Band 25, Heft 1-2

During childhood, the pituitary-testicular axis is partially dormant: testosterone secretion decreases following a drop in luteinising hormone levels; follicle-stimulating hormone (FSH) levels also go down. Conversely, Sertoli cells are most active, as revealed by the circulating levels of anti-Müllerian hormone (AMH) and inhibin B. Therefore, hypogonadism can best be evidenced, without stimulation tests, if Sertoli cell function is assessed. Serum AMH is high from fetal life until mid-puberty. Testicular AMH production increases in response to FSH and is potently inhibited by androgens. Inhibin B is high in the first years of life, then decreases partially while remaining clearly higher than in females, and increases again at puberty. Serum AMH and inhibin B are undetectable in anorchid patients. In primary or central hypogonadism affecting the whole gonad established in fetal life or childhood, all testicular markers are low. Conversely, when hypogonadism only affects Leydig cells, serum AMH and inhibin B are normal. In males of pubertal age with central hypogonadism, AMH and inhibin B are low. Treatment with FSH provokes an increase in serum levels of both Sertoli cell markers, whereas human chorionic gonadotrophin (hCG) administration increases testosterone levels. In conclusion, measurement of serum AMH and inhibin B is helpful in assessing testicular function, without need for stimulation tests, and orientates the aetiological diagnosis of paediatric male hypogonadism.

Congenital hypothyroidism (CH) is defined as thyroid hormone deficiency present at birth. Babies with CH who are not identified and treated promptly develop severe mental retardation. Most of the babies with CH do not manifest the typical known signs and symptoms of hypothyroidism, and this is most likely due to transplacental passage of some maternal thyroid hormone in addition to some residual neonatal thyroid function, as might be seen with thyroid hypoplasia, an ectopic gland, or mild dyshormonogenesis. Screening for CH has enabled the virtual eradication of the devastating effects of mental retardation due to sporadic CH in most developed countries of the world. CH is classified into permanent and transient forms, which in turn can be divided into primary, secondary, or peripheral etiologies. Permanent CH refers to a persistent deficiency of thyroid hormone that requires life-long treatment. Transient CH refers to a temporary deficiency of thyroid hormone that is discovered at birth but recovers to normal in the first few months or years of life. In the last several decades, there have been exciting advances in our understanding of fetal and neonatal thyroid physiology. In addition, advances in molecular biology have helped in understanding the early events in thyroid gland embryogenesis, mechanisms of thyroid action in the brain, the molecular basis for many of the inborn errors of thyroid hormonogenesis, and thyroid hormone action. However, many questions and challenges are still not answered. For example, the increasing numbers of surviving small and premature neonates with abnormalities in thyroid function need definite diagnostic criteria and whether they require medical therapy. Another challenge is the dilemma of finding the best screening methodology that is sensitive and cost effective.

A 12-year-old girl presented signs and symptoms of hyperthyroidism. She had a firm goiter (II°) and she stated that she felt constant warmth, nervousness and experienced palpitations. Autoimmune hyperthyroidism was diagnosed (TSH 0.022 mIU/L↓; fT4 21.0 pmol/L; fT3 7.5 pmol/L↑; antithyroperoxidase antibodies 1148.0 U/mL↑; antithyroglobulin antibodies 41.4 U/mL; thyroid-stimulating hormone receptor antibodies 2.3 U/L↑). Thyroid ultrasound showed multiple hypoechogenic areas with increased vascular flow. During treatment with methimazole, a small hyperpigmented and moderately irritated region was found on the right side of the umbilicus. It was not an allergic skin reaction to methimazole but the classic contact allergic dermatitis, probably a result of nickel in her belt. Two years after stopping the treatment she returned to clinics. She was euthyroid but manifested a firm goiter and ultrasonographic features of autoimmune thyroid disease. The diagnostic work-up concerning antithyroid antibodies is mandatory to confirm the ongoing autoimmune process with a long-term significance.

Objective: To determine if metformin improves markers of inflammation, thrombosis, and intrahepatic fat contents in children with uncomplicated obesity. Methods: Obese children with normal glucose tolerance but elevated highly sensitive C-reactive protein (hsCRP) and/or fibrinogen concentrations (>2 standard deviations) were randomized to structured diet/exercise or diet/exercise and metformin for 6 months. Blood samples, dual energy X-ray absorptiometry data, and liver magnetic resonance images were obtained. Results: Forty-two of 66 recruited children (7–18 years) completed 6 months. Weight loss was modest but more pronounced in the metformin group (–4.9±1.0 kg) than in the diet/exercise group (–1.7±1.1 kg, p<0.03), whereas hsCRP and fibrinogen decreased more in the diet/exercise pubertal group. Baseline intrahepatic fat was high but decreased only in the diet/exercise (not metformin) pubertal group. Conclusions: Six months of metformin therapy improved weight loss and reduced abdominal adiposity, but did not enhance the beneficial effect of diet and exercise on markers related to inflammation, thrombosis, or hepatic fat in obese children with normal glucose tolerance.

