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1.  Syndromic Disorders with Short Stature 
Short stature is one of the major components of many dysmorphic syndromes. Growth failure may be due to a wide variety of mechanisms, either related to the growth hormone (GH)/insulin-like growth factor axis or to underlying unknown pathologies. In this review, the relatively more frequently seen syndromes with short stature (Noonan syndrome, Prader-Willi syndrome, Silver-Russell syndrome and Aarskog-Scott syndrome) were discussed. These disorders are associated with a number of endocrinopathies, as well as with developmental, systemic and behavioral issues. At present, GH therapy is used in most syndromic disorders, although long-term studies evaluating this treatment are insufficient and some controversies exist with regard to GH dose, optimal age to begin therapy and adverse effects. Before starting GH treatment, patients with syndromic disorders should be evaluated extensively.
PMCID: PMC3986733  PMID: 24637303
short stature; Noonan syndrome; Prader-Willi syndrome; Aarskog syndrome; Silver-Russell syndrome
2.  Urinary Bisphenol A Levels in Girls with Idiopathic Central Precocious Puberty 
Ob­jec­ti­ve: Bisphenol A (BPA) is an industrial chemical, particularly used to harden plastics. BPA is thought to have negative health effects on both laboratory animals and humans. Consider ing the decline in age of onset of puberty noted in recent years, particularly among girls, the importance of BPA as an estrogenic endocrine disruptor has increased. In this study, we aimed to determine urinary BPA levels in girls with idiopathic central precocious puberty (ICPP).
Methods: Non-obese girls newly diagnosed with ICPP (n=28, age 4-8 years) constituted the study group. The control group consisted of 25 healthy age-matched girls with no history of ICPP or any other endocrine disorder. Urinary BPA levels were measured by using high-performance liquid chromatography.
Results: In the ICPP group, urinary BPA levels were significantly higher compared to the control group [median 8.34 (0.84-67.35) μg/g creatinine and 1.62 (0.3-25.79) μg/g creatinine, respectively (OR=8.68, 95% CI:2.03-32.72, p=0.001)]. There was no marked correlation between urinary BPA levels and body mass index in either group. In the ICPP group, no significant correlations were found between urinary BPA levels and serum luteinizing hormone, follicle-stimulating hormone and estradiol levels.
Conclusions: To our knowledge, this is the first study evaluating the urinary BPA levels in Turkish girls with ICPP. Our results indicate that the estrogenic effects of BPA may be an etiologic factor in ICPP.
PMCID: PMC3986734  PMID: 24637305
Bisphenol A; endocrine disruptor; idiopathic central precocious puberty; sex hormones
3.  Evaluation of Asymmetric Dimethylarginine (ADMA) Levels in Children with Growth Hormone Deficiency 
Ob­jec­ti­ve: To investigate serum asymmetric dimethylarginine (ADMA) levels in children with isolated growth hormone deficiency (GHD) and to determine the effect of GH replacement therapy on these levels.
Methods: 31 patients diagnosed with isolated GHD and 29 age-and sex-matched healthy children were enrolled in the study. Height, weight and waist circumference were measured in all subjects. Fasting serum insulin-like growth factor-1 (IGF-1), IGF binding protein-3, glucose, insulin and lipid levels were evaluated. Serum ADMA levels were assessed using the enzyme-linked immunosorbent assay technique. The same evaluations were repeated on the 3rd and 6th months of treatment in 28 of the GHD cases.
Results: There were no significant differences in ADMA levels between the patient and control groups [0.513±0.130 (0.291-0.820) µmol/L vs. 0.573±0.199 (0.241-1.049) µmol/L]. There was a positive correlation between serum ADMA and HbA1c levels in the control group. In the GHD cases, ADMA levels negatively correlated with high-density lipoprotein levels and positively correlated with low-density lipoprotein levels. There was also a significant increase in ADMA levels in patients receiving GH therapy compared to pre-treatment levels [serum ADMA level, 1.075±0.133 (0.796-1.303) µmol/L at the 3rd month and 0.923±0.121 (0.695-1.159) µmol/L at the 6th month of treatment]. There was a negative correlation between ADMA levels and homeostasis model assessment of insulin resistance values at the 6th month evaluation. There were no relationships between ADMA levels and age, sex, or pubertal state either before or during the treatment.
Conclusion: Serum ADMA levels were found to be similar in patients with GHD and in healthy children. However, serum ADMA levels showed a significant increase in GHD patients following GH replacement therapy.
