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Aims/hypothesis: Diabetes is one of the cardinal features of thiamine-responsive megaloblastic anaemia (TRMA) syndrome. Current knowledge of this rare monogenic diabetes subtype is limited. We investigated the genotype, phenotype and response to thiamine (vitamin B1) in a cohort of individuals with TRMA-related diabetes.Methods: We studied 32 individuals with biallelic SLC19A2 mutations identified by Sanger or next generation sequencing. Clinical details were collected through a follow-up questionnaire.Results: We identified 24 different mutations, of which nine are novel. The onset of the first TRMA symptom ranged from birth to 4 years (median 6 months [interquartile range, IQR 3-24]) and median age at diabetes onset was 10 months (IQR 5-27). At presentation, three individuals had isolated diabetes and 12 had asymptomatic hyperglycaemia. Follow-up data was available for 15 individuals treated with thiamine for a median 4.7 years (IQR 3-10). Four patients were able to stop insulin and seven achieved better glycaemic control on lower insulin doses. These 11 patients were significantly younger at diabetes diagnosis (p = 0.042), at genetic testing (p = 0.01) and when starting thiamine (p = 0.007) compared with the rest of the cohort. All patients treated with thiamine became transfusion-independent and adolescents achieved normal puberty. There were no additional benefits of thiamine doses >150 mg/day and no reported side effects up to 300 mg/day.Conclusions/interpretation: In TRMA syndrome, diabetes can be asymptomatic and present before the appearance of other features. Prompt recognition is essential as early treatment with thiamine can result in improved glycaemic control, with some individuals becoming insulin-independent.Data availability: SLC19A2 mutation details have been deposited in the Decipher database (https://decipher.sanger.ac.uk/). [ABSTRACT FROM AUTHOR]

Neonatal diabetes and hypothyroidism (NDH) syndrome was first described in 2003 in a consanguineous Saudi Arabian family where two out of four siblings were reported to have presented with proportionate IUGR, neonatal non-autoimmune diabetes mellitus, severe congenital hypothyroidism, cholestasis, congenital glaucoma, and polycystic kidneys. Liver disease progressed to hepatic fibrosis. The renal disease was characterized by enlarged kidneys and multiple small cysts with deficient cortico-medullary junction differentiation and normal kidney function. There was minor facial dysmorphism (depressed nasal bridge, large anterior fontanelle, long philtrum) reported but no facial photographs were published. Mutations in the transcription factor GLI-similar 3 ( GLIS3) gene in the original family and two other families were subsequently reported in 2006. All affected individuals had neonatal diabetes, congenital hypothyroidism but glaucoma and liver and kidney involvement were less consistent features. Detailed descriptions of the facial dysmorphism have not been reported previously. In this report, we describe the common facial dysmorphism consisting of bilateral low-set ears, depressed nasal bridge with overhanging columella, elongated, upslanted palpebral fissures, persistent long philtrum with a thin vermilion border of the upper lip in a cohort of seven patients with GLIS3 mutations and report the emergence of a distinct, probably recognizable facial gestalt in this group which evolves with age. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

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Background: Raising the awareness of childhood diabetes symptoms can reduce the frequency of diabetic ketoacidosis (DKA) at onset of type 1 diabetes (T1D). However, data on the effectiveness of such interventions are limited. The aim of the study was to describe trends of DKA at onset of childhood T1D during 2005-2014 and assess the impact of a diabetes awareness campaign launched late 2010. Methods: Data of children < 12 years presented with DKA at diagnosis were analyzed according to age, gender and year of diagnosis. The frequency and severity of DKA before and during the 4 years campaign were compared. Results: During 2005-2014, 44.9% (243/541) of children diagnosed with T1D presented with DKA. Of these, 22.7% had pH < 7.1. In both genders DKA was higher in children < 6 years (47.8% vs. 40%; p < 0.01) and more severe in < 3 years old compared to older children (30% vs. 20%; p < 0.01). Following the awareness campaign DKA rate dropped from 48% in 2010 to 39% in 2014 and 15.8% had severe DKA compared to 26.1% in 2005-2010 (p < 0.01). This trend was observed in both genders and across age groups. In children < 3 years the reduction in DKA frequency and severity was not statistically significant (p = 0.15 and p = 0.42, respectively). Conclusions: In NWSA, the frequency and severity of DKA at onset of childhood T1D were reduced following 4 years awareness campaign; but the rate is still high. Maintaining the campaign may result in further improvement following a longer period of observation. [ABSTRACT FROM AUTHOR]

