A 57 kB Genomic Deletion Causing CTNS Loss of Function Contributes to the CTNS Mutational Spectrum in the Middle East.

Background: Nephropathic Cystinosis, the most common cause of renal Fanconi syndrome, is a lysosomal transport disorder with an autosomal recessive inheritance pattern. A large number of mutations in CTNS have been identified as causative to date. A 57 kb deletion encompassing parts of CTNS is most commonly identified in Caucasians but this allele has not been identified in individuals of Eastern Mediterranean, Middle Eastern, Persian, or Arab origin to date. Methods and Results: Implementing whole exome sequencing (WES) in a consanguineous Iranian family, we identified this large deletion affecting CTNS in a patient initially presenting with hypokalemic metabolic alkalosis symptoms and considerable proteinuria. Conclusion: We show WES is a cost and time efficient genetic diagnostics modality to identify the underlying molecular pathology in Cystinosis individuals and provide a summary of all previously reported CTNS alleles in the Middle east population. Our work also highlights the importance to consider the 57-kb deletion as underlying genetic cause in non-European populations, including the Middle East. Limited diagnostic modalities for Cystinosis in developing countries could account for the lack of previously reported cases in these populations carrying this allele. Further, our findings emphasize the utility of WES to define genetic causes in clinically poorly defined phenotypes and demonstrate the requirement of Copy number variation (CNV) analysis of WES data

Volume CXIV, Number 4, November 7, 1996

Objective: Turner syndrome (TS) is a chromosomal disorder caused by complete or partial X chromosome monosomy that manifests various clinical features depending on the karyotype and on the genetic background of affected girls. This study aimed to systematically investigate the key clinical features of TS in relationship to karyotype in a large pediatric Turkish patient population.Methods: Our retrospective study included 842 karyotype-proven TS patients aged 0-18 years who were evaluated in 35 different centers in Turkey in the years 2013-2014.Results: The most common karyotype was 45,X (50.7%), followed by 45,X/46,XX (10.8%), 46,X,i(Xq) (10.1%) and 45,X/46,X,i(Xq) (9.5%). Mean age at diagnosis was 10.2±4.4 years. The most common presenting complaints were short stature and delayed puberty. Among patients diagnosed before age one year, the ratio of karyotype 45,X was significantly higher than that of other karyotype groups. Cardiac defects (bicuspid aortic valve, coarctation of the aorta and aortic stenosis) were the most common congenital anomalies, occurring in 25% of the TS cases. This was followed by urinary system anomalies (horseshoe kidney, double collector duct system and renal rotation) detected in 16.3%. Hashimoto's thyroiditis was found in 11.1% of patients, gastrointestinal abnormalities in 8.9%, ear nose and throat problems in 22.6%, dermatologic problems in 21.8% and osteoporosis in 15.3%. Learning difficulties and/or psychosocial problems were encountered in 39.1%. Insulin resistance and impaired fasting glucose were detected in 3.4% and 2.2%, respectively. Dyslipidemia prevalence was 11.4%.Conclusion: This comprehensive study systematically evaluated the largest group of karyotype-proven TS girls to date. The karyotype distribution, congenital anomaly and comorbidity profile closely parallel that from other countries and support the need for close medical surveillance of these complex patients throughout their lifespa

Update of the tolerable upper intake level for vitamin D for infants

Following a request from the European Commission, the Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to revise the tolerable upper intake level (UL) for vitamin D for infants ( 64 1 year) set in 2012. From its literature review, the Panel concluded that the available evidence on daily vitamin D intake and the risk of adverse health outcomes (hypercalciuria, hypercalcaemia, nephrocalcinosis and abnormal growth patterns) cannot be used alone for deriving the UL for infants. The Panel conducted a meta-regression analysis of collected data, to derive a dose\u2013response relationship between daily supplemental intake of vitamin D and mean achieved serum 25(OH)D concentrations. Considering that a serum 25(OH)D concentration of 200 nmol/L or below is unlikely to pose a risk of adverse health outcomes in infants, the Panel estimated the percentage of infants reaching a concentration above this value at different intakes of vitamin D. Based on the overall evidence, the Panel kept the UL of 25 \u3bcg/day for infants aged up to 6 months and set a UL of 35 \u3bcg/day for infants 6\u201312 months. The Panel was also asked to advise on the safety of the consumption of infant formulae with an increased maximum vitamin D content of 3 \u3bcg/100 kcal (Commission Delegated Regulation (EU) 2016/127 repealing Directive 2006/141/EC in 2020). For infants aged up to 4 months, the intake assessment showed that the use of infant formulae containing vitamin D at 3 \u3bcg/100 kcal may lead some infants to receive an intake above the UL of 25 \u3bcg/day from formulae alone without considering vitamin D supplemental intake. For infants aged 4\u201312 months, the 95th percentile of vitamin D intake (high consumers) estimated from formulae and foods fortified or not with vitamin D does not exceed the ULs, without considering vitamin D supplemental intake

Association between Anthropometric Hormonal Measurements and Bone MineralDensity in Puberty and Constitutional Delay of Growth and Puberty