Objective: To compare serum concentrations of inflammatory cytokines, interleukin 6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), adiponectin, and tumor necrosis factor α (TNFα), before and after 3 months treatment with metformin in obese adolescents with insulin resistance (IR). Design and subjects: This was a randomized, double-blinded, clinical trial of two groups of obese adolescents with IR, aged 9–18 years: a placebo group (n=14) and a metformin group (n=12) who received 500 mg metformin every 12 h for 3 months. Anthropometric and biochemical (metabolic and inflammatory cytokines) assessments were compared at the beginning and end of treatment. Results: After 3 months of treatment, body mass index (kg/m 2 ) was reduced in both groups: placebo group (32.82±6.37–32.10±6.52; p=0.011) and metformin group (33.44±5.82–32.71±5.77; p=0.015). Serum fasting insulin concentrations (pmol/L) increased in the placebo group (189.45±112.64–266.06±167.79; p=0.01) and showed a slight decrease in the metformin group (256.82±113.89–229.25±86.53; p=0.64). Adiponectin concentrations (μg/mL) decreased in the placebo group (13.17±7.31–5.65±6.69; p=0.02), while these remained stable in the metformin group (8.57±3.98–7.86±6.23; p=0.64). In the metformin group, significant reductions were found in the variances of serum TNFα concentrations (p=0.006; Levene test). Conclusion: These results suggest that treating obese adolescents with IR using metformin for 3 months is an option for patients without response to traditional lifestyle change because metformin improves inflammatory activity, which is an etiological factor in cardiovascular disease development.

Background/objectives: Extremes of birthweight (BW) have been associated with increased rates of metabolic risks. The objective was to study the prevalence of metabolic risks markers among obese and overweight (OW) subjects according to BW. Subjects/methods: A cross-sectional study was performed in a cohort of 1002 patients (2–18 years, 40.6% male) evaluated for OW or obese subjects in two private clinics. Anthropometrics, fasting lipids, glycemia, and insulin were obtained. Results: Of the subjects, 76.1% were born appropriate for gestational age (AGA), 10.9% small for gestational age (SGA), and 13% large for gestational age (LGA). Children born LGA presented a more severe degree of obesity compared with those born AGA and SGA (p<0.0001). No differences in glycemia, insulin, and lipid levels were detected among the groups. Abnormal glucose was found in 37 subjects: one with type 2 diabetes mellitus (from the previously glucose-intolerant subjects), 10 with glucose intolerance, and 27 with impaired fasting glucose. According to Boney criteria, 6.6% of the patients (6–18 years old) exhibited metabolic syndrome (MS) (69.4% AGA, 12.9% SGA, and 17.7% LGA). Conclusions: Being born LGA represents a higher risk of severe obesity. At this age, the most frequent component of MS was an abnormal lipid profile with low high-density lipoprotein and high triglycerides. Finally, the most frequent finding associated with abnormalities of glucose tolerance was a family history of diabetes. Thus, BW, lipid profile, and family history are mandatory when these patients are evaluated.

Aim: The aim of the study is to assess the association of overweight/obesity and early menarcheal age. Patients and methods: The study comprised 2127 healthy girls aged 9 to 16 years. Menarcheal age was estimated by status quo method. The girls’ body weight and height were measured and their body mass index (BMI) calculated. The diagnostic criteria of the WHO were used to define overweight and obesity. Girls with a BMI in the range of 1–2 for age and sex were considered overweight. Girls with a BMI >2 standard deviation (SD) for age and sex were considered obese. Girls with a BMI >1 SD for age and sex were considered overweight/obese. Social and economic status was analyzed according to years of education completed, parents’ occupations, and the number of children in the family. Results: Median menarcheal age was 12.83 years; 25% girls had menarche before 11.98 years and 75% by 13.69 years. By 11.21 years, 10% of girls had had menarche, and 95% by 14.91 years. Girls who had menarche before 11.98 years had higher body weight values (48.5 vs. 40.2 kg) (p<0.001), height (159.3 vs. 149.2 cm) (p<0.001), and BMI (18.9 vs. 17.8 kg/m 2 ) (p=0.003) than their peers without menarche. Girls with menarche before 11.98 years had significantly higher BMI values than girls with menarche after 13.69 years (18.94 vs. 17.84 kg/m 2 ) (p=0.008). Girls with menarche before 11.98 years and those after 13.69 years differ significantly in distribution of thinness (3.4% vs. 2.54%), normal weight (85.3% vs. 91.8%), and overweight/obesity (11.2% vs. 5.7%) (p=0.002). Conclusions: Girls who experienced early menarche are significantly more often overweight/obese. Overweight/obesity may be considered as one of the predictors for the early occurrence of menarche.

