Due to increasing life expectancy in thalassemia major (TM), osteoporosis is emerging as a significant problem. Its aetiology is multifactorial, culminating in increased bone resorption and impaired remodelling. Hypogonadism and marrow expansion seem to play an important role, but iron overload, deferoxamine toxicity, a defective growth hormone-insulin-like growth factor-1 axis and multiple endocrinopathies may represent additional causes of bone damage. Many of these patients, though under appropriate treatment programs, do not achieve normal peak bone mass. The receptor activator of nuclear factor kappa-ß (RANK)/RANK ligand/osteoprotegerin and the Wnt/ß-catenin systems work as major mediators of imbalanced bone turnover and bone loss. Additional genetic factors, such as collagen type 1 alpha 1 and vitamin D receptor gene polymorphisms, may exert some influence on the enhanced fracture risk observed in TM. To date, in spite of adequate hormone replacement, chelating therapy and acceptable haemoglobin levels, subjects with TM display impaired bone density and imbalanced bone turnover, thus the puzzle of the pathogenesis of TM-induced osteoporosis remains far from being solved.

Objective: While past research found family conflict, disordered eating, body image concerns and anxious self-doubts may affect adolescent diabetic glucose control, available measures of adherence mainly focus on management tasks. The current study aimed to combine measures of emotional distress and beliefs with decisions concerning management in a new measure of resistance to treatment adherence: the 12-item Glucose Control Resistance Scale (GCRS).
Methods: Participants included 135 adolescents and their parents from a pediatric diabetes clinic. Family conflict, body image concerns, anxious self-doubts and glucose control resistance were assessed.
Results: Factor analysis identified 12 items, with loadings of ?0.40, which were used to form the GCRS. The scale had adequate reliability and there was a significant correlation between child and parent GCRS scores. One factor, family conflict, was significantly related to hemoglobin A1c (HbA1c) levels, but a set of four factors explained a total of 12% of the variance in HbA1c levels. Of the demographic variables considered (gender, number of parents at home, age, body mass index z-score), only gender was significantly associated with adolescent perceptions of family conflict.
Conclusion: The GCRS may allow diabetic care teams to better understand the origin of family conflict perceptions and the motivational beliefs that modify behavior and contribute to independent self-management and glucose control. Each question was designed to be meaningful in interventions by addressing common items of resistance to adherence and impulsive management decisions. The GCRS may be used by providers as an initial short screening survey on an annual or semi-annual basis.

Objective: Hormones produced by fat tissue, adipokines, produced during intrauterine life have recently been implicated in fetal growth. Vaspin is an adipokine expressed in visceral adipose tissue and has insulin-sensitizing effects. Elevated serum vaspin concentrations are associated with alterations in insulin sensitivity. We aimed to determine if vaspin concentrations in cord blood from healthy, term newborns differ among those born small for gestational age (SGA), appropriate for gestational age (AGA), and large for gestational age (LGA). A secondary objective was to determine whether an association existed between vaspin and anthropometric measurements, glucose and insulin levels in the newborn.
Methods: The study population included healthy term newborns, 30 subjects in the SGA, 12 in the AGA, and 34 in the LGA group. Anthropometry was documented in all subjects. Blood was taken from the umbilical cord vein from each child for later analysis for vaspin, insulin and glucose concentrations.
Results: Cord blood vaspin, insulin and glucose concentrations were not different between the three study groups. A negative correlation between vaspin and glucose concentrations was demonstrated in the whole cohort (r=-0.364, p=0.001). This correlation was also observed in the LGA group (r=-0.482, p=0.004). Glucose concentrations significantly predicted vaspin concentrations (r2=0.132, p=0.001).
Conclusion: We found a negative association between glucose and vaspin concentrations in umbilical cord blood. In addition there was a predictive association between blood glucose and resulting vaspin concentration, suggesting that vaspin can be used as a predictor of alterations in the insulin-glucose metabolism from birth.

