Importance of Immediate Thiamine Therapy in Children with Suspected Thiamine-Responsive Megaloblastic Anemia-Report on Two Patients Carrying a Novel SLC19A2 Gene Mutation.

Thiamine-responsive megaloblastic anemia (TRMA) is an autosomal recessive disorder characterized by the development of megaloblastic anemia, diabetes mellitus, and sensorineural deafness. We report on the first two Croatian patients with TRMA, compound heterozygotes for nonsense, c.373C > T; p.(Gln125Ter) and novel missense variant, c.1214C > G; p.(Thr405Arg) in SLC19A2 gene. The first was diagnosed at 4 months with diabetes mellitus and severe anemia requiring transfusions. As TRMA was suspected, thiamine therapy was immediately started to prevent further transfusions and insulin therapy. His brother developed extreme anemia at 3 weeks of age while waiting for the results of the genetic test. Severe anemia in this sibling may have been prevented if thiamine had been initiated earlier.

Role of Parents in Body Mass Reduction in Children with Obesity-Adherence and Success of 1-Year Participation in an Intervention Program.

Background and Objectives: Obesity in children and adolescents results in a number of serious health-related consequences necessitating early treatment. Support from family members and family-focused lifestyle interventions can improve effectiveness of the treatment. The aim of the study was to assess the effects of parental characteristics and family-based dietary habits on the adherence and success of a body mass reduction program in children with obesity included in a lifestyle intervention program after 1 year. Materials and Methods: The program included dietetic, psychosocial, and endocrine counseling given to individuals either alone or in groups and was conducted by a multidisciplinary team (consisting of endocrinologists, nurses, psychologists, social counselors, dietitians, and physiotherapists). A total of 113 children aged 10-17 years (mean age 12.9 ± 2.0; 60 girls, 53 boys) were included in the program. After 1 year of participation, the rate of adherence and success were assessed. The effect of the participants' general characteristics, including anthropometric data, as well as parental characteristics (marital status, employment, education, body mass index (BMI), duration of breastfeeding) and the circumstances of meal consumption (eating at home or outside, fast food consumption), was analyzed. Results: The most important factors predicting body mass reduction success were baseline BMI (p < 0.0001) and waist-hip ratio (WHR) (p = 0.04), but they did not predict body mass reduction adherence. Conclusions: The meal consumption habits and support from family members may be among the determinants of adherence to a body mass reduction program for preadolescents and adolescents with obesity. However, the results of the presented study suggested that baseline BMI and WHR are the most important determinants of the body mass reduction success.

Plasma Fucosylated Glycans and C-Reactive Protein as Biomarkers of HNF1A-MODY in Young Adult-Onset Nonautoimmune Diabetes.

OBJECTIVE: Maturity-onset diabetes of the young (MODY) due to variants in HNF1A is the most common type of monogenic diabetes. Frequent misdiagnosis results in missed opportunity to use sulfonylureas as first-line treatment. A nongenetic biomarker could improve selection of subjects for genetic testing and increase diagnosis rates. We previously reported that plasma levels of antennary fucosylated N-glycans and high-sensitivity C-reactive protein (hs-CRP) are reduced in individuals with HNF1A-MODY. In this study, we examined the potential use of N-glycans and hs-CRP in discriminating individuals with damaging HNF1A alleles from those without HNF1A variants in an unselected population of young adults with nonautoimmune diabetes. RESEARCH DESIGN AND METHODS: We analyzed the plasma N-glycan profile, measured hs-CRP, and sequenced HNF1A in 989 individuals with diabetes diagnosed when younger than age 45, persistent endogenous insulin production, and absence of pancreatic autoimmunity. Systematic assessment of rare HNF1A variants was performed. RESULTS: We identified 29 individuals harboring 25 rare HNF1A alleles, of which 3 were novel, and 12 (in 16 probands) were considered pathogenic. Antennary fucosylated N-glycans and hs-CRP were able to differentiate subjects with damaging HNF1A alleles from those without rare HNF1A alleles. Glycan GP30 had a receiver operating characteristic curve area under the curve (AUC) of 0.90 (88% sensitivity, 80% specificity, cutoff 0.70%), whereas hs-CRP had an AUC of 0.83 (88% sensitivity, 69% specificity, cutoff 0.81 mg/L). CONCLUSIONS: Half of rare HNF1A sequence variants do not cause MODY. N-glycan profile and hs-CRP could both be used as tools, alone or as adjuncts to existing pathways, for identifying individuals at high risk of carrying a damaging HNF1A allele.