Chitotriosidase (ChT) is an enzyme secreted by activated macrophages and involved in defense against, and in degradation of chitin-containing pathogens, such as fungi, nematodes, and insects. In addition, it plays an important role in the development of atherosclerosis related with systemic low-grade inflammation. To this effect of activity of ChT, we aimed to investigate serum ChT activity in obese subjects and to determine to relation with insulin resistance and high-sensitive C-reactive protein (hsCRP). A total of 73 obese subjects (10.9±2.6 years of age, 44 male patients) and 41 age and gender-matched healthy lean subjects (11.6±2.9 years of age, 18 male patients) were included in this study, between 2007 and 2008. The criterion for diagnosing obesity was defined as the body mass index (BMI) being over 97th percentile of the same gender and age. Fasting serum glucose, insulin, hsCRP and ChT levels were measured. We compared the differences in variables between obese and lean subjects with Student’s t-test compared after ascertaining that the data were normally distributed. All data were expressed as mean±standard deviation. There was statistically significant increase in serum ChT activity of obese subjects, while there was statistically significant difference in serum hsCRP levels when compared to healthy lean subjects (30.0±17.9 and 23.0±17.8, p=0.045; 2.3±3.1 and 0.7±1.2, p=0.001). Obese subjects had significantly higher BMI-SDS, TG and HOMA-IR and lower HDL-C levels when compared with the healthy lean subjects (p<0.05). Correlation analysis showed no significant correlation between serum ChT activity and hsCRP, HOMA-IR and BMI-SDS (p>0.05). Although the data need to be validated by further investigation, the observations made in this study seem to indicate that serum ChT activity may not be a useful marker for monitoring systemic low-grade inflammation and insulin resistance in obese subjects.

Obesity is one of the major health problems of modern society. The prevalence of this condition has increased at an alarming rate, especially the most severe form (body mass index >40 kg/m 2 ). The cardiovascular problems that generally accompany obesity are the focus of a large number of studies. Conventional echogram and more current modalities, such as tissue Doppler, strain and strain rate are valuable tools for the detection of subclinical dysfunction and the early diagnosis and treatment of patients.

Behavioral changes are the first line of treatment for dyslipidemia in adolescents, but outcome data on the effectiveness of this approach are inconsistent. This study aims to assess the effect of a 13-week multicomponent wellness intervention program, which included weekly nutrition classes and structured cardiovascular, flexibility, and strength training on dyslipidemia in nine overweight/obese [body mass index (BMI) ≥85th percentile] and nine lean (BMI <85th percentile) adolescents. Clinical measurements and lipid profile assessment were performed before and after the intervention. At the completion of the study, the overweight/obese adolescents demonstrated a 15% increase in high-density lipoprotein cholesterol (HDL-C) levels (mean, 47±8 vs. 54±5 mg/dL), whereas there was no improvement in BMI or other measurements. The participants in the lean group showed no change in their anthropometric and serum parameters. A multicomponent wellness intervention resulted in a significant increase of cardioprotective HDL-C levels, which have been associated with coronary health in adulthood.

The prevalence of obesity among children and adolescents has been rapidly increasing in recent years. Obese individuals are at risk for vitamin D deficiency. The aim of this study was to investigate the relation of vitamin D deficiency with puberty and insulin resistance in obese children and adolescents. A total of 106 children and adolescents (48 prepubertal and 58 pubertal) between 8 and 16 years of age were included in the study. Fasting blood glucose, insulin, lipid profile, calcium, phosphorus, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D [25(OH)D] levels, as well as blood glucose and insulin concentrations at 120 min of oral glucose tolerance test were measured. Insulin resistance was calculated using the homeostasis model assessment. Daily vitamin D intake was questioned. Serum 25(OH)D level was normal in only 3.8%, insufficient in 34.0%, and deficient in 62.2% of the subjects. There was a statistically significant rate of 25(OH)D deficiency in the pubertal group compared with that in the prepubertal group. Those subjects with 25(OH)D deficiency were found to have greater insulin resistance. Vitamin D deficiency is common among obese children and adolescents. Low vitamin D levels in obese individuals may accelerate the development of metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease by further increasing insulin resistance.

Background: Ultrasonography of cortical and cingulum maturity patterns, were studied in newborns and infants with congenital hypothyroidism (CH). Method: Transversal study of 29 newborns and infants with CH, detected by neonatal screening and confirmed with thyroid function test, thyroid ultrasonography, and thyroid scintigraphy. During the first 2 months of life, transfontanelar brain ultrasonography was performed. Brain cortex maturity was assessed by normality referents provided by Slagle and Timor methods. Results: Cortical immaturity signs were observed in 69% of infants (20 patients with Slage’s method brain cortex development delay (Pearson’s p=0.05). Logistic nominal analysis for normality prediction demonstrated a correlation between brain cortex development and age, bone age, treatment duration, and type of CH. The most sensitive detecting technique was sagittal sight by Slagle’s method. Conclusions: Brain cortex delayed development is frequent in children with CH. Bone age, postnatal age at treatment start, and time since treatment start, correlates with neurological development, but not athyreosis or sublingual nodule.

