Natural history of Wolcott-Rallison syndrome: A systematic review and follow-up study.

BACKGROUND AND AIMS: To systematically review the literature for reports on Wolcott-Rallison syndrome, focusing on the spectrum and natural history, genotype-phenotype correlations, patient and native liver survival, and long-term outcomes. METHODS: PubMed, Livio, Google Scholar, Scopus and Web of Science databases were searched. Data on genotype, phenotype, therapy, cause of death and follow-up were extracted. Survival and correlation analyses were performed. RESULTS: Sixty-two studies with 159 patients met the inclusion criteria and additional 30 WRS individuals were collected by personal contact. The median age of presentation was 2.5 months (IQR 2) and of death was 36 months (IQR 50.75). The most frequent clinical feature was neonatal diabetes in all patients, followed by liver impairment in 73%, impaired growth in 72%, skeletal abnormalities in 59.8%, the nervous system in 37.6%, the kidney in 35.4%, insufficient haematopoiesis in 34.4%, hypothyroidism in 14.8% and exocrine pancreas insufficiency in 10.6%. Episodes of acute liver failure were frequently reported. Liver transplantation was performed in six, combined liver-pancreas in one and combined liver-pancreas-kidney transplantation in two individuals. Patient survival was significantly better in the transplant cohort (p = .0057). One-, five- and ten-year patient survival rates were 89.4%, 65.5% and 53.1%, respectively. Liver failure was reported as the leading cause of death in 17.9% of cases. Overall survival was better in individuals with missense mutations (p = .013). CONCLUSION: Wolcott-Rallison syndrome has variable clinical courses. Overall survival is better in individuals with missense mutations. Liver- or multi-organ transplantation is a feasible treatment option to improve survival.

Modern approaches to the management of homozygous familial hypercholesterolemia in the Middle East and North Africa.

Homozygous familial hypercholesterolaemia (HoFH) is a severe form of FH in which inheritance of two defective or null mutations in genes associated with metabolism of low-density lipoprotein cholesterol (LDL-C) results in extremely high LDL-C, premature atherosclerotic cardiovascular disease (ASCVD) and mortality. Treatment of HoFH comprises a multi-modal approach of statins, ezetimibe, lipoprotein apheresis; and inhibitors of proprotein convertase subtilisin/kexin type, angiopoietin-like protein 3 (ANGPTL3) and microsomal triglyceride transfer protein. These treatments are generally costly, and patients also often require treatment for ASCVD consequent to HoFH. Therefore, in the interests of both economics and preservation of life, disease prevention via genetic screening and counselling is rapidly becoming a key element in the overall management of HoFH. Guidelines are available to assist diagnosis and treatment of HoFH; however, while advancements have been made in the management of the disease, there has been little systematic attention paid to prevention. Additionally, the Middle East/North Africa (MENA) region has a higher prevalence of HoFH than most other regions - chiefly due to consanguinity. This has led to the establishment of regional lipid clinics and awareness programs that have thrown education and awareness of HoFH into sharp focus. Incorporation of principles of prevention, education, awareness, and data from real-world use of existing therapeutics will significantly enhance the effectiveness of future guidelines for the management of HoFH, particularly in the MENA region.

Diagnostic and New Therapeutic Approaches to Two Challenging Pediatric Metabolic Bone Disorders: Hypophosphatasia and X-linked Hypophosphatemic Rickets.

The diagnosis and management of metabolic bone disease among children can be challenging. This difficulty could be due to many factors, including limited awareness of these rare conditions, the complex pathophysiology of calcium and phosphate homeostasis, the overlapping phenotype with more common disorders (such as rickets), and the lack of specific treatments for these rare disorders. As a result, affected individuals could experience delayed diagnosis or misdiagnosis, leading to improper management. In this review, we describe the challenges facing diagnostic and therapeutic approaches to two metabolic bone disorders (MBD) among children: hypophosphatasia (HPP) and X-linked hypophosphatemia (XLH). We focus on explaining the pathophysiological processes that conceptually underpin novel therapeutic approaches, as well as these conditions' clinical or radiological similarity to nutritional rickets. Particularly in areas with limited sun exposure and among patients not supplementing vitamin D, nutritional rickets are still more common than HPP and XLH, and pediatricians and primary physicians frequently encounter this disorder in their practices. More recently, our understanding of these disorders has significantly improved, leading to the development of novel therapies. Asfotas alfa, a recombinant, human-tissue, nonspecific alkaline phosphatase, improved the survival of patients with HPP. Burosumab, a human monoclonal anti-FGF23 antibody, was recently approved as a specific therapy for XLH. We also highlight the current evidence on these two specific therapies' safety and effectiveness, though long-term data are still needed. Both HPP and XLH are multisystemic disorders that should be managed by multidisciplinary teams. Finally, recognizing these conditions in early stages will enable affected children and young adults to benefit from newly introduced, specific therapies.

