Band 28, Heft 9-10

Objective: The objective of this study was to investigate changes in the hypothalamic-pituitary-adrenal (HPA) axis after recombinant human growth hormone (rhGH) therapy. Subjects: Subjects included children with growth hormone deficiency (GHD). Methods: We conducted a multicenter, retrospective study that assessed 72 GHD patients treated with rhGH during 6 months. Patients were classified into two groups: isolated GHD (IGHD; n=20) and multiple pituitary hormone deficiencies (MPHD; n=52). The HPA axis and other hormones were evaluated at baseline and every 3 months. Results: In the MPHD group, 32 patients had adrenocorticotrophic hormone deficiency and received hydrocortisone before rhGH therapy. In the other 20/52 MPHD patients, the cortisol (COR) level was significantly reduced after rhGH therapy. Moreover, 10 patients showed low COR levels. In the IGHD group, COR levels also decreased, but remained within the normal range. Conclusion: During rhGH therapy, COR levels were reduced, particularly in patients with MPHD. HPA axis should be monitored during rhGH therapy.

Introduction : Diagnosis of isolated growth hormone deficiency (IGHD) can be challenging. As short stature is common in children, confirmed diagnosis is necessary prior to commencing treatment. Pituitary hypoplasia can be seen in children with IGHD. However, confirmatory studies are lacking. Aim: To test the application of pituitary size as a marker for IGHD in a population-matched control. Patient and Method: Subjects with IGHD were enrolled. Patients had brain magnetic resonance imaging, and the height and width of the pituitary were measured. Pituitary volume was calculated as (height×width) 3/2 . A control group was recruited. Results: Sixty patients and 130 controls were enrolled. The median and age range for the patients and controls were 11 and 3–16 years and 9 and 3–17 years, respectively. Cases had a significantly lower dimensions compared to controls (p<0.001). Conclusion: Pituitary volume can be a useful marker to compliment the diagnosis of IGHD in selected patients when population-relevant normative control data are used.

Background: There is an ongoing discussion whether high doses of growth hormone (GH) may lead to cardiovascular diseases. Therefore, we studied the relationships between GH treatment and carotid intima-media thickness (cIMT), which is predictive of the development of atherosclerosis. Methods: We measured cIMT in 38 children with supraphysiological doses of GH (mean age 10.9±2.2 years; 47% male; GH indication: small for gestational age, n=31; Turner syndrome, n=5; SHOX deficiency, n=2) and in 38 age- and gender-matched healthy children without GH treatment. Furthermore, we examined cIMT in 61 children with physiological doses of GH (mean age 12.0±3.1 years; 64% male; GH indication: GH deficiency) and in 61 age- and gender-matched healthy children without GH treatment. Moreover, we analyzed blood pressure, lipids, HbA 1c , IGF-1, and IGFBP-3 in children treated with GH. Results: The cIMT levels did not differ significantly between children with and without GH treatment either in high-dose GH treatment or in physiological GH doses. In backwards linear regression analyses, cIMT was significantly related to HbA 1c , but not to age, gender, BMI, pubertal stage, indication of GH treatment, duration or doses of GH treatment, IGF-1, IGFBP-3, or to any cardiovascular risk factor. Conclusions: We found no evidence that GH treatment is associated with changes in cIMT.

Objective: To establish the frequency of the c.301_302 delAG mutation of the PROP1 gene in Romanian patients with multiple pituitary hormone deficiency (MPHD). Subjects and methods: Somatic assessment, hormonal test, bone age, magnetic resonance imaging of the pituitary gland, and molecular diagnosis were performed in 26 patients with MPHD (7 patients with familial form of MPHD and 19 patients with sporadic form of MPHD). Results: The c.301_302delAG mutation was detected in the homozygous state in 10 patients belonging to 5 unrelated families (7 patients with familial history of MPHD and 3 patients with sporadic form of MPHD). Those 10 patients presented variable pituitary hormone deficiency and pituitary morphology. Conclusions: The c.301_302delAG homozygous genotype had a high frequency of 38% (10/26), reaching 100% (7/7) in group with familial cases of MPHD and 16% (3/19) in group with sporadic forms of MPHD.

Background: Infantile anorexia nervosa (AN) is a specific eating disorder of prepubertal children. Poor data are available on growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis in this disorder. Patient report: We report on a boy (4.5 years) with progressive growth impairment. At psychiatric assessment (DC: 0-3 R, AXIS I), he fulfilled all required criteria for diagnosis of infantile AN. Endocrine evaluation suggested impaired peripheral response to GH (high GH and low IGF-1 levels), likely related to energy deficiency. Methods: Auxological evaluation was shown as raw data and SDS using Italian reference values. GH secretion was assessed by arginine provocative test; IGFI generation test was done administering recombinant GH (0.05 mg/kg/day for four days). Psychiatric assessment was performed according to the DC:0-3R protocol. Conclusion: Impaired GH-IGF-1 axis may be involved in growth delay of children with infantile AN. A strict collaboration between endocrine pediatricians and child psychiatrists is advisable in the assessment of poor growing children without recognizable organic causes, showing normal/high GH levels and low IGF-1 values.