Objective: To study two subsets of patients with GH deficiency (GHD) during the transition period: childhood onset GHD (CO-GHD) and patients who develop GHD during the transition phase (TO-GHD) before and after GH replacement. Patients and measurements: In 1340 GHD subjects from KIMS (Pfizer International Metabolic Database), CO (n=586) or TO (n=754), background characteristics, anthropometric measurements, IGF-1, lipids and quality of life (QoL) were evaluated at baseline and after 3 years of GH replacement. Results: Both groups responded similarly to GH treatment. Changes of clinical outcomes were mainly determined by their value at baseline. Onset of the disease in childhood or transition period did not appear to be a significant predictor of response in any of the clinical outcomes. Conclusions: Age at GHD diagnosis was a significant predictor for many outcomes at baseline, but disease onset did not appear as an independent predictor concerning changes after 3 years of GH treatment. The results suggest that GH replacement during the transition period should be considered independently of the onset of the deficiency.

Background: Vitamin D deficiency can be treated with daily vitamin D supplementation for several weeks or single-day high-dose vitamin D therapy (stoss therapy). However, there are few studies comparing efficiency and side effects of these two treatment models. Objectives: We aimed to compare the efficiency and side effects of low-dose stoss therapy and lower-dose daily vitamin D supplementation in children with vitamin D deficiency. Materials and methods: Our subjects were 42 patients with ages between 5 months and 3 years with diagnosed vitamin D deficiency. All children had 25-hydroxyvitamin D level lower than 20 ng/mL. Serum biochemical markers and spot urine calcium/creatinine (Ca/Cr) ratio were measured before and after the therapy. Twenty-one patients were treated with stoss therapy (150,000 U/single-dose oral vitamin D3), and 21 patients were treated with daily high-dose vitamin D3 therapy (2000 U/day vitamin D, 6 weeks). Renal ultrasound was performed for both groups of patients after 1 month. Results: Biochemical parameters and Ca/Cr ratio at the end of therapy did not differ in each groups. However, vitamin D levels at the end of stoss therapy were significantly increased compared with daily lower-dose vitamin D therapy group (p<0.001). Nephrocalcinosis or renal stone was not detected by renal ultrasound. Conclusion: In both groups, hypocalcemia was not detected during the therapy. There was no evidence about the increasing risk of hypercalciuria in low-stoss therapy. Higher vitamin D levels were obtained in low-stoss therapy group.

Aim: The objective of this study is to compare the hormonal profile of children with isolated hypospadias to controls and hypospadiacs with associated anomalies. Materials and methods: Study design: Prospective observation at a tertiary referral hospital. Study subjects: One hundred consecutive children (0–12 years) with isolated hypospadias (H), 23 with hypospadias and associated anomalies (HO). Controls: One hundred children (0–12 years) without any genitourinary/endocrine abnormalities (C). Procedure: Pre-human chorionic gonadotropin (HCG) and post-HCG fasting blood samples were drawn for estimation of serum gonadotropins, dehydroepiandrosterone sulfate (DHEA-S), estrogen (E), progesterone (P), and testosterone (T) and dihydrotestosterone (DHT). Statistical analysis: Differences in hormonal levels between controls and subjects were computed with p≤0.05 as significant. Results: Compared with controls, “H” had significantly higher follicular stimulating hormone (FSH) (1.37 vs. 1.29 mIU/mL p=0.01), lower estrogen (8.08 vs. 13.78 pg/mL, p=0.00), and lower DHEA-S (27.34 vs. 40.24 μg/dL, p=0.03) levels; HO had higher FSH, lower basal T (0.13 vs. 0.46 ng/mL, p=0.01), and lower peak testosterone (1.53 vs. 2.32 ng/mL, p=0.01). “HO” had lower androgens (basal T, 0.13 vs. 0.29 ng/mL, p=0.03; peak T, 1.53 vs. 2.36 ng/mL, p=0.01), and higher estrogen (12.56 vs. 8.08 pg/mL, p=0.001) and progesterone (0.46 vs. 0.31 ng/mL, p=0.04) levels in comparison with H. Conclusion: Consistently lower output of androgens among HO explains the association of other anomalies (generally undescended testes) in them. High FSH among hypospadiacs hints at the possibility of Sertoli cell dysfunction and may have long-lasting sequelae for reproductive functions during adulthood. However, Leydig cell functions are affected more among HO.

