asplenia syndrome with complex heart disease, annular pancreas, and other extra-heterotaxic anomalies (e.g., musculoskeletal) in the form of a radius aplasia and partial syndactyly of the thumb and index finger of the left hand. These associated anomalies have not been reported before. CONCLUSIONS This case shows the need for paying increased attention to the implications of other extracardiac anomalies that can be associated with heterotaxy syndrome.

Congenital hypothyroidism, cardiac defects, and pancreatic agenesis in an infant with GATA6 mutation.

GATA6 pathogenic variants primarily manifest a phenotype with pancreatic agenesis and cardiac malformations. However, additional congenital malformations affecting the biliary system, congenital diaphragmatic hernia and developmental delay have been reported. We report a newborn, prenatally diagnosed with truncus arteriosus and intrauterine growth restriction, who was postnatally found to have pancreatic agenesis associated with neonatal diabetes and hepatobiliary abnormalities. Whole exome sequencing identified a de novo, heterozygous mutation in the GATA6 gene (c.1366C>T; p.Arg456Cys). Further investigations revealed abnormalities not previously associated with GATA6 mutation, including unilateral thyroid lobe agenesis associated with congenital hypothyroidism, absent gall bladder, possible adrenal insufficiency, thrombocytopenia, and neonatal stroke.

Successful laparoscopic resection for gastric duplication cyst: a case report.

BACKGROUND: Gastric duplication is a relatively rare congenital malformation, accounting for approximately 2.9-3.8% of gastrointestinal duplications. Gastric duplication cyst is a congenital anomaly that is rarely observed in adults. Accurate diagnosis of these cysts before resection is difficult. In this report, we describe a patient with gastric duplication cysts that were treated by laparoscopic resection. CASE PRESENTATION: A 46-year-old Japanese woman was referred to our institution because a cystic lesion in the pancreatic tail was detected by ultrasonography during a health examination. The lesion had a clearly defined boundary of approximately 40 mm. A thick cystic lesion of the septum was observed in the pancreatic tail, but invasion into the stomach wall was not recognized on a computed tomographic scan. Endoscopic ultrasonography revealed that the tumor appeared smooth with a marginal edge, which was characterized by echo with high homogeneity, and the presence of viscous mucus was suspected. The preoperative diagnosis of mucinous cystic neoplasm was the reason for laparoscopic tumor resection. The resected specimen was a smooth surface tumor, and it was full of mucus. Histopathological study revealed that the mucosa was covered with crypt epithelium, muscularis mucosae, intrinsic muscularis, and serosa, and the wall of the tumor had a structure very similar to that of the stomach wall. The mucosa was partially drained by intrinsic gastric glands, but most of them were denucleated. No pancreatic tissue was present, and the tumor had no continuity with the spleen. These findings indicated a diagnosis of gastric duplication cyst with no continuity with the stomach wall. CONCLUSIONS: In our experience, it is difficult to differentiate gastric duplication cyst from mucinous cystic neoplasm before laparoscopic resection. Events such as infection, bleeding, perforation, ulceration, fistula formation, obstruction, and compression have been linked to gastric duplication cysts, and malignant transformation of these cysts has been reported. Therefore, we suggest that resection should be the first treatment option for gastric duplication cysts.

A Specific CNOT1 Mutation Results in a Novel Syndrome of Pancreatic Agenesis and Holoprosencephaly through Impaired Pancreatic and Neurological Development.

We report a recurrent CNOT1 de novo missense mutation, GenBank: NM_016284.4; c.1603C>T (p.Arg535Cys), resulting in a syndrome of pancreatic agenesis and abnormal forebrain development in three individuals and a similar phenotype in mice. CNOT1 is a transcriptional repressor that has been suggested as being critical for maintaining embryonic stem cells in a pluripotent state. These findings suggest that CNOT1 plays a critical role in pancreatic and neurological development and describe a novel genetic syndrome of pancreatic agenesis and holoprosencephaly.

Pancreas divisum and recurrent pancreatitis: long-term results of minor papilla sphincterotomy.

Background and aims: Pancreas divisum (PD) is the most common congenital variant of the pancreatic ductal system and a potential cause of acute recurrent pancreatitis (ARP). Endoscopic therapy is a therapeutic option for symptomatic PD, but there is limited data on long-term results. We aimed to assess the effect of minor papilla endoscopic sphincterotomy (MiES) in the setting of ARP in patients with PD. Methods: Consecutive patients treated by MiES were included. Clinical data, including gender, age, smoking and drinking habits, number of episodes of acute pancreatitis (AP) as well as technical data pertaining to the endoscopic therapy were reviewed. Patients available for follow-up were contacted to assess the long-term impact of MiES using the Patient's Global Impression of Change (PGIC) questionnaire. Results: A total of 138 patients with PD including 77 patients with ARP underwent MiES; 48 patients were available for long-term follow-up using the PGIC score, with a mean follow-up period of 9.7 years. Procedure-related adverse events developed in 10 cases (12.9%): 5 post-MiES delayed bleeding and 5 mild pancreatitis. MiES was clinically successful in 35 patients (72.9%) who did not experience any more episodes of AP. Improvement in quality of life (PGIC ≥6) occurred in 41/48 patients (85.4%). On multivariate analysis, stenosis of the MiES was the only predictive factor for increased risk of recurrent pancreatitis after initial therapy. Conclusion: MiES resulted an efficient treatment for ARP in patients with PD with clinical benefit, patient satisfaction and improved quality of life even at long-term follow-up.

