Wolcott–Rallison syndrome due to the same mutation (W522X) in EIF2AK3 in two unrelated families and review of the literature*

Ozbek MN, Senée V, Aydemir S, Kotan LD, Mungan NO, Yuksel B, Julier C, Topaloglu AK. Wolcott–Rallison syndrome due to the same mutation (W522X) in EIF2AK3 in two unrelated families and review of the literature. Wolcott‐Rallison syndrome (WRS) is a rare autosomal recessive disorder characterized by an early‐infancy‐onset diabetes mellitus associated with a variety of multisystemic clinical manifestations. Here, we present six patients with WRS, carrying the same homozygous mutation (EIF2AK3‐W522X), from two unrelated Turkish families. This is the largest series of patients with the same mutation for this rare syndrome. In this communication we compare clinical features of these six patients with the other 34 patients who have been reported to date, and review the clinical features of WRS. All WRS patients presented first with symptoms of insulin dependent diabetes mellitus, with a mean age at onset of 2 months. All patients had skeletal dysplasia or early signs of it, and growth retardation. Many of the patients with WRS have been reported to have developmental delay, mental retardation, and learning difficulties; in contrast, none of our patients showed abnormal development at age up to 30 months. Acute attacks of hepatic failure were reported in 23 cases out of 37 patients; in 15 of those 23 cases an acute attack of renal failure accompanied the liver failure. Exocrine pancreatic deficiency has been reported in only four cases other than our four patients. Central hypothyroidism was observed in six of 28 cases. We propose that central hypothyroidism is not a component of WRS, but rather a reflection of euthyroid sick syndrome. Four of our patients experienced severe neutropenia, compared to only five of the 27 other cases, suggesting that the W522X mutation may be specifically associated with neutropenia. Other than the consistent features of diabetes mellitus and epiphyseal dysplasia, WRS patients are otherwise characterized by extensive phenotypic variability that correlates poorly to genotype.     

儿童糖尿病198例

目的 探讨儿童糖尿病(DM)的临床特点,为临床诊治提供理论依据.方法 对1999年1月-2009年3月在本院住院的198例DM患儿的临床表现和实验室检查进行回顾性临床分析.结果 198例DM患儿中,男97例,女101例.均为首诊病例;发病高峰年龄为5～6岁及9～11岁;首诊例数逐年增加,2008年较1999年增加了3.7倍;其中1型糖尿病(T1DM) 174例(占88.9％),2型糖尿病7例(占3.5％),新生儿DM 14例(占7.1％),其他3例(占1.5％).首诊的TlDM患者中,酮症酸中毒(DKA)的发生率为42.0％;发病前有感染史者55例,与无感染史者比较,DKA的发生率有统计学差异(P＜0.01).有DM家族遗传史者23例.并甲状腺功能亢进症2例;并暂时性甲状腺功能减低症31例;并肝功能异常30例,肾功能异常12例,血脂异常48例,尿蛋白阳性27例.糖化血红蛋白为(12.0±1.8)％;共分析了25例T1 DM患者的自身抗体,胰岛细胞抗体阳性率为28％,胰岛素自身抗体的阳性率为20％,谷氮酸脱羧酶自身抗体(GADA)阳性率为72％.结论 首诊的儿童DM逐年增加,以T1DM为主;新生儿DM增加明显;DKA是T1DM患者就诊的重要原因;首诊的T1DM者中,感染是发生DKA的重要诱因;儿童DM常合并暂时性甲状腺功能减低症、肝肾功能异常及血脂异常;糖尿病自身抗体中GADA的阳性率最高.     

