Extrapancreatic Features Research Articles

A deletion at 20p11.21 region involving FOXA2 causing Congenital Hyperinsulinism and extra pancreatic features

A deletion at 20p11.21 region involving <i>FOXA2</i> causing Congenital Hyperinsulinism and extra pancreatic features

Abstract #1412358: A Case of Neonatal Diabetes

Neonatal diabetes is a term commonly used to describe the different forms of monogenic diabetes that present in infancy. The average time of presentation is within six months of age however it can present up to 12 months of age. This contrasts to type 1 diabetes which rarely presents within the first six months of life. The incidence of neonatal diabetes is estimated to be 1 in 90,000 to 160,000 live births. There have been over 30 genetic mutations identified that affect pancreatic beta cell function. The phenotypic expression of these mutations varies from transient diabetes (20% of cases), to diabetes responsive to sulfonylurea (40% of cases), to permanent diabetes requiring lifelong insulin therapy (10% of cases), to syndromic and autoimmune diabetes with extra pancreatic features. Here we present a case of neonatal diabetes secondary to a KCNJ11 mutation being treated with sulfonylurea. A 24-year-old male with a past medical history of diabetes mellitus diagnosed at three months of age, behavioral disorders and developmental delay is being managed in Endocrinology clinic for uncontrolled diabetes complicated by multiple admissions with diabetic ketoacidosis. He has a family history of type 2 diabetes in his father. The patient was initially diagnosed and treated as a type I diabetic until at ten years of age genetic testing confirmed a heterozygous R201C mutation of the KCJN11 gene consistent with the diagnosis of neonatal diabetes. He was successfully switched from insulin to high doses of glyburide including 50mg with breakfast, 50mg with dinner, and 30mg at bedtime. The hemoglobin A1c ranged 11-12% due to issues with non-adherence, so Tresiba 22 units at bedtime was added. At the age of 19, the patient transferred care to adult Endocrinology. His exam was remarkable for a BMI of 23 and difficulty with serial seven count down and five-word recall. Relevant labs included c-peptide < 0.1, negative GAD65 Ab, A1c 13%. After an admission for DKA, the patient was prescribed Glargine 28 units daily and Humalog 20 units before meals. Due to difficulty titrating and adhering to this insulin regimen, he was recently restarted this year on glyburide 50mg twice a day with Tresiba 15 units at bedtime with plan to titrate up the doses of the sulfonylurea and discontinue insulin. Mutations in KCNJ11 and ABCC8 are the most common affecting around 46% of infants with neonatal diabetes. They encode for subunits of the ATP-sensitive potassium channel (KATP), which affects the membrane depolarization required for insulin exocytosis in the pancreatic beta cell. Infants with these mutations may also present with varying degrees of neurodevelopmental and psychiatric problems due to presence of KATP channels in the brain. Early treatment with sulfonylurea may improve neurologic outcomes. It is estimated that 80-90% of patients with these mutations will respond to sulfonylurea treatment with high doses of glyburide (up to 2.5mg/kg per day) and eliminate the need for insulin, while 10% may not respond and may still need insulin.

HNF1B-MODY Masquerading as Type 1 Diabetes: A Pitfall in the Etiological Diagnosis of Diabetes

Hepatocyte nuclear factor-1B (HNF1B) maturity-onset diabetes of the young (MODY), also referred to as “renal cysts and diabetes syndrome” or MODY-5, is a rare form of monogenic diabetes that is caused by a deletion or a point mutation in the HNF1B gene, a developmental gene that plays a key role in regulating urogenital and pancreatic development. HNF1B-MODY has been characterized by its association with renal, hepatic and other extrapancreatic features.We present the case of a 39-year-old female patient who was first diagnosed with type 1 diabetes, but then, owing to the absence of anti-islet autoantibodies and to the disease’s progression, was labeled later on as having atypical type 2 diabetes. She was finally recognized as having HNF1B-MODY, a diagnosis that had been suggested by the lack of metabolic syndrome and by the presence of unexplained chronically disturbed liver function tests and hypomagnesemia. There was a 10-year delay between the onset of diabetes and the molecular diagnosis. An atypical form of diabetes, especially in patients with multisystem involvement, should raise suspicion for an alternative etiology. A timely diagnosis of HNF1B-MODY is of utmost importance since it can greatly impact diabetes management and disease progression as well as family history.

