Imprinting disorders are a group of congenital diseases caused by dysregulation of genomic imprinting, affecting prenatal and postnatal growth, neurocognitive development, metabolism and cancer predisposition. Aberrant expression of imprinted genes can be achieved through different mechanisms, classified into epigenetic - if not involving DNA sequence change - or genetic in the case of altered genomic sequence. Despite the underlying mechanism, the phenotype depends on the parental allele affected and opposite phenotypes may result depending on the involvement of the maternal or the paternal chromosome. Imprinting disorders are largely underdiagnosed because of the broad range of clinical signs, the overlap of presentation among different disorders, the presence of mild phenotypes, the mitigation of the phenotype with age and the limited availability of molecular techniques employed for diagnosis. This review briefly illustrates the currently known human imprinting disorders, highlighting endocrinological aspects of pediatric interest.

Lipodystrophy is a heterogeneous group of disorders characterized by lack of body fat in characteristic patterns, which can be genetic or acquired. Lipodystrophy is associated with insulin resistance that can develop in childhood and adolescence, and usually leads to severe metabolic complications. Diabetes mellitus, hypertriglyceridemia, and hepatic steatosis ordinarily develop in these patients, and most girls suffer from menstrual abnormalities. Severe complications develop at a relatively young age, which include episodes of acute pancreatitis, renal failure, cirrhosis, and complex cardiovascular diseases, and all of these are associated with serious morbidity. Treatment of lipodystrophy consists of medical nutritional therapy, exercise, and the use of anti-hyperglycemic and lipid-lowering agents. New treatment modalities, such as metreleptin replacement, promise much in the treatment of metabolic abnormalities secondary to lipodystrophy. Current challenges in the management of lipodystrophy in children and adolescents include, but are not limited to: (1) establishing specialized centers with experience in providing care for lipodystrophy presenting in childhood and adolescence; (2) optimizing algorithms that can provide some guidance for the use of standard and novel therapies to ensure adequate metabolic control and to prevent complications; (3) educating patients and their parents about lipodystrophy management; (4) improving patient adherence to chronic therapies; (5) reducing barriers to access to novel treatments; and (5) improving the quality of life of these patients and their families.

Objective: The prevalence of childhood obesity is increasing and leads to co-morbidities such as hypertension. However, it is still not clear why some obese individuals are hypertensive and others not. Nesfatin-1 is a recently discovered anorexigenic peptide which also has effects on blood pressure (BP). Our aim was to evaluate the relationship between obesity-related hypertension and Nesfatin-1.
Methods: This cross-sectional study comprised 87 obese children. The patients were divided into two groups; hypertensive (n=30) and normotensive (n=57) obese. The American Academy of Pediatrics guidelines were used to diagnose hypertension. Blood samples were collected after 12 hours of fasting to investigate Nesfatin-1 concentrations. We also evaluated serum trace elements in addition to the routine blood tests.
Results: Body mass index (BMI), weight and serum Nesfatin-1 concentrations were higher in the hypertensive group (p=0.002, p=0.001, and p=0.007, respectively). There was no difference between serum zinc levels, but Copper (Cu) levels were significantly lower in the hypertensive group (p=0.248, p=0.007, respectively). There were positive correlations between BP and BMI and weight Z-scores and a negative correlation with Cu. The optimal cut-off value of Nesfatin-1 to predict hypertension was found to be >1.8 ng/mL, with a specificity of 71.9% and a sensitivity of 96.7% [area under the curve=0.703, 95% confidence interval (CI): 0.577-0.809; p=0.002]. In multiple logistic regression analysis Nesfatin-1 [Odds ratio (OR)=1.103, 95% CI: 1.039-1.171; p=0.001], Cu (OR=0.947, 95% CI: 0.915-0.979; p=0.001) and BMI for age Z-score (OR=56.277, 95% CI: 5.791-546.907; p=0.001) still remained significant predictors of hypertension.
Conclusion: Nesfatin-1 levels are higher and are an independent predictor of hypertension in obese subjects.