Introduction : Mitochondrial respiratory chain (MRC) disorders, defined as primary diseases of the oxidative phosphorylation system, are a protean group of metabolic disorders, difficult to diagnose and classify. The diagnosis is complex and requires the integration of information obtained by clinical, laboratory testing, imaging and muscle biopsy. They may be associated with endocrine disorders, including hypothyroidism, diabetes mellitus, hyperinsulinemia and growth hormone (GH) deficiency. Case report : We describe a case of five years old male with polymalformative syndrome with a systemic involvement. At 6 months of age, he was sent to metabolic consultation because of facial dysmorphy and short stature. During the investigation it was diagnosed at the boy a growth hormone deficiency and because of his multisystemic involvement, muscle biopsy was carried out and showed reduced activity of complex II (38%) of the mitochondrial respiratory chain. Currently, the boy is under GH therapy with growth in the 5th percentile and coenzime Q10. Discussion : Mitochondrial biology is one of the fastest growing areas in genetics and medicine. Disturbances in mitochondrial metabolism are now known to play a role not only in rare childhood diseases, but also in many common diseases of aging. In mitochondrial disorders, short stature is a common symptom, but its underlying lesion, growth hormone deficiency, is rarely investigated.

Perrault syndrome is a rare genetically heterogeneous autosomal recessive group of disorders described in 1951 by Perrault as gonadal dysgenesis with deafness. Here we present a rare case of sporadic Perrault syndrome with short stature and growth hormone deficiency (GHD). Although there was a report on partial GHD in Perrault, our case is a first of its kind with documented GHD (Nishi Y, Hamamoto K, Kajiyama M, Kawamura I. The Perrault syndrome: clinical report and review. Am J Med Genet 1988;31:623–9). We report this case because of the rarity of keeping this condition as a differential diagnosis while evaluating for short stature with amenorrhea.

Hypophosphatemic rickets (HR) is a syndrome of hypophosphatemia and rickets that resembles vitamin D deficiency, which is caused by malfunction of renal tubules in phosphate reabsorption. Phosphate is an essential mineral, which is important for bone and tooth structure. It is regulated by parathyroid hormone, 1,25-dihydroxyvitamin D and fibroblast-growth-factor 23 (FGF23). X-linked hypophosphatemia (XLH), autosomal dominant HR (ADHR), and autosomal recessive HR (ARHR) are examples of hereditary forms of HR, which are mainly caused by mutations in the phosphate regulating endopeptidase homolog, X-linked ( PHEX ) , FGF23, and, dentin matrix protein-1 ( DMP1 ) and ecto-nucleotide pyro phosphatase/phosphodiesterase 1 ( ENPP1 ) genes, respectively. Mutations in these genes are believed to cause elevation of circulating FGF23 protein. Increase in FGF23 disrupts phosphate homeostasis, leading to HR. This review aims to summarize phosphate homeostasis and focuses on the genes and mutations related to XLH, ADHR, and ARHR. A compilation of XLH mutation hotspots based on the PHEX gene database and mutations found in the FGF23 , DMP1, and ENPP1 genes are also made available in this review.

Disorders of sex development (DSD) are a generic definition including any problem noted at birth where the genitalia are atypical in relation to the chromosomes or gonads. The most important clinical problems in DSD comprise physical and psychological disturbances and the risk of gonadal tumor development. Germ cell tumor risk is lowest (<5%) in patients with defects in androgene action or synthesis (such as complete androgen insensitivity syndrome, 5α-reductase deficiency), whereas the highest risk (15%–60%) is observed in 46,XY gonadal dysgenesis. The presence of Y chromosomal material in the karyotype increases the risk for the development of gonadal tumors. The reported age of tumor development varies based on the etiology of DSD (gonadal dysgenesis, androgen insensitivity syndrome, androgen synthesis defects, mixed gonadal dysgenesis, etc.). In the past, early gonadectomy was recommended for all cases of 46,XY DSD, however, according to current approaches, gonadal tumor risk is predicted based on the molecular diagnosis and the timing of the gonadectomy depends on the result of molecular analysis. Until now, optimal protocol in the management of DSD is still controversial. In addition to that, safe and well-accepted guidelines are needed. There is limited number of prospective studies on timing of a gonadectomy in childhood and adolescence. Therefore, evidence-based data on timing and indications of gonadectomy in patients with DSD are needed. In this review, recent data regarding gonadal malignancy risk in DSD and recommendations on timing of gonadectomy are presented.

