Reports suggesting that vitamin D may have extraskeletal roles have renewed interest in vitamin D research and stimulated publication of an increasing number of new studies each year. These studies typically assess vitamin D status by measuring the blood concentration of 25-hydroxyvitamin D [25(OH)D], the principal circulating metabolite of vitamin D. Unfortunately, variations in assay format, inconsistency in interpreting 25(OH)D concentrations, cohort bias (age, body mass index, race, season of measurements etc.) and failure to measure critical variables needed to interpret study results, makes interpreting results and comparing studies difficult. Further, variation in reporting results (reporting mean values vs. percent of the cohort that is deficient, no clear statement as to clinical relevance of effect size, etc.) further limits interstudy analyses. In this paper, we discuss many common pitfalls in vitamin D research. We also provide recommendations on avoiding these pitfalls and suggest guidelines to enhance consistency in reporting results.

Objective: Longitudinal data regarding random luteinizing hormone (LH) concentrations in patients with idiopathic central precocious puberty (ICPP) during treatment are limited. Therefore, we sought to evaluate random LH and estradiol concentrations during monthly leuprolide injection and their associations with pubertal progression and final adult height (FAH) in girls with ICPP.
Methods: Medical records of 27 girls with ICPP who had attained FAH were reviewed. Patients’ height, weight, Tanner stage, growth rate (GR), bone age, random LH measured by both immunoradiometric and immunochemiluminescent methods, follicular-stimulating hormone (FSH) and estradiol levels were monitored until FAH.
Results: Treatment was started at a mean (±standard deviation) age of 8.1±0.6 years with mean duration of 3.9±0.2 years. At six months of follow-up, random LH (p=0.048), FSH (p<0.001) and estradiol (p=0.023) concentrations were decreased compared with baseline. Thereafter, random LHs were well suppressed. GRs gradually decreased to prepubertal norm by month 12. Seventeen patients (63%) exhibited pubertal LH concentrations at least once during treatment visits. Furthermore, 43 of a total 116 (37%) LH measurements were found elevated. However, those patients with elevated random LH did not show signs of pubertal progression. After treatment, mean FAH was greater than predicted adult height (p<0.0001) and target height (p=0.03). At no time points of treatment did random LH, FSH and estradiol correlate with GRs or FAH.
Conclusion: Elevated random LH is commonly found in ICPP girls during monthly leuprolide treatment. However, these elevations were not associated with clinical progression of puberty or decreased FAH, suggesting that it is not a reliable method for CPP monitoring.

Objective: To assess the association between age at menarche and adult height [and body mass index (BMI)] in young Korean females and also to investigate whether early menarche (<12 years) is a risk factor for short stature and obesity in young Korean females.
Methods: Data on 1148 females aged 18-30 years and 612 mother (612 pairs of mothers and daughters) from the 6th Korea National Health and Nutrition Examination Survey (2013-2015) were analyzed.
Results: Among 1148 females, 256 (22.3%) had early menarche. Their stature was approximately 0.445 cm shorter when menarche had occurred one year earlier. The prevalence of short stature (?153 cm) and obesity (BMI ?25) was higher in females with early menarche compared to those with later menarche (short stature: 10.5% vs 6.4%, obesity; 20.7% vs 13.1%, all p<0.001). In multivariate regression, the odds ratio (OR) for short stature was 2.62 [95% confidence interval (CI): 1.26-5.44] after adjusting for current age and mother’s height. OR for obesity was 1.74 (95% CI: 0.98-3.07) after adjusting for age and maternal BMI.
Conclusion: Final height in girls is influenced by age of menarche. Early menarche increased the risk for adult short stature in young Korean females.