PMCID: PMC3986735  PMID: 24637306
growth hormone; asymmetric dimethylarginine; child
4.  Z-Score Reference Values for Height in Turkish Children Aged 6 to 18 Years 
Ob­jec­ti­ve: Standard deviation score or Z-score reference charts are used in some countries in preference to percentile charts and are considered as better tools in assessing children with measurements outside the accepted limits of normality. Growth data for Istanbul children have previously been reported as percentiles; hence, the aim of this study is to present these data in Z-score reference tables. Data on secular trend in height in Turkish children will also be presented.
Methods: Height and weight data based on a total of 11 664 height and 11 655 weight measurements in 1100 boys and 1020 girls between 6 and 18 years of age obtained by biannual visits to schools were analyzed. All children came from well-to-do families and were all healthy. All measurements were made by two trained technicians. The LMS method was used in the analyses. The results were expressed as Z-score values for age.
Results: Heights of the boys and girls in all age groups were close to the updated USA growth references and showed an upward trend from previous data on Turkish children.
Conclusions: Height growth in Turkish school-age children of high socioeconomic level conforms to the updated growth data for USA children and also shows a secular trend. The data also point to the importance of updating local growth data periodically.
PMCID: PMC3986736  PMID: 24637307
Z-score; children; Turkish
5.  Thyroid Hormone Levels in Obese Children and Adolescents with Non-Alcoholic Fatty Liver Disease 
Ob­jec­ti­ve: We aimed to determine the association of thyroid functions with the components of metabolic syndrome (MS) and non-alcoholic fatty liver disease (NAFLD) in pediatric obese patients.
Methods: The study included 109 obese children (aged 9-15 years) and a control group of 44 healthy age and gender-matched children of normal weight. NAFLD was diagnosed by conventional ultrasound examination. We assessed the anthropometric data and serum biochemical parameters including lipid profile, alanine aminotransferase (ALT), fasting glucose and insulin levels and thyroid stimulating hormone (TSH), free thyroxine (fT4) and free triiodothyronine (fT3) levels. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated as a measure of IR.
Results: The mean age and gender distributions in the groups were similar (p=0.23). The mean body mass index (BMI) z-scores of obese children with grade 2-3 NAFLD were significantly higher than those of the obese children without hepatic steatosis (p<0.001). Mean ALT, triglyceride (TG) and LDL cholesterol increased and HDL-cholesterol significantly decreased as the hepatic steatosis increased (p<0.05). HOMA-IR levels in obese subjects with grade 2-3 NAFLD were significantly higher than those in both obese children without NAFLD and grade 1 NADFL (p=0.05 and 0.001, respectively). In the obese subjects, TSH levels were increased significantly as the degree of steatosis increased (p=0.04) but fT3 and fT4 levels were not different. In correlation analysis, TSH was significantly correlated with ALT, BMI SDS and the degree of steatosis.
Conclusions: Obese children demonstrate an increase in TSH levels as the degree of steatosis increased.
PMCID: PMC3986737  PMID: 24637308
Hepatic steatosis; insulin resistance; thyroid hormones
6.  Patient with Mutation in the Matrix Metalloproteinase 2 (MMP2) Gene - A Case Report and Review of the Literature 
Torg and Winchester syndromes and patients reported by Al-AqeelSawairi as well as nodulosis-arthropathy-osteolysis (NAO) patients, patients with multicentric NAO share autosomal recessive inheritance. The common presenting symptomatology includes progressive osteolysis chiefly affecting the carpal, tarsal and interphalangeal joints. Here, we report a patient with Torg syndrome. Torg syndrome is caused by homozygous or compound heterozygous mutations in the matrix metalloproteinase 2 (MMP2) gene. MMP2 codes for a gelatinase that cleaves type IV collagen, a major component of basement membrane. The clinical presentation of our patient included moderate osteolysis of the small joints of the hands and knees, hirsutism, nodulosis sparing the palms and soles, corneal opacities and mild facial dysmorphism without gum hypertrophy. Genetic analysis showed that the patient was homozygous for a novel base variant c538 G>A (p.D180N) in the MMP2 gene. Both parents were carriers of the same mutated variant. Our patient had some previously unreported endocrine manifestations such as premature thelarche and elevated follicle-stimulating hormone levels.