The Genetics of Type 2 Diabetes in Youth: Where We Are and the Road Ahead

The Genetics of Type 2 Diabetes in Youth: Where We Are and the Road Ahead

Neonatal diabetes caused by disrupted pancreatic and β-cell development.

Neonatal diabetes is diagnosed before the age of 6months and is usually caused by single-gene mutations. More than 30 genetic causes of neonatal diabetes have been described to date, resulting in severely reduced β-cell number or function. Seven of these genes are known to cause neonatal diabetes through disrupted development of the whole pancreas, resulting in diabetes and exocrine pancreatic insufficiency. Pathogenic variants in five transcription factors essential for β-cell development cause neonatal diabetes without other pancreatic phenotypes. However, additional extra-pancreatic features are common. This review will focus on the genes causing neonatal diabetes through disrupted β-cell development, discussing what is currently known about the genetic and phenotypic features of these genetic conditions, and what discoveries may come in the future.

Gene Panel Sequencing of Patients With Monogenic Diabetes Brings to Light Genes Typically Associated With Syndromic Presentations.

Gene panel sequencing (NGS) offers the possibility of analyzing rare forms of monogenic diabetes (MgD). To that end, 18 genes were analyzed in 1,676 patients referred for maturity-onset diabetes of the young genetic testing. Among the 307 patients with a molecular diagnosis of MgD, 55 (17.9%) had a mutation in a gene associated with a genetic syndrome. Of the patients with mutations, 8% (n = 25) carried the m.3243A>G variant associated with maternally inherited diabetes and deafness. At the time of referral very few had reported hearing loss or any other element of the typical syndromic presentation. Of the patients, 6% had mutation in HNF1B even though the typical extrapancreatic features were not known at the time of referral. Surprisingly, the third most prominent etiology in these rare forms was the WFS1 gene, accounting for 2.9% of the patients with pathogenic mutations (n = 9). None of them displayed a Wolfram syndrome presentation even though some features were reported in six of nine patients. To restrict the analysis of certain genes to patients with the respective specific phenotypes would be to miss those with partial presentations. These results therefore underlie the undisputable benefit of NGS strategies even though the situation implies cascade consequences both for the molecular biologist and for the clinician.

Expanding the Phenotype of TRMT10A Mutations: Case Report and a Review of the Existing Cases

The tRNA methyltransferase 10 homologue A (TRMT10A) gene encodes tRNA methyl transferase, and biallelic loss of function mutations cause a recessive syndrome of intellectual disability, microcephaly, short stature and diabetes. A case with intellectual disability and distinctive features including microcephaly was admitted. She was diagnosed with epilepsy at 2.5 years old. At 3.6 years of age, severe short stature related to growth hormone (GH) deficiency was detected. She had an incidental diagnosis of diabetes at age 11.4 years which was negative for diabetes antibodies with persistent C-peptide level and she was treated with metformin. Spontaneous puberty did not begin until 15.7 years of age and she was found to have primary ovarian failure. A homozygous p.Arg127* mutation in TRMT10A was detected. In addition to the typical clinical features which characterize TRMT10A syndrome, we observed an unusual form of impaired glucose metabolism which presented in early childhood with hypoglycemia followed by diabetes in late childhood. GH deficiency and primary ovarian failure may also be additional findings of this syndrome. Patients with slow onset diabetes who are negative for auto-antibodies and have extra-pancreatic features should be tested for all known subtypes of monogenic diabetes.

Monogenic diabetes in Pakistani infants and children: challenges in a resource poor country.