Trends and cyclical variation in the incidence of childhood type 1 diabetes in 26 European centres in the 25 year period 1989-2013: a multicentre prospective registration study.

AIMS/HYPOTHESIS: Against a background of a near-universally increasing incidence of childhood type 1 diabetes, recent reports from some countries suggest a slowing in this increase. Occasional reports also describe cyclical variations in incidence, with periodicities of between 4 and 6 years. METHODS: Age/sex-standardised incidence rates for the 0- to 14-year-old age group are reported for 26 European centres (representing 22 countries) that have registered newly diagnosed individuals in geographically defined regions for up to 25 years during the period 1989-2013. Poisson regression was used to estimate rates of increase and test for cyclical patterns. Joinpoint regression software was used to fit segmented log-linear relationships to incidence trends. RESULTS: Significant increases in incidence were noted in all but two small centres, with a maximum rate of increase of 6.6% per annum in a Polish centre. Several centres in high-incidence countries showed reducing rates of increase in more recent years. Despite this, a pooled analysis across all centres revealed a 3.4% (95% CI 2.8%, 3.9%) per annum increase in incidence rate, although there was some suggestion of a reduced rate of increase in the 2004-2008 period. Rates of increase were similar in boys and girls in the 0- to 4-year-old age group (3.7% and 3.7% per annum, respectively) and in the 5- to 9-year-old age group (3.4% and 3.7% per annum, respectively), but were higher in boys than girls in the 10- to 14-year-old age group (3.3% and 2.6% per annum, respectively). Significant 4 year periodicity was detected in four centres, with three centres showing that the most recent peak in fitted rates occurred in 2012. CONCLUSIONS/INTERPRETATION: Despite reductions in the rate of increase in some high-risk countries, the pooled estimate across centres continues to show a 3.4% increase per annum in incidence rate, suggesting a doubling in incidence rate within approximately 20 years in Europe. Although four centres showed support for a cyclical pattern of incidence with a 4 year periodicity, no plausible explanation for this can be given.

Arterial stiffness as a measure of cardiovascular risk in obese adolescents and adolescents with diabetes type 1.

Background Cardiovascular disease (CVD) is the end result of vascular aging and atherosclerosis, having its origins in childhood. The aim of our study was to compare arterial stiffness (AS) and intima-media thickness (IMT) as markers of an early vascular damage between obese adolescents, adolescents with diabetes type 1 (T1D) and lean control subjects. Methods We analyzed AS and IMT in 68 obese adolescents (13.27±2.31 years), 42 adolescents with T1D (14.95±2.35 years) lasting over 5 years and 38 controls (15.02±1.94 years). AS (measured by pulse wave velocity [PWV], arterial compliance [AC] and ß-stiffness) and IMT were assessed using an e-tracking ultrasound method. Results A significant difference between the groups was found for AC (p=0.022) and PWV (p=0.010), with the lowest compliance and higher velocities in T1D patients. When corrected for age, the difference in AC among the groups did not reach a statistical difference (p=0.059). Correlation analysis in the obese adolescents showed lower AC in females (p=0.041), with higher systolic blood pressure (SBP) (p=0.032). In T1D adolescents, disease duration was the strongest determinant of AS (AC p=0.028, ß p=0.029 and PWV p=0.003), followed by body mass index (BMI; PWV p=0.008; ß p=0.033), SBP (AC p<0.001; PWV p=0.023), diastolic BP (AC p=0.049; PWV p=0.048) and HbA1c (PWV p=0.048). No significant correlations were found for AS measures or IMT with sex, age, BMI, Tanner stage or BP levels in controls. Conclusions Early vascular damage is more pronounced in T1D adolescents than in obese or lean adolescents, which may emphasize the impact of hyperglycemia as a major threat for cardiovascular health.

