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Adrian Clark and colleagues report mutations in the NNT gene encoding nicotinamide nucleotide transhydrogenase in familial glucocorticoid deficiency (FGD). Using targeted exome sequencing, we identified mutations in NNT , an antioxidant defense gene, in individuals with familial glucocorticoid deficiency. In mice with Nnt loss, higher levels of adrenocortical cell apoptosis and impaired glucocorticoid production were observed. NNT knockdown in a human adrenocortical cell line resulted in impaired redox potential and increased reactive oxygen species (ROS) levels. Our results suggest that NNT may have a role in ROS detoxification in human adrenal glands.

Sitting height (SHt) measurements and sitting height/height (SHt/Ht) ratio are important criteria in the diagnosis of growth problems and particularly in the diagnosis of dysproportionate growth. It is known that body proportions are related to genetic influences and show variations among different populations. This study aimed to provide reference data on SHt and SHt/Ht ratios for Turkish children of ages 6–18 years. SHt measurements were performed on a sample of 1,100 boys and 1,020 girls between 6 and 18 years of age attending primary and secondary schools located in six different districts of Istanbul city. Criteria advanced by WHO for establishing reference standards for growth were observed in the study design. The sample consisted of a mixture of children measured only once and those measured at follow-up over different periods of time. Parallel to increase in Ht, SHt increased with age. Mean value for SHt/Ht ratio was 55–56 % at ages 6 to 8.5 years in both sexes. In girls, this value started to decrease at age 11.5 years and remained between 53 % and 54 % thereafter. In the boys, a decrease to 52–53 % was noted in the SHt/Ht ratio after age 12 years. In both sexes, SHt/Ht ratio decreased with puberty, demonstrating that growth in trunk length exceeded growth in limb length in midpubertal ages. These changes occurred at an earlier age in the girls. Values obtained for SHt/Ht ratios in Turkish children were high as compared to Dutch children and low as compared to Chinese children. Conclusion: This study, by providing reference data on sitting height and sitting height/height ratios in Turkish children of ages between 6 and 18 years, will be useful in the diagnosis and follow-up of children with growth problems. This study also supports the view that body proportions are influenced by genetic makeup.

To evaluate the epidemiologic, clinical and laboratory characteristics of a group of children with type 1 diabetes mellitus (T1DM) living in a Turkish city. The records of 395 (boys/girls: 199/196) children with newly diagnosed T1DM hospitalized in the years 1985-2004 were evaluated retrospectively. The data were assessed by gender and age subgroups (≤5, 6-10 and ≥11 years). Mean age of children at diagnosis was 8.1±4.1 years. At T1DM onset, the number of children ≤5, between 6-10 and ≥11 years old was 110 (27.9%), 147 (37.2%) and 138 (34.9%), respectively. The patients were mostly diagnosed at ages 6-8 years (24.1%), followed by cases aged 3-5 years (22.0%). Polyuria and polydipsia were the most common symptoms (94.7%). Mean duration of symptoms was 21.5±18.6 days. Although the patients mostly presented in autumn (30.7%), no season-related significant differences were found. The frequency of ketoacidosis was relatively high (48.5%). When compared to boys, the girls experienced higher rates of ketoacidosis (55.1% vs. 41.7%, p=0.042); had a higher frequency of anti-thyroid peroxidase antibodies (11.7% vs. 4.2%, p=0.049) and higher insulin requirement (0.89±0.41 vs. 0.77±0.36 IU/kg, p=0.005). Cases with a family history of T1DM were more likely to have anti-endomysial antibodies (42.9% vs. 8.1%, p=0.027) and higher initial blood glucose levels (510.5±145.0 vs. 436.1±156.5 mg/dL, p=0.005). The findings possibly indicate a decreasing age of T1DM onset. The high frequency of ketoacidosis at presentation is noteworthy. Girls had higher rates of ketoacidosis, higher frequency of anti-thyroid antibodies and higher insulin requirements as compared to boys. Patients with a family history of T1DM had higher initial glucose levels and higher frequency of anti-endomysial antibodies.

The CYP17A1 gene encodes the enzyme P450c17, which mediates both 17α-hydroxylase and 17,20-lyase activities and is essential for production of cortisol and sex steroids. Loss-of-function mutations of this gene cause 17α-hydroxylase/17,20-lyase deficiency, characterized by hypertension, hypokalemia and sexual infantilism. A 6-year-old phenotypically female patient presented with hypertension and hyperpigmentation. Her blood test results showed low cortisol and high adrenocorticotropic hormone (ACTH), progesterone, deoxycorticosterone and gonadotropin levels and were consistent with the diagnosis of 17α-hydroxylase/17,20-lyase deficiency. Her karyotype was 46XY. Genetic studies of the patient revealed a novel homozygous point mutation, c.1307G>A, within the coding sequence of the CYP17A1 gene. 17α-hydroxylase/17,20-lyase deficiency should be considered in the differential diagnosis of hypertension in children and adolescents, and physical examination of these patients should be done very carefully.

