Sukran Darcan

Rare Causes of Primary Adrenal Insufficiency: Genetic and Clinical Characterization of a Large Nationwide Cohort

Context: Primary adrenal insufficiency (PAI) is a life-threatening condition that is often due to monogenic causes in children. Although congenital adrenal hyperplasia occurs commonly, several other important molecular causes have been reported, often with overlapping clinical and biochemical features. The relative prevalence of these conditions is not known, but making a specific diagnosis can have important implications for management. Objective: The objective of the study was to investigate the clinical and molecular genetic characteristics of a nationwide cohort of children with PAI of unknown etiology. Design: A structured questionnaire was used to evaluate clinical, biochemical, and imaging data. Genetic analysis was performed using Haloplex capture and next-generation sequencing. Patients with congenital adrenal hyperplasia, adrenoleukodystrophy, autoimmune adrenal insufficiency, or obvious syndromic PAI were excluded. Setting: The study was conducted in 19 tertiary pediatric endocrinology clinics. Patients: Ninety-five children (48 females, aged 0–18 y, eight familial) with PAI of unknown etiology participated in the study. Results: A genetic diagnosis was obtained in 77 patients (81%). The range of etiologies was as follows: MC2R (n = 25), NR0B1 (n = 12), STAR (n = 11), CYP11A1 (n = 9), MRAP (n = 9), NNT (n = 7), ABCD1 (n = 2), NR5A1 (n = 1), and AAAS (n = 1). Recurrent mutations occurred in several genes, such as c.560delT in MC2R, p.R451W in CYP11A1, and c.IVS3ds+1delG in MRAP. Several important clinical and molecular insights emerged. Conclusion: This is the largest nationwide study of the molecular genetics of childhood PAI undertaken. Achieving a molecular diagnosis in more than 80% of children has important translational impact for counseling families, presymptomatic diagnosis, personalized treatment (eg, mineralocorticoid replacement), predicting comorbidities (eg, neurological, puberty/fertility), and targeting clinical genetic testing in the future.

Alterations of blood pressure in type 1 diabetic children and adolescents

The aim of this study was to assess the association between metabolic control, microalbuminuria, and diabetic nephropathy with ambulatory blood pressure monitoring (ABPM) in normotensive individuals with type 1 diabetes mellitus (DM). ABPM was undertaken in 68 normotensive type 1 diabetic patients with a mean age of 14.4±4.2 years. Microalbuminuria was diagnosed on the basis of a urinary albumin excretion rate grater than 20 μg/min in two of the three 24-h urine collections. Hypertension (HT) frequency was greater in the microalbuminuric patients than normoalbuminuric patients (54 vs 17.54%, p=0.05) with ABPM. Microalbuminuric patients had a higher diastolic pressure burden than normoalbuminuric patients. There were no differences in systolic and diastolic dips between the two groups. Diastolic pressure loads in all periods showed a significant correlation with duration of diabetes, mean HbA1c from the onset of diabetes, and level of microalbuminuria. Nocturnal dipping was reduced in 41.2% of the patients. In the normoalbuminuric group 41.1% and in the microalbuminuric group 63.6% were nondippers. Our data demonstrate higher 24-h and daytime diastolic blood pressure load and loss of nocturnal dip in type 1 diabetic adolescents and children. High diastolic blood pressure burden in diabetic patients could represent a risk for nephropathy.

Endocrine Complications in Patients with β‐thalassemia Major

Thirty-seven patients with thalassemina major (TM) were studied to determine the extent and rate of endocrine complications. Mean haemoglobin and ferritin concentrations were 8.8 +/- 0.6 and 3,597 +/- 1,931, respectively. Provocation tests for growth hormone secretion were applied in patients with standing heights below the third centile and/or growth velocities below the 10th centile. Sexual maturation was assessed by using the criteria of Tanner. Glucose metabolism was assessed by fasting plasma glucose and glucose tolerance test. Basal thyroid function was measured and thyrotropin-releasing hormone tolerance test was carried out. Growth retardation was found in 40 per cent of patients and growth hormone deficiency was a prominent cause of growth retardation. Gonadal dysfunction was detected in 47 per cent of patients. Hypothyroidism was observed in 16 per cent and impaired glucose metabolism in 10.8 per cent patients. The high rate of endocrine disturbances indicates the importance of regular follow-up of thalassemia major patients with regard to endocrine complications of the disease.

Maternal and fetal serum insulin-like growth factor-I (IGF-I) IGF binding protein-3 (IGFBP-3), leptin levels and early postnatal growth in infants born asymmetrically small for gestational age.