To review the data of infants and children with suspected monogenic diabetes who underwent genetic testing. Monogenic diabetes is a rare form of diabetes resulting from mutations in a single gene. It can be caused by dominant as well as recessive modes of inheritance. In a country like Pakistan where interfamily marriages are common the incidence of genetic disorders is increased. As Pakistan a resource-poor country, the diagnosis of insulin-dependent diabetes is often delayed and a genetic diagnosis of monogenic diabetes is extremely difficult. Children with clinical diagnosis of monogenic and syndromic diabates were recruited and blood samples were sent for genetic analysis. One thousand sixty four new cases diagnosed with type 1 diabetes were registered at the National Institute of Child Health, Karachi, in the last 10 years. Of these 39 patients were selected for genetic testing who were diagnosed with diabetes/had a sibling diagnosed with diabetes before the age of nine months (n = 27) or had extra pancreatic features ( n= 12). We identified mutations in 18/27 cases diagnosed with diabetes before nine months of age. The most common genetic subtype was WolcottRallison syndrome caused by EIF2AK3 mutations (seven cases). KCNJ11 mutations were identified in two cases, ABCC8mutations were identified in four cases from three families, GCK and INS mutations were each identified in two cases, and one SLC2A2 mutation was identified in one case. A genetic diagnosis was made in 12/12 children from six families with diabetes diagnosed after the age of nine months who had extrapancreatic features. Six patients had genetically confirmed Wolfram syndrome (WFS1), three had thiamine-responsive megaloblastic anemia (SLC19A2) and three were diagnosed with histocytosis lymphadenopathy plus syndrome (SLC29A3). Genetic testing is essential to confirm a diagnosis of monogenic diabetes which guides clinical management and future counselling. Our study highlights the importance of diagnosing monogenic diabetes in the largely consanguineously-married population of Pakistan.

De novo mutation in HNF-1β gene as a cause for Maturity-onset Diabetes of the Young type 5 with sustained hypomagnesemia

Maturity-onset Diabetes of the Young type 5 (MODY5) is clinically heterogeneous, and the genetic examination is important to provide the accurate diagnosis. Identification of more cases will better understand the genotype-phenotype correlations of this disorder. We collected the clinical and biochemical data, using the whole-exome gene detection and multiplex ligation–dependent probe Amplification to detect the pathogenic gene variants. The proband is a 39-year-old female, and presenting with symptoms including polyuria, polydipsia, and weight loss for 6 months. Her BMI was 17.6 kg/m2. Laboratory tests indicated hypokalemia (3.1 mmol/L), hypomagnesemia (0.4 mmol/L), and hypocalcemia (1.91 mmol/L). Glycated hemoglobin (HbA1c) was 13.7%, fasting C-peptide was 0.24 ng/mL (normal range: 0.3–3.73 ng/mL). Both glutamic acid decarboxylase and islet cell antibodies were negative. Abdominal magnetic resonance image showed the agenesis of the tail and body of the pancreas and the presence of disseminated cysts of the left kidney. Genetic examination displayed a de novo heterozygous deletion of the whole HNF-1Β gene (NM_000458.3). Three-year follow-up after the diagnosis showed that the patient has sustained hypomagnesemia and cannot maintain an appreciable increase in serum magnesium levels (0.52–0.61 mmol/L), although she was using the double-dose magnesium aspartate. Moreover, she cannot achieve good glucose control either. Our findings indicted that MODY is highly heterogeneous and patients with additional extrapancreatic clinical features and hypomagnesemia should be screened for MODY5.

Clinical Characteristics and Long-term Follow-up of Patients with Diabetes Due To PTF1A Enhancer Mutations.

ContextBiallelic mutations in the PTF1A enhancer are the commonest cause of isolated pancreatic agenesis. These patients do not have severe neurological features associated with loss-of-function PTF1A mutations. Their clinical phenotype and disease progression have not been well characterized.ObjectiveTo evaluate phenotype and genotype characteristics and long-term follow-up of patients with PTF1A enhancer mutations.SettingTwelve tertiary pediatric endocrine referral centers.PatientsThirty patients with diabetes caused by PTF1A enhancer mutations. Median follow-up duration was 4 years.Main Outcome MeasuresPresenting and follow-up clinical (birthweight, gestational age, symptoms, auxology) and biochemical (pancreatic endocrine and exocrine functions, liver function, glycated hemoglobin) characteristics, pancreas imaging, and genetic analysis.ResultsFive different homozygous mutations affecting conserved nucleotides in the PTF1A distal enhancer were identified. The commonest was the Chr10:g.23508437A>G mutation (n = 18). Two patients were homozygous for the novel Chr10:g.23508336A>G mutation. Birthweight was often low (median SDS = –3.4). The majority of patients presented with diabetes soon after birth (median age of diagnosis: 5 days). Only 2/30 presented after 6 months of age. All patients had exocrine pancreatic insufficiency. Five had developmental delay (4 mild) on long-term follow-up. Previously undescribed common features in our cohort were transiently elevated ferritin level (n = 12/12 tested), anemia (19/25), and cholestasis (14/24). Postnatal growth was impaired (median height SDS: –2.35, median BMI SDS: –0.52 SDS) with 20/29 (69%) cases having growth retardation.ConclusionWe report the largest series of patients with diabetes caused by PTF1A enhancer mutations. Our results expand the disease phenotype, identifying recurrent extrapancreatic features which likely reflect long-term intestinal malabsorption.