Objective: The aim of this study was to evaluate cases referred from the congenital hypothyroidism (CH) newborn screening program.
Methods: Infants referred to Pediatric Endocrinology between 30.09.2015 - 01.04.2018 because of suspected CH identified by National Neonatal Screening Program were prospectively evaluated.
Results: Of the 109 newborns referred to our clinic, 60 (55%) were diagnosed with elevated neonatal thyroid stimulating hormone (TSH). The diagnosis of elevated neonatal TSH was made in 52 (47.7%) and eight (7.3%) infants at initial evaluation and after follow up, respectively of all referrals with 86.7% (52/60) diagnosed at initial visit. The median first and second heel prick times were 1.8 (0-7) and 8.72 (4-30) days. The median age at starting treatment of the infants diagnosed as a result of initial evaluation was 22.13 (7-53) days. Clinical findings associated with CH were present in 19 (36%) of patients. Etiology in patients diagnosed with elevated neonatal TSH on admission was: agenesis in one (2.08%); ectopia in one (2.08%); hypoplasia in 14 (29.16%); normal gland in situ 16 (33.3%); and hyperplasia in 16 (33.3%). The median time to normalization of TSH and free thyroxine concentrations after treatment initiation was 11.02 (4-30) and 9.03 (3-30) days, respectively.
Conclusion: The rate of diagnosis in the first month was found to be 87%. The etiological incidence of both dysgenesis and dyshormonogenesis was equal at 33.3%. The majority of cases with normal thyroid gland will be diagnosed with transient hypothyroidism but some of them may be diagnosed with thyroid dyshormonogenesis so the rate of dyshormonogenesis will increase later after final diagnosis.

Objective: The prevalence of overweight and obesity in childhood and adolescence are rapidly increasing and influenced by genetic, familial, environmental, socioeconomic and cultural factors. The aim of the study was to compare risk factors for childhood obesity in Ukraine (UA) and Germany (DE) using comparable investigative tools.
Methods: Two groups of children, aged 8 to 18 years, from DE (93 children) and UA (95 children) were divided into overweight and obese groups. Anthropometric data and detailed medical history were collected.
Results: Risk factors in pregnancy (prematurity, weight gain >20 kg, early contractions) were equally frequent in both groups. Positive correlations of body mass index (BMI)-standard deviation score (SDS) between children and mothers were noted. The proportion of family members with diabetes mellitus was lower in the UA group. Obesity was more frequent at one year of age in DE children. The DE group also became overweight at an earlier age and remained overweight over a longer period of time compared to UA. The mean BMI-SDS of obese children was lower in the UA group. In both groups waist circumference to height ratio was >0.5, indicating presence of a cardiometabolic risk factor. About half of the patients in both groups had blood pressure values exceeding the 95th percentile.
Conclusion: Similar risk factors for obesity were observed among two groups of children in UA and DE. Differences were observed regarding the prevalence of specific risk factors for childhood obesity. Population-specific distribution of risk factors needs to be considered in order to optimize prevention and treatment strategies.

Objective: IGF1 concentration is the most widely used parameter for the monitoring and therapeutic adaptation of recombinant human growth hormone (rGH) treatment. However, more than half the variation of the therapeutic response is accounted for by variability in the serum concentrations of IGF1 and IGFBP3. We therefore compared the use of IGF1/IGFBP3 molar ratio with that of IGF1 concentration alone.
Methods: We selected 92 children on rGH for this study and assigned them to three groups on the basis of growth deficiency etiology: small for gestational age (SGA), GH deficiency (GHD) and Prader-Willi syndrome (PWS). Plasma IGF1 and IGFBP3 concentrations and their molar ratio were determined.
Results: Before rGH treatment, mean IGF1/IGFBP3 molar ratio in the SGA, GHD and PWS groups was 0.14±0.04, 0.07±0.01 and 0.12±0.02, respectively. After the initiation of rGH treatment, these averages were 0.19±0.07, 0.20±0.08 and 0.19±0.09, within the normal range for most children, even at puberty and despite some significant increases in serum IGF1 levels.
Conclusion: We consider IGF1/IGFBP3 molar ratio to be a useful additional parameter for assessing therapeutic safety in patients on rGH, and for maintaning the values within the normal range for age and pubertal stage.