Abstract This study was planned to investigate the relationship between birth weight and insulinlike growth factor-I (IGF-I),IGF binding protein-3 (IGFBP-3), and leptin levels in neonates with normal growth (appropriate for gestational age: AGA) and retarded growth (small for gestational age: SGA); and to evaluate these growth factors’ effects in early postnatal growth. All newborns were full-term: gestational age 38-41 weeks. Of 50 neonates, 25 were SGA. IGF-I, IGFBP-3 and leptin levels were measured in maternal serum and venous cord blood at birth and at 15 days of life of neonates using specific RIAs. Maternal serum leptin concentrations were significantly higher than cord blood leptin concentrations (p <0.001). Maternal serum IGF-I, IGFBP-3 and leptin levels did not show correlations with birth weight. In contrast, there were significantly positive correlations between birth weight and venous cord blood IGF- I, IGFBP-3 and leptin levels (p <0.001). In the SGA group, the newborns with a slow postnatal growth pattern had lower umbilical cord serum IGF-I levels compared with newborns with a normal growth pattern. A similar result was also found in the AGA group. Similar results were not found for serum leptin and IGFBP-3. In conclusion, cord blood IGF-I, IGFBP-3 and leptin levels play an important role in the regulation of fetal and neonatal growth. It is likely that IGF-I has a more important role than the other factors in early postnatal growth.

Effect of enalapril on proteinuria, phosphaturia, and calciuria in insulin-dependent diabetes.

Abstract. Elevated urinary calcium and phosphate excretion have been observed in children with insulin-dependent diabetes mellitus (IDDM). This may be related to a defect in tubular reabsorption. It is well known that converting enzyme inhibition decreases microalbuminuria and may prevent or retard diabetic nephropathy. We investigated whether enalapril also improves the defect in calcium and phosphate reabsorption. We studied 16 children and young adults (age 12–21 years) with IDDM and persistent microalbuminuria before and during 12 weeks of enalapril treatment. Before treatment microalbuminuria, urinary calcium excretion, and fractional tubular phosphorus reabsorption (TPR) were 153±53 μg/min, 5.5±0.9 mg/kg per day, and 71.4±3.6%, respectively. At the end of the 12th week, microalbuminuria had decreased to 20.3±7.9 μg/min and calcium excretion to 3.3±0.4 mg/kg per day (P<0.01), while the TPR increased to 80.1±3.8% (NS). The renal threshold phosphate concentration increased from 1.8±0.15 to 2.92±0.23 mg/dl (P<0.01). The fasting serum glucose and hemoglobin Alc levels did not change significantly during the study. Systolic and diastolic blood pressures were 120.4±2.2/79.3±1.4 mm Hg and 110.5±1.8/ 71.3±0.9 mm Hg before and after 12 weeks, respectively. We conclude that enalapril treatment improves not only microalbuminuria but also abnormal calcium and phosphate excretion in microalbuminuric children with IDDM.

The effects of Pilates on metabolic control and physical performance in adolescents with type 1 diabetes mellitus

UNLABELLED Physical activity is a substantial method in the management of children and adolescents with Type 1 diabetes mellitus but it is not considered as a treatment for diabetes. The aim of this study was to investigate the effects of Pilates exercises on metabolic control and physical performance in patients with type 1 diabetes mellitus. Thirty one sedentary patients with type 1 diabetes mellitus, ranging in age from 12 to 17 (experimental group, n=17 and control group, n=14) were submitted to 12 weeks of Pilates training. Participants underwent tests to determine the physical performance and metabolic control before and after 12 weeks of Pilates session. At the end of study, there were significant alterations in physical performance of the study group. Peak power, mean power, vertical jump and flexibility of study group increased. There were no alterations for this parameters in the control group. There was no significant difference for glycated hemoglobin (HbA1c) in both groups. CONCLUSIONS Physical performance increased via Pilates exercises in the patients with type 1 DM. However there were no changes in metabolic control. In the present study, the positive effects of exercise on metabolic control could not be shown in patients with Type 1 DM.

Effects of pesticides used in agriculture on the development of precocious puberty

The present study aims to evaluate the effects of pesticides on premature breast development. Forty-five girls (group 1) with premature breast development living in the Menderes region, where greenhouse cultivation is the main income, 16 girls (group 2) living in Izmir city with early puberty, and 33 girls (group 3) who had no signs of puberty were included in the study. Endosulphan 1, endosulphan 2, endosulphan sulphate, methoxychlor, vinclozolin, 4,4-dichlorodiphenyldichlorethylene (DDE), 4,-dichlorodiphenyltrichloroethane (DDT), and 2,4-DDT were evaluated in the serum and adipose tissues of the groups by using a gas chromatography–mass spectrometry method. With the exception of 4,4′-DDE, the pesticides studied were undetectable in the serum and adipose tissue samples. The levels of basal luteinizing hormone (LH), stimulated LH, follicle-stimulating hormone, and the long axis of the uterus and both ovaries were significantly different in the girls who had premature thelarche and detectable 4,4′-DDE levels compared to the girls who had premature thelarche and undetectable 4,4′-DDE levels in serum and adipose tissues. The presence and levels of pesticides in serum and adipose tissues were not related to precocious puberty (PP). The mechanisms that lead to PP may also result in obesity, and obesity may be the underlying cause for PP in this group.

