Pinar Isguven

PAPSS2 mutations cause autosomal recessive brachyolmia

Background Brachyolmia is a heterogeneous group of skeletal dysplasias that primarily affects the spine. Clinical and genetic heterogeneity have been reported; at least three types of brachyolmia are known. TRPV4 mutations have been identified in an autosomal dominant form of brachyolmia; however, disease genes for autosomal recessive (AR) forms remain totally unknown. We conducted a study on a Turkish family with an AR brachyolmia, with the aim of identifying a disease gene for AR brachyolmia. Methods and results We examined three affected individuals of the family using exon capture followed by next generation sequencing and identified its disease gene, PAPSS2 (phosphoadenosine-phosphosulfate synthetase 2). The patients had a homozygous loss of function mutation, c.337_338insG (p.A113GfsX18). We further examined three patients with similar brachyolmia phenotypes (two Japanese and a Korean) and also identified loss of function mutations in PAPSS2; one patient was homozygous for IVS3+2delT, and the other two were compound heterozygotes for c.616-634del19 (p.V206SfsX9) and c.1309-1310delAG (p.R437GfsX19), and c.480_481insCGTA (p.K161RfsX6) and c.661delA (p.I221SfsX40), respectively. The six patients had short-trunk short stature that became conspicuous during childhood with normal intelligence and facies. Their radiographic features included rectangular vertebral bodies with irregular endplates and narrow intervertebral discs, precocious calcification of rib cartilages, short femoral neck, and mildly shortened metacarpals. Spinal changes were very similar among the six patients; however, epiphyseal and metaphyseal changes of the tubular bones were variable. Conclusions We identified PAPSS2 as the disease gene for an AR brachyolmia. PAPSS2 mutations have produced a skeletal dysplasia family, with a gradation of phenotypes ranging from brachyolmia to spondylo-epi-metaphyseal dysplasia.

Anti-HBs response to standard hepatitis B vaccination in children and adolescents with diabetes mellitus.

Patients with type 1 diabetes mellitus are expected to respond poorly to hepatitis B (HB) vaccination. In this study we tested this hypothesis for the standard vaccination schedule. Ninety-nine patients (age 10.8 +/- 3.5 years) were vaccinated against HB (10 pg/dose at 0, 1, and 6 months) using a vaccine containing no pre-S2 antigen (Engerix Bs). The sero-conversion and -protection rates after the completion of three doses, the relation of anti-HBs titers to clinical parameters, and comparison with those of healthy counterparts (51 children, aged 9.7 +/- 4.4 years) were analyzed. The vaccine used was pre-S2 antigen containing (Genhevac B) in 23 and Engerix B in 28; both types yielded a similar response. The geometric mean of the anti-HBs titer was 322.9 vs 1476.8 IU/l (non-significant), sero-convertion rate 96.9% vs 100%, and seroprotection rate 93.9% vs 99% in the diabetic and control groups, respectively. In the diabetic group, there was no correlation between anti-HBs titer and clinical characteristics except for age. We concluded that the standard vaccination schedule is less effective but still effective enough in children and adolescents with type 1 diabetes mellitus.

Self‐efficacy and its interrelation with family environment and metabolic control in Turkish adolescents with type 1 diabetes

To explore the relationship between self‐efficacy, family environment (cohesion and organization) and metabolic control.

Evaluation of glucose intolerance in adolescents relative to adults with type 2 diabetes mellitus.

AIM There is an increasing trend in the prevalence of type 2 diabetes mellitus (DM2) in childhood and adolescence, while positive family history of DM2 and obesity are the most important risk factors. To study the influence of family history and obesity on glucose intolerance in our country was the aim of this study. STUDY DESIGN AND METHODS A total of 105 children and adolescents aged 10-18 years (mean 13.3 +/- 2.5 years) were included in the study. All children and adolescents were divided into three groups according to positive family history of DM2 and obesity, and an oral glucose tolerance test (OGTT) was performed for all. Prediabetes was defined as impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG). Insulin secretion and insulin resistance were estimated using the insulinogenic index; and the homeostatic model assessment for insulin resistance (HOMA-IR) and Matsuda index, respectively. RESULTS The prevalence of prediabetes was 15.2% in the whole group, while it was 25.5% in obese children who also had a positive family history of DM2. The frequency of hyperinsulinism was 57.1% in all groups. Prediabetic children had significant insulin resistance (HOMA-IR 11.5 +/- 7.1 and 4.1 +/- 6.4, respectively, p = 0.034). CONCLUSIONS Obesity and glucose intolerance are also a problem in developing countries. The risk of prediabetes in children is highest in obese children who also have a positive family history of DM2. There is a need for a lifelong preventive program starting in childhood to avoid DM2 and decrease cardiovascular risk factors

