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We report on a patient with a 6.5 Mb interstitial de novo deletion in 3q24q25.2, characterized by array CGH. The patient is a 4-year and 2-month-old girl, who presented to us with mild developmental delay, absence of language, facial dysmorphism, hirsutism, strabismus, and Dandy-Walker Malformation. The main clinical signs typical of WS (Wisconsin syndrome) are evident in the patient. The molecular mapping of WS in 3q23q25 allowed geneticists to define the syndrome more accurately. Comparing the present patient's phenotype with that of cases with a molecular characterization so far reported, it was possible to narrow the critical region for WS to an interval of 750 Kb, where two genes (MBNL1 and TMEM14E) are harbored. The potential role of MBNL1 in causing the WS phenotype is discussed. © 2016 Wiley Periodicals, Inc.

The Italian Consensus Position Statement on Diagnosis, Treatment and Prevention of Obesity in Children and Adolescents integrates and updates the previous guidelines to deliver an evidence based approach to the disease. The following areas were reviewed: (1) obesity definition and causes of secondary obesity; (2) physical and psychosocial comorbidities; (3) treatment and care settings; (4) prevention. The main novelties deriving from the Italian experience lie in the definition, screening of the cardiometabolic and hepatic risk factors and the endorsement of a staged approach to treatment. The evidence based efficacy of behavioral intervention versus pharmacological or surgical treatments is reported. Lastly, the prevention by promoting healthful diet, physical activity, sleep pattern, and environment is strongly recommended since the intrauterine phase. Electronic supplementary material The online version of this article (10.1186/s13052-018-0525-6) contains supplementary material, which is available to authorized users.

Vitamin D plays a pivotal role in the regulation of calcium-phosphorus metabolism, particularly during pediatric age when nutritional rickets and impaired bone mass acquisition may occur. Besides its historical skeletal functions, in the last years it has been demonstrated that vitamin D directly or indirectly regulates up to 1250 genes, playing so-called extraskeletal actions. Indeed, recent data suggest a possible role of vitamin D in the pathogenesis of several pathological conditions, including infectious, allergic and autoimmune diseases. Thus, vitamin D deficiency may affect not only musculoskeletal health but also a potentially wide range of acute and chronic conditions. At present, the prevalence of vitamin D deficiency is high in Italian children and adolescents, and national recommendations on vitamin D supplementation during pediatric age are lacking. An expert panel of the Italian Society of Preventive and Social Pediatrics reviewed available literature focusing on randomized controlled trials of vitamin D supplementation to provide a practical approach to vitamin D supplementation for infants, children and adolescents.

We investigated whether improving 25-hydroxyvitamin D status in young type 1A diabetic patients reduces reactivity of peripheral blood mononuclear cells against islet autoantigens and associates with beta-cell functional changes.Eight patients with 25-hydroxyvitamin D deficiency (20 ng/ml), out of 15 consecutive young type 1A diabetic subjects received 25-hydroxyvitamin D3 to achieve and maintain levels above 50 ng/ml for up to one year. Peripheral blood mononuclear cell reactivity (Interferon-γ spots) against beta-cell autoantigens (glutamic acid decarboxylase 65-kD isoform, proinsulin and tyrosine phosphatase-like protein IA-2) and C-peptide during mixed meal were assessed before and after 25-hydroxyvitamin D3 replenishment.Target 25-hydroxyvitamin D blood levels were safely reached and maintained. Peripheral blood mononuclear cell reactivity against glutamic acid decarboxylase 65-kD isoform (3.8 ± 4.0 vs. 45 ± 16) and proinsulin (3.5 ± 3.2 vs. 75 ± 51) decreased significantly (p 0.001 and p 0.02) upon 25-hydroxyvitamin D3 replenishment, which was correlated with 25-hydroxyvitamin D concentrations. C-peptide values remained stable after one year of treatment.Safely restored and maintained 25-hydroxyvitamin D levels associated with reduced peripheral blood mononuclear cell reactivity against beta-cell autoantigens with no significant decrease of beta-cell function in this cohort of patients.

The aim of this review is to highlight recent findings in prevention, diagnosis, and treatment of pediatric osteoporosis.Several genes are involved in bone mass acquisition, and various monogenic bone disorders characterized by reduced bone mineral density and increased bone fragility have been recently described. Moreover, many chronic diseases and/or their treatment have been associated with impaired bone mass acquisition. Pediatric osteoporosis should be adequately suspected and properly diagnosed in children at risk of fractures. Particularly, detection of vertebral fracture allows the diagnosis regardless of densitometric evaluation. Dual X-ray absorptiometry remains the most widely used densitometric technique in childhood, but interpretation of results should be made with caution because of different confounding factors. Bisphosphonates represent one of the main medical treatments of pediatric osteoporosis, and many different protocols have been proposed. Bisphosphonates administration should be characterized by a first phase, followed by a period of maintenance. Optimal route of administration, duration of therapy, and long-term safety of bisphosphonates treatment require further investigation.Careful monitoring of children at risk of fractures is essential to pose early diagnosis of osteoporosis. In children with persistent risk factors and reduced probability of spontaneous recovery, medical treatment with bisphosphonates should be considered.