PMCID: PMC3986738  PMID: 24637309
Torg syndrome; MMP2; osteolysis
7.  Autoimmune Polyglandular Syndrome Type 3c with Ectodermal Dysplasia, Immune Deficiency and Hemolytic-Uremic Syndrome 
Autoimmune polyglandular syndrome (APS) is a disorder which is associated with multiple endocrine gland insufficiency and also with non-endocrine manifestations. The pathophysiology of APS is poorly understood, but the hallmark evidence of APS is development of autoantibodies against multiple endocrine and non-endocrine organs. These autoantibodies are responsible for the dysfunction of the affected organs and sometimes may also cause non-endocrine organ dysfunction. The hemolytic-uremic syndrome (HUS) is a serious and life-threatening disease which develops due to many etiological factors including autoimmune disorders. Here, we present an unusual case of APS. Ectodermal dysplasia with immune deficiency and HUS occurred concomitantly in the same patient with APS type 3c. Once the autoantibody generation was initiated in the human body, development of multiple disorders due to organ dysfunction and also autoantibody-related diseases may have occurred.
PMCID: PMC3986739  PMID: 24637310
Polyglandular syndrome; ectodermal dysplasia; immune deficiency; Hemolytic uremic syndrome
8.  Features of Two Cases with 18q Deletion Syndrome 
The 18q Deletion syndrome is seen in 1 out of 10 000 live births. The main features of the syndrome are short stature, hearing loss, hypotonia, mental retardation, endocrine disorders and autoimmunity. Here, we present 2 patients with this syndrome admitted to our clinic who were found to have insulin resistance in addition to mental retardation, short stature, autoimmune thyroiditis and hearing loss. The need to perform a karyogram analysis in cases presenting with these features is emphasized.
PMCID: PMC3986740  PMID: 24637311
18q deletion; MC4R; Autoimmunity
9.  Cardio-Facio-Cutaneous Syndrome with Precocious Puberty, Growth Hormone Deficiency and Hyperprolactinemia 
Cardio-facio-cutaneous (CFC) syndrome is a rare disorder characterized by craniofacial dysmorphia, ectodermal abnormalities, cardiac malformations, as well as growth and developmental delay. Although some endocrine abnormalities have been reported in this syndrome, very little is known about CFC syndrome-related endocrine disorders. A 7.5-year-old boy was admitted to our endocrinology clinic with the complaint of short stature. He had a height of 103 cm [-4 standard deviation (SD)], a weight of 16 kg (<3th percentile, -1.7 SD), a facial appearance typical for the CFC syndrome, optic nerve hypoplasia and pulmonary stenosis. Genetic investigation revealed a heterozygous mutation in exon 3 of the MEK1 gene, c.389A>G (p. Y130C). During his long-term follow-up, the patient developed a variety of endocrine disorders including precocious puberty, growth hormone deficiency and hyperprolactinemia.
PMCID: PMC3986741  PMID: 24637312
Cardio-facio-cutaneous syndrome; MAPK; Precocious puberty; Growth hormone deficiency; hyperprolactinemia
10.  Isovaleric Acidemia Presenting as Diabetic Ketoacidosis: A Case Report 
Isovaleric acidemia (IVA) is characterized by periodic vomiting, lethargy, coma, ketoacidosis and a ‘sweaty feet’ odor. Hyperglycemia, ketonemia, ketonuria and metabolic acidosis are the main clinical features of diabetic ketoacidosis (DKA) and these same symptoms can also be seen in acute attacks of metabolic diseases. We report a 2-year-old patient who presented with acute encephalopathy, hyperglycemia, metabolic acidosis, increased anion gap, ketosis and a preliminary diagnosis of DKA. Further investigation revealed IVA. This case is of interest because of the rarity of this presentation and detection of a splicing mutation in the isovaleryl-CoA dehydrogenase gene.
PMCID: PMC3986742  PMID: 24637313
Hyperglycemia; ketoacidosis; isovaleric acidemia
11.  Epidemiology of Childhood Type 1 Diabetes Mellitus in Nile Delta, Northern Egypt - A Retrospective Study 
Ob­jec­ti­ve: The geographical incidence of type 1 diabetes mellitus (T1DM) varies widely worldwide. Both genetic and environmental factors have been implicated, although environmental factors are still speculative and elusive. More epidemiological studies are needed to uncover such factors. To date, there are no reported studies on the epidemiology of childhood T1DM in Nile Delta, Egypt. We aimed to define the incidence, prevalence and demographic characteristics of T1DM in children (0-18 years) living in the Nile Delta region, one of the most densely populated areas in Egypt.
Methods: The study included all T1DM patients aged 0-18 years who lived in the Nile Delta region of Egypt and who were either diagnosed at or referred to Mansoura University Children’s Hospital (MUCH) between 1 January 1994 and 31 December 2011. The hospital files of the patients were reviewed. General population data on the 0-18 year age group in the Nile Delta governorates were also presented.