Objective: Shear wave elastography (SWE) is a user-independent ultrasonographic technique that evaluates tissue elasticity. It is used especially in the evaluation of thyroiditis and thyroid nodules when it is capable of distinguishing malignant from benign thyroiditis in adults. To date, no studies have evaluated SWE in pediatric thyroid patients. The aim of this study was to measure the elasticity of normal thyroid tissue in children and adolescents using SWE and to investigate its role in the diagnosis of pediatric autoimmune thyroiditis.
Methods: In total, 113 healthy children of whom 66 (58.4%) were girls and 57 children with autoimmune thyroiditis of whom 45 (78.9%) were girls were evaluated by SWE after B-mode ultrasound. The quantitative evaluation of normal thyroid tissue in healthy children and those with autoimmune thyroiditis was performed using shear wave velocity (SWV) values (m/s). Thyroid antibodies were consistent with autoimmune thyroiditis. Data were compared using descriptive and analytical statistics and receiver-operating characteristic curves.
Results: The mean ± standard deviation (range) of SWV value in thyroid parenchyma of the healthy children was 1.82±0.3 m/s (1.32-2.37) m/s. There was a significant positive correlation between age and SWV values which increased with age. The average SWV value of thyroid parenchyma in children with autoimmune thyroiditis was 3.7±1.2 (2.59-6.25) m/s which was statistically significantly greater than in healthy children (p=0.00). The cut-off value for elasticity with the highest diagnostic accuracy was 2.39 m/s; sensitivity and specificity were 97.4% and 100% respectively. There was no correlation between elasticity, thyroid function tests and autoantibody concentrations (p>0.05).
Conclusion: SWE is a useful imaging method that can be used with routine ultrasonography in evaluation of the thyroid in children.

Objective: No large study has been conducted to date to compare the effectiveness of prednisolone, alendronate and pamidronate as first-line treatment in children with hypercalcemia due to vitamin D intoxication. The aim was to perform a multicenter, retrospective study assessing clinical characteristics and treatment results.
Methods: A standard questionnaire was uploaded to an online national database system to collect data on children with hypercalcemia (serum calcium level >10.5 mg/dL) due to vitamin D intoxication [serum 25-hydroxyvitamin D (25(OH)D) level >150 ng/mL] who were treated in pediatric endocrinology clinics.
Results: Seventy-four children [median (range) age 1.06 (0.65-1.60) years, 45 males (61%) from 11 centers] were included. High-dose vitamin D intake was evident in 77% of the cases. At diagnosis, serum calcium, phosphorus, alkaline phosphatase, 25(OH)D and parathyroid hormone concentrations were 15±3.2 mg/dL, 5.2±1.2 mg/dL, 268±132 IU/L, 322 (236-454) ng/mL, and 5.5 (3-10.5) pg/mL, respectively. Calcium levels showed moderate correlation with 25(OH)D levels (rs=0.402, p<0.001). Patients were designated into five groups according to the initial specific treatment regimens (hydration-only, prednisolone, alendronate, pamidronate, and combination). Need for another type of specific drug treatment was higher in children who initially received prednisolone (p<0.001). Recurrence rate of hypercalcemia was significantly lower in children who were treated with pamidronate (p=0.02).
Conclusion: Prednisolone is less effective in the treatment of children with severe hypercalcaemia secondary to vitamin D intoxication and timely implementation of other treatment regimens should be considered.

Objective: We aimed to report the characteristics at admission, diagnosis, treatment, and follow-up of cases of pediatric hyperprolactinemia in a large multicenter study.
Methods: We reviewed the records of 233 hyperprolactinemic patients, under 18 years of age, who were followed by different centers. The patients were divided as having microadenomas, macroadenomas, drug-induced hyperprolactinemia and idiopathic hyperprolactinemia. Complaints of the patients, their mode of treatment (medication and/or surgery) and outcomes were evaluated in detail.
Results: The mean age of the patients with hyperprolactinemia was 14.5 years, and 88.4% were females. In terms of etiology, microadenomas were observed in 32.6%, macroadenomas in 27%, idiopathic hyperprolactinemia in 22.7% and drug-induced hyperprolactinemia in 6.4%. Other causes of hyperprolactinemia were defined in 11.3%. Common complaints in females (n=206) were sorted into menstrual irregularities, headaches, galactorrhea, primary or secondary amenorrhea and weight gain, whereas headache, gynecomastia, short stature and blurred vision were common in males (n=27). Median prolactin levels were 93.15 ng/mL, 241.8 ng/mL, 74.5 ng/mL, 93.2 ng/mL, and 69 ng/mL for microadenomas, macroadenomas, idiopathic hyperprolactinemia, drug-induced hyperprolactinemia, and other causes of hyperprolactinemia, respectively. Of 172 patients with hyperprolactinemia, 77.3% were treated with cabergoline and 13.4% with bromocriptine. 20.1% of the patients with pituitary adenomas underwent pituitary surgery.
Conclusion: We present the largest cohort of children and adolescents with hyperprolactinemia in the literature to date. Hyperprolactinemia is more common in females and cabergoline is highly effective and practical to use in adolescents, due to its biweekly dosing. Indications for surgery in pediatric cases need to be revised.