Increasing literature suggests the need to explore for post-traumatic stress disorder (PTSD) and post-traumatic stress symptoms in parents and caregivers of children with acute and chronic illnesses but scant data are available on epilepsy. The aim of the present study was to estimate full and partial PTSD rates among parents of children with epilepsy comparing DSM-5 and DSM-IV-TR criteria. Further, the aim of the present study was to examine possible gender differences between mothers and fathers. Results showed 9.1% and 12.1% PTSD rates in the total sample, according to DSM-5 or DSM-IV-TR criteria, respectively, with an overall consistency of 92.9% (Kohen's K = 0.628, p = .453). Significant gender differences emerged for Avoidance/Numbing and Hyperarousal symptoms diagnosed by means of DSM-IV-TR criteria, as well as for Negative alterations in cognitions/mood and Hyperarousal symptoms, when adopting DSM-5 criteria. This study underscores the relevance of detecting PTSD in parents of children with a chronic illness such as epilepsy.

BACKGROUND To evaluate the rate of nocturnal enuresis (NE), body weight and obstructive sleep apnea in children 5 to 10 years of age in South Italy and the possible association among these disorders. METHODS We have administered 1100 validated questionnaires, in Italian language, to parents and we have analyzed data with a logistic regression. RESULTS Forty-two percent of children had a BMI≥85th (group 1) vs 58.0% normal weight children at the same age (group 2). There is a higher number of overweight males compared to females without statistically differences. In group 1 there was a higher number of children with NE and obstructive sleep disorders and some children present with the association among these three disorders. CONCLUSIONS There are no statistically differences between two study groups for the association body weight-NE, body weight-NE-obstructive sleep disorders.

Background Primary ciliary dyskinesia (PCD) is a rare autosomal recessive genetic disorder characterised by dysfunction of motile cilia. Ciliary dysmotility causes poor mucociliary clearance and leads to impairment of pulmonary function and severe respiratory infections. PCD has no specific therapy. With the aim to permanently restore gene function and normalise ciliary motility, we used gene editing to replace mutated with wild-type sequence in defective cells. Methods The target gene was dynein heavy chain 11 ( DNAH11 ), an essential component of ciliary structure. Airway ciliated cells were collected from two patients with PCD with DNAH11 nonsense mutations and altered ciliary beating and pattern. Repair of the genetic defect was performed ex vivo by site-specific recombination using transcription activator-like effector nucleases (TALENs). Results In an epithelial cell line engineered to contain the DNAH11 target site, TALENs cleaved over 80% of the mutated DNAH11 sequence and replaced the mutated sequence with wild-type sequence in about 50% of cells. In airway ciliated cells of patients with PCD, site-specific recombination and normalisation of ciliary beating and pattern occurred in 33% and 29% of cells, respectively. Conclusion This study demonstrates that gene editing can rescue ciliary beating ex vivo, opening up new avenues for treating PCD.

Childhood obesity, often characterized by a chronic low-grade inflammation, has been associated with an increased risk of developing some types of cancer later in life. Nuclear γ-H2AX foci represent the first detectable response of cells to DNA tumorigenesis lesions, such as the double-strand breaks (DSBs). An excess of micronucleated peripheral lymphocytes was found in subjects with cancer or inflammation-based diseases. We set out to investigate the expression of genome damage, from DNA lesions to chromosome mutations (micronuclei), in overweight and obese children. Using the γ-H2AX focus assay and micronucleus (MN) test, we analyzed peripheral lymphocytes from 119 Italian children classified as normal weight (n=38), overweight (n=20), or obese (n=61). Cultures treated with bleomycin (BLM) were also set up for each child in both assays to check functioning of the apparatus that ensures DNA integrity. We measured serum TNF-α, IL-6, and C-reactive protein (CRP) as markers of inflammation. Overweight and obese children had significantly higher levels of H2AX phosphorylation (0.0191±0.0039 and 0.0274±0.0029 γ-H2AXF/n) and increased MN frequencies (2.30±0.25 and 2.45±0.22‰) than normal-weight children (0.0034±0.0006 γ-H2AXF/n, and 0.92±0.12‰ MN), while all subjects responded to BLM induction, irrespective of their weight status. The fold increase of spontaneous MN frequencies in overweight and obese subjects was 2.5 and 2.7, respectively, well below the corresponding increase in the γ-H2AX foci (5.6- and 8.0-fold, respectively). IL-6 and CRP mean values were significantly higher in obese and overweight children than in controls. Here, we demonstrated that peripheral cells of overweight and obese children showed increased levels of DSBs, which were not completely repaired as part of them has been converted into micronuclei. Characterization of childhood obesity inflammation could be implemented using molecular markers of genome damage.