The aim of this study was to assess the association between serum uric acid concentration (SUAC) and the parameters of the metabolic syndrome (MetS) and insulin resistance (IR). The secondary aim was to evaluate whether hyperuricemia is associated with renal injury and cardiovascular risk in obese (OB) and overweight (OW) children.
Methods: The subjects of this study consisted of OB/OW children and adolescents (ages: 8-18 years). Sex and age specific serum uric acid (SUA) olarak deðiþtirilecek percentiles were used and a SUA >75th percentile was accepted as hyperuricemia. Anthropometric data, blood pressure (BP) measurements and biochemical parameters, including fasting blood glucose, insulin, total cholesterol, high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol, triglycerides (TG), aspartate aminotransferase, alanine aminotransferase, homeostatic model assessments of IR (HOMA-IR) and SUAC were recorded. Oral glucose tolerance tests (OGTT) were performed in all patients. MetS was defined according to the International Diabetes Federation criteria. Total cholesterol/HDL-c ratio >4 and TG/HDL-c ratio >2.2 were used as the atherogenic index (AI) indicating cardiovascular risk. Urinary albumin excretion in a 24-hour and also in a first-morning urine sample were measured. Renal injury was assessed by microalbuminuria according to the National Kidney Foundation criteria.
Results: There were 128 participants; 52 (40%) had elevated (SUA >75th percentile) and 76 had (60%) normal SUAC. The mean±SD age was 13.1±2.6 years and 87 (67.4%) were female. The mean±SD weight was 73±18.97 kg and mean±SD height was 155.4±12.11 cm. There was no statistical difference between the groups with and without hyperuricemia in terms of age, sex, puberty stage and degree of obesity. Increased SUAC were significantly associated with higher waist-to-hip ratio (WHR), fasting insulin levels and insulin at 30 and 60 minutes during OGTT, HOMA-IR, lower HDL-c and presence of hypertriglyceridemia as well as with decreased HDL-c, increased AI, presence of IR and MetS. BP and microalbuminuria were not associated with SUAC. SUAC showed significant positive correlations with waist circumference, WHR, post-challenge glucose level at 60 minutes, with fasting insulin, post-challenge insulin levels at 30, 60, 90 and 120 minutes and also with HOMA-IR, total cholesterol/HDL-c ratio, TG/HDL-c ratio and a number of other criteria related to MetS. Also, an inverse correlation with HDL-c was noted.
Conclusion: In OB/OW children frequency of MetS, IR and dislipidemia increases with increased SUAC, a finding independent of age, puberty, gender and body mass index. Patients meeting all of the MetS criteria had the highest SUAC. These results demonstrate that the association between UA and metabolic and cardiovascular risk factors can be detected early in childhood. Thus, we recommend monitoring SUAC in OB children and we believe that prevention of SUAC elevation in early life has a potential protective effect on metabolic impairment and subsequent comorbidities.

Objective: Studies have reported inconsistent results on the associations between lipids and insulin resistance (IR) and asthma. The purpose of this study was to examine the associations between abnormal serum lipid levels and homeostatic model assessment-IR (HOMA-IR) and the presence of current asthma in children and adolescents.
Methods: The United States National Health and Nutrition Examination Survey database from 1999 to 2012 was randomly searched for children (aged 3-11 years) and adolescents (aged 12-19 years) with and without asthma and with complete demographic and clinical data of interest. Logistic regression analyses were performed to examine associations between abnormal serum lipids, glucose and HOMA-IR and the current presence of asthma.
Results: The data of 11,662 children (3 to 11 years of age) and 12,179 adolescents (12 to 19 years of age) were included in the analysis. The study group included 3,703 participants with asthma and 20,138 participants without asthma. The prevalence of self-reported current asthma was higher among participants aged between 3-11 years (52.9%) than among those aged between 12-19 years (50.7%). Multivariate analyses, after adjusting for sex, race, income-to-poverty ratio, low birth weight, prenatal maternal smoking, tobacco exposure, C-reactive protein level and body mass index Z-score, revealed no associations between elevated fasting plasma glucose, reduced high-density lipoprotein cholesterol, elevated low-density lipoprotein cholesterol, total cholesterol, triglycerides and HOMA-IR and the presence of current asthma in children or adolescents.
Conclusion: In this cross-sectional study, no association was found between abnormal serum lipids or HOMA-IR and the presence of current asthma in children or adolescents.