Clinical characteristics at presentation of type 1 diabetes mellitus in children younger than 15 years in Croatia

The aim of the study was to determine the clinical and biochemical characteristics of type 1 diabetes mellitus (DM) at presentation in children younger than 15 years in Croatia during a 9-year period, with special attention to diabetic ketoacidosis (DKA) incidence. The registered data set comprised blood glucose, pH, serum bicarbonate levels, and clinical symptoms at disease manifestation. During the study period, 692 children were diagnosed with type 1 DM. Polydipsia (96.7%), polyuria (96.05%), and weight loss (82.7%) were the most frequent symptoms anticipating disease detection. Enuresis was recorded in 11.55%. A total of 36.41% patients had DKA (pH < 7.3) at disease onset. During the 9-year period, the percentage of children presenting with DKA at time of diagnosis decreased from 41.67% to 33.33% (z = 1.68, p = 0.046). A positive family history of DM, the only factor with an impact on the DKA incidence rate in our population, lowers the probability of the development of ketoacidosis. This study confirms the importance of the detection of the classic symptoms of polyuria, polydipsia, and weight loss in patients with new-onset type 1 DM. The percentage of patients with DKA at diabetes onset decreased during the observed period but is still high and includes one-third of all patients. This is why in every acutely ill child, especially at a younger age, one should evaluate the possibility of type 1 DM to avoid the development of ketoacidosis.     

Diabetes mellitus in Asian Indian children and adolescents

AIM: To study the clinical and metabolic profile of type 1 and type 2 diabetes mellitus in children and adolescents in a South Asian population. RESEARCH DESIGN AND METHODS: Sixty children were recruited. They were divided into three groups: Group I--type 2 diabetes mellitus (DM2), Group II--type 1 diabetes mellitus (DM1), and Group III--healthy controls. The clinical history and biochemical parameters (HbA1c, serum insulin, C-peptide, triglycerides, total cholesterol and HDL-cholesterol) were recorded. Homeostasis model assessment for insulin resistance (HOMAIR) and quantitative insulin sensitivity check index (QUICKI) were calculated. RESULTS AND CONCLUSIONS: Children and adolescents with DM2 had a significant family history of DM and clinical features of insulin resistance, including increased body mass index, waist:hip ratio and acanthosis nigricans. They also had decreased insulin sensitivity together with dyslipidemia of metabolic syndrome, i.e. high triglyceride, high total cholesterol and low HDL-cholesterol. The presence of these predictors of cardiovascular disorders is known to contribute to morbidity and mortality. Hence, DM2 needs to be recognized early in Asian Indian children.     

5岁以下1型糖尿病患儿21例

目的探讨5岁以下婴幼儿糖尿病的临床特点、诊断及酮症酸中毒(DKA)的抢救措施。方法回顾性分析21例5岁以下婴幼儿糖尿病患儿的发病情况、临床特点、误诊情况,并探讨急救治疗体会。结果婴幼儿糖尿病临床症状不典型,糖尿病自身抗体阳性率低,初诊误诊率达52.4%,DKA发生率也高达52.4%。感染是诱发DKA的常见原因,患儿无1例死亡,1例放弃治疗,出院后治疗依从性不一。结论婴幼儿糖尿病多为特发性,临床症状不典型,易误诊、漏诊。感染可能导致患儿糖尿病的进展和临床表现出现。小剂量胰岛素持续静滴、调节酸碱平衡和纠正电解质紊乱是急救的关键。     

Difficulties or mistakes in diagnosing type 1 diabetes in children?—demographic factors influencing delayed diagnosis

Background: Diabetic ketoacidosis (DKA) development in children with new‐onset type 1 diabetes (T1DM) is often the main consequence of delayed diagnosis. The aim of the study was to estimate the frequency of difficulties in T1DM diagnosis and to investigate if and how the demographic factors (gender, patient's age at presentation, family history of T1DM, level of maternal education, place of residence, and health service unit the patient called at) have any influence on diagnostic delays. Subjects and methods: Retrospective analysis of 474 children (243 boys—51.27% and 231 girls ?48.73%) with new‐onset T1DM aged below 17 yr and living in the Pomeranian region of Poland was carried out. The delay in diagnosis was recognized if the patient was not diagnosed on the first visit because of omission, wrong interpretation of main diabetic symptoms, exclusive treatment of additional signs, or concomitant diseases. Results: Difficulties in diagnosing T1DM were found in 67 cases (14.13%) and they are the main cause of DKA development in these children (p = 0.00). Among the examined demographic factors, mainly the patient's age at presentation has a significant influence on diagnostic delays (p = 0.01), especially in children below 2 yr (p = 0.00). Most frequently family doctors were responsible for wrong preliminary diagnosis. Conclusions: Difficulties in diagnosing T1DM are a significant cause of DKA development in children with new‐onset disease. Patient's age at presentation is the main risk factor of delayed diagnosis, especially in children below 2 yr. The increase in awareness among pediatricians concerning the possibility of T1DM development in children is needed.     