Effects of Growth Hormone on Growth, Insulin Resistance and Related Hormones (Ghrelin, Leptin and Adiponectin) in Turner Syndrome

Background:Concomitant evaluation of the metabolic and growth-promoting effects of growth hormone (GH) therapy in Turner syndrome (TS) may be used in the prediction of the growth response to GH therapy. Aim: To evaluate the metabolic effects of GH therapy in TS and correlation with the short-term growth response. Patients: 24 prepubertal children with TS, aged 9.4 ± 2.6 years were followed for auxology and IGF-I, IGFBP-3, leptin, ghrelin, adiponectin, lipids and OGTT results in a prospective multicenter study. Intervention: GH (Genotropin®) in a dose of 50 µg/kg/day for 1 year. Results: Height standard deviation score (SDS) increased from –3.9 ± 1.5 to –3.5 ± 1.4 (p = 0.000) on therapy. BMI did not change. IGF-I SDS increased from –2.3 ± 0.4 to –1.6 ± 1.1 at 3 and 6 months (p = 0.001) and decreased thereafter. Serum leptin decreased significantly from 2.3 ± 3.9 to 1.7 ± 5.3 ng/ml (p = 0.022) at 3 months and increased afterwards. Serum ghrelin decreased from 1.2 ± 0.8 to 0.9 ± 0.4 ng/ml (p = 0.005) with no change in adiponectin. Basal and stimulated insulin levels also increased significantly. Δ height SDS over 1 year showed a significant correlation with Δ IGF-I0–3 months (r = 0.450, p = 0.027). Conclusion: IGF-I may be considered as a marker of growth response in TS at short term. Leptin shows a decrease at short term but does not have a correlation with growth response. The decrease in ghrelin in face of unchanged weight seems to be associated with increase in IGF-I and insulin levels. The unchanged adiponectin levels in spite of an increase in insulin levels indicates that adiponectin is mainly affected by weight, not insulin.

Adherence to Growth Hormone Therapy: Results of a Multicenter Study

OBJECTIVE To evaluate the adherence to growth hormone (GH) therapy and identify the influencing factors and outcomes in children. METHODS A total of 217 GH-naïve patients in 6 pediatric endocrinology clinics were enrolled in the study. Structured questionnaires were filled out and patients were evaluated at the initiation and 3rd, 6th, and 12th months of therapy. Patients were categorized into 4 adherence segments based on percentage of doses omitted at each evaluation period, classified as excellent if 0%, good if 5%, fair if 5 to 10%, and poor if > 10%. RESULTS There was a decrement in adherence to GH therapy during the study period (P = .006). Patients who showed excellent and good adherence to therapy had better growth velocity and growth velocity standard deviation scores (SDSs) (P = .014 and P = .015, respectively). A negative correlation between growth velocity SDS and number of missed injections was also observed (r = -.412; P = .007). A positive correlation between delta insulin-like growth factor-1 (IGF-1) SDS and growth velocity was demonstrated (r = .239; P = .042). IGF-1 levels were significantly higher in patients who showed excellent and good adherence to therapy (P = .01). Adherence was better in boys than in girls (P = .035), but adherence rates were not associated with age, cause of GH treatment, socioeconomic status, person who administered the injections, type of injection device, or GH product. CONCLUSION Poor adherence to GH therapy was common in our group of patients and was one of the factors underlying suboptimal growth during therapy. Before considering other problems that can affect growth, clinicians should confirm good adherence to therapy.

Low density lipoprotein apheresis in pediatric patients with homozygous familial hypercholesterolemia.

The aim of the present study is to clarify the low density lipoprotein apheresis procedure for pediatric patients with homozygous familial hypercholesterolemia (FH) in terms of efficacy, adverse effects and difficulties. The follow‐up was carried out using an open, prospective uncontrolled clinical design. Data were collected from 10 patients (with an average age of 8.4 ± 4.7 years) with FH treated with double filtration plasmapheresis. The total time span of follow‐up covered five years (30.2 ± 17.8 months [range 9–60 months]) and more than 600 sessions (62.1 ± 35.5 sessions per patient [range 18–120 sessions]) were evaluated. The mean low density lipoprotein cholesterol (LDL‐C) pre‐treatment value was 375.5 ± 127.5 mg/dL, and the post‐treatment value was 147.5 ± 73.9 mg/dL. This corresponded to a 62.8 ± 10.3% (43–73%) acute reduction of LDL‐C, while the mean high density lipoprotein cholesterol losses amounted to 41%. The chronic reduction in LDL‐C ranged from 18 to 52%, with a mean level of 36.4 ± 11.7%. The most frequently occurring technical problems were related to blood lines: puncture difficulties (4.5%), insufficient blood flow (3.5%), and obturation of the blood lines (2.4%). The main clinical adverse effects were hypotension (0.2%), chills/feeling cold (0.1%), and nausea and vomiting (0.2%). We observed that the low pediatric patient tolerance is the main problem in compliance with treatment. In conclusion, LDL apheresis, started under the age of eight years, combined with lipid‐lowering drugs, provides a safe and effective lowering of the mean LDL‐C levels in pediatric homozygous FH; and there are more problems with compliance for pediatric LDL apheresis than in the adult population.