We aimed to determine whether precocious adrenarche (PA) has a different impact on screening tests for metabolic issues and pubertal timing in boys and girls born appropriate for gestational age (AGA). Puberty and initial metabolic screening results of 47 girls and 23 boys with PA born AGA followed up from our outpatient endocrinology clinic between May 2000 and October 2009 were reviewed. Initial anthropometric measurements except for body mass index standard deviation score (SDS) being higher in boys than girls ( p  = 0.01), bone age (BA) SDS, homeostasis model assessment of insulin resistance, and plasma lipids were similar between sexes. Hormone levels except for significantly higher dehydroepiandrosterone sulfate levels in boys than girls ( p  = 0.0006) were also similar between the sexes. BA SDS and BA/chronological age were significantly advanced ( p  < 0.05) with respect to initial evaluation in 28 girls at onset of gonadarche unlike the case in 13 boys with PA ( p  > 0.05). In conclusions, PA in children born AGA does not herald any significant differences with respect to adverse metabolic screening results between sexes, and it appears to be a discrete process from onset of puberty in girls unlike boys, in whom it is likely a variant of normal puberty.

In several cases of familial glucocorticoid deficiency (FGD), referred to as FGD type 1, mutations have been described in the coding exon of the adrenocorticotropin receptor (melanonocortin receptor type 2, MC2R) gene. However, for the majority of cases (FGD type 2), no mutations were found in this gene. In the more informative families, the involvement of the MC2R locus could be excluded by linkage or sequencing analysis and, as there was no obvious candidate gene, a genome linkage scan was performed. Fourteen families were studied in this report. Evidence of linkage was found with markers on chromosome 8q in three out of the 14 families (maximum heterogeneity LOD score of 2.81 at D8S1763). These three families were consanguineous and the gene could be located by homozygosity mapping between markers D8S285 and D8S1718 in a 8.8-cM region. No potential candidate genes were apparent in the region. Linkage to this region could be excluded in some families from our sample giving highly negative LOD scores with the markers of the region. This result suggests that at least one other gene, located on a different region, must be responsible for FGD in these families and provides new evidence of genetic heterogeneity of this disorder.

Abstract Context Limited data are available on the exact incidence of disorders of sex development (DSD) with genital ambiguity at birth. Objective To determine frequency of ambiguous genitalia in newborns. Design Prospective multicenter study. Setting Three tertiary care hospitals. Patients or Other Participants All 14,177 babies born during the study period were included. Main Outcome Measures All newborns were examined at birth; data on weeks of gestation, birth weight, and length were collected. A structured questionnaire was used for data collection. Quigley and Prader scales were used for phenotypic grading. Clinical and genetic investigations were performed. Results Eighteen babies with ambiguous genitalia were found among 14,177 newborns (1.3/1000). Fifteen newborns had 46,XY DSD, one had 46,XX congenital adrenal hyperplasia, and one had 45,X/46,XY mixed gonadal dysgenesis. Karyotype analysis was not done in one baby who died in the neonatal period. The ratio of prematurity was higher in the DSD group (44% vs 11%; P < 0.001) and the ratio of small for gestational age was also higher in the DSD group (22% vs 5%; P = 0.007). Eight babies with DSD had mothers who had additional medical conditions, such as preeclampsia, depression, insulin resistance, and gestational diabetes mellitus. Conclusion The frequency of ambiguous genitalia was higher than in previous studies, but, as with any experiment, the finding should be met with caution because this study was conducted in tertiary care hospitals. In addition, lower birth weight in the DSD group supports the hypothesis that early placental dysfunction might be important in the etiology of male genital anomalies.

No abstract available Copyright © 2012 S. Karger AG, Basel [PUBLICATION ABSTRACT]

Background: Testicular microlithiasis (TM) is characterized by calcium deposits within the seminiferous tubules and is associated with benign and malign conditions. Aim: To determine TM prevalence in patients with congenital adrenal hyperplasia (CAH) and its association with testicular adrenal rest tumors (TART). Patients and Methods: Scrotal ultrasound using a high-frequency linear transducer (12 MHz) was performed in 41 patients aged 12.1 ± 4.7 (range 3.5–23.3) years and 49 healthy similarly aged controls. TM was classified with respect to the number of microliths per ultrasound field as limited (LTM, <5 microliths) and classic (CTM, ≧ 5 microliths). CTM was graded as grade 1 (5–10 microliths), grade 2 (11–20 microliths), and grade 3 (>20 microliths). Results: TM was detected bilaterally in 9 (21.9%) patients and 2 (4.1%) control cases (1 bilateral, 1 unilateral). Four patients had LTM, one evaluated as grade 1, one as grade 2, and three as grade 3. There were 9 patients with TART. Four patients had TM and TART concomitantly. Conclusion: Because TM is frequently found in patients with CAH and may also exist concomitantly with TART, we recommend that these patients be followed annually by testicular ultrasound.

The aim of this study was to provide normative data for the onset and tempo of puberty in healthy boys. The analyses are based on data that were collected and evaluated biannually on 1112 Turkish school children aged from 8 to 18 years and a subsample of 30 boys who had reached final height (FH). The data were analyzed cross-sectionally in the total group and longitudinally in the subsample. Mean age and height (Ht) at onset of puberty were 11.6 +/- 1.2 years and 146.1 +/- 7.7 cm, respectively. Peak height velocity (HtV) was 10.1 +/- 1.6 cm. Total pubertal height gain was 26.4 +/- 4.3 cm. The duration of puberty was 4.9 +/- 0.6 years. Height at onset of puberty was positively correlated with FH (p < 0.0001) and with duration of puberty (p = 0.03). Body mass index at onset of puberty correlated negatively with age at onset of puberty (p < 0.009) and with the duration of puberty (p = 0.05) but not with FH. In conclusion, these results provide normative data for Ht and HtV for each testicular volume stage for boys in puberty. Height at onset of puberty is the most important determinant of FH. There is no secular trend for the onset of puberty. Weight does seem to affect the onset and tempo of puberty but not FH.