Refinement of the critical genomic region for congenital hyperinsulinismin the Chromosome 9p deletion syndrome.

Background: Large contiguous gene deletions at the distal end of the short arm of chromosome 9 result in the complex multi-organ condition chromosome 9p deletion syndrome. A range of clinical features can result from these deletions with the most common being facial dysmorphisms and neurological impairment. Congenital hyperinsulinism is a rarely reported feature of the syndrome with the genetic mechanism for the dysregulated insulin secretion being unknown. Methods: We studied the clinical and genetic characteristics of 12 individuals with chromosome 9p deletions who had a history of neonatal hypoglycaemia. Using off-target reads generated from targeted next-generation sequencing of the genes known to cause hyperinsulinaemic hypoglycaemia (n=9), or microarray analysis (n=3), we mapped the minimal shared deleted region on chromosome 9 in this cohort. Targeted sequencing was performed in three patients to search for a recessive mutation unmasked by the deletion. Results: In 10/12 patients with hypoglycaemia, hyperinsulinism was confirmed biochemically. A range of extra-pancreatic features were also reported in these patients consistent with the diagnosis of the Chromosome 9p deletion syndrome. The minimal deleted region was mapped to 7.2 Mb, encompassing 38 protein-coding genes. In silico analysis of these genes highlighted SMARCA2 and RFX3 as potential candidates for the hypoglycaemia. Targeted sequencing performed on three of the patients did not identify a second disease-causing variant within the minimal deleted region. Conclusions: This study identifies 9p deletions as an important cause of hyperinsulinaemic hypoglycaemia and increases the number of cases reported with 9p deletions and hypoglycaemia to 15 making this a more common feature of the syndrome than previously appreciated. Whilst the precise genetic mechanism of the dysregulated insulin secretion could not be determined in these patients, mapping the deletion breakpoints highlighted potential candidate genes for hypoglycaemia within the deleted region.

Refinement of the critical genomic region for congenital hyperinsulinism in the Chromosome 9p deletion syndrome

Background: Large contiguous gene deletions at the distal end of the short arm of chromosome 9 result in the complex multi-organ condition chromosome 9p deletion syndrome. A range of clinical features can result from these deletions with the most common being facial dysmorphisms and neurological impairment. Congenital hyperinsulinism is a rarely reported feature of the syndrome with the genetic mechanism for the dysregulated insulin secretion being unknown. Methods: We studied the clinical and genetic characteristics of 12 individuals with chromosome 9p deletions who had a history of neonatal hypoglycaemia. Using off-target reads generated from targeted next-generation sequencing of the genes known to cause hyperinsulinaemic hypoglycaemia (n=9), or microarray analysis (n=3), we mapped the minimal shared deleted region on chromosome 9 in this cohort. Targeted sequencing was performed in three patients to search for a recessive mutation unmasked by the deletion. Results: In 10/12 patients with hypoglycaemia, hyperinsulinism was confirmed biochemically. A range of extra-pancreatic features were also reported in these patients consistent with the diagnosis of the Chromosome 9p deletion syndrome. The minimal deleted region was mapped to 7.2 Mb, encompassing 38 protein-coding genes. In silico analysis of these genes highlighted SMARCA2 and RFX3 as potential candidates for the hypoglycaemia. Targeted sequencing performed on three of the patients did not identify a second disease-causing variant within the minimal deleted region. Conclusions: This study identifies 9p deletions as an important cause of hyperinsulinaemic hypoglycaemia and increases the number of cases reported with 9p deletions and hypoglycaemia to 15 making this a more common feature of the syndrome than previously appreciated. Whilst the precise genetic mechanism of the dysregulated insulin secretion could not be determined in these patients, mapping the deletion breakpoints highlighted potential candidate genes for hypoglycaemia within the deleted region.