Aim: To assess carotid intimal medial thickness (cIMT) in adolescent type 1 diabetic patients and to detect its relation with echocardiographic changes and flow mediated dilatation (FMD) in the brachial artery. Methods: The study included 62 type 1 diabetic patients and 30 healthy volunteer of the same age and sex. A blood sample was taken for analysis of glycosylated hemoglobin and lipid profile and a urine sample was taken for analysis of albumin/creatinine ratio. cIMT, echocardiography, and FMD via ultrasound were also done; t-test or Mann-Whitney U-test (for non-symmetrically distributed data) for independent variables and Pearson’s or Spearman correlation were used. Results: The mean age of patients was 16.3±1.5 years and mean duration of diabetes was 9.4±2.9 years. cIMT (Rt, Lt, and both Rt and Lt) were significantly higher, while FMD and FMD/nitrate mediated dilatation (NMD) ratio was significantly lower in diabetics. Rt cIMT had a significant negative correlation with FMD and FMD/NMD. cIMT had a significant positive correlation with left ventricular end diastolic dimension, inter ventricular septum thickness, peak mitral flow velocity during early diastole/peak mitral flow velocity during late diastole, left ventricular mass, and left ventricular mass index (p<0.05). In addition, cIMT had a significant correlation with waist circumference, waist/height ratio, albumin/ creatinine ratio, total cholesterol, and triglyceride. Conclusion: We conclude that alteration in myocardial function and vascular endothelial dysfunction induced by diabetes mellitus may begin early with the association of early atherosclerotic changes.

Background: Subjects with impaired glucose tolerance (IGT) are at risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease. The predictors of IGT in obese youth are not well described. Methods: We studied 115 obese Thai children who underwent an oral glucose tolerance test (OGTT). Plasma glucose and insulin levels were calculated for assessment of β-cell function. Hemoglobin A1c (HbA1c), lipid profile, and clinical parameters were also used to determine predictors of IGT. Results: We found that three patients had T2DM and 30 subjects had IGT. IGT patients had significantly higher fasting glucose (FG), 1-h postload glucose, 2-h postload insulin, and lower whole-body insulin sensitivity indices than in normal glucose tolerance subjects whereas other indices were comparable. By ROC curve analyses, 1-h postload glucose was the best predictor of IGT, but FG or HbA1c represented a poor diagnostic tool for prediabetes screening. Subjects with 1-h OGTT glucose >155 mg/dL had significantly lower high-density lipoprotein levels, lower insulin sensitivity, and more insulin resistance than those with 1-h postload glucose of ≤155 mg/dL. Conclusions: Abnormal glucose tolerance is highly prevalent in obese Thai youth. Several fasting indices and HbA1c fail to predict IGT. An 1-h OGTT glucose of >155 mg/dL appears to be more associated with adverse insulin dynamics and metabolic profile than 2-h postload glucose.

In a cross-sectional study of 54 patients with adolescence-onset hypogonadism (33 females, 21 males; age range: 19–40 years), medical care, quality of life, and health status were assessed. Most patients had received adequate medical care with short cumulative periods of interruption of hormone replacement. The prevalence of the metabolic syndrome was 27% in females and 19% in males. In comparison to the general population, females had both a lower bone mineral density (dual-energy X-ray absorptiometry, Z-score=−0.8, p<0.001) and a higher prevalence of obesity (age 19–29 years: study population 35%, general population 4%). The body fat percentage (dual-energy X-ray absorptiometry) was significantly elevated (age 19–29 years: females Z-score=+1.8, p<0.001, males Z-score=+2.4, p=0.001). Quality of life (SF-36) was normal. Despite adequate treatment, patients with early-onset hypogonadism are prone to develop signs and symptoms consistent with inadequate hormone replacement. A successful transition from pediatric to adult medicine seems important to optimize treatment outcomes.