Background: Translocation of the SRY gene to the paternal X chromosome is the explanation for testis development in the majority of subjects with 46,XX testicular disorder of sexual development (DSD). However, nearly all subjects with 46,XX ovotesticular DSD and up to one third of subjects with 46,XX testicular DSD lack SRY . SRY -independent expression of SOX9 has been implicated in the etiology of testis development in some individuals. Methods: We amplified microsatellite markers in the region of SOX9 from a cohort of 30 subjects with either 46,XX testicular or 46,XX ovotesticular DSD to detect SOX9 duplications. Results: Duplication of the SOX9 region in 17q was not detected in any subject. Conclusion: Duplication in the region of 17q that contains SOX9 is not a common cause of testis development in subjects with SRY -negative 46,XX testicular or ovotesticular DSD.

Background: Self-assessment of puberty has been reported to correlate well with staging by a physician. No previous study has evaluated the use of an orchidometer to assess testicular size in boys. Study design: This study included 44 girls and 56 boys, 10–16 years old, with assessed Tanner staging. The boys also used an orchidometer. The correlation with a professional’s staging was analyzed using percentage agreement (PA). Results: For girls, the PA for breast development was 52%, and for pubic hair, 64%. There was no case of the difference being greater than one stage. For boys, the PA for pubic hair was 75%. For testicular volume, the PA was 36%; in 95%, the difference was only one size. Conclusions: We found pubertal self-assessment, including the use of an orchidometer for boys, to be a useful method. However, if the purpose is to determine exact pubertal onset, the assessment should be made by a trained professional.

Objective: To assess the association between seroconversion and catch-up growth during the first year of a gluten-free diet (GFD) program in children with celiac disease (CD). Methods: All prepubertal and biopsy-proven children diagnosed with CD between January 1999 and August 2009 were included in a retrospective study (n=55). Growth parameters and celiac antibodies were documented before and after 6 (period 1) and 12 months (period 2) of GFD, respectively. Results: Mean height velocity-standard deviation score (SDS) was significantly higher in period 1 compared with that in period 2 (2.90±3.20 vs. 0.20±2.08, p<0.001) irrespective of the serology status, with marginal difference in mean weight-SDS gain (p=0.074). Mean levels of height velocity-SDS and the weight-SDS gain were similar in the seropositive and seronegative groups in both periods of the study. Mean height-SDS and weight-SDS levels after 6 months were higher than those in baseline levels, both in seropositive (–0.47±0.91 vs. –0.82±0.82, p<0.001 and –0.59±1.17 vs. –1.11±1.33, p<0.001, respectively) and seronegative patients (–1.02±1.14 vs. –1.50±1.12, p<0.001 and –1.19±1.27 vs. –1.45±1.40, p=0.048, respectively). These growth parameters were higher at the end compared with the beginning of period 2, but only in seropositive patients. Conclusions: The most remarkable catch-up growth in children with CD can be expected during the first 6 months of GFD, irrespective of the serology status.

Background: Premature adrenarche (PA), the appearance of pubic hair before the age of 8 years in girls and before 9 years in boys, may predict future morbidity, such as metabolic syndrome (MS). Objective: The purpose of this study is to assess carotid artery ultrasound changes in children with PA. Design/methods: PA children were matched with a group of prepubertal controls without PA. Subjects and controls underwent clinical and biochemical evaluation and sonograms of the carotid arteries. Results: Twelve children with PA and their matched controls were studied. Carotid artery ultrasonography showed elevation of the inner and outer diameter of the left carotid, and the cross-sectional area of the lumen and outer wall, and the outer diameter of the right carotid artery in PA. However, none of the above results maintained statistical significance when a Hochberg correction was applied. Conclusions: Carotid artery diameter and cross-sectional area may be useful non-invasive markers of vascular pathology and MS in premature pubarche.

Determining the precise cause of adrenal insufficiency occurring in infancy is of critical importance for both the correct management of affected children and the provision of correct genetic advice to their families. We report a case of a 24-year-old, male patient bearing a new mutation in the DAX1 gene. The patient was born at term, from a healthy pregnancy. Adrenal insufficiency was diagnosed in the fourth week of life with a salt-wasting syndrome, but it was mistakenly believed to be secondary to congenital adrenal hyperplasia (CAH). On hydrocortisone substitution, the child continued to develop normally, but the diagnosis of CAH was questioned, which led to an episode of an abrupt withdrawal of hydrocortisone substitution and subsequently caused a reoccurrence of a life-threatening salt-wasting syndrome. Owing to close follow-up, the patient’s gonadal axis deficiency was promptly identified, which allowed an assisted but successful onset of puberty. We proposed the diagnosis of adrenal hypoplasia congenita (AHC) in this patient and identified a hemizygous mutation (c.1130delAinsGT, p.E377GfsX12) in exon 1 of the NR0B1 gene. To our knowledge, the detected mutation has not been described previously (HGMD Professional 2010.4, Human Gene Mutation Database, Biobase, Beverly, MA, USA). It leads to a frameshift, a premature stop codon, and, most likely, non-sense-mediated decay of the mutant mRNA. In this case, close patient follow-up minimized the detrimental consequences of an incorrect diagnosis. Nevertheless, it highlights the importance of the early precise diagnosis of patients with AHC.