Results: From a total of 1600 T1DM patients, 891 (55.7%) were females (p=0.000) and 935 (58.4%) were from rural areas (p=0.000). Calculated age-adjusted incidence of T1DM in 1996, 2006 and 2011 were 0.7, 2.0 and 3.1/105/year, respectively, while calculated age-adjusted prevalence of T1DM in the same years were 1.9, 15.5 and 26.8/105/year, respectively. Patients presented most frequently in the 5-10 year age group (p<0.000) and in winter months (p=0.009).
Conclusion: In this first childhood T1DM epidemiology study in the Nile Delta region of Egypt, T1DM incidence and prevalence were found to show an increase over the past 18 years (1994-2011). Incidence and prevalence were higher in females and more cases were found to originate from rural areas.
PMCID: PMC3986743  PMID: 24637304
type 1 diabetes mellitus; Egypt; Epidemiology
12.  Micropenis: Etiology, Diagnosis and Treatment Approaches 
Micropenis is a medical diagnosis based on correct measurement of length. If stretched penile length is below the value corresponding to - 2.5 standard deviation of the mean in a patient with normal internal and external male genitalia, a diagnosis of micropenis is considered. Micropenis can be caused by a variety of factors including structural or hormonal defects of the hypothalamic-pituitary-gonadal axis. It can also be a component of a number of congenital syndromes. For the etiological evaluation, endocrinologic tests are important. This article reviews the etiology, diagnosis, treatment and management of micropenis.
Conflict of interest:None declared.
PMCID: PMC3890219  PMID: 24379029
Micropenis; etiology; diagnosis; treatment
13.  Relationship Between Total Body Adiposity Assessed by Dual-Energy X-ray Absorptiometry, Birth Weight and Metabolic Syndrome in Young Thai Adults 
Objective: The aim of this study was to compare body fat distribution using dual-energy X-ray absorptiometry (DXA) in young adult subjects with metabolic syndrome (MS) with those without MS and also to determine whether a significant association existed between total body fat mass (FM) and MS along with the effect of birth weight.
Methods: This cross-sectional study was conducted on 393 young adult subjects (175 male, 218 female). Body mass index (BMI), waist circumference, blood pressure, triglyceride, high-density lipoprotein cholesterol and glucose levels were determined. Total body FM, lean mass (LM) and percentage of body fat (%BF) were assessed by DXA. Adult Treatment Panel III criteria were used for the diagnosis of MS.
Results: The prevalence of MS was 5.6% among this group of young adult subjects aged 18.5-21.8 years. Subjects with MS (n=22) had significantly higher values for weight, height, BMI, waist circumference, %BF, total body FM, total body LM, and regional FM and LM. There was no statistically significant difference in bone mineral density between the two groups. There was also no association between birth weight and MS. Multiple logistic regression analysis showed that every 5 kg of total body FM (OR 1.68; 95%CI 1.06-2.66) adjusted for gender, birth weight status, and total body LM were significantly associated with MS.
Conclusion: Total body FM measured by DXA was related to MS in Thai young adults. Thus, body composition analysis might have a role in the identification of subjects with MS status.
Conflict of interest:None declared.
PMCID: PMC3889991  PMID: 24379035
Body composition; fat mass; birth weight; metabolic syndrome; dual-energy x-ray absorptiometry
14.  Weight for Length/Height Percentiles in Infants and Young Children in Kayseri/Turkey 
Objective: To produce weight for length/height (WLH) percentiles to be used for the screening of growth and assessment of failure to thrive in infancy and early childhood.
Methods: The data (2009-2010) of the Anthropometry of Turkish Children aged 0-6 years (ATCA-06) study were used. A cross-sectional study was designed to calculate the WLH references. Reference weight values for each 5-cm LH intervals were determined using the LMS Chart Maker Pro version 2.3 software program (The Institute of Child Health, London).
Results: A total of 3123 children (1573 female, 1550 male) aged 0-6 years were included in the calculation of the 3rd, 5th, 10th, 25th, 50th, 75th, 85th, 90th, 95th, and 97th WLH percentiles. The difference between the 3rd and the 97th percentiles for males was 2.02 cm to 12.64 cm in the 50-54.99 cm and 125-130 cm LH ranges. In the girls, the differences between the 3rd-97th percentiles ranged from 2.02 cm to 12.64 cm in the 50-54.99 cm and 125-130 cm LH groups. The maximum difference between the 3rd and 97th percentiles was about half the variation of mean WLH throughout the first six years of life. The most rapid change in WLH was observed in the 0-2-year period. Turkish references for WLH were not different from the World Health Organization standards.
Conclusions: This is the first study in Turkey presenting WLH references in 0-6 year old children. We suggest that the use of WLH in the first two years of life may be more useful than age-adjusted references in assessment of nutritional status and diagnosis of failure to thrive.