Monogenic diabetes: A single center experience from South India

Monogenic forms of diabetes in children are frequently misclassified as either type 1 diabetes or young‐onset type 2 diabetes. There is a paucity of literature regarding pediatric monogenic diabetes in the Indian population. A retrospective analysis of case records of 37 children with monogenic diabetes who were diagnosed between 2008 and 2019 in a South Indian tertiary care center was performed. The write‐up describes the clinical, biochemical, and genetic characterization of these patients with the diagnoses of neonatal diabetes mellitus (15 patients), MODY (five patients), and various forms of syndromic diabetes (13 with Wolfram syndrome, two with H syndrome, one with mitochondrial diabetes, and one with thiamine responsive megaloblastic anemia).     

Beta-cell autoantibodies in children with type 2 diabetes mellitus: subgroup or misclassification?

BACKGROUND: In adults, a fraction of diabetic individuals with beta-cell autoantibodies has initially non-insulin requiring diabetes clinically appearing as type 2 diabetes mellitus (T2DM), named latent autoimmune diabetes in adulthood (LADA). The occurrence of beta-cell autoantibodies in European children and adolescents with T2DM has not been reported so far. METHODS: The frequency of beta-cell autoantibodies (anti-GAD, anti-IA-2, and anti-ICA) was determined in 7050 diabetic children and adolescents. The type of diabetes was classified by paediatric diabetic specialists based on the clinical presentation. Children with non-insulin dependent T2DM over a one year period were studied separately. RESULTS: A total of 6922 children were clinically classified as having type 1 diabetes (T1DM) and 128 children as having T2DM. Thirty six per cent of the children with T2DM had at least one detectable beta-cell autoantibody. These children did not differ significantly from the children with T2DM and without autoantibodies in respect of age, gender, weight status, lipids, blood pressure, C-peptide, glucose, and HbA1c at manifestation, as well as frequency of anti-thyroidal antibodies and insulin treatment during follow up. In the subgroup of the 38 children with T2DM without insulin requirement over a one year period, autoantibodies occurred in 32%. These 12 children were predominantly obese (67%), female (67%), and in the pubertal age range. CONCLUSION: beta-cell autoantibodies were detectable in a subgroup of initially non-insulin dependent diabetic children and adolescents with the clinical appearance of T2DM. Following the terminology "latent autoimmune diabetes in adulthood (LADA)", this subgroup might be classified as "LADY" (latent autoimmune diabetes in youth).     

Annual screening detects celiac disease in children with type 1 diabetes

Objective:  To investigate the prevalence of celiac disease (CD) in a cohort of type 1 diabetes mellitus (T1DM) children and adolescents at the time of clinical diagnosis and to evaluate the screening procedure and possible role of human leukocyte antigen (HLA)-DQ during a 5-yr follow-up.
Research design and methods:  The study group was a cohort of 300 newly diagnosed T1DM children and youths younger than 20 yr followed for 5 yr at six clinical centers for pediatric diabetes in the region Skåne in Sweden. Immunoglobulin A endomysium antibodies were used to screen the patients annually to be considered for an intestinal biopsy. All patients were analyzed for HLA-DQA1-B1 genotypes.
Results:  While 0.7% (2/300) already had a diagnosed symptomatic CD, an additional 3% (10/300) had silent CD at the diagnosis of T1DM. During follow-up, another 6% (17/300) developed CD as follows: 10 after 1 yr, 5 after 2 yr, 1 after 3 yr, and 1 after 5 yr. Therefore, the cumulative frequency of CD confirmed by intestinal biopsies was 10% (29/300). HLA genotypes among T1DM patients developing CD were not different from those among patients with T1DM alone.
Conclusions:  Our study confirmed the low prevalence (0.7%) of diagnosed symptomatic CD at the time of clinical diagnosis but document by screening an increasing prevalence of silent CD during a 5-yr follow-up to reach an overall prevalence of 10%. We suggest that children with T1DM should be screened for CD at the onset of T1DM and annually for a minimum of at least 2 yr. HLA genotypes among T1DM patients developing CD were not different from those among patients with T1DM alone.     