We report on a 7-year-old girl with generalized seizures, somnolence, fever, and respiratory distress. The increase of sinus tachycardia with good hydration, sufficient analgesia, and hyperthermia in our patient led to the determination of thyroid hormones, and therefore finally to the diagnosis of a thyrotoxic crisis in Graves’ disease. Thyrotoxic crisis is a very rare but severe disease with an incidence of 0.1/100,000–3/100,000 among children. Important differential diagnoses of hyperthyroidism are Hashimoto thyroiditis, paraneoplastic thyroid-stimulating hormone production, thyroid autonomy, as well as central hyperthyroidism. Although symptoms disappear by thyrostatic therapy (thiamazole, carbimazole, dexamethasone), a euthyroid status could only be achieved by thyroidectomy. Thyrotoxic crisis should be considered a differential diagnosis in case of resistant unexplained sinus tachycardia, seizures, and encephalopathy. Immediate and adequate therapy contributes significantly to a reduction in the high morbidity and mortality rates. A combination of several treatment approaches for hyperthyroidism can lead to a successful outcome.

Consumptive hypothyroidism is a rare condition related to massive infantile hemangiomas producing an excess of the thyroid-hormone-inactivating enzyme type 3 iodothyronine deiodinase. We report the first case of consumptive hypothyroidism secondary to a large parotid hemangioma, highlighting the difficulties in selecting an adequate therapeutic strategy. The affected child was initially referred to our center for congenital hypothyroidism with a hypoplastic thyroid gland. l-Thyroxine (l-T4) replacement therapy was started at seven days of life. In the following weeks, the hemangioma rapidly increased in volume and the child developed severe hypothyroidism refractory to high doses of l-T4 therapy. The concentration of reverse triiodothyronine was elevated, suggesting that the underlying cause was an excessive conversion of thyroid hormones by high type 3 iodothyronine deiodinase levels in the tumor. Corticosteroid treatment showed only partial benefit. Introduction of propranolol instead led to normalization of thyroid hormones along with a dramatic involution of the hemangioma.

Background: The etiology of hypospadias is multifactorial. Abnormal androgenic secretion and/or action during the development of external genitalia may be involved in the etiology of this congenital malformation. This study explored CAG and GGN polymorphisms in the androgen receptor (AR) gene, which may affect its transcriptional activity, in patients with isolated hypospadias. Methods: The length of the CAG/GGN polymorphisms was determined in 44 boys with non-severe (glandular) or severe (penile or penoscrotal) isolated hypospadias and with a normal hormonal evaluation. In addition, 79 healthy men, as controls, were studied. Results: Mean CAG repeats were significantly higher in total and severe cases compared to controls (24.4±2.8 and 24.7±3.1 vs. 22.7±3.3, respectively; p<0.05, Student’s t and Bonferroni test). In addition, a frequency of CAG alleles >23 was significantly different in total and severe cases compared to controls (70.5% and 74.1% vs. 39.2%, respectively, p<0.05, χ 2 and Bonferroni test). The median number and the distribution of GGN polymorphisms were similar in cases and controls. Conclusion: Boys with isolated hypospadias have longer CAG alleles in their AR, which may be related with the development of this congenital malformation.

Bloody nipple discharge is an uncommon finding in the pediatric population, without clear diagnostic and therapeutic guidelines established. We noted a case of a 3-month-old male infant who presented with bilateral blood-stained nipple discharge, with unremarkable medical history. Sonographic findings revealed bilaterally dilated ducts and cysts with mixed iso- and hypoechoic intraductal content. Possible causes of this condition include hyperlaxity syndrome with decreased function of elastic fibers and fibrocystic changes in breasts, and unusual response to maternal hormones, transferred to the neonate either transplacentally or through breastfeeding. Given the most probable benign etiology and self-limiting nature of the described condition, a conservative approach is suggested. Unnecessary invasive procedures should be avoided.

The 49, XXXXY syndrome is a rare sex chromosome polysomy, first described by Fraccaro and colleagues in 1960. The approximate incidence of this disorder is 1 in 85,000 male births. To date, >100 cases had been published in the literature. Patients with 49, XXXXY syndrome show some peculiar clinical features, such as mental retardation, facial dysmorphism, ambiguous genitalia, and multiple skeletal and cardiac defects. We report a new case of 49, XXXXY syndrome; the first Italian case to our knowledge.

The subdermal implant is an effective delivery system for the gonadotropin-releasing hormone analog histrelin in the treatment of central precocious puberty. In younger patients, implantation and replacement of the implant is performed under general anesthesia. This obviates the need for frequent intramuscular injections and has been shown to be preferable to patients and families. However, the implantation procedures have been complicated by fracture during surgical withdrawal. This paper discusses one such case and the intraoperative technique that led to effective withdrawal of the fractured implant.