Objective: The aim of the study was to develop an Insulin Treatment Self-management Scale; both Child Form and Parent Form for children ages 8-18 with type 1 diabetes.
Methods: Children with type 1 diabetes and their parents participated in the study. Development of a methodologically designed scale was conducted to investigate insulin treatment self-management of children with type 1 diabetes.
Results: A total of 331 children and their parents were recruited. Children and parents completed the data collection tools by themselves. The final scale had two subscales; one was related to cognitive and behavioural expressions regarding insulin treatment (self-efficacy) and the other to emotional aspects of self-maagement of insulin treatment (emotional impacts). The scale was shown to be valid and reliable.
Conclusion: This study was a valid and reliable scale for measuring insulin treatment self-management in children with type 1 diabetes. Thus can be used to assess insulin treatment self-management in children with type 1 diabetes and their parents as well as a tool for effective nursing care.

Objective: Antimüllerian hormone (AMH) concentrations in mini puberty are higher than those reported for the prepubertal period. In this study we investigated AMH concentrations in infants with premature thelarche (PT). A healthy control group was used for comparison.
Methods: Forty five female infants with PT, aged between one and three years and a control group consisting of 37 healthy girls in the same age range were included in the study. Bone age, pelvic ultrasonography, and concentrations of luteinizing hormone, follicle-stimulating hormone (FSH), estradiol and AMH of the patient group were evaluated. Only serum AMH concentration of the control group was evaluated.
Results: Median (range) serum AMH concentrations in the subjects were 1.66 ng/mL (11.85 pmol/L) [0.15-6.32 ng/mL (1.07-45.12 pmol/L)] and were significantly lower (p=0.025) than for the control group; 1.96 ng/mL (13.99 pmol/L) [0.60-8.49 ng/mL (4.28-60.64 pmol/L)]. AMH and FSH were negatively correlated (r=-0.360, p=0.015) in infants with PT. There was no correlation between AMH and uterine size, uterine volume, endometrial thickness, fundocervical ratio, ovarian size or volume, follicle size and follicle number.
Conclusion: This is the first study that investigates AMH concentrations in infants with PT. The low AMH levels in these infants and the negative correlation between AMH and FSH suggests that AMH may play a role in suppressing pubertal findings during infancy and that decreased AMH may cause PT in infancy.

Objective: Insulin like growth factors-1 (IGF-1) is essential for normal in utero and postnatal human growth. It mediates its effects through the IGF-1 receptor (IGF1R), a widely expressed cell surface tyrosine kinase receptor. The aim of the study was to analyze pre- and post-natal growth, clinical features and laboratory findings in a small for gestational age (SGA) girl in whom discordant postnatal growth persisted and her appropriate for gestational age (AGA) brother.
Methods: A girl born with a low weight and length [-2.3 and -2.4 standard deviation (SD) score (SDS), respectively] but borderline low head circumference (-1.6 SD) presented with a height of -1.7 SDS, in contrast to a normal height twin brother (0.0 SDS). IGF-1 resistance was suspected because of elevated serum IGF-1 levels.
Results: Sequencing revealed the presence of a previously described pathogenic heterozygous mutation (p.Glu1050Lys) in the SGA girl which was not present in the parents nor in the AGA twin brother.
Conclusion: The pathogenic IGF1R mutation in this girl led to intrauterine growth retardation followed by partial postnatal catch-up growth. Height in mid-childhood was in the lower half of the reference range, but still 1.7 SD shorter than her twin brother.