Diagnostic value of the acute angle between the prestenotic and poststenotic duodenum in neonatal annular pancreas.

OBJECTIVES: To analyze the ability of upper gastrointestinal (GI) saline-contrast ultrasound (US) to detect neonatal annular pancreas. METHODS: Sixty-two neonates, who presented duodenal obstruction and were examined by upper GI saline-contrast US before treatment, were retrospectively analyzed and categorized into four groups according to their final diagnosis: group A, annular pancreas (n = 28); group B, duodenal atresia (n = 2); group C, descending duodenal septum (n = 25); and group D, normal (n = 7). The ultrasonic characteristics were analyzed that especially focused on whether the angle between the prestenotic and poststenotic descending duodenum (at or below a derived cutoff) could identify neonatal annular pancreas. RESULTS: To detect annular pancreas using the concave contour of the distal prestenotic duodenum, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were determined at 71.4%, 100%, 100%, and 80.9%, respectively. When using the hyperechogenic band around the constricted duodenum, the sensitivity, specificity, PPV, and NPV were determined at 82.1%, 94.1%, 92%, and 86.5%, respectively. For using the 40.7° acute angle cutoff between prestenotic and poststenotic descending duodenum, the values of sensitivity, specificity, PPV, and NPV were determined at 100%, 97.1%, 96.6%, and 100%, respectively, of which the area under the receiver operating characteristic curve was 0.979. CONCLUSIONS: Upper GI saline-contrast US has a lower possibility for misdiagnosis of neonatal annular pancreas when considering the acute angle between the prestenotic and poststenotic descending duodenum. KEY POINTS: • This study includes the largest series of neonates with annular pancreas of which the characteristics were analyzed using the upper GI saline-contrast US. • Neonatal annular pancreas may be diagnosed by the characteristics-concave contour of the distal prestenotic duodenum; acute angle cutoff of 40.7° between the prestenotic and poststenotic duodenum; the "S" shape formed by the pylorus, the duodenal bulb, and the prestenotic and poststenotic descending duodenum. • The acute angle with the highest diagnostic value can be used to quantitatively diagnose neonatal annular pancreas and avoid potential misdiagnosis caused by sonographers' subjectivity.

GATA6 Cooperates with EOMES/SMAD2/3 to Deploy the Gene Regulatory Network Governing Human Definitive Endoderm and Pancreas Formation.

Heterozygous de novo mutations in GATA6 are the most frequent cause of pancreatic agenesis in humans. In mice, however, a similar phenotype requires the biallelic loss of Gata6 and its paralog Gata4. To elaborate the human-specific requirements for GATA6, we chose to model GATA6 loss in vitro by combining both gene-edited and patient-derived pluripotent stem cells (hPSCs) and directed differentiation toward ß-like cells. We find that GATA6 heterozygous hPSCs show a modest reduction in definitive endoderm (DE) formation, while GATA6-null hPSCs fail to enter the DE lineage. Consistent with these results, genome-wide studies show that GATA6 binds and cooperates with EOMES/SMAD2/3 to regulate the expression of cardinal endoderm genes. The early deficit in DE is accompanied by a significant reduction in PDX1+ pancreatic progenitors and C-PEPTIDE+ ß-like cells. Taken together, our data position GATA6 as a gatekeeper to early human, but not murine, pancreatic ontogeny.

A newborn patient with both annular pancreas and Meckel's diverticulum: A case report of an unusual association.

RATIONALE: Annular pancreas (AP) is recognized as a cause of duodenal obstruction in children, while children with Meckel's diverticulum (MD) are usually asymptomatic. Here we present a rare case with both AP and MD, which was identified by abdominal exploration during diamond-shaped duodenoduodenostomy. PATIENT CONCERNS: A "double-bubble" sign was found by ultrasound at 35 week of pregnancy. After 39 weeks of pregnancy, the male patient was transferred to the Department of General Surgery, Children's Hospital of Soochow University because of a suspected duodenal stenosis. DIAGNOSES: Preoperative abdominal X-ray examination indicated "double-bubble" sign. AP was confirmed by exploratory surgery, with an MD located 30 cm above the ileocecal valve. INTERVENTIONS: Diamond-shaped duodenoduodenostomy and a wedge resection of the intestine with end-to-end anastomosis were performed OUTCOMES:: The patient recovered and his appetite was good without vomiting. LESSONS: Our experience demonstrates that abdominal exploration is essential for children with gastrointestinal malformations.

Pancreas Divisum in Children and Duodenum-Preserving Resection of the Pancreatic Head.