Background : Septo-optic dysplasia (SOD) is a rare condition with variable clinical pictures and spectrum of findings. Objective : To analyze the spectrum of findings, frequency and age of onset of hypothalamic-pituitary dysfunctions in children with SOD. Method: A retrospective electronic medical record (EMR) chart review was done for patients with SOD seen in a tertiary care center’s pediatric endocrinology clinic between January 1, 2012, and March 31, 2014. The diagnostic criteria for SOD included presence of ≥2 of the following: (i) optic nerve hypoplasia, (ii) agenesis/hypoplasia of septum pellucidum and/or corpus callosum and (iii) hypothalamic-pituitary dysfunction. Results: Eighty patients fitting the diagnostic criteria of SOD were included in this study. The majority of patients (96%) had optic nerve hypoplasia on magnetic resonance imaging and were diagnosed due to visual issues including nystagmus (36%) or strabismus (13.8%). Hypothalamic-pituitary dysfunction was most common (51%) when optic nerve hypoplasia was present with (36%) or without (15%) dysgenesis of septum pellucidum and/or corpus callosum compared to dysgenesis of septum pellucidum and/or corpus callosum alone (4%). Hypothalamic-pituitary dysfunction was noted in 55% of patients, and most (86%) were diagnosed ≤2 years of age. Central hypothyroidism and growth hormone deficiency were most common followed by secondary/tertiary adrenal insufficiency and diabetes insipidus. Conclusions : The risk of hypothalamic-pituitary dysfunction in SOD is highest ≤2 years of age and when both optic nerve hypoplasia and dysgenesis of septum pellucidum/corpus callosum are present, suggesting a need for more frequent follow-up and screening tests for hypothalamic-pituitary dysfunction in these patients.

Objectives: To investigate serum concentrations of vaspin, apelin, and visfatin in underweight children and their association with anthropometric and nutritional markers of malnutrition. Subjects and methods: We recruited 44 underweight prepubertal children (youngest age=2 years) with thinness grades of 1, 2, and 3, and body weights <90% of ideal body weight due to loss of appetite and less frequent hunger episodes. Forty-one healthy age- and gender-matched controls were also included in the study. Serum fasting vaspin, apelin, and visfatin concentrations were measured by enzyme immunoassay technique. Results: Mean vaspin and apelin levels were significantly lower in underweight children compared to controls (vaspin: 0.44±0.18 vs. 0.58±0.35 pg/mL, p=0.024; apelin: 483.37±333.26 vs. 711.71±616.50 pg/mL, p=0.041). Visfatin levels were lower in underweight children compared to controls, but the values were not statistically significant (177.81±158.01 vs. 221.15±212.94 pg/mL, p=0.119). Conclusions : In underweight children, decreased vaspin and apelin levels should be considered in the etiology of anorexia.

Hyperinsulinaemic hypoglycaemia (HH) is caused by mutations in the key genes involved in regulation of insulin secretion from the pancreatic β-cells and mutations in ABCC8 and KCNJ11 are the most common causes of HH. Mutations in HADH (which encodes the enzyme 3-hydroxyacyl-CoA dehydrogenase) are a rare cause of HH. We report three siblings (21, 9, and 7 years old) from a consanguineous Saudi family with HH due to a homozygous mutation in HADH . All three siblings presented with HH in the 1st year of life. HH responded well to medical therapy (diazoxide/octreotide) although the 1st sibling suffered neurological damage. The protein load test revealed protein sensitivity in the 21-year-old proband, the oldest reported patient with HH secondary to a HADH mutation. Genetic analysis revealed a homozygous HADH splicing mutation (c.133-1G>A) in all three siblings. HADH mutations can present in later infancy or childhood with severe HH that is usually diazoxide responsive. Severe neurological complications such as epilepsy and developmental delay can be associated with HADH mutations. This is the 1st report of HH due to HADH mutation in an adult suggesting that HH could persist into adulthood possibly becoming milder over the years.

Objective: The purpose of the present study was to investigate the relationship between waist-to-height ratio (WHtR) and the hypertriglyceridemic waist (HTGW) phenotype to test the hypothesis that WHtR can identify adolescents at high risk of the HTGW phenotype. Methods: In 2006, anthropometric measurements were assessed in a cross-sectional population-based study of 3136 Han adolescents aged 13–17 years. Blood samples were collected to measure triacylglycerol concentrations. WHtR was calculated by waist circumference/height. The HTGW phenotype was represented by the simultaneous presence of elevated serum triglycerides and increased waist circumference. The ability of WHtR to accurately define the HTGW phenotype was assessed by area under the curve (AUC). Results: The prevalence of the HTGW phenotype was 3.3% (boys 3.6% vs. girls 2.9%, χ 2 =1.424, p=0.233). The prevalence of the HTGW phenotype increased with WHtR (p<0.001). The accuracy of WHtR in the identification of the HTGW phenotype (as assessed by AUC) was over 0.85, both in boys and girls (AUC: 0.956 in boys and 0.961 in girls). WHtR cutoff values, chosen to maximize sensitivity plus specificity, for the HTGW phenotype were calculated to be 0.48 in boys and 0.46 in girls. The sensitivities were 98.3% in boys and 97.7% in girls. The specificities were 88.0% in boys and 86.8% in girls. Conclusions: WHtR is simpler than the HTGW phenotype and does not require blood tests. The prevalence of the HTGW phenotype increased with WHtR. Higher WHtR can identify adolescents with high risk of the HTGW phenotype.

