Nazli Gonc

The Relationship Between Serum Adiponectin, Tumor Necrosis Factor-Alpha, Leptin Levels and Insulin Sensitivity in Childhood and Adolescent Obesity: Adiponectin is a Marker of Metabolic Syndrome

Objective: This study aimed (a) to investigate the relationship between the degree of obesity and serum adiponectin, tumor necrosis factor (TNF)−α, leptin, insulin levels and the lipid profile; (b) to clarify the relationship between insulin resistance/glucose tolerance and adipocytokine levels; and (c) to investigate the value of adipocytokine levels as a marker of metabolic syndrome (MS). Methods: We studied 151 obese children and adolescents (86 boys and 65 girls; mean age was 12.3±2.4 years). We defined obesity as a body−mass index (BMI) z−score more than 2 SD above the mean for age and sex. The control group consisted of 100 children (48 boys, 52 girls, mean age 12.4±2.5 years). Fasting glucose, insulin levels and lipid profiles were measured in all cases and controls after a 12−hour fast. Adiponectin, TNF−α, and leptin levels were measured in the subjects who participated in the adipocytokine branch of the study. An oral glucose tolerance test (OGTT) was also performed in all obese patients. Obese patients were grouped into three subgroups according to their glucose tolerance and insulin sensitivity assessment, and also according to whether they were grouped as MS or not. Results: Serum levels of total cholesterol, LDL and VLDL cholesterol, log triglyceride, insulin, leptin and TNF−α were higher, whereas HDL and square root adiponectin levels were lower in the obese group when compared with controls. Multiple regression analysis among BMI−z score, LDL, triglyceride, HOMA−IR, leptin and TNF−α as determinants of adiponectin revealed that BMI−z score was the only determinant for adiponectin (r:−0.45, p<0.0001). Adiponectin levels in hyperinsulinemic and impaired glucose tolerance groups (IGT) tended to be lower than in normoinsulinemic obese children, however, the difference was not significant. There was a weak negative correlation between adiponectin levels and increasing severity of insulin resistance (r=−0.23, p=0.005) in the groups of obese subjects. Mean serum adiponectin level in subjects with MS was lower than in subjects without MS (p=0.008). Conflict of interest:None declared.

Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency

Significance Congenital adrenal hyperplasia resulting from mutations in the CYP11B1 gene, which encodes a steroidogenic enzyme 11β-hydroxylase, is a rare inherited disorder associated with hyperandrogenemia, short stature, hypertension, and virilization of female newborns. We present a comprehensive clinical, genetic, and hormonal characterization for 68 of 108 patients with a genotype from an International Consortium on Rare Steroid Disorders. We also use computational modeling to define the effect of each of the missense mutations on the structure of 11β-hydroxylase, information that can be used to predict clinical severity prenatally in high-risk mothers. Congenital adrenal hyperplasia (CAH), resulting from mutations in CYP11B1, a gene encoding 11β-hydroxylase, represents a rare autosomal recessive Mendelian disorder of aberrant sex steroid production. Unlike CAH caused by 21-hydroxylase deficiency, the disease is far more common in the Middle East and North Africa, where consanguinity is common often resulting in identical mutations. Clinically, affected female newborns are profoundly virilized (Prader score of 4/5), and both genders display significantly advanced bone ages and are oftentimes hypertensive. We find that 11-deoxycortisol, not frequently measured, is the most robust biochemical marker for diagnosing 11β-hydroxylase deficiency. Finally, computational modeling of 25 missense mutations of CYP11B1 revealed that specific modifications in the heme-binding (R374W and R448C) or substrate-binding (W116C) site of 11β-hydroxylase, or alterations in its stability (L299P and G267S), may predict severe disease. Thus, we report clinical, genetic, hormonal, and structural effects of CYP11B1 gene mutations in the largest international cohort of 108 patients with steroid 11β-hydroxylase deficiency CAH.

Cyclic pamidronate therapy in children with osteogenesis imperfecta: results of treatment and follow-up after discontinuation.