Objective: Doses of gonadotropin releasing hormone (GnRH) analogues used to treat idiopathic central precocious puberty (iCPP) vary among clinicians. Study aims were to evaluate the efficacy of a monthly 3.75 mg dose of leuprolide acetate (LA) to suppress the hypothalamo-pituitary-gonadal (HPG) axis in girls with iCPP and to determine factors that may have an impact on the supressing dose.
Methods: Study subjects were 220 girls receiving LA for iCPP. LA was started at a dose of 3.75 mg/28 days. Suppression was assessed using the GnRH test at the third month. To assess clinical suppression signs and symptoms of puberty were also evaluated. The dose of LA was increased to 7.5 mg/28 days in those who had a peak luteinising hormone (LH) ?2 IU/L and in whom adequate clinical suppression of puberty was absent. Receiver operating characteristic curves were used to determine thresholds for clinical and hormonal factors affecting the suppressing dose of LA. Logistic regression analyses were used to investigate thresholds which might differentiate between those requiring high dose for suppression and those in whom lower dose LA was adequate.
Results: Peak stimulated LH <2 IU/L was achieved in 88.6% with a dose of LA of 3.75 mg (0.11±0.03 mg/kg). Significant variables for differentiating the two doses were body weight (Wt) of 36.2 kg and/or body mass index (BMI)-standard deviation scores (SDS) of 1.64 (p<0.001). Multiple logistic regressions showed that Wt and BMI-SDS values above thresholds indicated requirement of LA at a dose of 7.5 mg/28 days (p<0.001).
Conclusion: Monthly injections of 3.75 mg LA is an effective treatment in the majority of girls with iCPP. However, a higher initial dose may be preferred in patients with a Wt ?36 kg or BMI-SDS ?1.6 for effective suppression of the HPG axis.

Objective: There is an association between obesity and several inflammatory and oxidative markers in children. In this study, we analyzed thiol/disulfide homeostasis and serum ischemia-modified albumin (IMA) levels for the first time in order to clarify and determine the oxidant/antioxidant balance in metabolically healthy and unhealthy children.
Methods: This study included obese children and healthy volunteers between 4-18 years of age. The obese patients were divided into two groups: metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO). Biochemical parameters including thiol/disulfide homeostasis, and IMA concentrations were analyzed.
Results: There were 301 recruits of whom 168 (55.8%) were females. The obese children numbered 196 (MHO n=58 and MUO n=138) and healthy controls numbered 105. No statistically significant difference could be found in ages and genders of the patients among all groups (p>0.05, for all). Native thiol (SH), total thiol (SH+SS), and native thiol/total thiol (SH/SH+SS) ratio were statistically significantly lower in the MUO group than the control group (p<0.001, p=0.005, and p=0.005; respectively). Disulfide (SS), disulfide/native thiol (SS/SH), disulfide/total thiol (SS/SH+SS) and IMA levels were statistically significantly higher in the MUO group than the control group (p=0.002, p<0.001, p<0.001, and p=0.001, respectively).
Conclusion: Chronic inflammation due to oxidative stress induced by impaired metabolic parameters in MUO children caused impairment in thiol redox homeostasis. Our data suggested that the degree of oxidant imbalance in obese children worsened as obesity and metabolic abnormalities increased. It is hypothesized that thiol/disulfide homeostasis and high serum IMA levels may be reliable indicators of oxidant-antioxidant status in MUO children.