Mutations in XRCC4 cause primary microcephaly, short stature and increased genomic instability

DNA double-strand breaks (DSBs) are highly toxic lesions, which, if not properly repaired, can give rise to genomic instability. Non-homologous end-joining (NHEJ), a well-orchestrated, multistep process involving numerous proteins essential for cell viability, represents one major pathway to repair DSBs in mammalian cells, and mutations in different NHEJ components have been described in microcephalic syndromes associated, e.g. with short stature, facial dysmorphism and immune dysfunction. By using whole-exome sequencing, we now identified in three affected brothers of a consanguineous Turkish family a homozygous mutation, c.482G>A, in the XRCC4 gene encoding a crucial component of the NHEJ pathway. Moreover, we found one additional patient of Swiss origin carrying the compound heterozygous mutations c.25delG (p.His9Thrfs*8) and c.823C>T (p.Arg275*) in XRCC4. The clinical phenotype presented in these patients was characterized by severe microcephaly, facial dysmorphism and short stature, but they did not show a recognizable immunological phenotype. We showed that the XRCC4 c.482G>A mutation, which affects the last nucleotide of exon 4, induces defective splicing of XRCC4 pre-mRNA mainly resulting in premature protein truncation and most likely loss of XRCC4 function. Moreover, we observed on cellular level that XRCC4 deficiency leads to hypersensitivity to DSB-inducing agents and defective DSB repair, which results in increased cell death after exposure to genotoxic agents. Taken together, our data provide evidence that autosomal recessive mutations in XRCC4 induce increased genomic instability and cause a NHEJ-related syndrome defined by facial dysmorphism, primary microcephaly and short stature.

Insulin detemir improves glycemic control and reduces hypoglycemia in children with type 1 diabetes: findings from the Turkish cohort of the PREDICTIVE™ observational study

Background:  Insulin detemir is a basal insulin analog designed to produce a superior pharmacokinetic profile to basal formulations of human insulin. It has shown consistently improved tolerability in comparison to neutral protamine Hagedorn (NPH) insulin in adult cohorts, but there are relatively few publications involving pediatric cohorts.

The role of leptin, soluble leptin receptor, resistin, and insulin secretory dynamics in the pathogenesis of hypothalamic obesity in children.

IntroductionIn this study, we have investigated the role of leptin, soluble leptin receptor(sOb-R), resistin, and insulin secretory dynamics in the development of hypothalamic obesity.Materials and methodsChildren who had hypothalamo-pituitary tumor were divided into two groups. First group included obese-overweight (hypothalamic obese = HOB group, n = 23) and second group included non-obese children (hypothalamic non-obese = HNOB group, n = 16). Exogenously obese-overweight children (OB group, n = 22) were included as controls. Basal and second-hour serum glucose and insulin in oral glucose tolerance test (OGTT), basal serum leptin, sOb-R, resistin levels, and homeostasis model assessment (HOMA) indexes were compared between the groups.ResultsAge, sex, and pubertal status were similar in study groups. Median and interquartile ranges of body mass index (BMI) z scores were similar in HOB and OB groups (2.0 (1.5–2.1) and 2.1 (1.8–2.3), respectively). Serum leptin levels corrected for BMI were highest and total leptin/sOb-R ratios (free leptin index (FLI)) tended to be higher in HOB than HNOB and OB groups, indicating leptin resistance (leptin/BMI, 4.0 (1.6–5.2), 1.5 (0.8–3.1), and 2.5 (1.8–3.5); FLI, 2.0 (0.8–3.5), 0.6 (0.3–1.2), and 1.5 (1–2.3) in HOB, HNOB, and OB groups; respectively). Serum resistin levels were similar in groups (2.6 (1.9–3.1), 2.8 (1.7–3.4), and 3.0 (2.2–3.5) ng/ml in HOB, HNOB, and OB groups, respectively). Basal serum glucose, basal and second-hour insulin levels in OGTT, and HOMA index were higher in OB group than the HOB and HNOB groups, indicating insulin resistance in simple obesity; however, increment of insulin to same glycemic load in OGTT was highest in the HOB group indicating insulin dysregulation (p < 0.05).ConclusionHypothalamic obesity seems to be related to both dysregulated afferent (leptin) and efferent (insulin) neural outputs through the autonomic nervous system resulting in energy storage as fat.