Human Leukocyte Antigen class II polymorphisms among Croatian patients with type 1 diabetes and autoimmune polyglandular syndrome type 3 variant.

This study included 161 patients: 92 patients had type 1 diabetes (T1D) while 69 patients had a combination of T1D and autoimmune thyroiditis, the so-called autoimmune polyglandular syndrome type 3 variant (APS3v). Those patients, as well as 93 controls, were typed for HLA-DRB1 and -DQB1 genes to assess their possible contribution to the development/protection of T1D with/without autoimmune thyroiditis. Both HLA-DRB1*04 and -DRB1*03 frequencies were significantly higher among T1D and APS3v patients than in controls. The frequencies of HLA-DRB1*11 and -DRB1*15 were lower among T1D patients, while HLA-DRB1*07 and -DRB1*11 occurred significantly less frequently among APS3v patients in comparison to controls. HLA-DQB1*03:01 and -DQB1*03:02 were associated with a higher risk of developing T1D and APS3v; HLA-DQB1*02 was significantly more present among APS3v patients while HLA-DQB1*03:03 was observed with a significantly lower frequency only among T1D patients. HLA-DRB1*03~DQB1*02 and HLA-DRB1*04~DQB1*03:02 were associated with both diseases. The higher frequency of HLA-DRB1*03/DRB1*03 among APS3v patients was the only significant difference in genotype frequency when compared to T1D patients, while high risk (HLA-DRB1*03/DRB1*04) and medium risk genotypes for T1D (HLA-DRB1*04/DRB1*04) occurred with similar frequencies in both patient groups. Although some of the results point toward shared genetic susceptibility of T1D and APS3v, observed differences in both susceptible/protective HLA profiles indicate the necessity of further studies in order to elucidate the pathogenesis of these diseases.

ACUTE RESPIRATORY DISTRESS SYNDROME IN A FOUR-YEAR-OLD BOY WITH DIABETIC KETOACIDOSIS - CASE REPORT.

- Among many disease states as known initiators of acute respiratory distress syndrome (ARDS), diabetic ketoacidosis (DKA) is the rarest one. We present a 4-year-old boy with DKA as the first manifestation of insulin-dependent diabetes mellitus who developed ARDS, required tracheal intubation and mechanical ventilation, and survived without significant sequels. To improve survival of patients with ARDS as a complication of DKA, physicians should be aware of this rare pulmonary complication and its appropriate management.

Type 1 diabetes from adolescence to adulthood: is there a permanent need for nutrition education and re-education?

BACKGROUND: The transition for type 1 diabetes patients from pediatric to adult diabetology care is challenging process for both medical team and patients. Adult diabetology usually insists on stricter goals and focuses on increased empowerment and self-care. We set to find a more practical and effective way to determine patient knowledge and skills during the transition. The aim of the study was to identify screening questions which best represent knowledge in management of type 1 diabetes and to explore the differences in the effect of a structured educational program for type 1 diabetes patient diagnosed in childhood versus adulthood. METHODS: It was an observational study exploring effect of a structured educational program for 39 participants diagnosed with type 1 diabetes in childhood (group 1) vs. 20 patients diagnosed in adulthood (group 2). Main outcome measures were A1C and knowledge questionnaire results change before and after education. RESULTS: The effect of education was equal in both groups, with higher basal level of knowledge in group 1. There was a significant correlation between questions regarding carbohydrate counting and A1C after 3 and 6-12 months in group 1. We found that questions regarding carbohydrate counting may predict glycemic control and represent general knowledge. CONCLUSIONS: Carbohydrate counting is crucial in predicting glycemic control and representing general knowledge about diabetes. Patients diagnosed in childhood may be more knowledgeable in diabetes management, but their practical skill in matching insulin dose and carbohydrate content is poor. Both groups improved their knowledge in similar proportion with same educational program.