Objective: To determine the prevalence of obesity and metabolic syndrome (MetS) in children and adolescents with type 1 diabetes (T1D) and to compare the widely accepted and used diagnostic criteria for MetS established by the International Diabetes Federation (IDF), World Health Organisation (WHO) and National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII).
Methods: We conducted a descriptive, cross sectional study including T1D patients between 8-18 years of age. The three sets of criteria were used to determine the prevalence of MetS and findings compared. Risk factors related to MetS were extracted from hospital records.
Results: The study included 200 patients with T1D (52% boys). Of these, 18% (n=36) were overweight/obese (body mass index percentile ?85%). MetS prevalence was 10.5%, 8.5% and 13.5% according to IDF, WHO and NCEP criteria, respectively. There were no statistically significant differences in age, gender, family history of T1D and T2D, pubertal stage, duration of diabetes, hemoglobin A1c levels and daily insulin doses between patients with or without MetS. In the overweight or obese T1D patients, the prevalence of MetS was 44.4%, 38.8% and 44.4% according to IDF, WHO and NCEP-ATPIII criteria, respectively.
Conclusion: Obesity prevalence in the T1D cohort was similar to that of the healthy population of the same age. Prevalence of MetS was higher in children and adolescents with T1D compared to the obese population in Turkey. The WHO criteria include microvascular complications which are rare in childhood and the NCEP criteria do not include a primary criterion while diagnosing non-obese patients according to waist circumference as MetS because the existence of diabetes is considered as a direct criterion. Our study suggests that IDF criteria which allows the diagnosis of MetS with obesity and have accepted criteria for the childhood are more suitable for the diagnosis of MetS in children and adolescents with T1D.

Objective: Macular damage may be observed in obesity and metabolic syndrome (MetS), a condition which leads to chronic subclinical inflammation and affects most organ systems.
To investigate the association between macular variability and anthropometric measurements, metabolic parameters, and inflammatory markers in children and adolescents with MetS.
Methods: Two hundred and twenty eyes of 62 obese and 48 healthy children and adolescents were examined. Bilateral macular retinal thickness (MRT) and macular retinal volume (MRV) were measured in all subjects using optical coherence tomography. Associations between mean MRT and mean MRV and age, auxological measurements including body mass index standard deviation scores (BMI-SDS) and waist circumference-SDS (WC-SDS), metabolic parameters and inflammatory parameters including neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio and systemic immune-inflammatory index (SIII) were investigated.
Results: No statistically significant difference was observed between the groups in terms of age or sex distribution (p>0.05). Mean MRT (r=-0.326, p=0.007) and MRV (r=-0.303, p=0.007) values in the obese group with MetS decreased as homeostasis model assessment-insulin resistance (HOMA-IR) values increased. SIII values were higher in obese groups, but particularly in obese subject with MetS, compared to the control group (p=0.021). The decrease in mean MRT (r=-0.544, p=0.046) and MRV (r=-0.651, p=0.031) in the obese subjects with MetS was negatively correlated with NLR. Mean MRT and MRV decreased in all obese subjects as SIII increased (p<0.05).
Conclusion: This is the first study to show that mean MRT and MRV values decrease as BMI-SDS, WC-SDS and HOMA-IR increase in obese children and adolescents with MetS. NLR and SIII may serve as markers of chronic inflammation in obese children with MetS associated with macular damage.

Objective: The aim was to assess growth velocity (GV) during human recombinant growth hormone (hGH) treatment of children with multiple pituitary hormone deficiency (MPHD) caused by pituitary stalk interruption syndrome (PSIS) and to analyze the characteristics of patients that attained normal adult heights.
Methods: Data from 74 (16 female) children with MPHD caused by PSIS with GH, thyroid stimulating hormone, gonadotropin and adrenocorticotropic hormone deficiencies were collected. Subjects were divided into groups: 12 pre-pubescent females (Female-Group) and 36 pre-pubescent males (Male-Group 1). The remaining 22 males were further sub-divided into two groups (Male-Group 2 and Male-Group 3) according to the initiation of gonadotropin replacement treatment, based on bone age and height.
Results: No differences in change in height standard deviation score (?HtSDS) and GV were observed at different time points of hGH treatment between the Female-Group and Male-Group 1 (p>0.05). GV was significantly greater in the first year of hGH therapy than in subsequent years: Female-Group p=0.011; Male-Group 1 p<0.001; Male-Group 2 p=0.005; and Male-Group 3 p=0.046. Adult height was achieved by 23 (19 males and 4 females) patients. The total gain in height positively correlated with the GV during the first year (r=0.626, p<0.001).
Conclusion: GV during hGH treatment were similar amongst pre-pubescent males and females with MPHD caused by PSIS. GV during the first year of hGH treatment appears to be an effective predictor of final height in patients with MPHD caused by PSIS.