Pitfalls in the diagnosis of thyroid dysgenesis by thyroid ultrasonography and scintigraphy

OBJECTIVES We aimed to investigate the reliability of thyroid ultrasonography (US) and scintigraphy in determining the type of thyroid dysgenesis (TD). METHODS The study included 82 children (8.0±5.6 years) with a diagnosis of TD by thyroid scintigraphy with (99m)Tc and/or US. The patients were re-evaluated 6.0±5.1 years after the diagnosis. Thyroid US was performed in all cases, regardless of the previous US imaging. Scintigraphy images performed at the time of diagnoses (n=60) were re-evaluated during the study. Those who had no scintigraphy at the time of diagnosis (n=22) or had discordant findings with US (n=6) underwent a new scintigraphy. RESULTS Scintigraphies revealed no uptake in 37, ectopia in 35, and hypoplasia in 10 cases. The sensitivity vs specificity for US to detect athyreosis, ectopia, and hypoplasia at the time of initial diagnoses was 90.5 vs 47.8, 10 vs 100, and 100 vs 80.4% respectively. The sensitivity vs specificity for scintigraphy at the time of initial diagnoses was 96.2 vs 100, 92 vs 97.1, and 100 vs 96%, respectively, for each diagnosis. Re-scintigraphy at the time of the study led to a change in the initial diagnosis of 3/6 cases. Repeated US showed disappearance of previously reported hypoplastic thyroid tissues in eight patients. CONCLUSION US alone could not differentiate ectopia and athyreosis, whereas scintigraphy alone is also prone to mistakes in newborns and young ages. Dual thyroid imaging is important for precise structural definition of TD.

Reevaluation of Growth Hormone Deficiency During and After Growth Hormone (GH) Treatment: Diagnostic Value of GH Tests and IGF-I and IGFBP-3 Measurements

Retesting of patients with growth hormone (GH) deficiency (GHD), especially those with idiopathic GHD, has yielded normalization of the results in several studies. The aim of this study was to reevaluate patients diagnosed as GHD at completion or reconfirm the diagnosis before completion of GH treatment by retesting with provocative tests, and to evaluate the value of IGF-I and IGFBP-3 levels in the diagnosis of GHD. Fifty (33 M, 17 F) patients with GHD (peak GH level <0.46 pmol/l (10 ng/ml]) in two pharmacological tests were retested and IGF-I and IGFBP-3 levels measured. The age of the patients at retest was 15.2+/-5.0 yr. Thirteen of 50 patients (26%) normalized their GH secretion. According to the initial diagnosis, 69% of those with partial GHD (peak GH level 0.32-0.46 pmol/l [7-10 ng/ml]), 43% with isolated GHD, 33% idiopathic and 11% of those with complete GHD (peak GH level <0.32 pmol/l [7 ng/ml]) normalized their GH level at retesting. None of the patients with multiple hormone deficiency and none with small pituitary on MRI normalized GH levels at retest. The sensitivities of IGF-I and of IGFBP-3 were 70% and 67%, respectively, and the specificities were 100%, when peak GH cutoff is taken as 0.46 pmol/l (10 ng/ml) for the diagnosis of GHD. The sensitivities of IGF-I and IGFBP-3 increased to 76.5% and 73.5% when the cutoff level for GHD is taken as 0.32 pmol/l (7 ng/ml). Those patients who normalized their GH levels at retest showed a satisfactory height velocity when GH therapy was discontinued. In conclusion, reevaluation of GH status may also be undertaken while patients are still on treatment as well as at completion of treatment, especially in patients with idiopathic, partial and isolated GHD, by retesting and by IGF-I and IGFBP-3 measurements. Lowering the cutoff level of GH peak at pharmacological tests to 0.32 pmol/l (7 ng/ml) will lower the number of false positive results in the diagnosis of GHD.

Real-time sonography for screening of gallbladder dysfunction in children with type 1 diabetes mellitus.

The aim of this study was to evaluate the occurrence of gallbladder dysfunction in children with type 1 diabetes mellitus using real-time ultrasonography. The study population consisted of 20 diabetic children (11 male, 9 female; age 11.7+/-2.8 years; diabetes duration 0.5-7 years) with clinically negative neuropathy findings and 15 healthy controls (11 male, 4 female; age 10.5+/-3.7 years). Three-dimensional measurements of the gallbladder were made before and 15, 30, 45, 60 min after intake of diet chocolate. Gallbladder volumes were calculated by the ellipsoid formula. Fasting gallbladder volume of diabetic children (16.9+/-9.5 ml) was significantly greater than that of the controls (10.6+/-5.3 ml; p=0.017). Ejection fraction and maximal contraction showed no significant difference between the two groups. Diabetic patients with multiple microvascular complications had diminished gallbladder motility. There was a negative correlation between BMI and maximal contraction (p<0.05). Nerve conduction velocity was diminished in 45% of the diabetic patients. In conclusion, gallbladder function is preserved in pediatric type 1 diabetic patients with a disease duration less then 10 years, but dilated gallbladder at rest may be an early sign of gastrointestinal autonomic neuropathy and a risk factor for gallstone formation.