Differential diagnosis of type 1 diabetes: which genetic syndromes need to be considered?

Abstract:  Recently it has become apparent that not all diabetes presenting in childhood is type 1. Increasingly type 2 diabetes, secondary diabetes, maturity onset diabetes of the young, and rare syndromic forms of diabetes such as Wolfram syndrome and Alstrom syndrome have been identified in children. Although individually rare, collectively they make up about 5% of children seen in diabetes clinics. The importance of these syndromes for children lies in the recognition of treatable complications, and for their parents, the possibility of genetic counselling. The scientific importance is enormous as they are experiments of nature that reveal basic mechanisms of insulin and glucose metabolism. We are now able to offer mutation analysis to correlate the clinical pattern to the genotype, and seek novel therapeutic approaches based on the developing knowledge of gene and protein functions. This review focuses on monogenic syndromes of diabetes, particularly where significant advances have been made in our understanding recently. Neonatal diabetes is a specialist field in its own right and is not included, except to discuss Kir6.2 diabetes which may develop in infancy. This review is written for the paediatric diabetes specialist and aims to provide information on the clinical features, natural history, genetics and management of children with diabetes as part of a syndrome. Finally there is information on useful investigations to aid diagnosis.     

Host and environmental factors defining the epidemiology of type 1 diabetes mellitus in a group of Lebanese children and young adults

The effect of a number of host and environmental factors on the onset of type 1 diabetes mellitus (DM1) in a group of Lebanese children and young adults was studied. Results showed that DM1 in a group of 253 patients presented no gender preference and that the age of onset was similar in both genders. The overall body mass index reflected good metabolic control. HbA1c had a mean value of 8.98%, suggesting poor glucose control. Family history of DM1 and type 2 diabetes mellitus as well as consanguinity in patients' families were not different from those reported in the literature. Finally, onset of DM1 showed seasonal variation, peaking during winter months. DM1 showed a higher prevalence of onset among children born first and a decreased incidence as birth order increased. This study provides valuable data for the diagnosis, control and prevention of DM1 in children.     

Identification of infants with increased type 1 diabetes genetic risk for enrollment into Primary Prevention Trials—GPPAD‐02 study design and first results

Primary prevention of type 1 diabetes (T1D) requires intervention in genetically at‐risk infants. The Global Platform for the Prevention of Autoimmune Diabetes (GPPAD) has established a screening program, GPPAD‐02, that identifies infants with a genetic high risk of T1D, enrolls these into primary prevention trials, and follows the children for beta‐cell autoantibodies and diabetes. Genetic testing is offered either at delivery, together with the regular newborn testing, or at a newborn health care visits before the age of 5 months in regions of Germany (Bavaria, Saxony, Lower Saxony), UK (Oxford), Poland (Warsaw), Belgium (Leuven), and Sweden (Region Skåne). Seven clinical centers will screen around 330 000 infants. Using a genetic score based on 46 T1D susceptibility single‐nucleotide polymorphisms (SNPs) or three SNPS and a first‐degree family history for T1D, infants with a high (>10%) genetic risk for developing multiple beta‐cell autoantibodies by the age of 6 years are identified. Screening from October 2017 to December 2018 was performed in 50 669 infants. The prevalence of high genetic risk for T1D in these infants was 1.1%. Infants with high genetic risk for T1D are followed up and offered to participate in a randomized controlled trial aiming to prevent beta‐cell autoimmunity and T1D by tolerance induction with oral insulin. The GPPAD‐02 study provides a unique path to primary prevention of beta‐cell autoimmunity in the general population. The eventual benefit to the community, if successful, will be a reduction in the number of children developing beta‐cell autoimmunity and T1D.     