Objective: 5-Hydroxymethylfurfural (HMF) is formed when sugars are heated in the presence of amino acids. HMF is naturally present in many foods. To investigate the toxic effects of HMF on the reproductive system of peripubertal rats.
Methods: In the study, 24 immature female Wistar rat were divided into three groups: control (CT) fed with no HMF; low dose fed with 750 mg/kg/day of HMF and high dose (HD) groups fed with 1500 mg/kg/day of HMF. All groups received these diets for three weeks from postnatal day (PND) 21. The vaginal opening (VO) was monitored daily and euthanasia occurred on PND 44. Gonadotropin, estradiol (E2), progesterone and anti-Müllerian hormone (AMH) concentrations were measured. Reproductive organ weights and ovarian follicle counts were compared.
Results: The HD HMF group had earlier VO. Higher mean luteinising hormone (2.9±1.2 vs 1.3±0.3 mIU/mL) and mean E2 (34.7±8.8 vs 21.2±3.9 pg/mL) and lower mean AMH (2.7±0.5 vs 4.7±0.7 ng/mL) concentrations were found in the HD compared to the CT group. The HD group also had increased number of secondary atrophic follicles.
Conclusion: These results indicate that peripubertal exposure to HMF at HD result in precocious puberty and decreased AMH levels in female Wistar rats.

Objective: There is general concern regarding environmental chemical exposure and the impact it may have on human health. This is particularly important for vulnerable populations such as infants and children during critical periods of development. Bisphenol A (BPA) is an endocrine disrupting chemical used worldwide over the last 30 years in many consumer products. Evidence points to widespread human exposure to BPA. The aim of this study was to evaluate the exposure of Turkish preschool children to BPA.
Methods: This study was conducted as a preliminary investigation of BPA in urine, collected from 3-6 year old children living in Ankara. After spot urine samples were taken from preschool children, free BPA, ß-D-glucuronide and total BPA were determined using high-performance liquid chromatography tandem mass spectrometry and adjusted by creatinine concentration.
Results: Preschool children from Ankara (n=125; males n=70, females n=55; mean age: 4.50±1.26) were recruited. BPA was detected in 76.8% of children from Ankara city, with urinary concentrations ranging from < limit of quantification to 18.36 µg/g creatinine. Total BPA levels were not statistically different between boys (1.26 µg/g creatinine) and girls (2.24 µg/g creatinine) (p>0.05).
Conclusion: This study is an important contribution to the limited information about childhood exposure to BPA. The estimated daily BPA intake in this study is substantially lower than the European Food Safety Authority derived tolerable daily intake of 4 µg/kg BW/day.

Objective: Turner syndrome (TS) is one of the most common chromosomal abnormalities and an important cause of short stature and infertility due to ovarian failure in females. The aim was to evaluate the knowledge of TS among physicians and parents of children with TS and to enhance awareness about this subject.
Methods: One hundred and forty physicians were included in the study. The study population comprised 37 pediatricians (26.4%), 15 gynecologists (10.7%), 88 family physicians (62.9%) and 30 parents who had daughters with a diagnosis of TS. Two separate questionnaires were administered to evaluate TS knowledge of physicians and parents.
Results: According to the self-reports of physicians, 49% had insufficient knowledge of TS, while 15.7% indicated that they had no knowledge of TS. The mean percentage of correct answers was 50.71±16.17% for all physicians. When the entire group of physicians was considered, 67.1% of them did not know the approximate incidence of TS, while 14.3% of them incorrectly indicated that TS was a condition that was seen in boys. The mean percentage of correct answers among parents was 68±15%, and there was no difference between the mothers’ and fathers’ correct answer rates (p=0.063). The majority of parents was not aware of TS-associated diseases and increased malignancy risk in TS.
Conclusion: Physician knowledge of TS was poor and that there is a need for continued education about TS at the medical faculty and post-graduate levels.