Amplitude-dependent speed of sound (AD-SoS) and bone transmission time (BTT) are the quantitative ultrasound (QUS) variables usually assessed at proximal phalanges of the hand to estimate bone mineral status. The aim of the study was to provide a reference database for some additional QUS variables reflecting morphology of the ultrasound graphic trace according to gender, age, height, weight, and body mass index (BMI), and to assess their clinical usefulness. Fifty-two patients (age 3.1-20.9 years) affected by cerebral palsy with spastic tetraplegia (CPST, n=38) or polyarticular active juvenile idiopathic arthritis (JIA, n=14) were examined. In addition to AD-SoS and BTT, two QUS variables derived from the morphological analysis of ultrasound graphic trace, such as energy, extrapolated from the area under the ultrasound signal received, and weighted-slope (W-slope), derived from the angular coefficient of the regression line fitting the top point of the peaks of the ultrasound signal, were measured by phalangeal QUS (DBM Sonic, IGEA). The values of all the QUS variables measured in the patients were compared with our own sex- and age-reference values (n=1083, 587 males and 496 females, aged 3-21 years). The mean values of AD-SoS, BTT, energy, and W-slope were reduced (P

Treatment of adolescents with growth hormone deficiency (GHD) during the transition period is a controversial issue. This paper is a contribution from the Italian community of paediatric and adult endocrinologists surveyed in a Delphi panel. The Delphi method is a structured communication technique, originally developed as a systematic, interactive forecasting method that relies on a panel of experts. The experts answer questionnaires in two or more rounds. There was substantial agreement on the definition of the problems associated with the diagnosis and treatment of adolescents with GHD in the transition period, as well as on the identification of the controversial issues which need further studies. There is general consensus on the need of re-testing all isolated idiopathic GHD after at least 30-day withdrawn from treatment, while in patients with multiple pituitary deficiency and low IGF-I levels there is generally no need to re-test. In patients with permanent or confirmed GHD, a starting low rhGH dose (0.01-0.03 mg per day) to be adjusted according to IGF-I concentrations is also widely accepted. For those continuing treatment, the optimal therapeutic schedule to obtain full somatic maturation, normalization of body composition and bone density, cardiovascular function and Quality of Life, need to be evaluated.

GH plays an important role in longitudinal bone growth and maturation during childhood and adolescence. However, GH has important metabolic functions other than bone growth, which become more apparent during young adulthood, when growth has been completed. Indeed, GH deficiency (GHD) in adult life is a recognized clinical syndrome which includes symptoms such as increased central adiposity, decreased lean body mass, reduced bone mineral density (BMD), increased atherogenic risk, cerebrovascular and cardiac morbidity and mortality, and reduced quality of life. As approximately one quarter of the children with GHD should continue GH administration in adulthood, it is important to reconfirm GHD at the end of growth in order to select patients with severe GHD who need to resume GH therapy with an appropriate age-related dosage. Some evidence indicates that most peak bone mass (PBM) is achieved by the end of adolescence but small increases in BMD continue during the period of transition from late adolescence to young adulthood. Some young adults with GHD show a persistent increase of lumbar BMD after the completion of growth even after discontinuation of treatment suggesting a spontaneous progression towards lumbar PBM or a continuing effect of the treatment. The data indicates that adolescents with GHD who do not reach lumbar PBM at the time of discontinuation of GH treatment can achieve a BMD lower than their genetic potential if they are not treated during the transition to young adulthood.