1638-P: Functional Characterization of HNF1B Variants Can Enhance Diabetes Precision Medicine

Genetic variants in HNF1B encoding the transcription factor hepatocyte nuclear factor-1 beta (HNF-1B) cause Maturity-Onset Diabetes of the Young type 5 (MODY5; HNF1B-MODY) and are the most common known monogenic cause of developmental kidney disease. The aim of this study was to assess pathogenicity of HNF1B variants identified among 312 patients suspected of monogenic diabetes from the Personalized Diabetes Medicine Program (PDMP) at the University of Maryland. Patients suspected of monogenic diabetes underwent next generation sequencing for 40 genes, including HNF1B. Variants were classified according to ACMG/AMP variant interpretation guidelines. To investigate the effect of HNF1B variants on normal HNF-1B transcriptional activity, we used a Dual-Luciferase assay system in transfected HeLa cells. DNA-binding ability was studied by EMSA and protein localization was determined by fractionation and confocal microscopy. Seven HNF1B variants were identified in 7 unrelated individuals. One variant (p.H336Pfs*22) was classified as pathogenic, 5 (p.T88A, p.A167P, p.N394D, p.V458G, p.T544A) as unknown significance (VUS) and 1 variant as benign (p.D82N). Two variants, p.A167P and p.H336Pfs*22, inferred severely reduced transactivation potential (25% and 34% of WT, respectively). In addition, p.A167P demonstrated decreased protein expression (26% of WT) and a significant loss in DNA binding ability (19% of WT). The p.H336Pfs*22 variant carrier has renal agenesis, often associated with HNF1B mutations, while the p.A167P carrier lacks extra-pancreatic features. The functional evidence allowed p.A167P to be reclassified as likely pathogenic when added to existing evidence (computationally predicted deleteriousness and absence from population databases). Obtaining functional data can improve variant interpretation and enable a more precise diagnosis in patients carrying an HNF1B variant. Disclosure B.B. Johansson: None. A. Pavithram: None. H. Zhang: None. K.A. Maloney: None. M. Ringdal: None. A. Kaci: None. J.V. Sagen: Other Relationship; Self; Novo Nordisk A/S. J. Kleinberger: None. L. Jeng: None. P. Njølstad: None. T.I. Pollin: None. J. Molnes: None. Funding Western Norway Regional Health Authority; University of Bergen; Norwegian Diabetes Foundation

Molecular diagnosis of maturity-onset diabetes of the young in a cohort of Chinese children.

The purpose of this study was to investigate the molecular basis of maturity-onset diabetes of the young (MODY) by whole-exome sequencing (WES) and estimate the frequency and describe the clinical characteristics of MODY in southern China. Genetic analysis was performed in 42 patients with MODY aged 1 month to 18 years among a cohort of 759 patients with diabetes, identified with the following four clinical criteria: age of diagnosis ≤18 years; negative pancreatic autoantibodies; family history of diabetes; or persistently detectable C-peptide; or diabetes associated with extrapancreatic features. GCK gene mutations were first screened by Sanger sequencing. GCK mutation-negative patients were further analyzed by WES. Mutations were identified in 24 patients: 20 mutations in GCK, 1 in HNF4A, 1 in INS, 1 in ABCC8, and a 17q12 microdeletion. Four previously unpublished novel GCK mutations: c.1108G>C in exon 9, and c.1339C>T, c.1288_1290delCTG, and c.1340_1343delGGGGinsCTGGTCT in exon 10 were detected. WES identified a novel missense mutation c.311A>G in exon 3 in the INS gene, and copy number variation analysis detected a 1.4 Mb microdeletion in the long arm of the chromosome 17q12 region. Compared with mutation-negative subjects, the mutation-positive subjects had lower hemoglobin A1c and initial blood glucose levels. Most MODY cases in this study were due to GCK mutations, which is in contrast to previous reports in Chinese patients. Diabetes associated with extrapancreatic features should be a clinical criterion for MODY genetic analysis. Mutational analysis by WES provided a precise diagnosis of MODY subtypes. Moreover, WES can be useful for detecting large deletions in coding regions in addition to point mutations.