X-linked Hypophosphatemic Rickets: Awareness, Knowledge, and Practice of Pediatric Endocrinologists in Arab Countries.

X-linked hypophosphatemic rickets (XLHR) is a genetic disease caused by inactivating pathogenic variants in PHEX , which results in reduced mineralization of bone, teeth, and renal phosphate wasting. XLHR is traditionally treated by phosphate and vitamin D analogs. Recently, burosumab, a recombinant anti-fibroblast growth factor-23 (FGF-23) monoclonal antibody was approved as specific XLHR therapy. We aimed to assess the awareness, knowledge, and management of XLHR among members of the Arab Society for Pediatric Endocrinology and Diabetes (ASPED). Of the 97 physicians who answered the online questionnaire, 97% were aware of XLHR, and while 90% screen family members of the index case, only 29% manage children with XLHR. In children with rickets, 40% of participants measure serum/urine phosphate routinely, and 31% request serum FGF-23 in suspected XLHR cases. Almost all responders use conventional XLHR therapy, and 4% used Burosomab. Only 14% were satisfied with the conventional treatment, and 69% reported therapeutic complications in up to 25% of their patients. Multidisciplinary care for XLHR is practiced by 94%, but 82% of providers did not have transition clinics. Pediatric endocrinologists in ASPED countries are aware of XLHR but have variable practice and are unsatisfied with its conventional treatment. Raising awareness of the recognition and modern management of XLHR is needed.

Further evidence supporting the role of DUT gene in diabetes with bone marrow failure syndrome.

In 2017, a homozygous DUT mutation was reported to cause a syndrome of diabetes and bone marrow failure. However, no further patient with this combination has been reported and the phenotype of heterozygous DUT mutation is unknown. We describe the genotype, phenotype, and post bone marrow transplantation (BMT) data of two unrelated families with this rare syndrome. Whole-exome and/or direct sequencing of the DUT gene were performed in all family members. Each family has two children presented within the first 10 years of life with thrombocytopenia, macrocytosis, with or without anemia, followed by non-autoimmune diabetes. The same homozygous missense DUT mutation, reported in 2017 (c.425A>G p.(Tyr142Cys), was detected in all affected children. The heterozygous carriers have no BM failure, one developed type 2 diabetes, and the rest have normal fasting glucose, insulin, HbA1c, and c-peptide. Multiple nevi were detected in homozygous and heterozygous mutation carriers. Allogenic BMT normalized BM aplasia without impact on diabetes. Post BMT follow-up revealed normal puberty and school performance; but three have height <2.5 SDS. We add two families with this syndrome supporting a role of DUT in bone marrow and ß-cell function. The heterozygous carriers of this DUT mutation appear to be healthy.

Monitoring Haematocrit in Paediatric Patients Receiving Testosterone Therapy in Arab Countries.

Objectives Testosterone is the main agent used to induce puberty in boys in Arab countries. It is recommended to monitor haematocrit before and during androgen replacement. However, data from single centre studies indicated that this recommendation is rarely practiced by paediatricians compared to adult physicians. The aim of this study is to evaluate the monitoring of haematocrit of patients on Testosterone therapy by paediatric endocrinologists practicing in Arab countries. Methods A cross-sectional study using an online survey that was sent to all members of the Arab Society for Paediatric Endocrinology and Diabetes (ASPED), who they practice in all Arab countries. The study was carried out between July and October 2019. Ethical approval was granted by ASPED council in May 2019 (MRE2019-02Q).  Results One hundred four physicians responded to the survey from 17 countries. 81/104 (77.8%) answered the question about Testosterone monitoring (42 paediatric endocrinologists, 11 general paediatrician consultants with interest in endocrine, 16 specialists, four fellows and eight residents). Of the 81 responders 18 clinicians (22.2%) thought of monitoring the haematocrit; 15 (18.5%) thought no laboratory monitoring is needed at all. Conclusion The survey indicated that most paediatric endocrinologists in Arab countries do not monitor haematocrit in patients on testosterone replacement and majority are not aware that secondary erythrocytosis can result from androgen therapy. Raising the awareness on monitoring haematocrit during androgen replacement therapy is needed especially when reaching the adult dose.