Incidence of type 1 diabetes mellitus in 0 to 14-yr-old children in Croatia--2004 to 2012 study.

BACKGROUND: The incidence of type 1 diabetes mellitus (T1DM) among children and adolescents increased during the last 50 yr. The T1DM incidence in Croatia was 8.87/100.000/yr over 1995-2003, with an annual increase of 9%, which placed Croatia among countries with moderate risk for T1DM. AIM: To investigate incidence rates and trends of T1DM from 2004 to 2012 in 0 to 14-yr-old Croatian children, and to compare the results with previous studies in Croatia and other European countries. METHODS: T1DM crude incidence rates are estimated for the entire group and three subgroups: 0-4, 5-9, and 10-14 yr. Standardized incidence is calculated using the method of direct standardization according to World Health Organization (WHO) standard world population. The incidence rates by gender, age groups, seasonality, and calendar year, and their interactions were analyzed using Poisson regression model. RESULTS: A total of 1066 cases were ascertained over 2004-2012. The standardized incidence was 17.23/100.000/yr (95% CI: 16.19-18.26), with no significant differences in incidence rates or trends between boys and girls. Statistically significant annual increase of 5.87% (p < 0.001) was found for the whole group, and for the subgroups 5-9 yr (6.82%; p < 0.001) and 10-14 yr (7.47%; p < 0.001). In the youngest subgroup (0-4 yr), annual increase was lower (2.43%; p = 0338) and not statistically significant. CONCLUSION: The incidence of childhood T1DM is increasing in Croatia, thus placing Croatia among countries with high risk for T1DM. The annual increment of 5.87% is considerably lower than 9.0% reported earlier, but still higher than the European average (3.9%). The increase in incidence ceased in youngest children.

Primary hypothyroidism and nipple hypoplasia in a girl with Wolcott-Rallison syndrome.

UNLABELLED: Wolcott-Rallison syndrome (WRS), caused by mutation in the EIF2AK3 gene encoding the PERK enzyme, is the most common cause of permanent neonatal diabetes mellitus (PNDM) in consanguineous families and isolated populations. Besides PNDM, it also includes skeletal abnormalities, liver and renal dysfunction, and other inconsistently present features. We present two siblings, who are WRS patients, and are Albanians from Kosovo born to unrelated parents. The older sister presented with PNDM, exocrine pancreatic insufficiency, short stature, microcephaly, normocytic anemia, delay in speech development, skeletal abnormalities, primary hypothyroidism, and hypoplastic nipples. Sequencing of the EIF2AK3 gene identified a homozygous mutation R902X in exon 13. The younger brother was diagnosed with PNDM and died from hepatic failure suggesting that he has been suffering from WRS as well. Including one previously reported patient from Kosovo carrying the same homozygous mutation, there are three WRS patients from this very small, ethnically homogenous region suggesting founder effect in this population. CONCLUSION: We postulate that thyroid hypoplasia with primary subclinical hypothyroidism already reported in two WRS patients and nipple hypoplasia could also be the phenotypic reflection of the mutation of pleiotropic EIF2AK3 gene in secretory cells.

Two siblings with triple A syndrome and novel mutation presenting as hereditary polyneuropathy.