Cleidocranial dysplasia (CCD) is a rare congenital autosomal dominant skeletal disorder that is characterized by hypoplasia or aplasia of clavicles, failure of cranial suture closure, dental anomalies, short stature and other changes in skeletal patterning and growth. The gene responsible for pathogenesis has been mapped to the short arm of chromosome 6p21, core binding factor alpha-1 (CBFA1) or runt related transcription factor-2 (RUNX2). Here we describe a CCD patient with a novel mutation in the RUNX2 gene. A five-and-a-half year old girl presented with severe short stature, dysmorphic facial appearance (hypertelorism, prominent forehead, high palate, midfacial hypoplasia), macrocephaly, large anterior fontanelle, increased anteroposterior chest diameter. Her shoulders were close to each other and her bilateral clavicles appeared short on physical examination. Bilateral hypoplastic clavicles, coxa valga, hypoplasia of iliac bones, wide symphysis pubis and phalangeal dysplastic features were detected on her skeletal X-ray examination. She was diagnosed as having CCD. Molecular analysis detected a novel heterozygous mutation ‘NM_001024630.3p.T155P(c.463A>C)’ in the RUNX2 gene. At age seven years and two months old, because of her severe short stature, growth hormone (GH) treatment was started and she responded well to GH therapy with no adverse effects. In conclusion, hypoplasia or aplasia of the clavicles, failure of cranial suture closure, dental anomalies and short stature should bring CCD to mind. We present a novel mutation in the RUNX2 gene for CCD. We obtained growth velocity gain with GH treatment in our patient.

Hypophosphatasia (HPP) is a rare disease caused by mutations in the ALPL gene encoding tissue-non-specific isoenzyme of alkaline phosphatase (TNSALP). Duplications of the ALPL gene account for fewer than 1% of the mutations causing HPP. It has been shown that asfotase alfa enzyme replacement treatment (ERT) mineralizes the skeleton and improves respiratory function and survival in severe forms of HPP. Our patient was a newborn infant evaluated for respiratory failure and generalized hypotonia after birth. Diagnosis of HPP was based on low-serum ALP activity, high concentrations of substrates of the TNSALP and radiologic findings. On day 21 after birth, ERT using asfotase alfa (2 mg/kg three times per week, subcutaneous injection) was started. His respiratory support was gradually reduced and skeletal mineralization improved during treatment. We were able to discharge the patient when he was seven months old. No mutation was detected in the ALPL gene by all exon sequencing, and additional analysis was done by quantitative polymerase chain reaction (qPCR). As a result, a novel homozygote duplication encompassing exons 2 to 6 was detected. Early diagnosis and rapid intervention with ERT is life-saving in the severe form of HPP. qPCR can detect duplications if a mutation cannot be detected by sequence analysis in these patients.

Generalized arterial calcification of infancy (GACI) is a rare autosomal-recessive disorder, characterized by calcification of the internal elastic lamina, fibrotic myointimal proliferation of muscular arteries and resultant arterial stenosis. Treatment with bisphosphonates has been proposed as a means of reducing arterial calcifications in GACI patients, although there is no formalized treatment approach. The case reported here was a patient with severe GACI diagnosed at three months of age who had no response to bisphosphonate treatment, but clinically improved after the initiation of magnesium and anti-phosphate (using calcium carbonate) treatments. In patients unresponsive to bisphosphonate, magnesium and anti-phosphate treatment may be attempted.

Primary polyneuropathy in the context of Seip-Berardinelli type 1 seipinopathy, or congenital generalized lipodystrophy type 1 (CGL1) has not been previously reported. We report the case history of a 27 year old female CGL1 patient presenting with an unusual additional development of non-diabetic peripheral neuropathy and learning disabilities in early adolescence. Whole exome sequencing (WES) of the patient genome identified a novel variant, homozygous for a 52 bp intronic deletion in the AGPAT2 locus, coding for 1-acylglycerol-3-phosphate O-acyltransferase 2, which is uniquely associated with CGL1 seipinopathies, with no molecular evidence for dual diagnosis. Functional studies using RNA isolated from patient peripheral blood leucocytes showed abnormal RNA splicing resulting in the loss of 25 amino acids from the patient AGPAT2 protein coding sequence. Stability and transcription levels for the misspliced AGPAT2 mRNA in our patient nonetheless remained normal. Any AGPAT2 protein produced in our patient is therefore likely to be dysfunctional. However, formal linkage of this deletion to the neuropathy observed remains to be shown. The classical clinical presentation of a patient with AGPAT2-associated lipodystrophy shows normal cognition and no development of polyneuropathy. Cognitive disabilities and polyneuropathy are features associated exclusively with clinical CGL type 2 arising from seipin (BSCL2) gene mutations. This case study suggests that in some genetic contexts, AGPAT2 mutations can also produce phenotypes with primary polyneuropathy.