Hajdu-Cheney syndrome is an autosomal dominant disorder characterized by acroosteolysis of the distal phalanges associated with digit abnormalities, distinctive craniofacial changes, dental anomalies, and a proportionate short stature. The pubertal development of children with Hajdu-Cheney syndrome is usually normal in the literature, although we here first describe a girl who was found to have Hajdu-Cheney syndrome accompanied with premature ovarian failure. She showed a follicle-stimulating hormone-dominant response on luteinizing hormone-releasing hormone test and did not show any sex differentiation abnormality or adrenal steroid hormone deficiency. On the basis of the findings in our patient, premature ovarian failure may be a complication of Hajdu-Cheney syndrome and thus an early endocrinological evaluation of patients is important.

Proopiomelanocortin (POMC) is the polypeptide precursor of several biologically active melanocortin peptides that have important roles in the regulation of food intake and energy homeostasis, adrenal steroidogenesis, melanocyte stimulation, and immune modulation. Mutation of the POMC gene has been associated with adrenal insufficiency, early-onset obesity, and red hair pigmentation. We describe an Indian boy with secondary hypocortisolism, hyperphagia, early-onset obesity, and skin pigmentation problem. Genetics analysis revealed a novel homozygous mutation in the POMC gene (p.Arg86Term). The boy also had central hypothyroidism in addition to the secondary hypocortisolism. Genetics analysis for the POMC gene should be considered in patients with secondary hypocortisolism, early-onset obesity, and pigmentary problems.

Background/Aims: The effect of the rising prevalence of nonalcoholic fatty liver disease on the 25-hydroxylation of pre-vitamin D in the liver, and consequent glycemic control in children with diabetes mellitus is not known. Our aim was to determine whether mild hepatic dysfunction was associated with impaired 25-hydroxylation of pre-vitamin D, and if this vitamin D deficiency was associated with impaired glycemic control in children and adolescents with type 1 diabetes (TIDM) and type 2 diabetes (T2DM). Methods: We analyzed simultaneously measured HbA1c, ALT, AST, and 25OHD levels and clinical parameters in 121 children and adolescents with T1DM (n=81) and T2DM (n=40). The subjects, ages 11–21 years, all had diabetes of >6 months duration. Multivariate linear regression was used to analyze the associations, while comparisons between subgroups were made using two-tailed Student’s t-test. Results: Vitamin D deficiency (25OHD <15 ng/mL (37.5 nmol/L) was more prevalent in T2DM patients (47.5%) compared to T1DM patients (18.5%). Subjects with T2DM had significantly elevated transaminases (AST 39.3±2.0 vs. 22.4±1.4, p<0.001; ALT 30.6±1.8 vs. 18.7±1.3, p<0.001) compared to T1DM patients, and demonstrated a significant inverse relationship between their HbA1c and 25OHD levels (β=–0.42, p=0.02), compared to T1DM subjects (β=–0.06, p=0.62). Conclusions: The association of elevated ALT with vitamin D deficiency suggests that hepatic dysfunction could impair vitamin D metabolism and negatively impact glycemic control in youth with T2DM.

Williams-Beuren syndrome (WBS) is a multisystem disorder that has a broad range of clinical findings including characteristic facial appearance, supravalvular aortic stenosis, dental and developmental abnormalities, and endocrinologic disorders including but not limited to the development of hypercalcemia. We present the case of a 10-month-old girl, with a history of intrauterine growth restriction, who presented with symptoms of weight loss and poor feeding. She was found to have severe elevation of her serum calcium to 20 mg/dL. She was subsequently diagnosed with WBS by fluorescent in situ hybridization analysis. The exact etiology of hypercalcemia in patients with WBS is unknown, but there are several hypotheses. Treatment of hypercalcemia in WBS is achieved with intravenous (IV) fluids, loop diuretics, and a low calcium diet; bisphosphonate therapy is required if adequate decreases in the serum calcium level are not achieved with traditional therapy.

Mucolipidosis type II (ML II) is a rare disease. Its diagnosis is often missed, as it may present with rickets-like picture. ML II and rickets both may have physical fi ndings including fractures, kyphoscoliosis, as well as similar biochemical and radiographic studies. Their similarities often lead to delayed diagnosis and treatment for ML II patients. We describe two cases of ML II, both confi rmed by DNA sequencing of the GNPTAB gene and by plasma enzymes assays. The second patient had a much better outcome because of prompt diagnosis and was able to undergo bone marrow transplant as a result. We also review all literature in the English language for cases of ML II presenting with rickets-like pictures.