The clinical and molecular data on triple A syndrome in two siblings (girl 3.5 years and boy 5.5 years at presentation) with early onset of neurological dysfunction are described. Both patients showed delayed developmental milestones and neurological dysfunctions (motor and sensory demyelinating neuropathy, marked hyperreflexia, calves hypothrophy, pes cavus, gait disturbance) in early childhood, when erroneously diagnosed with hereditary polyneuropathy, most likely Charcot-Marie-Tooth disease. After a severe adrenal crisis in the younger sister at the age of 3 years, the older brother aged 5.5 years was also evaluated and latent adrenal insufficiency was discovered. As both of the siblings had alacrima, hyperkeratosis of palms, cutis anserina, and nasal speech, diagnosis of triple A syndrome was considered. Sequencing of the AAAS gene detected a compound heterozygous mutation consisting of a novel mutation p.Ser296Tyr (c.887C>A) in exon 9 and a previously described p.Ser263Pro (c.787T>C) missense mutation in exon 8 in both siblings. In conclusion, triple A syndrome should be considered in patients presenting with early neurological dysfunction and developmental delay. Alacrima as the earliest and most consistent clinical sign should be investigated by Schirmer test. Patients should be regularly tested for adrenal dysfunction to prevent life-threatening adrenal crises.

[Marden-Walker syndrome--a case report]. / Marden-Walkerov sindrom--prikaz bolesnice.

Up to now 36 cases of Marden Walker syndrome (MIM # 248700) have been reported. The underlying pathological mechanism has not yet been clearly established, but it is assumed that it is a developmental disorder of the central nervous system which is inherited in an autosomal recessive manner. Three main diagnostic criteria are blepharophimosis, congenital joint contractures and mask-like face, but numerous other anomalies have been described in these patients. We present a girl with clinical characteristics of Marden Walker syndrome, which has not yet been reported in our literature. Together with three major and many other clinical signs which confirm the diagnosis, our girl also has a vesicoureteral reflux and umbilical hernia, which have not yet been described in these patients.

[Diagnostic value of myocardial biopsy in the diagnostic algorithm in cardiomyopathies in children]. / Dijagnosticka vrijednost biopsije miokarda u dijagramu dijagnostickog toka kardiomiopatija u djece.

The purpose of this work was to show the importance of myocardial bioptate analysis using different methods in the diagram of diagnostic flow in primary cardiomyopathies in children. According to the guidelines of the Task Force on Cardiomyopathies of the WHO/ISFC, we identified 121 children (50 f and 71 m) as having cardiomyopathy, giving an average occurrence for all cardiomyopathies of 38.81 for each 10,000 pts examined in our outpatient clinics for paediatric cardiology. The dilated cardiomyopathy (DCM) was identified in 52 pts (42.9%), hypertrophic cardiomyopathy (HCM) in 43 pts (35.5%) and restrictive cardiomyopathy (RCM) in 6 pts (4.8%). We placed 11 pts (9.0%) in the group of specific cardiomyopathies. In nine pts (7.4%), it was impossible to classify the cardiomyopathy. Most of those with DCM had been diagnosed prior to the age of 3 years (RR 1.9, 95% CI 1.4-2.47). There were no statistically significant differences in the incidences of DCM as compared to HCM (Z 0.923, p < 0.1779), but we encountered a significantly lower occurrence of RCM (Z 6.044, p < 0.001). The biopsy of endocardium and myocardium was done to confirm the etiology of primary cardiomyopathy in 22 pts, 12 m and 10 f, age 1 to 17 (average age 9.5y). The bioptates were analysed by light microscope (Dallas criteria) in all pts, 13 bioptates by direct immunofluorescence, 8 by immunohystochemical method (two hystochemically by the method of coloring with Kongo red, one by the microscopy in polarised light), 7 by electron microscope, and 5 by PCR method where DNA and RNA of cardiotrophic viruses was used. Out of 10 pts with DCM, in 4 myonecrosis as a consequence of acute myocarditis and in 6 signs of late inflammatory processes, as a consequence of chronic immunologic myocarditis, were found. In 4 of them rebiopsy proved complete healing. In 5 pts with HCM the diagnosis was confirmed hystologically. One bioptate was analysed by electron microscope to rule out mitochondriopathy. Out of 4 pts with RCM due to inflammation, in 3 pathohistological findings proved diagnosis and in one showed primary amyloidosis. In one patient pathohystological finding showed fibroelastosis. In one patient heart tumor (fibroma) has been found.