Background: Wolcott-Rallison syndrome (WRS) is caused by recessive EIF2AK3 mutations and characterized by early-onset diabetes and skeletal dysplasia. Hepatic dysfunction has been reported in 60% of patients. Aims: To describe a cohort of WRS patients and discuss the pattern and management of their liver disease. Methods: Detailed phenotyping and direct sequencing of EIF2AK3 gene were conducted in all patients. Results: Twenty-eight genetically confirmed patients (67% male; mean age 4.6 years) were identified. 17 different EIF2AK3 mutations were detected, of which 2 were novel. The p.S991N mutation was associated with prolonged survival and p.I650T with delayed onset. All patients presented before 25 months with diabetes with variation in the frequency and severity of 10 other features. Liver disease, first manifested as non-autoimmune hepatitis, was the commonest extra-pancreatic feature identified in 85.7% (24/28). 22/24 had at least one episode of acute hepatic failure which was the cause of death in all deceased patients (13/28). One child was treated by liver transplantation and had no liver disease and better diabetes control for the following 6 years. Conclusions: Liver disease in WRS is more frequent than previously described and carries high mortality. The first experience with liver transplantation in WRS is encouraging. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Wolcott-Rallison syndrome (WRS) is caused by recessive EIF2AK3 gene mutations and characterized by permanent neonatal diabetes (PNDM), skeletal dysplasia, and recurrent hepatitis. The frequency of this rare syndrome is largely unknown. Objectives: To define the frequency and spectrum of WRS in the Kingdom of Saudi Arabia (KSA) based onpublished data. Methods: The Medline database was searched for published articles on WRS. The number of reported cases from KSA was compared to the total number of WRS cases reported worldwide. The genotype and phenotype of WRS patients from KSA were reviewed. Results: Ten articles describing 23 WRS patients from 12 Saudi families from 1995 to 2012 were identified. This figure accounts for 27.7% (23/83) of the patients and 22.2% (12/54) of the families with WRS reported worldwide until January 2013. All Saudi patients with WRS presented with PNDM, and they represent 59% of all PNDM cases from WRS. At reporting, 73% of patients experienced recurrent hepatitis, 56.5% had skeletal abnormalities, and 39.1% of them were dead. There was a variation in the phenotype even between affected siblings. Genetic diagnosis was confirmed in all 12 families with no correlation between the genotype and phenotype. Eight of the nine EIF2AK3 mutations were only reported in these families, and one was shared with a patient from Qatar, a neighboring Arab state. Conclusions: No study on the frequency of WRS has been published. However, the available data indicate that KSA has the largest collection of patients with WRS worldwide, and nine of the identifiable EIF2AK3 mutations appear to be confined to Arabs. Establishing a national or international registry for WRS would provide more reliable data on this rare condition. [ABSTRACT FROM AUTHOR]

Habeb AM, Al-Magamsi MSF, Eid IM, Ali MI, Hattersley AT, Hussain K, Ellard S. Incidence, genetics, and clinical phenotype of permanent neonatal diabetes mellitus in northwest Saudi Arabia. Background: Permanent neonatal diabetes mellitus (PNDM) in European population has an incidence of at least 1 in 260 000 live births and is most commonly due to mutations in KCNJ11 and ABCC8. However, data on this condition in other populations are limited. Objective: To define the incidence, genetic aetiology, and clinical phenotype of PNDM in Al-Madinah region, northwest Saudi Arabia. Methods: Patients with PNDM diagnosed between 2001 and 2010 were identified and clinically phenotyped. Sequencing of KCNJ11, ABCC8, and INS were performed initially on all subjects, and EIF2AK3, GLIS3, SLC2A2, SLC19A2, GCK, IPF1, and NEUROD1 genes were sequenced according to the clinical phenotype. Results: In total, 17 patients from 11 consanguineous families were diagnosed with PNDM and the incidence was 1 in 21 196 live births. Six different mutations in four genes were identified, of which two GLIS3 and one SLC2A2 were novel and no patient had KCNJ11, ABCC8, or INS mutations. Fourteen (82.4%) patients had identifiable genetic aetiology and their PNDM was part of known autosomal-recessive syndromes including Wolcott Rallison (41.1%), neonatal diabetes and hypothyroidism (29.4%), Fanconi-Bickel (5.8%), and thiamine-responsive megaloblastic anaemia (5.8%). Two patients with isolated PNDM and one with intermediate developmental delay, epilepsy and neonatal diabetes had no identifiable cause. Conclusions: Al-Madinah region has the highest reported incidence of PNDM worldwide. In this region with high consanguinity, PNDM has different genetic aetiology and in the majority of cases presents as a part of rare familial autosomal-recessive syndrome rather than in isolation. [ABSTRACT FROM AUTHOR]

Permanent neonatal diabetes mellitus ( PNDM) is diagnosed within the first 6 months of life, and is usually monogenic in origin. Heterozygous mutations in ABCC8, KCNJ11, and INS genes account for around half of cases of PNDM; mutations in 10 further genes account for a further 10%, and the remaining 40% of cases are currently without a molecular genetic diagnosis. Thiamine-responsive megaloblastic anaemia ( TRMA), due to mutations in the thiamine transporter SLC19 A2, is associated with the classical clinical triad of diabetes, deafness, and megaloblastic anaemia. Diabetes in this condition is well described in infancy but has only very rarely been reported in association with neonatal diabetes. We used a combination of homozygosity mapping and evaluation of clinical information to identify cases of TRMA from our cohort of patients with PNDM. Homozygous mutations in SLC19 A2 were identified in three cases in which diabetes presented in the first 6 months of life, and a further two cases in which diabetes presented between 6 and 12 months of age. We noted the presence of a significant neurological disorder in four of the five cases in our series, prompting us to examine the incidence of these and other non-classical clinical features in TRMA. From 30 cases reported in the literature, we found significant neurological deficit (stroke, focal, or generalized epilepsy) in 27%, visual system disturbance in 43%, and cardiac abnormalities in 27% of cases. TRMA should be considered in the differential diagnosis of diabetes presenting in the neonatal period. [ABSTRACT FROM AUTHOR]