Rett syndrome (RS) is a neurodevelopmental disorder mainly affecting girls. It is characterized by a normal prenatal and perinatal period, apparently normal development for the first 6 months of life, and then a decelaration in head growth, loss of hand and communication skills, psycho­motor retardation, as well as the development of sterotyped hand movement and truncal or gait apraxia. It has been shown to be related to mutations in the MECP2 gene located on Xq28. Diabetes mellitus (DM) type 1 may be associated with certain genetic disorders such as Down syndrome, Turner syndrome, and Klinefelter syndrome. In this work, we report the case of a 9-year-old girl with RS who developed DM at the age of 6. To our knowledge, our patient is the third case reported to date of DM associated with Rett syndrome.

A 9-year-old boy presented with recurrent episodes of hypoglycemic seizures. He had classical facies and body asymmetry suggestive of Russell-Silver syndrome. On eva­luation, he was found to have ketotic hypoglycemia with growth hormone deficiency.

Conn syndrome, which is rarely encountered in children, is characterized by increased aldosterone, low renin level, and arterial hypertension. Severe complications, such as impaired vascular smooth muscle function secondary to increased aldosterone, endothelial dysfunction, deterioration of left ventricular functions, acute effects on the cardiovascular system, and proteinuria, may be observed. We present a case of primary aldosteronism in a patient who has been followed up for ~2 years. A 15-year-old girl complained of headache lasting for ~1.5 years, which was diagnosed as severe hypertension. All of her systemic examinations were normal other than the hypertension. Primary aldosteronism was diagnosed on the basis of hypokalemia and alkalosis accompanied by plasma renin activity of 3.9 ng/mL/h and an aldosterone level of 1007 pg/mL (normal: 40–480). Left adrenalectomy was performed because a 10×12×12 mm adenoma was detected on abdominal magnetic resonance imaging. Although aldosterone levels returned to normal values after the surgery, antihypertensive treatment was continued because of the persistent hypertension. As the 24-h ambulatory blood pressure values of the patient were normal at 10 months after the operation, the treatment was stopped, and she was followed up for 15 months without any treatment. Since then, she has been normotensive.

The established facts to date relating to Floating-Harbor syndrome (FHS) are its characteristic typical triangular facies with bulbous nose and thin lips, short stature, delayed bone age, and mild mental retardation with delay in expressive speech; its sporadic occurrence without Mendelian inheritance; and its unknown cause. Little is known about the growth hormone-insulin-like growth factor 1 (GH-IGF-1) axis and the effect of GH treatment in children with this syndrome. We report on a 9-year-old girl born small for gestational age (SGA, birth length –2.2 standard deviation score) with persistent short stature who has been treated with GH from 3.5 years onward with a modest growth response. Revision of the case led to the diagnosis of FHS. No abnormalities were found in the sequence or copy number of IGF-1 receptor or in the genomic single-nucleotide polymorphism array. GH treatment led to an increase in serum IGF-1 in the upper normal range, but the growth response was modest, suggesting a defect in IGF-1 signaling. Early recognition of this entity is important, as it enables specific diagnostic tests targeted at other abnormalities associated with FHS.

Background: Rare cases of human glucocorticoid receptor (hGRα) ( NR3C1) gene mutations have been described in the gemline or somatic state in Cushing’s disease (CD). Aim: We describe a pediatric patient with CD with clinical evidence of partial glucocorticoid resistance (GR) due to the relative absence of stigmata of Cushing’s syndrome (CS). Case description: A 14-year-old boy with slow growth and hypertension, but no other signs of CS was admitted for CD evaluation. Urinary free cortisol levels (UFC) were consistently 2-3-fold the upper normal range. Pituitary magnetic resonance imaging (MRI) revealed a 3×4 mm hypoenhancing lesion in the right side of the pituitary gland anteriorly (microadenoma). A graded dexamethasone suppression test indicated that the patient had partial GR. Histology confirmed an adrenocorticotrophin (ACTH)-producing pituitary adenoma. We hypothesized that a NR3C1 mutation was present. Sequencing of the entire coding region of the gene produced normal results in both peripheral and tumor DNA. Conclusion: We present the case of a pediatric patient with an ACTH-producing tumor but little evidence of CS. No mutations in the coding sequence of NR3C1 were detected. We conclude that low level somatic mosaicism for NR3C1 mutations or a mutation in another molecule participating in hGRα-signaling may account for this case.

Decreased bone mineral density (BMD) has been documented in adults with Cushing disease (CD), and allelic variants of the vitamin D receptor (VDR) gene have been associated with osteopenia. Genetic factors play an important role in bone accrual and its response to various diseases; among them, the most studied are the allelic variants of the VDR gene. There is debate as to whether described variants in the VDR gene have an effect on BMD. In the current study, we sought to analyze whether BMD differences in patients with CD were associated with the Taq1 and Apa1 VDR allelotypes. The data showed lack of association between BMD and these widely studied VDR polymorphisms, suggesting that the effect of endogenous hypercortisolism on bone in the context of CD does not depend on VDR genotypes.

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No abstract available