Perioperative control of paroxysmal hypertension using esmolol with alpha-blockade in a child with a germline mutated paraganglioma.

SUMMARY: The use of antihypertensive medications in patients with pheochromocytomas and paragangliomas (PCC/PG) is usually a challenge. We report a case of familial paraganglioma that was successfully treated by esmolol and other antihypertensive medications without associated perioperative complications. Our patient was an 11-year-old girl who presented with classic symptoms and signs of PCC/PG and a CT scan of the abdomen that showed a right-sided paravertebral mass. Her father was diagnosed with paraganglioma a few years ago. Prazosin had been started but she continued to experience uncontrolled paroxysms of blood pressure (BP). She was known to have asthma; hence, she developed serious bronchospasm with atenolol. She was, therefore, switched to esmolol that successfully controlled her BP in addition to prazosin and intermittent doses of hydralazine prior to laparoscopic surgery with no side effects of medications or postoperative complications. Esmolol could be a good alternative to routinely used beta-blockers in children with PCC/PG with labile hypertension and related symptoms in the pre and intra-operative periods. It is titrable, effective, and can be weaned rapidly helping to avoid postoperative complications. Further larger studies on the use of esmolol in children with PCC/PG are needed to confirm our observation. LEARNING POINTS: In addition to alpha-blockers, esmolol could be a good alternative for routinely used beta-blockers to control paroxysmal hypertension and tachycardia in the pre- and intra-operative periods. Esmolol is titrable and an effective beta-blocker. It can be weaned rapidly helping to avoid postoperative complications in children with PCC/PG. Children with PCC/PG and other comorbidity like asthma may particularly benefit from the use of esmolol due to no or less side effects on airway resistance and the advantage of rapid titration of the medication compared to other beta-blockers.

Diagnosis and management of X-linked hypophosphatemia in children and adolescent in the Gulf Cooperation Council countries.

INTRODUCTION: X-linked hypophosphatemia (XLH) is a rare inherited cause of hypophosphatemic rickets and osteomalacia. It is caused by mutations in the phosphate-regulating endopeptidase homolog, X-linked (PHEX). This results in increased plasma fibroblast growth factor-23 (FGF23), which leads to loss of renal sodium-phosphate co-transporter expression leading to chronic renal phosphate excretion. It also leads to low serum 1,25-dihydroxyvitamin D (1,25(OH)2D), resulting in impaired intestinal phosphate absorption. Chronic hypophosphatemia in XLH leads to impaired endochondral mineralization of the growth plates of long bones with bony deformities. XLH in children and adolescents also causes impaired growth, myopathy, bone pain, and dental abscesses. XLH is the most frequent inherited cause of phosphopenic rickets/osteomalacia. Hypophosphatemia is also found in calcipenic rickets/osteomalacia as a result of secondary hyperparathyroidism. Thus, chronic hypophosphatemia is a common etiologic factor in all types of rickets. RESULTS: There is considerable overlap between symptoms and signs of phosphopenic and calcipenic rickets/osteomalacia. Wrong diagnosis leads to inappropriate treatment of rickets/osteomalacia. Nutritional rickets and osteomalacia are common in the Gulf Cooperation Council countries which include Saudi Arabia, United Arab Emirates, Kuwait, Qatar, Bahrain, and Oman. Due to high levels of consanguinity in the region, genetic causes of phosphopenic and calcipenic rickets/osteomalacia are also common. CONCLUSION: This guideline was developed to provide an approach to the diagnosis of XLH, especially where there is no family history of the disease, and that other related conditions are not mistaken for XLH. We also guide the medical management of XLH with conventional treatment and with burosumab, a recombinant human IgG1 monoclonal antibody to FGF23.