Habeb AM, Al-Magamsi MSF, Halabi S, Eid IM, Shalaby S, Bakoush O. High incidence of childhood type 1 diabetes in Al-Madinah, North West Saudi Arabia (2004-2009). Background: There is a geographical variation in the incidence of childhood type 1 diabetes mellitus (T1DM) with a steady increase reported from some countries. However, data on the incidence of childhood T1DM in Kingdom of Saudi Arabia are limited. Objective: To identify the incidence rate (IR) and epidemiological trends of childhood T1DM in the largest city of northwest Saudi Arabia. Methods: All patients with newly diagnosed T1DM aged 0-12 yr living in the city between 2004 and 2009 were identified from different sources. The data were analyzed according to age, sex, and month of presentation. Results: In total, 419 patients (249 girls) were diagnosed between 2004 and 2009 inclusive. The mean age at diagnosis was 6.9 ± 3.5 yr. The mean annual age-standardized IR was 29.0 (95% confidence interval 26.0-32.0). The incidence was significantly higher in the 10-12-yr age group than in younger children (p < 0.001) and higher in girls than in boys (33.0 vs. 22.2 per 100 000; p < 0.001). There was no significant increase in the annual incidence during the 6-yr period (p = 0.68) and more cases were diagnosed during autumn and winter months (p = 0.002). Conclusions: Al-Madinah city has the highest reported incidence of childhood T1DM in the Middle East and North Africa region. Further studies to identify the reasons for this high incidence are needed. [ABSTRACT FROM AUTHOR]

Habeb AM, Al-Magamsi MSF, Halabi S, Eid IM, Shalaby S, Bakoush O. High incidence of childhood type 1 diabetes in Al-Madinah, North West Saudi Arabia (2004-2009). Background: There is a geographical variation in the incidence of childhood type 1 diabetes mellitus (T1DM) with a steady increase reported from some countries. However, data on the incidence of childhood T1DM in Kingdom of Saudi Arabia are limited. Objective: To identify the incidence rate (IR) and epidemiological trends of childhood T1DM in the largest city of northwest Saudi Arabia. Methods: All patients with newly diagnosed T1DM aged 0-12 yr living in the city between 2004 and 2009 were identified from different sources. The data were analyzed according to age, sex, and month of presentation. Results: In total, 419 patients (249 girls) were diagnosed between 2004 and 2009 inclusive. The mean age at diagnosis was 6.9 ± 3.5 yr. The mean annual age-standardized IR was 29.0 (95% confidence interval 26.0-32.0). The incidence was significantly higher in the 10-12-yr age group than in younger children (p < 0.001) and higher in girls than in boys (33.0 vs. 22.2 per 100 000; p < 0.001). There was no significant increase in the annual incidence during the 6-yr period (p = 0.68) and more cases were diagnosed during autumn and winter months (p = 0.002). Conclusions: Al-Madinah city has the highest reported incidence of childhood T1DM in the Middle East and North Africa region. Further studies to identify the reasons for this high incidence are needed. [ABSTRACT FROM AUTHOR]

Objective Mutations in the KCNJ11 and ABCC8 genes that encode the pancreatic KATP channel are the commonest cause of permanent neonatal diabetes mellitus (PNDM). The authors aimed to define the genetic causes of PNDM in a large cohort of Arab patients and compare them with a British cohort tested in the same laboratory. Design Retrospective observational study. Setting International genetics centre. Patients Arab and British subjects with PNDM who were referred for genetic testing over the same period. Intervention Comparison of genotypes and phenotypes between the two cohorts. Main outcome measures The aetiology and phenotype of PNDM in an Arab compared to a British cohort. Results 88 Arab and 77 British probands were referred between 2006 and 2011, inclusive. Consanguinity was higher among Arabs (63.6% vs 10.4%) and a higher percentage had a genetic diagnosis compared to the British cohort (63.6% vs 41.6%). Recessive EIF2AK3 gene mutations were the commonest cause of PNDM in the Arab cohort (22.7%) followed by INS (12.5%), and KCNJ11 and GCK (5.7% each), whereas KATP channel mutations were the commonest cause (29.9%) in the British cohort. In 37.5% of Arab patients PNDM was part of a genetic syndrome compared to 7.8% of the British cohort. Conclusion PNDM in the Arab population has a different genetic spectrum compared to British patients where KATP channel mutations are the commonest cause, similar to other European populations. In Arabs, PNDM is more likely to be part of a recessively inherited syndrome, possibly due to the higher rate of consanguinity. [ABSTRACT FROM AUTHOR]