Conflict of interest:None declared.
PMCID: PMC3890220  PMID: 24379030
Length; height; weight; children
15.  Psychiatric Approaches for Disorders of Sex Development: Experience of a Multidisciplinary Team 
Objective: Disorders of sex development (DSD) are a group of congenital medical conditions that affect life as a whole. In this study, we aimed to reflect the experience of a multidisciplinary team in the clinical/psychiatric follow-up of a group of children and adolescents with DSD.
Methods: The study group consisted of 51 patients diagnosed with DSD. The Kiddie-Schedule for Affective Disorders and Schizophrenia, Wechsler Intelligence Scale for Children-Revised, Draw a Person Test and Children’s Apperception Test, and the Clinical Global Impression Scale (CGIS) were used for psychiatric evaluations.
Results: The mean age of the patients was 7.8 years (median: 7.8; min: 1.0; max: 18.0). Genetic evaluation showed 46,XX configuration in 15 patients (29.4%) and 46,XY in 35 (68.6%). One patient (2.0%) was diagnosed to have a sex chromosome disorder. Forty patients (78.4%) had no problems with their given gender identity and gender role. Thirty-four (66.7%) patients had normal intellectual capacity. Twenty-eight (54.9%) patients did not have any psychiatric problem. Depression, anxiety disorders, attention deficit/hyperactivity disorder, and adjustment disorders were the common diagnoses. The mean score of symptom severity on CGIS-severity-baseline was 6.15±0.68 and after one year, it was 1.46±0.51 (Z=-3.236 p=0.001). The mean score of CGI–Improvement was 1.23±0.44.
Conclusion: It is important to identify and treat the psychiatric disorders encountered in patients with DSD. A psychiatrist needs to be included in the professional team following these patients. Examination and observation results need to be shared by holding periodic team meetings to establish a wholesome point of view for every unique child.
Conflict of interest:None declared.
PMCID: PMC3890221  PMID: 24379031
Disorders of sex development; psychiatric disorders; gender identity
16.  Effect of Pioglitazone on the Course of New-Onset Type 1 Diabetes Mellitus 
Objective: Type 1 diabetes mellitus (T1DM) is caused by insulin deficiency resulting from progressive destruction of β cells. The histological hallmark of the diabetic islet is mononuclear cell infiltration. Thiazolidinediones (TZDs) activate PPARg and enhance the actions of insulin. Studies in non-obese diabetic and streptocotozin-treated mouse models demonstrated that pretreatment with TZDs prevented the development of T1DM. The purpose of this study was to examine whether pioglitazone, given with insulin, preserved β cell function in patients with new-onset T1DM.
Methods: This was a randomized, double-blind, placebo-controlled 24-week study. Subjects received pioglitazone or placebo. Blood sugar, glycated hemoglobin (HbA1c), C-peptide, and liver enzymes were measured at baseline. Boost© stimulated C-peptide responses were measured at baseline and at 24 weeks. Blood sugar, insulin dose, height, weight, and liver enzymes were monitored at each visit. HbA1c was performed every 12 weeks.
Results: Of the 15 patients, 8 received pioglitazone, and 7 - placebo. There was no clinical improvement in HbA1c between or within groups at the completion of the study. Mean peak C-peptide values were similar between groups at baseline. Mean peak C-peptide level was slightly higher at 24 weeks in the pioglitazone group compared to the placebo (1.8 vs. 1.5
ng/mL) which was considered as clinically insignificant. The interaction of HbA1c and insulin dose (HbA1c* insulin/kg/day), which combines degree of diabetic control and dose of insulin required to achieve this control, showed transient improvement in the pioglitazone group at 12 weeks but was not sustained at 24 weeks.
Conclusion: In this pilot study, pioglitazone did not preserve β cell function when compared to placebo.
Conflict of interest:None declared.
PMCID: PMC3890222  PMID: 24379032
type 1 diabetes; children; thiazolidinedione; β cell function
17.  L-thyroxine Stabilizes Autoimmune Inflammatory Process in Euthyroid Nongoitrous Children with Hashimoto’s Thyroiditis and Type 1 Diabetes Mellitus 
Objective: To investigate if L-thyroxine (T4) treatment may influence the clinical course of autoimmune thyroiditis (AIT) or prevent progression to subclinical or overt hypothyroidism in euthyroid nongoitrous pediatric patients with type 1 diabetes mellitus (T1DM) and AIT.