Objective: Histopathological changes in the kidney in type 1 diabetes mellitus (T1DM) begin before detection of microalbuminuria. Therefore, there is interest in finding a better biomarker for the early detection of diabetic kidney injury. The aim of this present study was to determine whether urinary indicators of fibrosis are detectable early in the development of T1DM in children and if they may predict progressive renal injury.
Methods: Urinary matrix metalloproteinase 2 and 9 (MMP2 and MMP9), tissue inhibitor of metalloproteinase 1 and 2 (TIMP1 and TIMP2) and transforming growth factor-ß1 (TGF-ß1) were assessed in 33 patients with T1DM with normal renal functions and in 24 healthy controls. Microalbuminuria was not present in the patient group with the exception of three patients. The results were adjusted to urine creatinine (Cr) and the differences between patients and controls were evaluated. These measurements were repeated after one year and the results were compared with the first year results.
Results: Urine MMP2/Cr, MMP9/Cr, TIMP1/Cr, TIMP2/Cr, TGF-ß1/Cr were not different between the patient and control groups (p>0.05). There were also no significant differences between the first and second year results for these biomarkers (p>0.05). None of these parameters were correlated with hemoglobin A1c, body mass index and duration of T1DM. Interestingly, all parameters were negatively correlated to age of onset of T1DM (p<0.05).
Conclusion: Our findings suggest that urinary biomarkers of fibrosis do not show an increase in diabetic children without microalbuminuria. The results also indicate that the risk of early fibrosis may increase as age of onset of T1DM decreases.

Objective: To determine the demographic and biochemical features of childhood and juvenile thyrotoxicosis and treatment outcome.
Methods: We reviewed the records of children from 22 centers in Turkey who were diagnosed with thyrotoxicosis between 2007 to 2017.
Results: A total of 503 children had been diagnosed with thyrotoxicosis at the centers during the study period. Of these, 375 (74.6%) had been diagnosed with Graves’ disease (GD), 75 (14.9%) with hashitoxicosis and 53 (10.5%) with other less common causes of thyrotoxicosis. The most common presenting features in children with GD or hashitoxicosis were tachycardia and/or palpitations, weight loss and excessive sweating. The cumulative remission rate was 17.6% in 370 patients with GD who had received anti-thyroid drugs (ATDs) for initial treatment. The median (range) treatment period was 22.8 (0.3-127) months. No variables predictive of achieving remission were identified. Twenty-seven received second-line treatment because of poor disease control and/or adverse events associated with ATDs. Total thyroidectomy was performed in 17 patients with no recurrence of thyrotoxicosis and all became hypothyroid. Ten patients received radioiodine and six became hypothyroid, one remained hyperthyroid and restarted ATDs and one patient achieved remission. Two patients were lost to follow up.
Conclusion: This study has demonstrated that using ATDs is the generally accepted first-line approach and there seems to be low remission rate with ATDs in pediatric GD patients in Turkey.