Background: Fat mass (FM) has been shown to have an effect on bone mass accrual. Though gender and ethnic differences in body composition and bone accrual during puberty have been reported, there are limited data available for Indian children and adolescents. Objective: To generate age and gender based percentile charts of FM among urban Indian children and adolescents and to evaluate the relationship with pubertal status and bone mineral content (BMC). Subjects: There were 1403 children and adolescents (boys: 826; girls: 577) in the study. Methods: Total and regional FM, BMC, and pubertal staging were assessed. Fat mass index (FMI), FM/height ratio and BMC/FM ratio, were calculated. Results: The age of the study population ranged from 5 to 18 years, with a mean age of 13.2±2.7 years (boys: 13.0±2.7; girls: 13.4±2.8 years). Total and regional FM as well as FMI increased with increasing age in both genders. The highest percent increase in mean total FM occurred in the age group >8–11 years and decreased thereafter. The total and regional FM was higher in more advanced stages of pubertal maturation. There was no difference in total and regional FM between genders in prepubertal group. The age and pubertal associated increase in FM was significantly higher in girls than boys (p<0.0001). Total as well as regional FM and FMI were positively correlated with age, body mass index, total lean mass, and BMC even after adjusting for age, lean mass, and biochemical parameters. Conclusions: Total and regional FM increased with age and pubertal maturation in both genders. FM was positively correlated with BMC.

Background: The prevalence of obesity and related cardiovascular comorbodities is increasing rapidly. Adipokines play a major role in the pathogenesis of obesity-related inflammation and hypertension. Aim: The aim of this study was to evaluate the serum adropin levels in obese children and to determine the relationship between adropin levels and blood pressure (BP) in the pediatric age group. Methods: Forty obese children (mean age: 12.5±2.5 years; male/female ratio: 18/22) and 15 healthy controls (mean age: 15±3.14 years; male/female ratio: 5/15) were included in the study. Serum adropin levels, and a number of laboratory and clinical variables were compared. Ambulatory blood pressure monitoring was performed on obese subjects. Relationship between adropin levels and BP variables was examined. Results: Serum adropin levels were significantly lower in obese subjects than in healthy controls (193.56±94 vs. 289±187 pg/mL, p=0.03). Adropin levels were correlated negatively with body mass index z -score ( r =−0.56; p=0.034). There was no correlation between serum adropin levels and laboratory variables in obese subjects. Five of the patients (12.5%) were nondipper, and nine of the patients (22.5%) had hypertension. There was no significant correlation between serum adropin levels and BP variables. Conclusion: Serum adropin levels were significantly lower in obese children; however, there was no correlation between serum adropin levels and BP variables. Further studies are needed to determine the role of adipokines on BP.

Objective: The purpose of this study was to examine the effect of chronic swallowed glucocorticoids on adrenal function during the treatment of eosinophilic esophagitis (EoE) in children. Methods: Serum cortisol levels were obtained in children with EoE pre- and post-treatment with swallowed glucocorticoids. Exclusion criteria included those on any additional steroid therapy. Once diagnosed with EoE by esophageal biopsy, subjects were treated based on current standard of care with either swallowed fluticasone or budesonide. At the time of follow-up, esophagogastroduodenoscopy and blood sampling was repeated. Both pre- and post-treatment serum cortisol samples were collected fasting, between 07:00 and 10:00, and determined using a competitive binding method assay. The distribution of differences in cortisol levels between the pre- and post-treatment samples satisfied the assumption for normality and were subsequently analyzed using the paired t-test. Results: Pre- and post-treatment serum cortisol levels were examined in 14 children who met clinical and histological diagnostic criteria for EoE. Mean age was 10.1 years (range 2–17 years) with 71% male and 29% female subjects. Swallowed glucocorticoid treatment included fluticasone in 79% and budesonide in 21% of subjects. Mean dosage of fluticasone was 704 μg daily (range 220–880 μg daily) and budesonide 0.8 mg daily (range 0.5–1 mg daily), along with a mean treatment length of 17 weeks (range 8–43 weeks). No significant difference in serum cortisol was found following treatment with swallowed fluticasone or budesonide (mean change 1.9 μg/dL, p=0.75, SD of the change=21.2). Conclusions: Swallowed glucocorticoid therapy does not appear to significantly affect the adrenal axis in children, and therefore, may represent a safe therapy for EoE.