The aim of this study is to evaluate the acquisition of bone mineral in healthy children throughout puberty and in children with constitutional delay of growth and puberty (CDGP), and to relate changes in bone mass to age, weight, height, sitting height, body mass index and sex hormones in healthy boys. A total of 90 boys: 15 boys with CDGP and 75 healthy boys in different pubertal stages were examined. The number of children assigned to each Tanner stages was 15. Although bone age, weight and Body Mass Index (BMI) were significantly higher in stages II, III, IV, V compared to stage I and CDGP, mean height and sitting height values were higher in stages III, IV, V compared to stage I and CDGP. Also, serum FSH, LH, oestradiol, total and free testosterone levels progressively increased, although serum sex hormone binding globulin (SHBG) levels decreased, in healthy children with progression of sexual development. Significant increase was observed for serum oestradiol levels at stage II and above (p < 0.001), for serum total and free testosterone levels at stage III and above (p < 0.001), for serum FSH and LH levels at stage IV and above (p < 0.01 and p < 0.001) respectively. Also, it was shown that bone mineral content (BMC) and bone mineral density (BMD) measurements were significantly higher for pubertal stage lll and above groups according to both the CDGP group and stage I group. When BMD and BMC measurements of children with CDGP (0.62 ± 0.05 gr/cm2 and 23.4 ± 2.8 gr) were compared with bone age, age, BMI and height-matched controls, there was no significant difference between children with CDGP and controls, except for age. Bone mineral density and BMC measurements in children with CDGP were significantly lower than those of age-matched controls (for pubertal stage lll: p < 0.05, for pubertal stage IV: p < 0.01). The strongest correlation coefficients were found between BMD and height among auxological parameters (r = 0.63, p < 0.001) and serum oestradiol levels among hormones (r = 0.55, p < 0.001). The most important findings of this investigation was the determination of body composition and hormonal measurement changes during puberty in boys; oestradiol was the most potent determinant of BMD among pubertal boys. We suggested that there is a critical age period for accumulation of bone mass according to the results. Longitudinal studies will elucidate why sufficient mineralization does take place after puberty starts in CDGP. Keywords: Bone mineralization, constitutional delay of growth and puberty, gonadotropins, oestradiol level, puberty "Asociación Entre las Mediciones Hormonales Antropométricas y la Densidad Mineral Ósea en la Pubertad y el Retraso Constitucional del Crecimiento y la Pubertad" RESUMEN El objetivo de este estudio es evaluar la adquisición de mineral óseo del hueso en niños saludables a través de la pubertad y en niños varones con retraso constitucional del crecimiento y la pubertad (RCCP), y relacionar los cambios de masa ósea a la edad, el peso, la altura, la altura sentado, el índice de masa corporal, y las hormonas del sexo en niños varones saludables. Examinamos un total de 90 niños, 15 niños con RCCP y 75 niños saludables en diferentes etapas de la pubertad. El número de niños asignados a cada etapa de Tanner fue 15. Aunque la edad ósea, el peso y el IMC fueron significativamente más altos en las etapas II, III, IV, V, comparados con la etapa I y el RCCP; la altura promedio y los valores de la altura sentado fueron más altos en las etapas III, IV, V, comparados con la etapa I y el RCCP. Por otra parte, los niveles séricos de HEF, HL, estradiol y testosterona total y libre, aumentaron progresivamente, aunque los niveles séricos de SHBG disminuyeron en los niños saludables con el avance del desarrollo sexual. Se observó un aumento significativo en los niveles de estradiol sérico en la etapa II y por encima (

Familial pericentric inversion chromosome 3 and R448C mutation of CYP11B1 gene in Turkish kindred with 11 beta-hydroxylase deficiency

11 beta-hydroxylase deficiency is the second most common cause of congenital adrenal hyperplasia (CAH). This isoenzyme is coded by two highly homologous genes of cytochrome P450: CYP11B1 and CYP11B2 which were mapped to the chromosomal band 8q24. The aim of this study was to perform a series of molecular and cytogenetic analyses in two families with 11 P-hydroxylase deficiency of the Turkish kindred. Mutational analysis was carried out by directly sequencing the PCR products of CYP11B1 gene. We performed fluorescence in situ hybridisation (FISH) experiments with consecutive bacterial artificial chromosome (BAC) clones to map the breakpoints of the inversion of chromosome 3 which was detected during the karyotypic analysis of the propositus. Homozygous R448C mutations were detected in 2 individuals with 11 beta-hydroxylase deficiency. Interestingly, karyotypic change of pericentric inversion [inv(3)(p13q24)] was detected in both individuals who are cousins, one transmitted paternally and the other maternally. The breakpoint at 3p included one interesting gene PPP4R2. Here we present the data of two Turkish families' members having 11 beta-hydroxylase deficiency coupled with the familial chromosomal aberration of inv(3)(p13q24). Our data suggest that codon 448, which is a mutational hot spot in CYP11B1 causing 11 beta-hydroxylase cleficiency, is not restricted to Jews of Moroccan origin. Phenotypic variations observed in former studies in patients homozygous for R448H were stated to be due to other factors outside the CYP11B1 locus. The breakpoint in 3p might be a candidate region affecting variations in phenotypes of 11 beta-hydroxylase deficiency

Intragastric alendronate therapy in two infants with vitamin D intoxication: A new method

In recent years, alendronate, an oral biphosphonate, has been added to therapy of hypercalcemia secondary to vitamin D intoxication in children. Alendronate may cause mucosal ulcerations in the mouth and esophagus. We report our experience in two infants with vitamin D intoxication to whom alendronate therapy was administered through nasogastric tube, an alternate route for alendronate administration