Objective: Increased risk of unfavorable cardiovascular risk factors has been recognised in ageing patients with haemophilia (PwH), but needs further studies in younger patients. The purpose of this study was to assess obesity, hypertension (HT), metabolic variables, insulin resistance and metabolic syndrome in young PwH.
Methods: Forty-eight haemophilia A and B patients and 35 age and sex matched healthy controls were included in the study. Anthropometric measurements, blood pressure (BP), fasting glucose and insulin levels, serum lipids and diet were evaluated. The metabolic syndrome was defined according to the criteria of the International Diabetes Federation for pediatric and adult age groups.
Results: The mean age of PwH was 21±9 years (range, 6-40 years). Of those ?18 years, 46% were were obese/overweight while there were no obese/overweight cases in the <18 year-old patients. Obesity was more prevalent in PwH with arthropathy (p=0.017). Seven percent of the PwH between 10 and 18 years-old and 25% of those ?18 years had metabolic syndrome. There was no difference in metabolic syndrome frequency between PwH and controls >10 years-old (19.5% vs 10% respectively, p=0.34). Fifty percent of the PwH ?18 years-old had elevated BP or HT. Fasting blood glucose levels of PwH were significantly higher compared to controls (p=0.02).
Conclusion: Our study showed that obesity, HT and metabolic syndrome are frequent problems, especially in PwH with arthropathy. Early prevention and management of overweight, obesity and their sequelae must be addressed in clinical practice in order to maximize the overall health of the haemophilia population.

Objective: This study aimed to determine the ratio of seasonal vitamin D deficiency and insufficiency in elementary school children aged between 6-9 years old, living in one of the largest metropols of Europe, Ýstanbul.
Methods: Serum 25(OH)D levels of 640 children aged 6-9 years old were scanned retrospectively from the hospital information system records between September 2017-August 2018 period. Vitamin D deficiency was defined as a serum 25(OH)D level less than 12 ng/mL (30 nmol/L) and insufficiency as levels between 12 and 20 ng/mL (30-50 nmol/L).
Results: Serum 25(OH)D levels ranged from 3.90 to 64.60 ng/mL, the median value was 25.95 ng/mL for all subjects. Of all the primary school children, 485 (75.78%) had adequate levels of 25(OH)D. Vitamin D deficiency was observed in 36 of children (5.62%), whereas insufficient levels of 25(OH)D were found in 119 children (18.60%). The ratio of vitamin D insufficiency and deficiency together was highest in spring (31.87%) and lowest in summer (13.12%).
Conclusion: Vitamin D deficiency is a widely observed and preventable public health problem among children of different ages. It is necessary to increase the awareness among health professionals, and providing 25(OH)D supplements will yield generations with healthy bone structure and well growth.

Objective: The aim of this study was to determine the prevalence of impaired hypoglycemia awareness (IHA) in children and adolescents with type 1 diabetes mellitus using a professional continuous glucose monitoring (CGM) system and to show the effect of structured education on glycemic variability (GV) in children and adolescents with IHA.
Methods: Forty type 1 diabetic children and adolescents with a diabetes duration of at least five years were eligible for inclusion in this prospective, quantitative study. All subjects were asked about their history of being aware of the symptoms of hypoglycemia using a questionnaire. Professional CGM was conducted in all of the patients for six days. The frequency of IHA detected by comparison of CGM and logbook reports were analyzed. Patients with identified IHA underwent a structured training program. After three months, CGM was re-applied to patients with IHA.
Results: The study was completed by 37 diabetic children and adolescents. After the initial CGM, nine patients (24.3%) were found to have had episodes of IHA. Area under the curve (AUC) for hypoglycemia and number of low excursions were; 1.81±0.95 and 8.33±3.60 for the IHA group at the beginning of the study. AUC for hypoglycemia was 0.43±0.47 after three months of structured education the IHA patients (p=0.01). Coefficient of variation which shows primary GV decreased significantly although unstable at the end of education in IHA patients (p=0.03).
Conclusion: CGM is a valuable tool to diagnose IHA. IHA, GV and time in range can be improved by education-based intervention.