Objective: The objective of this study was to evaluate the relationship between 25(OH)D, Vitamin D Binding Protein (DBP), and free vitamin D in premature infants. Methods: Thirty-two infants <32 weeks’ gestation were randomized to two different levels of vitamin D3 supplementation (400 vs. 800 IU/day). 25(OH)D levels were measured by LC-MS/MS; DBP was measured by validated ELISA. Free vitamin D was calculated using molar ratios of 25(OH)D and DBP. The Wilcoxon signed rank test was used to compare DBP, free D and 25(OH)D levels; Spearman’s correlation coefficients were used to assess correlations. Results: The mean gestational age at birth was 30.5 weeks; mean birth weight was 1405 g. Mean 25(OH)D levels at birth were 17.3 ng/mL; DBP levels were 297 mg/L, and estimated free vitamin D levels were 18.9. There was a statistically significant change in 25(OH)D levels after 8 weeks (24.6 vs. 39.1 ng/mL in the 400 vs. 800 group, respectively, p=0.02). DBP levels from birth to 8 weeks showed a statistically significant decrease (267 vs. 208, p=0.04). Estimated free 25(OH)D concentrations increased over the study period, from 18.9 at birth to 64.7 at 8 weeks of age (p=0.0001). Free vitamin D levels at birth were associated with global DEXA bone mineral content at discharge from the NICU (r=0.58, p=0.05). Conclusion: Supplementation with vitamin D3 increased the free portion of the vitamin D metabolite, providing increased bioavailable substrate. Improved free vitamin D levels may improve measurable outcomes such as bone mineral content and deserve further evaluation.

Objective: To evaluate the prevalence of growth disorders and obesity in schoolchildren and determine whether school health check-ups are effective in their screening. Subjects-methods: Analysis of anonymized growth and body mass index (BMI) data from 2887 children attending the 3rd grade from 2008 to 2009 after selection of 75 elementary schools in Paris. Results: Linear growth velocity was abnormal in 198 children. Height and weight were above the French reference values (+0.9±1.2 SD and +1±1.7 SD, respectively). BMI was higher, compared to reference values (+0.4±1.4 SD). At their last check-up, 20.9% of children had a BMI>+2 SD. Conclusions: School health check-ups constitute a good screening tool for growth and obesity. However, further work is needed to determine the most effective modality. The reference values currently used in France are no longer suitable and new reference charts need to be established. The high prevalence of obesity in schoolchildren remains a public health challenge.

Background: The term disorders of sex development (DSD) includes congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical. The spectrum of the 46XY (DSD) is so broad. In this study, we reviewed the clinical spectrum of a cohort of patients with 46XY DSD in a tertiary institute in the Middle East over two decades. Objective: To define the clinical spectrum of 46XY DSD in a major teaching hospital, Riyadh, Saudi Arabia. Materials and methods: This is a retrospective, case series hospital-based study. The case notes, laboratory investigations, and imaging studies were reviewed for patients with 46XY DSD over a 20 years period (1989–2010) at King Khalid University Hospital, Riyadh, Saudi Arabia. Molecular genetics were not available in all patients. Results: During the period under review; a total of 56 patients were seen with 46XY DSD due to variable etiologies. Androgen insensitivity syndromes (AIS) and 5-α-reductase deficiency were among the commonest (44.6%), with multiple siblings involvement within the family. Of these, 16 patients were showing variable degrees of insensitivity ranging between complete (n=5, 31.2%) and partial (n=11, 68.8%) insensitivity, whereas in nine patients the diagnosis of 5-α-reductase deficiency was entertained based on hormonal studies. Of interest to see was a high number of patients (n=14, 25%) either with a localized congenital anomalies such as the cloacal anomalies or generalized congenital malformations following the pattern of certain syndromes. Conclusion: A wide spectrum of causes were noted. Androgen insensitivity syndrome was the commonest. In Saudi Arabia, where consanguineous mating is high, 5-α-reductase is also a common cause of 46XY DSD.

Background: X-linked adrenal hypoplasia congenita (AHC) is caused by NR0B1 (DAX1) gene mutations. Affected male children suffer from adrenal insufficiency, leading to a salt-wasting crisis in early infancy and hypogonadotropic hypogonadism in adulthood. Objective: To characterize clinically and at the molecular level a cohort of Spanish patients with AHC. Patients and methods: Nine boys (from five families) with AHC were screened for NR0B1 mutations. Clinical and endocrine evaluations were recorded. Results: NR0B1 gene mutations were found in all analyzed patients, one of them being novel (p.Gln305*). One patient presented with preserved hypothalamic-pituitary-gonadal axis. Salt-wasting episodes, delayed puberty, and hypogonadotropic hypogonadism were common, although no association was observed between AHC phenotype and genetic mutations. None of the patients has had descendants. Conclusions: AHC phenotype cannot be predicted based on genetic results as there is no definite genotype-phenotype relationship, including intrafamilial variability. Nevertheless, genetic testing for NR0B1 mutations is indicated if there is a suspicion of an X-linked adrenal insufficiency in order to proceed with the appropriate therapy and genetic counseling.