Methods: The study was performed in four Polish pediatric diabetes centers. Of 330 children with T1DM and AIT followed between 2008 and 2012, 101 received L-T4 and 160 underwent clinical observation for 24 months. Thyroid stimulating hormone (TSH), free T4 (fT4), anti thyroid peroxidase antibody (anti-TPO), anti thyroglobulin antibody (anti-TG), glycosylated hemoglobin (HbA1c) levels, and lipid profile were assessed in all patients. Ultrasonographic evaluation was also performed in all children at each examination.
Results: Patients treated with thyroid hormones had higher TSH levels (3.99; interquantile 3.5 to 4.52 vs. 2.09 mIU/L; interquantile 1.55 to 3.06; p<0.0001). A fall in TSH level (0.87 mIU/L 95% CI 0.43-1.30; p<0.0001) was documented after the first year of treatment. FT4 level did not differ between the groups at baseline (p=0.7434), but rose in the treatment group and fell in the control group [mean difference 0.78 95% CI
-0.22-1.53 pmol/L (p=0.02) after 12 months and 0.98 95% CI 0.04-1.76 (p=0.005) after 24 months]. Higher levels of anti-TPO were initially found in the treated patients (p<0.0001) and significantly decreased over the 24-month period (p<0.0001). Children in the treatment group had higher anti-TG levels (p<0.0001), which showed a borderline decrease (p=0.08) in time. In the control group, anti-TG levels rose marginally (p=0.06) during the study.
Conclusions: The data demonstrate that treatment with L-T4 in euthyroid pediatric patients with T1DM and AIT stabilizes autoimmune inflammation in the thyroid gland and is to be recommended as soon as the diagnosis is established.
Conflict of interest:None declared.
PMCID: PMC3890223  PMID: 24379033
autoimmune thyroiditis; type 1 diabetes mellitus; L-thyroxine treatment; lipid profile; glycemic control; thyroid volume SDS
18.  A Study of Insulin Resistance by HOMA-IR and its Cut-off Value to Identify Metabolic Syndrome in Urban Indian Adolescents 
Objective: Insulin resistance (IR) and associated metabolic abnormalities are increasingly being reported in the adolescent population. Cut-off value of homeostasis model of assessment IR (HOMA-IR) as an indicator of metabolic syndrome (MS) in adolescents has not been established. This study aimed to investigate IR by HOMA-IR in urban Indian adolescents and to establish cut-off values of HOMA-IR for defining MS.
Methods: A total of 691 apparently healthy adolescents (295 with normal body mass index (BMI), 205 overweight, and 199 obese) were included in this cross-sectional study. MS in adolescents was defined by International Diabetes Federation (IDF) and Adult Treatment Panel III (ATP III) criteria. IR was calculated using the HOMA model.
Results: Mean height, waist circumference (WC), waist/hip ratio (WHR), waist/height ratio (WHtR), and blood pressure were significantly higher in boys as compared to girls. The HOMA-IR values increased progressively from normal weight to obese adolescents in both sexes. Mean HOMA-IR values increased progressively according to sexual maturity rating in both sexes. HOMA-IR value of 2.5 had a sensitivity of >70% and specificity of >60% for MS. This cut-off identified larger number of adolescents with MS in different BMI categories (19.7% in normal weight, 51.7% in overweight, and 77.0% in obese subjects) as compared to the use of IDF or ATP III criteria for diagnosing MS. Odds ratio for having IR (HOMA-IR of >2.5) was highest with WHtR (4.9, p <0.0001) and WC (4.8, p <0.0001), compared to WHR (3.3, p <0.0001).
Conclusions: In Indian adolescents, HOMA-IR increased with sexual maturity and with progression from normal to obese. A HOMA-IR cut-off of 2.5 provided the maximum sensitivity and specificity in diagnosing MS in both genders as per ATP III and IDF criteria.
Conflict of interest:None declared.
PMCID: PMC3890224  PMID: 24379034
insulin resistance; metabolic syndrome; HOMA-IR; adolescents
19.  46,XX Male Disorder of Sexual Development: A Case Report 
The main factor influencing sex determination of an embryo is the sex-determining region Y (SRY), a master regulatory gene located on the Y chromosome. The presence of SRY causes the bipotential gonad to differentiate into a testis. However, some individuals carry a Y chromosome but are phenotypically female (46,XY females) or have a female karyotype but are phenotypically male (46,XX males). 46, XX male is rare (1:20 000 in newborn males), and SRY positivity is responsible for this condition in approximately 90% of these subjects. External genitalia of 46,XX SRY-positive males appear as normal male external genitalia, and such cases are diagnosed when they present with small testes and/or infertility after puberty. Herein, we report an adolescent who presented with low testicular volume and who was diagnosed as a 46,XX male. SRY positivity was demonstrated in the patient by fluorescence in situ hybridization method.