Hypophosphatasia, a rare genetic disease affecting bone metabolism, is characterized by decreased activity of tissue non-specific alkaline phosphatase (TNAP). The gene encoding TNAP (ALPL) has considerable allelic heterogeneity, which could explain different degrees of enzyme activity resulting in a wide clinical variability. We report the case of a preterm newborn in whom a corneal opacity was detected at birth. Blood tests performed to investigate this finding showed low alkaline phosphatase concentrations. The corneal opacity disappeared within a week but alkaline phosphatase remained persistently low. With persistently decreased levels of alkaline phosphatase, upon suspicion of hypophosphatasia, plain radiography detected changes suggestive of rickets. Sequencing of the ALPL gene revealed a heterozygous variant that has not been described in the literature to date. Our patient’s condition may be an atypical neonatal form of the syndrome, with a mild phenotype, very different from the classic neonatal form, which can lead to severe skeletal disease and respiratory failure. However, it could also be an early diagnosis of the childhood form, which is associated with a better prognosis.

Aromatase deficiency rarely causes a 46,XX sexual differentiation disorder. The CYP19A1 gene encodes the aromatase enzyme which catalyses the conversion of androgens to oestrogens. In cases with 46,XX karyotype, mutations in the CYP19A1 gene can lead to disorders of sex development. Clinical findings in aromatase deficiency vary depending on the degree of deficiency. The effect of increased androgens, including acne, cliteromegaly and hirsutism, can be observed in mothers with placental aromatase deficiency. A decrease in maternal virilisation symptoms is observable in the postpartum period. It is rarely reported that there is no virilization in pregnancy. In this study, two 46,XX sibling having the p.R115X (c.343 C>T) novel pathogenic variant in the CYP19A1 gene and raised as different genders, with no maternal virilisation during pregnancy, are presented. In conclusion, 46,XX virilised females should be examined in terms of aromatase deficiency once congenital adrenal hyperplasia has been excluded, even if there is no history of maternal virilisation during pregnancy.

Neurofibromatosis Noonan syndrome (NFNS) is a rare RASopathy syndrome, resulting from NF1 gene mutations. NFNS is characterized by phenotypic features of both neurofibromatosis type 1 (NF1) and Noonan syndrome. Plexiform neurofibromas (PNFs) are an unusual finding in NFNS. A seven year-old girl with typical clinical features of NF1 was referred to our clinic due to short stature and abnormal genital appearance. Due to dysmorphic features, a clinical diagnosis of NFNS was considered in the patient and, following molecular analysis, revealed a novel heterozygous c.3052_3056delTTAGT (p.L1018X) variant in the NF1 gene. Although evaluation for genital virilization, including karyotype and hormonal studies were normal, imaging studies revealed a diffuse genital PNF. Although PNFs are seen rarely in NFNS, this should be considered in the differential diagnosis of genital virilization in these patients to prevent unnecessary testing.

Carney complex (CNC) is a multiple neoplasia syndrome, characterized by pigmented lesions of the skin and mucosa, cardiac, cutaneous and other myxomas and multiple endocrine and non-endocrine tumors. Most of the cases have an inactivating mutation in the PRKAR1A gene. Osteochondromyxoma (OMX) is an extremely rare myxomatous tumor of bone, affecting 1% of CNC patients. Large cell calcifying Sertoli cell tumor (LCCSCT) is a testicular tumor affecting more than 75% of males with CNC. Here, we report an atypical case of CNC without typical pigmented skin lesions, presenting with a bone based tumor as the first manifestation. Initial presentation was for a recurrent, locally invasive intranasal tumor without definite diagnosis. Further clinical developments during follow up, central precocious puberty and testicular tumor with calcification, led to the diagnosis of LCCSCT, a CNC-related tumor. Histopathologic examination of the intranasal tumor was re-evaluated with this knowledge and OMX was diagnosed. Coexistence of OMX and LCCSCT suggested CNC. Genetic analysis revealed a heterozygous non-sense p.Trp 224* (c.672G>A) in the PRKAR1A gene. In our case, the diagnosis of OMX was delayed, because it is extremely rare and little is known about this tumor. Thus the aim of this report was to alert other clinicians to consider CNC if OMX is diagnosed.