Background: Signs of puberty in very young children are often benign, but the evaluation needed and follow-up are controversial. Objectives: The study had three objectives: 1) to analyze the frequency of diagnoses in children <3 years referred for early puberty; 2) to examine the usefulness of lab testing; and 3) to identify red flags indicating a more serious diagnosis. Methods: Charts of all children younger than age 3 referred for early puberty between 7/09 and 6/13 were reviewed. Results: Of 275 patients, 156 (57%) were diagnosed with premature thelarche (PT), 69 (25%; 56 F/13M) with genital hair of infancy (GHI) and 37 (13%, all F) with both (GHI/PT). Six patients had axillary odor only. Four patients had more serious diagnoses, one each with congenital adrenal hyperplasia (CAH), non-classical CAH, McCune-Albright syndrome and central precocious puberty (CPP). Diagnoses did not change in those who returned for follow-up. Hormone tests revealed that none of the PT patients had elevation of both luteinizing hormone (LH) and estradiol, and half of the GHI patients tested had mildly elevated DHEA-S but normal testosterone and 17-OH progesterone. Conclusions: Very few children referred for puberty at <3 years appear to have a serious underlying diagnosis, and progression of PT to CPP was not identified in this series. Hormone testing is unlikely to be helpful in typical cases of PT, GHI or both, and many such cases may be followed in the primary care setting after initial clinical evaluation.

Introduction and purpose: This study aims to investigate the effect of Gonadotropin-releasing hormone analogues (GnRHa) treatment on anterior pituitary hormones in female children with central precocious puberty (CPP). Subjects and method: There were 62 female children who had been diagnosed with CPP and received GnRHa (Leuprolide acetate, 3.75 mg intramuscular/subcutaneous/28 days) included in the study. All subjects were clinically evaluated prior to treatment and every 3 months during treatment with serum LH, FSH, ACTH, TSH, PRL as pituitary hormones, and the end hormones such as plasma E 2 , cortisol, fT 3 , fT 4 levels were measured. IGF-1 and IGFBP-3 levels were measured, and SDS was evaluated according to age and gender. Results : Prolactin levels were higher during GnRHa treatment compared to pre-treatment values although the increase was statistically significant only at month 3. In addition, while 2 (3.2%) of the patients had hyperprolactinemia before treatment, 11 (17.7%) patients developed hyperprolactinemia at different time points during treatment. Conclusion: This study concluded that GnRHa treatment resulted in hyperprolactinemia and had no significant effect other pituitary hormones.

Background: Anti-Müllerian hormone (AMH) is produced by Sertoli cells of the testes and granulosa cells of the ovary. There are limited prospective longitudinal data assessing AMH concentrations throughout childhood in both sexes. Objective: This study aimed to examine AMH throughout childhood with particular reference to the relationship of AMH to pubertal development in both sexes. Design: This is a prospective longitudinal non-intervention cohort study with annual sampling for participants aged 5–14 years. Setting: Community cohort study. Participants: A total of 307 healthy children (170 boys) recruited at 5 years from randomly selected schools in Plymouth, UK, participated in this study. Data sets are complete in 76% of the children at 14 years of age. Main outcome measure(s): Annual measures of serum AMH, follicle stimulating hormone (FSH) and luteinising hormone (LH), Tanner stage (TS). Results: Boys: AMH was stable from 5 to 7 years, increased slightly from 8 to 10 years, then declined at TS2. This decline was preceded by rising FSH and the appearance of LH. AMH correlated inversely with gonadotrophic hormones during puberty. Girls: AMH increased slightly between 6 and 10 years, peaking during the final prepubertal year before returning to near baseline levels at TS3. Inverse correlations between AMH and FSH were apparent during the prepubertal years. Conclusions: Our longitudinal data clarified the development of individual AMH levels over a 10-year period. We described modest late prepubertal peaks in both boys and girls, and confirmed the pubertal decline in boys. The inverse association of AMH with gonadotrophins in young females supports its role as a marker of ovarian function, while the precise role for AMH in relation to testicular function in young males remains unclear.

Niemann-Pick disease type C (NPC) is a fatal autosomal recessive lipid storage disease associated with impaired trafficking of unesterified cholesterol and glycolipids in lysosomes and late endosomes. This disease is commonly characterized by hepatosplenomegaly and severe progressive neurological dysfunction. There are two defective genes that cause this illness. One of these genes is NPC1 gene which is the cause of illness in 95% of the patients. The other gene is the rare type NPC2 which is the cause of illness in 5% of the patients. Patients with NPC2 usually present with respiratory distress in early infancy, which is rather unusual with NPC1 . This article discusses about a patient who died at an early age from pulmonary involvement and who subsequently was found to have a novel homozygous mutation of NPC2 gene.