INTRODUCTION: A retrospective study was performed to evaluate the clinical features, diagnostic methods, and treatment alternatives in children with pancreas divisum (PD). MATERIALS AND METHODS: Patients who underwent treatment for PD between 1999 and 2014 at our department were evaluated for sex, age, presenting symptoms, physical examination findings, biochemical markers, diagnostic methods, treatment modalities, and results of treatment during follow-up. RESULTS: Seven patients who underwent treatment of symptomatic PD were included in the study. The median for follow-up period was 8 years (from 26 months to 16 years). Male-to-female ratio was 4:3 and the median age at presentation was 11 years (2-14 years). Presenting symptoms were recurrent episodic epigastric pain. Pancreatitis was documented by elevated amylase or lipase levels. Endoscopic retrograde cholangiopancreatography (ERCP) was the method of diagnosis of PD in all patients. Five patients had complete PD and two had incomplete variants. Three patients improved after ERCP papillotomy. In three patients, papillotomy was unsuccessful but they have only mild episodes of pancreatitis. One patient presented at the age of 4 years with recurrent pancreatitis. She was treated surgically by duodenum-preserving resection of the pancreatic head (DPRPH) because of severe recurrent pancreatitis occurring even after ERCP papillotomy. The patient is 26 months after operation without any reported problems. CONCLUSION: Patients with symptomatic PD are indicated for ERCP papillotomy attempt. If there is not improvement after ERCP, then recurrent bouts of severe pancreatitis are considered as an indication for surgical procedure. DPRPH is a safe and feasible surgical alternative.

Ultrasound of congenital and inherited disorders of the pediatric hepatobiliary system, pancreas and spleen.

Ultrasound is often the initial imaging examination performed of the solid organs of the pediatric abdomen. The sonographic appearance of the hepatobiliary system, pancreas and spleen changes with growth and development. This article reviews the normal US appearance of these organs in children and illustrates, through case examples, congenital and inherited conditions that affect them.

Biliary Anomalies in Patients With HNF1B Diabetes.

Context: The clinical spectrum of organogenetic anomalies associated with HNF1B mutations is heterogeneous. Besides cystic kidney disease, diabetes, and various other manifestations, odd cases of mainly neonatal and posttransplantation cholestasis have been described. The biliary phenotype is incompletely defined. Objective: To systematically characterize HNF1B-related anomalies in the bile ducts by imaging with magnetic resonance imaging (MRI) or magnetic resonance cholangiopancreatography (MRCP). Setting and Patients: Fourteen patients with HNF1B mutations in the catchment area of the Helsinki University Hospital were evaluated with upper abdominal MRI and MRCP. Blood samples and clinical history provided supplemental data on the individual phenotype. Main Outcome Measure(s): Structural anomalies in the biliary system, medical history of cholestasis, other findings in abdominal organs, diabetes and antihyperglycemic treatment, hypomagnesemia, and hyperuricemia. Results: Structural anomalies of the bile ducts were found in seven of 14 patients (50%). Six patients had choledochal cysts, which are generally considered premalignant. Conclusions: Structural anomalies of the biliary system were common in HNF1B mutation carriers. The malignant potential of HNF1B-associated choledochal cysts warrants further studies.

Symptomatic pancreatic duct stones in the disconnected bile duct: A case series.

BACKGROUND: Pancreaticobiliary maljunction (PBM) refers to the union of the pancreatic and biliary ducts outside of the duodenal wall. Patients are at increased risk of bile duct and gallbladder cancer, likely secondary to pancreatic juice refluxing into the biliary tree, and it is recommended that they undergo biliary diversion. METHODS: This is a case series of all patients in our institution with PBM and bilioenteric anastomosis who presented with symptomatic pancreatic duct stones in a disconnected bile duct. IRB approval was obtained prior to the initiation of the study. RESULTS: We describe eight cases of this finding. All patients underwent ERCP, with stones successfully removed from the disconnected bile duct in seven patients and from the pancreatic duct in one patient. CONCLUSION: This novel finding has not been described in the medical literature, and may become more prevalent as more patients with PBM undergo bilioenteric anastomosis.

Fetal anomalies associated with HNF1B mutations: report of 20 autopsy cases.

OBJECTIVES: To describe macroscopic and microscopic anomalies present in fetuses carrying hepatocyte nuclear factor-1 ß mutation, their frequency, and genotype/phenotype correlations. METHODS: Clinical data, ultrasound findings, genetic studies, and autopsy reports of 20 fetal autopsies were analyzed. Histology was reviewed by two pathologists. RESULTS: Macroscopic findings were typically unilateral or bilateral renal enlargement and cortical cysts. Renal lesions were associated with congenital anomalies of the kidney and urinary tract in 25% of cases. Microscopic renal anomalies were dominated by glomerulocystic kidney and renal dysplasia. Extra-renal manifestations such as pancreatic hypoplasia (75%) and genital anomalies (68%) were only detected at autopsy. In 40% of cases, there was heterozygous deletion of the whole gene. There were de novo mutations in 40%. CONCLUSION: This study underlines the importance of considering hepatocyte nuclear factor-1 ß mutations in fetuses with congenital anomalies of the kidney and urinary tract, especially when associated with pancreatic hypoplasia. No correlation between phenotype and genotype was found, highlighting high intra-familial variability in cases with inherited mutations. © 2016 John Wiley & Sons, Ltd.