Hyperglycemic hyperosmolar non-ketotic syndrome in children with type 2 diabetes*

OBJECTIVE: Hyperglycemic hyperosmolar non-ketotic (HHNK) syndrome is thought to be a rare entity in the pediatric population, associated with significant mortality based on case reports in the literature. As obesity and type 2 diabetes in childhood grow in prevalence, such related complications may also increase. This study will serve to provide updated information regarding typical clinical course and sequelae of HHNK syndrome in childhood. METHODs: Patients diagnosed with type 2 diabetes at Children's Hospital of Philadelphia (CHOP) over a period of 5 yr were screened retrospectively for any laboratory evidence of previous episodes of HHNK syndrome. The standard diagnostic criteria of blood glucose >600 mg/dL and serum osmolality >330 mOsm/L with only mild acidosis (serum bicarbonate >15 mmol/L and small ketonuria 15 mg/dL or less) were utilized. RESULTS: The records of all patients with type 2 diabetes mellitus (DM) diagnosed over a 5-yr period were reviewed (n=190). Seven patients were found to have one episode of HHNK syndrome by diagnostic criteria (five males, mean age at presentation 13.3 yr, age range 10.1--16.9 yr), yielding a frequency of 3.7%. All were African-American. HHNK syndrome was the clinical presentation at diagnosis of new onset diabetes for all seven children. Three of seven children had a previously diagnosed developmental delay. The average Glasgow Coma Scale (GCS) score at presentation was 13 (range 9--15). Mean body mass index (BMI) at presentation was 32.7 kg/m(2) (n=6). Mean serum osmolality was 393 mOsm/L (n=7), and mean blood glucose was 1604 mg/dL (n = 7). The average time until mental status returned to baseline among survivors was 3 d (range 1--7 d). The average number of hospital days for survivors was 10 (range 5--24 d). Four of seven patients had an uncomplicated course. One patient developed multisystem organ failure and died on hospital day 4. The case fatality rate was 14.3% (one of seven). Survivors had no appreciable neurodevelopmental sequelae. CONCLUSIONS: This retrospective chart review provides updated information regarding the entity of HHNK syndrome in children. This study supports the need for increased awareness of type 2 diabetes in children so that morbidity and mortality related to HHNK syndrome can be prevented.     

Clinical characteristics of non-immune-mediated, idiopathic type 1 (type 1B) diabetes mellitus in Japanese children and adolescents

To clarify the characteristics of idiopathic type 1 (type 1B) diabetes mellitus (DM), we compared the clinical features of immune-mediated type 1 (type 1A) DM and type 1B DM in 85 Japanese children and adolescents with DM. The prevalence of type 1B DM was 16.5%. The patients with type 1B DM were significantly younger at diagnosis and had a higher frequency of preceding viral infection before onset, compared to those with type 1A DM. They displayed more severe metabolic decompensation with a higher frequency of ketoacidosis at diagnosis than patients with type 1A DM. They had strong, HLA-defined genetic susceptibility, similar to that in type 1A DM. Some patients with type 1B DM exhibited a remarkably abrupt onset and rapid loss of beta-cell capacity. From these findings, it is considered that type 1B DM differs from type 1A DM with respect to age at onset and the trigger event, such as viral infection, leading to rapid destruction of beta-cells without autoimmunity in the etiology of the disease.     

Prevalence and risk factors for microalbuminuria in a population-based sample of children and adolescents with T1DM in Western Australia

OBJECTIVE: To define the prevalence and describe the natural history of microalbuminuria (MA) in a population-based sample of children with type 1 diabetes mellitus (T1DM). METHODS: Children with T1DM diagnosed or=20 and <200 microg/min, developed in 128 subjects (13.4%) at mean diabetes duration of 7.6 yrs. Cumulative probability for MA was 16% after 10 yrs. Determinants for MA were HbA1c [hazard ratio (HR) 1.21; 95% confidence interval (CI) 1.05-1.38; p = 0.007], onset of puberty (HR 8.01; 95% CI 3.18-20.16; p < 0.001) and age at diagnosis (HR 1.25; 95% CI 1.18-1.33; p < 0.001). Females had a higher probability for MA during puberty than males (p = 0.03). The total incidence of MA (subjects with MA/100 person-years) was 1.26, 1.85 and 2.44 for those who developed diabetes at ages <5 yrs, 5-11 yrs and >11 yrs, respectively. CONCLUSIONS: Onset of puberty, diabetes duration and metabolic control are major factors predisposing the development of MA. Children diagnosed with T1DM at younger ages have a prolonged time for developing MA.     