BACKGROUND Cyclic intravenous pamidronate treatment is widely used for symptomatic therapy of osteogenesis imperfecta (OI). However, data after discontinuation are very limited. AIM The results of cyclical pamidronate treatment in 14 patients with moderate/severe OI and follow up of six of them after discontinuation are presented to assess the effects of pamidronate and its discontinuation. PATIENTS AND METHODS Pamidronate was administered at a dosage of 0.5 mg/kg for 3 successive days every 2 months in 14 patients with OI aged 5.10 +/- 3.68 years. Treatment was stopped in six patients after a duration of 16.33 +/- 4.63 months, due to stable bone mineral density (BMD) values and/or no fracture in the last 6 months, or due to family demand. The main outcome measures were areal BMD (aBMD) of the lumbar spine, biochemical markers of bone metabolism, fracture rate, and clinical evaluation. RESULTS Areal BMD and aBMD z-scores showed significant improvement during the treatment period. Both serum and bone-specific alkaline phosphatase values were significantly decreased. Fracture rate reduced significantly from 3.5 +/- 1.01 to 0.83 +/- 0.77 fractures/year. Bone pain, which was severe in five patients, disappeared just after the first cycle, and the activity and mobility of patients increased. aBMD and aBMD z-scores were decreased 1.5 years after discontinuation, although not statistically significant. Annual fracture rate increased significantly. Bone pain recurred in four patients. Pamidronate treatment was reinstituted in five of these patients at the end of 1.5 years. CONCLUSION Cyclical pamidronate treatment is very effective in children with moderate/severe OI. This treatment should be started early enough before the occurrence of irreversible deformities and must be given for a longer time during the growth period.

Hypophosphatasia Presenting with Pyridoxine-Responsive Seizures, Hypercalcemia, and Pseudotumor Cerebri: Case Report

Hypophosphatasia (HPP) is an inborn error of metabolism characterized by defective bone mineralization caused by a deficiency in alkaline phosphatase (ALP) activity due to mutations in the tissue-nonspecific ALP (TNALP) gene. The clinical expression of the disease is variable. Six forms of HPP are identified according to age at presentation and clinical features. Patients with the infantile form are normal at birth. First symptoms appear within the first 6 months of life. Along with skeletal findings, HPP patients may present with hypercalcemia, seizures, pseudotumor cerebri, and pulmonary insufficiency. Seizures in HPP are refractory to conventional antiepileptic drugs, but are responsive to pyridoxine. Herein, we report a case of HPP who presented with pyridoxine-responsive seizures in the early neonatal period and was found to have hypercalcemia, skeletal demineralization and increased intracranial pressure. Key words: Hypophosphatasia, pyridoxine-responsive seizures, bisphosphonates, alkaline phosphatase, bone resorption, hypercalcemia Conflict of interest:None declared.

17beta-hydroxysteroid dehydrogenase type 3 deficiency as a result of a homozygous 7 base pair deletion in 17betaHSD3 gene.

Abstract 17-β-Hydroxysteroid dehydrogenase type 3 (17βHSD-3) converts Δ4 androstenedione (A) to testosterone (T) in the testes. This enzyme plays a key role in androgen synthesis and it is essential for normal fetal development of male genitalia. 17βHSD-3 deficiency is a rare cause of 46,XY disorders of sexual development. Here, we report a 16-year-old 46,XY patient with 17βHSD-3 deficiency raised as a female and significantly virilized in puberty. A homozygous 7 base pair deletion on exon 10 was determined in HSD17B3 gene (c.777-783del_GATAACC). Our patient had one of the very rare mutations, which was previously unencountered in Turkish patients with 17βHSD type 3, and she is the second reported case with this deletion.

Assessment of gonadotrophin suppression in girls treated with GnRH analogue for central precocious puberty; validity of single luteinizing hormone measurement after leuprolide acetate injection

Objective  Intravenous GnRH stimulation test has often been used as gold standard test for the evaluation of hypothalamic–pituitary–gonadal axis in the diagnosis of central precocious puberty (CPP) and in the assessment of pubertal suppression. However, this test is time‐consuming, costly and uncomfortable for the patients. We aimed to analyse the validity of single LH sample 90 min after GnRH analogue (GnRHa) administration in the evaluation of gonadotrophin suppression during CPP therapy and to determine a cut‐off level for LH indicating adequate suppression.