Conflict of interest:None declared.
PMCID: PMC3890225  PMID: 24379036
Disorder of sexual development; XX male; SRY gene
20.  Thyroid Involvement in Two Patients with Bannayan-Riley-Ruvalcaba Syndrome 
Bannayan-Riley-Ruvalcaba syndrome (BRRs) is an overgrowth disorder characterized by macrocephaly, pigmented maculae of the glans penis, and benign mesodermal hamartomas (primarily subcutaneous and visceral lipomas, multiple hemangiomas, and intestinal polyps). Dysmorphic features as well as delayed neuropsychomotor development can also be present. These patients have also a higher risk of developing tumors, as the gene involved in BRRs is phosphatase and tensin homologue (PTEN), and up to 30% of the patients have thyroid involvement consistent with multinodular goiter, thyroid adenoma, differentiated non-medullary thyroid cancer, or Hashimoto’s thyroiditis. Here, we report two cases of BRRs at opposite ends of its phenotypic spectrum: clinical manifestations of the first patient were more severe, while the second one showed only few signs and had no family history of the disease. Both cases developed thyroid disorders detected by thyroid ultrasound screening. We believe that it is important for clinicians, specifically pediatric endocrinologists, to know that this syndrome can appear in very subtle ways and also to be aware that thyroid nodules and intestinal polyps seem to be its most frequently encountered features.
Conflict of interest:None declared.
PMCID: PMC3890226  PMID: 24379037
Bannayan-Riley-Ruvalcaba syndrome; PTEN; Thyroid; thyroid ultrasound; thyroid neoplasm
21.  Primary Hyperparathyroidism Masquerading as Rickets: Diagnostic Challenge and Treatment Outcomes 
Primary hyperparathyroidism (PHPT) is extremely uncommon among children and is more likely to be associated with genetic syndromes, multiglandular involvement, and more severe symptoms. Rickets can very rarely be the presenting feature of PHPT in children. Rickets was diagnosed in a 12-year-old girl presenting with short stature, genu valgum, eversion deformity at the ankle joints, and flat feet. Radiograms showed generalized osteopenia, widening of the distal ends of the long bones along with splaying, cupping and fraying. Biochemical evaluation revealed low serum calcium (7.8 mg/dL), low phosphorus (1.4 mg/dL), vitamin-D deficiency [25-hydroxy-vitamin-D (25(OH)D): 8.7 ng/mL], and elevated intact parathyroid hormone (PTH, 811 pg/mL). Re-evaluation due to lack of clinical improvement following vitamin-D and calcium supplementation revealed hypercalcemia 11.9 mg/dL, normal 25(OH)D 41 ng/mL, persistence of elevated PTH 632 pg/mL. A 99mTc-sestamibi scan showed increased uptake at the lower pole of the right lobe of the thyroid. A right inferior parathyroidectomy was performed. Histopathology revealed chief cell type parathyroid adenoma. Last evaluated 4 months after surgery, the bone pains and proximal weakness had resolved, with significant improvement in the patient’s quality of life. Rickets in the setting of PHPT often masks the classical phenotype of PHPT. In a child with rickets, lack of improvement following vitamin-D supplementation, hypercalcemia at presentation or following vitamin-D supplementation are warning signs which necessitate further evaluation to rule out PHPT.
Conflict of interest:None declared.
PMCID: PMC3890227  PMID: 24379038
primary hyperparathyroidism; rickets; Parathyroid adenoma
22.  Polyarthritis Caused by Methimazole in Two Japanese Patients with Graves’ Disease 
In many countries, methimazole (MMI) therapy is the first-line treatment in children with Graves’ disease (GD). The rate of side effects of antithyroid drugs (ATDs) in children has been reported to range between 6% and 35%. Of these side effects, polyarthritis is uncommon but serious, and can also develop as a part of the antineutrophil cytoplasmic antibody-associated vasculitis that is induced by ATDs. Here, we describe two GD girl patients aged 15 years and 11 years who developed polyarthritis. The onset of polyarthritis in these patients was 24 days and 28 days after the initiation of MMI therapy, respectively. MMI was suspected of causing the polyarthritis in the two patients and was withdrawn. The symptoms of polyarthritis disappeared rapidly following cessation of treatment. Subsequently, one patient was treated with 131I therapy and the other patient was subjected to thyroidectomy. Although it rarely occurs in pediatric GD patients, severe polyarthritis is a serious side effect of MMI and is an indication for prompt cessation of treatment.
Conflict of interest:None declared.