Timing and regimen of puberty induction in children with hypogonadism: a survey on the practice in Arab countries.

Objectives There are some variations in the practice of puberty induction between different regions; however, data from Arab countries are lacking. We aimed to survey the practice of pediatric endocrinologists in Arab countries on the timing and regimen for puberty induction in girls and boys with hypogonadism. Methods An online questionnaire was emailed to physicians registered in the Arab Society for Paediatric Endocrinology and Diabetes. Results In total, 106 replies from 17 countries were received. In non Turner syndrome (TS) girls, puberty was induced by 49.4% of participants at 12-13 years and by 32.5% at  ≥14 years. Ethinyl estradiol and conjugated estrogen were the most popular preparations used (29.7 and 16.6%, respectively). Of the participants, 60% introduce progesterone either at 2-3 years after starting estrogen or following a significant breakthrough bleeding on estrogen. In girls with TS, 84.2% of participants prescribed estrogen to those aged 11 years and older (51.5% at 11-12 years) and 5.3% prescribed it to those at the prepubertal age. In boys, 57.3% of participants induce at ≥14 years, 80.6% use intramuscular testosterone and 46.5% start with 50 mg/kg/month. Human chorionic gonadotropin is more used in non-Gulf Arab countries (18.2 vs. 2.9%; p 0.036) with a trend of using oral testosterone undecanoate in Gulf states (12.2 vs. 2.0%; p 0.051). Conclusions We describe the approach to puberty induction in boys and girls among pediatric endocrinologists in Arab countries. The observed variation in practice would be useful in developing regional consensus guidelines on puberty induction in children with hypogonadism.

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

AIM: To ascertain the awareness and practice of neonatal diabetes mellitus (NDM) among paediatricians in Arab countries. METHODS: An online questionnaire was distributed to physicians associated with the Arab Society for Paediatric Endocrinology and Diabetes (ASPED). RESULTS: We 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. CONCLUSIONS: The 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.

Management of diabetes during Ramadan fasting in children and adolescents: A survey of physicians' perceptions and practices in the Arab Society for Paediatric Endocrinology and Diabetes (ASPED) countries.

AIM: To ascertain the pattern of diabetes management during Ramadan fasting in childhood and adolescence among physicians in Arab countries. METHODS: An online electronic survey questionnaire was distributed to physicians registered in the Arab society for Paediatric Endocrinology and Diabetes (ASPED). RESULTS: Of the 167 responders, 114 (86.0%) were paediatricians and the remaining 14.4% were adult physicians. 117 (79.6%) would allow patients to fast and 60.7% of them emphasized providing education before fasting. 69.1% of physicians thought that their patients complete >50% of fasting days. 46.9% recognized those with hypoglycemia unawareness among the very high-risk group for fasting. 62% reported that fasting should be broken if symptomatic hypoglycemia regardless of glucose level and 48.2% indicated that blood glucose above 300 mg/dl is another indication. 63.4% of respondents would decrease basal insulin by 25%, and 52.8% reported that using insulin pump during fasting reduced the frequency of hypoglycemia. 81.1% recommend several dietary adjustments and 56.4% used rapid-acting insulin analog according to carbohydrate counting. CONCLUSIONS: There is a wide variation in the management of children and adolescents with diabetes during Ramadan in ASPED countries. A targeted educational program for physicians and establishing a guideline for this challenging area is needed.

Pharmacogenomics in diabetes: outcomes of thiamine therapy in TRMA syndrome.

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/ ).

Homozygous Resistance to Thyroid Hormone ß: Can Combined Antithyroid Drug and Triiodothyroacetic Acid Treatment Prevent Cardiac Failure?