Diagnosis and management of neonatal diabetes mellitus: A survey of physicians’ perceptions and practices in ASPED countries

AimTo ascertain the awareness and practice of neonatal diabetes mellitus (NDM) among paediatricians in Arab countries. MethodsAn online questionnaire was distributed to physicians associated with the Arab Society for Paediatric Endocrinology and Diabetes (ASPED). ResultsWe received 126 replies, from 16 countries. All except one classified the survey’s case scenario as NDM and 94% agreed that NDM patients should have detailed assessment to identify extra-pancreatic features. Although 92% felt that genetic testing is necessary, only 72% requesting them routinely and 32% unaware of the availability of free genetic testing. Insulin is considered the initial therapy for 93% and 80% diluted insulin to deliver accurate doses. Basal-bolus regimen was preferred by 36% and similar percentage used insulin pump. The remaining 28% favour long acting insulin alone. Oral sulfonylureas would be tried empirically by 34% and 69% would do so if genetic testing is unavailable. Whilst 70% have no local NDM management guidelines, 41% are unaware of any international guidelines. ConclusionsThe ASPED surveyed clinicians have good awareness of NDM diagnosis with marked variation in their practice raising the need to establish management guideline for the condition. The survey highlights areas to focus on in developing consensus and educational activities.

Refinement of the critical genomic region for hypoglycaemia in the Chromosome 9p deletion syndrome

Background: Large contiguous gene deletions at the distal end of the short arm of chromosome 9 result in the complex multi-organ condition chromosome 9p deletion syndrome. A range of clinical features can result from these deletions with the most common being facial dysmorphisms and neurological impairment. Congenital hyperinsulinism is a rarely reported feature of the syndrome with the genetic mechanism for the dysregulated insulin secretion being unknown. Methods: We studied the clinical and genetic characteristics of 12 individuals with chromosome 9p deletions who had a history of neonatal hypoglycaemia. Using off-target reads generated from targeted next-generation sequencing of the genes known to cause hyperinsulinaemic hypoglycaemia (n=9), or microarray analysis (n=3), we mapped the minimal shared deleted region on chromosome 9 in this cohort. Targeted sequencing was performed in three patients to search for a recessive mutation unmasked by the deletion. Results: In 10/12 patients with hypoglycaemia, hyperinsulinism was confirmed biochemically. A range of extra-pancreatic features were also reported in these patients consistent with the diagnosis of the Chromosome 9p deletion syndrome. The minimal deleted region was mapped to 7.2 Mb, encompassing 38 protein-coding genes. In silico analysis of these genes highlighted SMARCA2 and RFX3 as potential candidates for the hypoglycaemia. Targeted sequencing performed on three of the patients did not identify a second disease-causing variant within the minimal deleted region. Conclusions: This study identifies 9p deletions as an important cause of hyperinsulinaemic hypoglycaemia and increases the number of cases reported with 9p deletions and hypoglycaemia to 15 making this a more common feature of the syndrome than previously appreciated. Whilst the precise genetic mechanism of the dysregulated insulin secretion could not be determined in these patients, mapping the deletion breakpoints highlighted potential candidate genes for hypoglycaemia within the deleted region.

Dominant ER Stress-Inducing WFS1 Mutations Underlie a Genetic Syndrome of Neonatal/Infancy-Onset Diabetes, Congenital Sensorineural Deafness, and Congenital Cataracts.

Neonatal diabetes is frequently part of a complex syndrome with extrapancreatic features: 18 genes causing syndromic neonatal diabetes have been identified to date. There are still patients with neonatal diabetes who have novel genetic syndromes. We performed exome sequencing in a patient and his unrelated, unaffected parents to identify the genetic etiology of a syndrome characterized by neonatal diabetes, sensorineural deafness, and congenital cataracts. Further testing was performed in 311 patients with diabetes diagnosed before 1 year of age in whom all known genetic causes had been excluded. We identified 5 patients, including the initial case, with three heterozygous missense mutations in WFS1 (4/5 confirmed de novo). They had diabetes diagnosed before 12 months (2 before 6 months) (5/5), sensorineural deafness diagnosed soon after birth (5/5), congenital cataracts (4/5), and hypotonia (4/5). In vitro studies showed that these WFS1 mutations are functionally different from the known recessive Wolfram syndrome-causing mutations, as they tend to aggregate and induce robust endoplasmic reticulum stress. Our results establish specific dominant WFS1 mutations as a cause of a novel syndrome including neonatal/infancy-onset diabetes, congenital cataracts, and sensorineural deafness. This syndrome has a discrete pathophysiology and differs genetically and clinically from recessive Wolfram syndrome.