Aromatase deficiency is a rare, autosomal recessive disorder in which affected patients fail to synthesize normal estrogen. Herein, we report a 46, XX patient born with virilised external genitalia. A novel homozygous mutation in the CYP19A1 gene, causing aromatase deficiency, was detected. A 30-day infant registered as a male was referred to pediatric endocrinology because of a uterus detected on ultrasonography. The infant was born at 23 gestational weeks by C-section because of preeclampsia and premature membrane rupture. The parents were consanginenous. There was no evidence of virilisation, such as acne, hirsutism, deep voice or clitoral enlargement in the maternal history. Physical examination of the infant revealed complete scrotal fusion and a single urogenital meatus, consistent with Prader stage-3. A standard dose adrenocorticotropic hormone (ACTH) test revealed an inadequate cortisol response and high 17-hydroxy progesterone levels, suggesting simple virilising congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. However, no mutation in the CYP21A2 gene was detected. At age 2.5 years the ACTH test was repeated, after suspension of hydrocortisone treatment for 48 hours, when resulting cortisol and androgen levels were normal. The patient was re-evaluated in terms of 46, XX disorders of sex development (DSD), especially with a suspicion of aromatase deficiency. A novel, homozygous, exon 6 deletion was identified in the CYP19A1 gene. Aromatase deficiency may be confused with CAH in the newborn period. In this case 46, XX DSD aromatase deficiency was present in the absence of a history of maternal virilisation or large and multicystic ovaries.

Inappropriate antidiuretic hormone syndrome (SIADH) may develop after intracranial surgery. SIADH in the pediatric age group is usually encountered in patients with an intracranial mass both before and after surgery. Fluid restriction is the standard therapy in SIADH. However, a resistant, hyponatremic pattern may be encountered in some cases. Vaptans have been recently introduced for treatment of hyponatremia due to SIADH. There is inadequate data concerning tolvaptan treatment in pediatric patients. We present a 13 year-old female with SIADH of triphasic episode who was transferred to our clinic after surgery for craniopharyngioma. Resistant hyponatremia did not resolve despite fluid restriction and hypertonic saline support. The patient responded rapidly to a single dose of tolvaptan, with no adverse effect, which resulted in successful control of her SIADH.

Prostaglandin I2 (PGI2) causes hyperthyroidism, a critical complication in patients with pulmonary arterial hypertension (PAH). However, it remains unknown whether PGI2 may have unfavorable effects on thyroid function in children with congenital portosystemic venous shunt syndrome (CPSVS). We present a boy with CPSVS who developed PAH at seven years of age. During ongoing PGI2 therapy, he experienced thyrotoxicosis at 17 years of age. The literature review showed that the reported 12 patients with PAH (median 11 years of age) developed hyperthyroidism during between one and 11 years of PGI2 treatment. Only one patient survived the acute PAH crisis due to hyperthyroidism. These data provide evidence that prophylactic intervention for hyperthyroidism is indicated for children with CPSVS during PGI2 treatment.

The LHCGR gene encodes a G-protein coupled receptor that plays a pivotal role in sexual differentiation in males, ovarian development in females and in fertility via its interaction with luteinizing hormone and chorionic gonadotropin. Inactive variants of the LHCGR gene cause Leydig cell hypoplasia (LCH), which is a rare disease and one of the causes of disorder of sexual differentiation (DSD) in males. The aim of this work was to clarify the clinical and molecular characteristics of a 2.75 year old patient with type 1 LCH. Whole exome sequencing was performed for the patient family and variants in the LHCGR gene were validated by Sanger sequencing. Pathogenicity of the missense variant was evaluated by multiple in silico tools. Our Chinese patient, who exhibited DSD, had female external genitalia (normal labia majora and minora, external opening of urethra under the clitoris and blind-ended vagina) and bilateral testis tissues in the inguinal region. Genetic sequencing revealed compound heterozygous variants in the LHCGR gene in the patient, including a novel missense variant in exon 4 (c.349G>A, p.Gly117Arg) and a novel nonsense variant in exon 10 (c.878C>A, p.Ser293*). The missense variant is in the first leucine-rich repeat domain of the LHCGR protein, which is predicted to affect ligand recognition and binding affinity and thus protein function. The patient is molecularly and clinically diagnosed with type 1 LCH, which is caused by novel, compound heterozygous variants of the LHCGR gene. We believe this report will serve to expand the genotypic spectrum of LHCGR variants.