Resistance to thyroid hormone ß (RTHß) due to homozygous THRB defects is exceptionally rare, with only five kindreds reported worldwide. Cardiac dysfunction, which can be life-threatening, is recognized in the disorder. Here we describe the clinical, metabolic, ophthalmic, and cardiac findings in a 9-year-old boy harboring a biallelic THRB mutation (R243Q), along with biochemical, physiologic, and cardiac responses to carbimazole and triiodothyroacetic acid (TRIAC) therapy. The patient exhibits recognized features (goiter, nonsuppressed thyroid-stimulating hormone levels, upper respiratory tract infections, hyperactivity, low body mass index) of heterozygous RTHß, with additional characteristics (dysmorphic facies, winging of scapulae) and more markedly elevated thyroid hormone levels, associated with the homozygous form of the disorder. Notably, an older sibling with similar clinical features and probable homozygous RTHß had died of cardiac failure at age 13 years. Features of early dilated cardiomyopathy in our patient prompted combination treatment with carbimazole and TRIAC. Careful titration of therapy limited elevation in TSH levels and associated increase in thyroid volume. Subsequently, sustained reduction in thyroid hormones with normal TSH levels was reflected in lower basal metabolic rate, gain of lean body mass, and improved growth and cardiac function. A combination of antithyroid drug and TRIAC therapy may prevent thyrotoxic cardiomyopathy and its decompensation in homozygous or even heterozygous RTHß in which life-threatening hyperthyroid features predominate.

Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ.

CONTEXT: Lower TSH screening cutoffs have doubled the ascertainment of congenital hypothyroidism (CH), particularly cases with a eutopically located gland-in-situ (GIS). Although mutations in known dyshormonogenesis genes or TSHR underlie some cases of CH with GIS, systematic screening of these eight genes has not previously been undertaken. OBJECTIVE: Our objective was to evaluate the contribution and molecular spectrum of mutations in eight known causative genes (TG, TPO, DUOX2, DUOXA2, SLC5A5, SLC26A4, IYD, and TSHR) in CH cases with GIS. Patients, Design, and Setting: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico. PATIENTS, DESIGN, AND SETTING: We screened 49 CH cases with GIS from 34 ethnically diverse families, using next-generation sequencing. Pathogenicity of novel mutations was assessed in silico. RESULTS: Twenty-nine cases harbored likely disease-causing mutations. Monogenic defects (19 cases) most commonly involved TG (12), TPO (four), DUOX2 (two), and TSHR (one). Ten cases harbored triallelic (digenic) mutations: TG and TPO (one); SLC26A4 and TPO (three), and DUOX2 and TG (six cases). Novel variants overall included 15 TG, six TPO, and three DUOX2 mutations. Genetic basis was not ascertained in 20 patients, including 14 familial cases. CONCLUSIONS: The etiology of CH with GIS remains elusive, with only 59% attributable to mutations in TSHR or known dyshormonogenesis-associated genes in a cohort enriched for familial cases. Biallelic TG or TPO mutations most commonly underlie severe CH. Triallelic defects are frequent, mandating future segregation studies in larger kindreds to assess their contribution to variable phenotype. A high proportion (∼41%) of unsolved or ambiguous cases suggests novel genetic etiologies that remain to be elucidated.

The spectrum of congenital heart diseases in down syndrome. A retrospective study from Northwest Saudi Arabia.

OBJECTIVES: To to define the frequency and patterns of congenital heart disease (CHD) among children with Down syndrome (DS) in Northwest Saudi Arabia.  METHODS: We included children with confirmed DS referred to the regional pediatric cardiology unit in Madinah Maternity and Children Hospital between January 2008 and December 2013. Children were identified from the unit's data-base and the charts were reviewed retrospectively. We excluded term and preterm children with patent ducts arteriosus (PDA) and persistent foramen oval spontaneously resolved during the first 4 weeks of life.  RESULTS: A total of 302 children with DS were identified (50.3% male). Of these, 177 (58.6%) had CHD. Atrioventricular septal defect (AVSD) was the most frequent lesion identified in 72/177 (40.7%) followed by mixed left to right shunt defects (14.7%) and secundum atrial septal defect (ASD) (11.8%). Ventricular septal defect was detected in 10.7% and 8.5% had PDA beyond the neonatal period. There was no gender difference in the frequency of CHD (p=0.9) and the presence of CHD was not related to the genetic cause of DS (p=0.9).  CONCLUSION: The frequency of CHD in our DS cohort is comparable with Europe, Asia ,and other KSA regions. However its pattern appears to be different from some areas in KSA.

An emerging, recognizable facial phenotype in association with mutations in GLI-similar 3 (GLIS3).

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.

Reduced frequency and severity of ketoacidosis at diagnosis of childhood type 1 diabetes in Northwest Saudi Arabia.

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.