Clinical characteristics of type 1 diabetes over a 40 year period in Turkey: secular trend towards earlier age of onset.

Abstract Objective: To determine the demographic and clinical characteristics of type 1 diabetes (T1D) in the past two decades, and to analyze changing trends over the past 40 years. Methods: Patients with a diagnosis of T1D in 1990–2010 were included. Patients diagnosed in the first half of the period comprised Period I, and those from the second half comprised Period II. Age at onset, gender, seasonal distribution, infectious etiology, and clinical picture at onset are analyzed and compared in two periods. In addition, we compared these data with that of the preceding two decades (1969–1991), which was reported in a previous publication. Results: A total of 354 children with T1D were included in the study. The median age at diagnosis of T1D was 7 years in the period 1990–2010 in comparison to 9.5 years during the period 1969–1991. Patients were diagnosed mostly in winter and autumn, and 32.3% of the children had an infection at the time of diagnosis. Frequency of diabetic ketoacidosis was 50.8% at diagnosis. The peak age at onset was 4 to 6 years. Conclusions: Our study provides substantial information about the clinical characteristics of Turkish children. The age of onset of T1D decreased in the past 20 years, as observed in other parts of the world. Our findings also suggest seasonality at onset of T1D. This study shows the changes of demographic and clinical characteristics of T1D in central and northeastern parts of our country over a 40 year period.

Hyperthyroidism After Allogeneic Hematopoietic Stem Cell Transplantation: A Report of Four Cases.

Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for many hematological disorders, primary immunodeficiencies, and metabolic disorders. Thyroid dysfunction is one of the frequently seen complications of HSCT. However, hyperthyroidism due to Graves’ disease, autoimmune thyroiditis, and thyrotoxicosis are rare. Herein, we report a series of 4 patients who were euthyroid before HSCT but developed hyperthyroidism (3 of them developed autoimmune thyroid disease) after transplantation.

Combined pituitary hormone deficiency due to gross deletions in the POU1F1 (PIT-1 ) and PROP1 genes

Pituitary development depends on a complex cascade of interacting transcription factors and signaling molecules. Lesions in this cascade lead to isolated or combined pituitary hormone deficiency (CPHD). The aim of this study was to identify copy number variants (CNVs) in genes known to cause CPHD and to determine their structure. We analyzed 70 CPHD patients from 64 families. Deletions were found in three Turkish families and one family from northern Iraq. In one family we identified a 4.96 kb deletion that comprises the first two exons of POU1F1. In three families a homozygous 15.9 kb deletion including complete PROP1 was discovered. Breakpoints map within highly homologous AluY sequences. Haplotype analysis revealed a shared haplotype of 350 kb among PROP1 deletion carriers. For the first time we were able to assign the boundaries of a previously reported PROP1 deletion. This gross deletion shows strong evidence to originate from a common ancestor in patients with Kurdish descent. No CNVs within LHX3, LHX4, HESX1, GH1 and GHRHR were found. Our data prove multiplex ligation-dependent probe amplification to be a valuable tool for the detection of CNVs as cause of pituitary insufficiencies and should be considered as an analytical method particularly in Kurdish patients.

Severe Undervirilisation in a 46,XY Case Due to a Novel Mutation in HSD17B3 Gene.

17-β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is an important enzyme involved in the final steps of androgen synthesis and is required for the development of normal male external genitalia. 46,XY individuals with deficiency of this enzyme present a wide clinical spectrum from a female appearance of the external genitalia through ambiguous genitalia to a predominantly male genitalia with micropenis or hypospadias. This paper reports a one-year-old 46,XY patient with 17β-HSD3 deficiency who presented with female external genitalia and bilaterally palpable gonads in the inguinal region. The low T/Δ4 ratio after human chorionic gonadotropin (hCG) stimulation suggested 17β-HSD3 deficiency. A homozygous mutation, c.761_762delAG, was determined at the intron 9/exon 10 splice site of the HSD17B3 gene. To the best of our knowledge, this mutation has not been reported thus far, but its localization and type would imply a complete disruption of the 17β-HSD3 which may explain the phenotype of our patient.