Graves’ disease is the most prevalent cause of hyperthyroidism in children. The treatment commonly involves antithyroid therapy using a thionamide. We present a case of a 13-year-old girl with the antithyroid arthritis syndrome, presenting as a migratory polyarthritis, after the initiation of thionamide treatment for Graves’ disease. Antithyroid arthritis syndrome warranted immediate cessation of thionamide. Improvement of the arthritis was seen in subsequent days. As there are no other reversible treatment modalities for Graves’ disease in children, definitive treatment with radioactive iodine was needed to control the hyperthyroidism in this child. Antithyroid arthritis syndrome presenting as a migratory polyarthritis is a severe adverse effect of a common pediatric disease and should therefore be recognized by pediatricians.

Congenital hypothyroidism is a main congenital endocrine disorder, affecting 1 in 4000 births. It is not well described in sub-Saharan countries, and to draw attention to that issue, we decided to describe affected pediatric patients. We retrospectively analyzed the records of eight patients over a period of 6 years. We analyzed clinical sings of hypothyroidism and psychomotor development; hormonal assays and thyroid ultrasound were performed. We included four boys and four girls aged from 3 to 84 months at diagnosis with a median thyroid-stimulating hormone (TSH) level of 156.5 mUI/L. All except one present with a moderate psychomotor delay. Other clinical signs were classical for hypothyroidism. Thyroid ultrasound performed showed a goiter in half of patients, a normal gland in three of them and a hypoplasic gland in the last one, consonant with dyshormonogenesis. We therefore concluded that dyshormonogenesis seems to be more frequent in our context, and this raised the issue of neonatal screening of hypothyroidism in Africa.

Systemic primary carnitine deficiency is an autosomal recessive disorder caused by the deficiency of carnitine transporter. Main features are cardiomyopathy, myopathy and hypoglycemic encephalopathy. We report a Turkish case with a novel SLC22A5 gene mutation presented with a pure cardiac phenotype. During the 14-year follow-up study, cardiac functions were remained within a normal range with oral L-carnitine supplementation.

Cerebral infarction is one of the serious neurological complications of diabetic ketoacidosis (DKA). Especially in patients who are genetically prone to thrombosis, cerebral infarction may develop due to inflammation, dehydration, and hyperviscocity secondary to DKA. A 6-year-old child with DKA is diagnosed with cerebral infarction after respiratory insufficiency, convulsion, and altered level of consciousness. Femoral and external iliac venous thrombosis also developed in a few hours after central femoral catheter had been inserted. Heterozygous type of factor V Leiden and PAI-1 4G/5G mutation were detected. In patients with DKA, cerebral infarction may be suspected other than cerebral edema when altered level of consciousness, convulsion, and respiratory insufficiency develop and once cerebral infarction occurs the patients should also be evaluated for factor V Leiden and PAI-1 4G/5G mutation analysis in addition to the other prothrombotic risk factors.

Objective: The nicotinamide nucleotide transhydrogenase (NNT) enzyme is the main generator of nicotinamide adenine dinucleotide phosphate-oxidase in the mitochondrion. Mutations of the NNT gene have been recently implicated in familial glucocorticoid deficiency. We describe the long-term clinical course of a NNT-deficient 20-year-old patient with combined adrenal failure who had developed a testicular adrenal rest tumor and precocious puberty. Methods: The patient’s medical records were reviewed. Whole-exome sequencing was performed on DNA obtained from the patient and family members. Results: The patient experienced Addisonian crisis at 10 months of age. Enlarged testicular volume and precocious puberty, accompanied by increased testosterone levels, were noted at 6 years. Testicular biopsy revealed a adrenal rest tumor, which regressed after intensification of glucocorticoid treatment. Genetic studies disclosed a c.1163A>C, p.Tyr388Ser substitution on the NNT gene. This mutation is predicted to be damaging to NNT function. Conclusion: We demonstrated for the first time that the clinical spectrum of NNT deficiency may consist of mineralocorticoid deficiency and testicular involvement as well.

Tamoxifen, a selective estrogen receptor modulator, has been used in the treatment of peripheral precoccious puberty. A 5-year and 3-month-old girl, diagnosed with McCune-Albright syndrome, came in with abnormal hair growth approximately 2 months after the initiation of tamoxifen. The pattern of terminal hair on the skin following the administration of the drug and the exclusion of other causes suggested tamoxifen-induced hirsutism.