PMCID: PMC3890228  PMID: 24379039
Graves’ disease; methimazole; adverse event; polyarthritis
23.  Pubertal Gynecomastia Coincides with Peak Height Velocity 
Objective: Pubertal gynecomastia (PG) occurs in up to 65% of adolescent boys. In this study, we investigated the relationship between the ages at which PG and peak height velocity occur in pubertal boys.
Methods: This was a prospective study that was designed to detect PG within three months of its emergence. We examined one hundred and six boys who were followed for short stature and/or delayed puberty at three month intervals, and gynecomastia was observed in 43 of these boys (40.5%).
Results: PG occurred in the 43 boys within a year of their peak height velocity, and most of these boys were at Tanner stage 3 for pubic hair and had testicular volumes between 8-10 mL.
Conclusion: It is recommended that evaluation of height growth be included in the diagnostic approach to PG in boys with short stature and/or delayed puberty. The coincidence of age of peak height velocity and PG suggests a causal relationship between the two events and a role of insulin-like growth factor-1.
Conflict of interest:None declared.
PMCID: PMC3814527  PMID: 24072080
Insulin-like growth factor-1; gynecomastia; peak height velocity; puberty; growth
24.  Relationship Between Aspartate Aminotransferase-to-Platelet Ratio Index and Carotid Intima-Media Thickness in Obese Adolescents with Non-Alcoholic Fatty Liver Disease 
Objective: There is increasing evidence for an association between non-alcoholic fatty liver disease (NAFLD) and an increased risk of cardiovascular morbidity and mortality. The aim of this study was to investigate the association between aspartate aminotransferase-to-platelet ratio index (APRI) and carotid intima-media thickness (IMT) in obese adolescents with NAFLD.
Methods: Seventy-six obese adolescents and 36 lean subjects were enrolled in this cross-sectional single-centre study. The obese subjects were divided into two subgroups based on the presence or absence of fatty liver with high transaminase levels (NAFLD group and non-NAFLD group). Fasting blood samples were assayed for transaminase, glucose, and insulin levels. Insulin resistance was calculated by the homeostasis model assessment (HOMA-IR).
Results: APRI values were higher in both obese groups (NAFLD and non-NAFLD) in comparison with the lean group. The NAFLD group had significantly higher APRI values than the non-NAFLD obese group and the lean group. Carotid IMT was higher in both obese groups (NAFLD and non-NAFLD) in comparison with the lean group. The NAFLD group had significantly higher measurements of carotid IMT than the non-NAFLD group and the lean group. APRI was positively correlated with most of the metabolic parameters (total cholesterol, low-density lipoprotein cholesterol, glucose, insulin, HOMA-IR) and with carotid IMT in the NAFLD obese group.
Conclusions: This study demonstrated that a significant relationship exists between APRI and carotid IMT in obese adolescents with NAFLD. We suggest that an increased APRI score in obese adolescents with NAFLD can possibly serve to predict a more adverse cardiovascular risk profile.
Conflict of interest:None declared.
PMCID: PMC3814245  PMID: 24072087
adolescent; aspartate aminotransferase-to-platelet ratio index; carotid intima-media thickness; insulin resistance; Non-alcoholic fatty liver disease; obesity
25.  Microvascular Complications in Adolescents with Type 1 Diabetes Mellitus 
Objective: Screening of complications is an important part of diabetes care. The aim of this study was to investigate diabetic complications and related risk factors in adolescents with type 1 diabetes mellitus (T1DM).
Methods: This cross-sectional study was conducted on type 1 diabetics who were over 11 years of age or had a diabetes duration of 2 years and included 155 adolescents with T1DM (67 male, 88 female). The mean age of the patients was 14.4±2.1 years. Mean diabetes duration was 6.3±2.9 years. The patients were screened for diabetic nephropathy, retinopathy and peripheral neuropathy.
Results: Mean glycosylated hemoglobin (HbA1c) level of the study group was 8.4%. The frequency of microalbuminuria and peripheral neuropathy were 16.1% and 0.6%, respectively. None of the patients had diabetic retinopathy. Dyslipidemia and hypertension rates were 30.3% and 12.3%, respectively. Risk factors associated with microalbuminuria were hypertension, higher HbA1c levels, longer diabetes duration and dyslipidemia.
Conclusion: Early diagnosis and treatment of hypertension and dyslipidemia as well as achieving a better metabolic control are important in prevention or postponement of complications in patients with T1DM. Yearly screening for diabetic nephropathy should be started 2 years after the onset of the diabetes.
Conflict of interest:None declared.
PMCID: PMC3814528  PMID: 24072081
type 1 diabetes mellitus; adolescent; complication; screening; consensus

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