Clinical characteristics and predictors of severe ketoacidosis at onset of type 1 diabetes mellitus in children in a North Rhine-Westphalian region,Germany

Diabetic ketoacidosis is the most serious complication at the onset of type 1 diabetes mellitus (DM). In Germany, population-based data on its occurrence at DM onset are not yet available. In a population-based study in a North Rhine-Westphalian region, Germany, during 1993-95, data on the clinical presentation at type 1 DM onset were obtained from hospital records for 262 patients under 15 years of age (81% of eligible patients). Information on social status was obtained from 148 families by a standardized questionnaire. The most frequently reported symptoms were polyuria (93.9%), fatigue (64.2%) and weight loss (59.4%). Mean duration of symptoms was 3.5 weeks. At diagnosis 18.3% of the children presented impaired consciousness and 3.5% coma. Mean glucose level was 25.1 mmol/l. Severe ketoacidosis (pH < or = 7.2) was present in 16.0% of the children. Metabolic derangement was more severe in children under 5 years. Low social status was significantly associated with increased risk of severe ketoacidosis (OR = 3.54, 95% CI: 1.10-11.35). Frequency of ketoacidosis at DM onset needs to be reduced through increased public and medical awareness of the presenting characteristics of childhood DM.     

Health‐related quality of life (HRQoL) of children with type 1 diabetes mellitus (T1DM): self and parental perceptions

Kalyva E, Malakonaki E, Eiser C, Mamoulakis D. Health‐related quality of life (HRQoL) of children with type 1 diabetes mellitus (T1DM): self and parental perceptions. The aim of the study was to evaluate health‐related quality of life (HRQoL) in children and adolescents with type 1 diabetes mellitus (T1DM) in Greece compared with healthy controls and to identify the effect of age, gender, age of onset of disease, and metabolic control on perceptions of HRQoL. A total of 117 children and adolescents with T1DM aged 5–18, their parents, and 128 matched healthy children and adolescents participated. Children and adolescents completed PedsQL? 4.0 Generic Core Scales. Children and adolescents with T1DM also completed the PedsQL? 3.0 Diabetes Module, while their parents completed the proxy‐reports of both the PedsQL? 4.0 Generic Core Scales and the PedsQL? 3.0 Diabetes Module. The results demonstrated that children and adolescents with T1DM had lower general HRQoL compared with healthy matched children and adolescents. Parents of children and adolescents with diabetes reported that the illness has a greater affect on their children's lives than the children themselves. Finally, the results indicated that later age of onset of diabetes, less hyperglycemic episodes, lower glycosylated hemoglobin (HbA1c), older age, and male gender were associated with better general HRQoL and diabetes‐specific HRQoL. The findings have implications for designing effective therapeutic interventions aimed at improving the HRQoL of children and adolescents with T1DM.     

Thyroid autoimmunity in children with coexisting type 1 diabetes mellitus and celiac disease: a multicenter study

BACKGROUND: Children with type 1 diabetes mellitus (DM1) are more prone to developing thyroid autoimmunity (TAI); TAI also occurs more frequently in patients with celiac disease (CD). AIM: To determine whether TAI occurs more frequently in children with coexisting DM1 and CD compared to children with DM1 only, and whether the clinical course of DM1 is influenced by concomitant TAI. PATIENTS AND METHODS: We performed a multicenter retrospective case-control study comparing data from 84 diabetic children with CD (group 1) to 167 diabetic children without CD (group 2), matched by age at DM1 onset, duration of DM1 and center. Markers of TAI, thyroid function and HbA1c were recorded. The TAI follow-up lasted 4.9 +/- 2.8 years. RESULTS: TAI was diagnosed in 13% of children in group 1 and 19% of children in group 2 (ns). Diabetes control was not influenced by TAI in either group. CONCLUSIONS: Occurrence of TAI in diabetic children is not related to coexisting CD. TAI does not lead to worsening of metabolic control in children with DM1.