Genetic characteristics, clinical spectrum, and incidence of neonatal diabetes in the Emirate of AbuDhabi, United Arab Emirates.

Neonatal diabetes mellitus (NDM) can be transient (TNDM) or permanent (PNDM). Data on NDM from the Gulf region are limited to few studies on PNDM.The objective of this study was to describe the genetic and clinical spectrum of NDM and estimate its incidence in AbuDhabi, capital of the United Arab Emirate (UAE). Patients were identified from the pediatric diabetes clinics and sequencing of known NDM genes was conducted in all families. Twenty-five patients were identified. Incidence during 1985-2013 was 1:29,241 Live births. Twenty-three out of twenty-five had PNDM (incidence 1:31,900) and 2/25 had TNDM (incidence 1:350,903). Eleven out of twenty-five had extra-pancreatic features and three had pancreatic aplasia. The genetic cause was detected in 21/25 (84%). Of the PNDM patients, nine had recessive EIF2AK3 mutations, six had homozygous INS mutations, two with deletion of the PTF1A enhancer, one was heterozygous for KCNJ11 mutation, one harboured a novel ABCC8 variant, and 4/21 without mutations in all known PNDM genes. One TNDM patient had a 6q24 methylation defect and another was homozygous for the INS c-331C>G mutation. This mutation also caused permanent diabetes with variable age of onset from birth to 18 years. The parents of a child with Wolcott-Rallison syndrome had a healthy girl following pre-implantation genetic diagnosis. The child with KCNJ11 mutation was successfully switched from insulin to oral sulphonylurea. The incidence of PNDM in Abu Dhabi is among the highest in the world and its spectrum is different from Europe and USA. In our cohort, genetic testing has significant implications for the clinical management.

Pancreatic and Extrapancreatic Features in Autoimmune Pancreatitis

Autoimmune pancreatitis (AIP) accounts for approximately 5% of chronic pancreatitis cases and is an important consideration in the differential diagnosis of pancreatic pathologies. The underlying pathophysiology of AIP is thought to involve lymphocyte infiltration and associated sclerosis. Although AIP is a benign condition that is treatable with corticosteroids, it can have imaging and clinical findings indistinguishable from pancreatic cancer. As such, the radiologist plays an important management role in distinguishing AIP from more sinister conditions. In addition, there are several extrapancreatic imaging findings in the context of AIP that have been recently described. This pictorial review outlines both the pancreatic and extrapancreatic imaging features in AIP and the response to steroid therapy. Important imaging features that allow AIP to be differentiated from other pancreatic pathology, including adenocarcinoma, lymphoma, and acute pancreatitis will be discussed.

Autoimmune pancreatitis, a single centre experience within the United Kingdom

Objective Autoimmune pancreatitis is a rare form of chronic pancreatitis characterized by a dramatic response to steroids. We describe our single centre experience of autoimmune pancreatitis over a ten-year period. Methods Between 2004 and 2014 seventeen patients were treated for Autoimmune Pancreatitis within our institution. Patterns of recurrence and the use of corticosteroid therapy are described. Results Seventeen patients with a median age of 61 (29-81) years were identified from a retrospective clinical database review. Extra-pancreatic involvement was common and was seen in eleven of seventeen patients. Nine patients received steroid therapy, two underwent pylorus preserving pancreaticoduodenectomy for presumed malignant disease and six had spontaneously resolving disease. Six patients suffered from relapsing disease. Extra-pancreatic involvement correlated with disease relapse (P=0.0427) however the use of corticosteroids at presentation failed to correlate with disease relapse (P=0.131). Conclusion Autoimmune pancreatitis although rare is becoming increasingly recognised in the United Kingdom. Extra-pancreatic features at presentation were common along with spontaneous resolution of disease among our patients. A multidisciplinary approach is recommended to avoid un-necessary surgical intervention or indeed the misdiagnosis of underlying malignancy.