Objective: To examine the hypothesis of an influence of leptin on growth factors and on biochemical markers of bone turnover of prepubertal overweight children. Design and Methods: 395 prepubertal children, 6–13 years of age, were selected and the relationships between circulating serum levels of leptin and insulin-like growth factor I (IGF-I), insulin growth factor binding protein-3 (IGFBP-3) and some biochemical markers of bone turnover (osteocalcin, OC; carboxyterminal propeptide of type I procollagen, PICP, and carboxyterminal propeptide of type I collagen, ICTP) were analyzed. The subjects were subdivided into normal weight (NW, n = 163) and weight excess (WE, n = 232) subjects. Results and Conclusions: Significant differences between the two groups were found for leptin (p < 0.01), IGF-I (p < 0.01) and IGFBP-3 (p < 0.01), with higher values in WEs, and for OC (p < 0.01) with higher values in NWs. A significant reduction of leptin (p < 0.01) and IGFBP-3 (p < 0.01) serum values and an increase of those of OC (p < 0.01) and PICP (p < 0.05), but not of ICTP, were registered in 103 WEs who showed a drop in weight excess during a weight-excess reduction program. No variations were observed in 26 non-responsive subjects. In a multivariate analysis in which leptin, corrected by BMI and sex, was the independent variable, a significant negative correlation was found with PICP (β = –0.235, p < 0.01), IGF-I (β = –0.180, p < 0.01) and height velocity (β = –0.155, p < 0.01). There was no correlation with OC, ICTP and IGFBP-3. The results demonstrate that nutritional status and leptin levels are involved in the regulation of growth factors and biochemical markers of bone formation.

Puberty is a crucial period of life during which dramatic hormonal changes induce notable modifications in linear growth, bone mass and body composition. These changes are associated with variations in some biochemical parameters such as markers of bone turnover and leptin, which may reflect changes in bone growth and fat mass, respectively. Children with growth hormone (GH) deficiency have reduced concentrations of bone markers, which increase during GH administration, while the levels of leptin decrease. There have been few studies analysing the behaviour of bone markers during puberty in GH-treated GH-deficient patients and no studies analysing the behaviour of leptin. Results from a longitudinal study showed that there was no change in serum osteocalcin, carboxy-terminal propeptide of type I procollagen, and cross-linked carboxy-terminal telopeptide of type I collagen levels during puberty in GH-treated GH-deficient children. Some studies have shown that changes in markers of bone turnover and leptin after short-term GH treatment may predict the growth response (at 6–12 months) to GH administration in GH-deficient children. At present, insufficient data are available for the clinical use of these parameters as markers of growth response during pubertal development and as predictors of long-term growth response to GH treatment in children with GH deficiency. Nevertheless, the use of more and possibly new markers might improve the accuracy of growth prediction models in the future.

Puberty has a key role for bone development. Skeletal mass approximately doubles at the end of adolescence. The main determinants of pubertal gain of bone mass are the sex steroids, growth hormone and insulin-like growth factors (by their effects on bone and muscle mass), 1,25-dihydroxyvitamin D (by stimulating calcium absorption and retention) and muscle mass (by regulating modelling/remodelling thresholds). Calcium intake is an additional factor influencing bone formation. The interactions among these factors are undefined. The accrual of bone mass during puberty is a major determinant of peak bone mass and, thereby, of the risk of osteoporotic fractures during advanced age.

Vitamin D is a key hormone in the regulation of calcium and phosphorus metabolism and plays a pivotal role in bone health, particularly during pediatric age when nutritional rickets and impaired bone mass acquisition may occur. Great interest has been placed in recent years on vitamin D's extraskeletal actions. However, while recent data suggest a possible role of vitamin D in the pathogenesis of several pathological conditions, including infectious and autoimmune diseases, the actual impact of vitamin D status on the global health of children and adolescents, other than bone, remains a subject of debate. In the meantime, pediatricians still need to evaluate the determinants of vitamin D status and consider vitamin D supplementation in children and adolescents at risk of deficiency. This review is the result of an expert meeting that was held during the congress "Update on vitamin D and bone disease in childhood" convened in Pisa, Italy, in May 2013. CONCLUSION: The collaboration of the international group of experts produced this "state of the art" review on vitamin D in childhood and adolescence. After dealing with vitamin D status and its determinants, the review outlines the current debate on vitamin D's health benefits, concluding with a practical approach to vitamin D supplementation during childhood and adolescence. WHAT IS KNOWN: • Vitamin D deficiency is a worldwide health problem. • Vitamin D deficiency affects not only musculoskeletal health but also a potentially wide range of acute and chronic diseases. What is New: • We reviewed the literature focusing on randomized controlled trials of vitamin D supplementation during childhood and adolescence. • This review will help pediatricians to appreciate the clinical relevance of an adequate vitamin D status and it will provide a practical approach to vitamin D supplementation.

OBJECTIVE. Bone health is a major concern in patients with Turner syndrome (TS). There are few studies assessing bone mineral status in TS adolescents and none have reported a clear relationship with the risk of fracture. We assessed bone mineral status at three different skeletal sites by two different densitometric techniques in a group of TS adolescents. DESIGN. In 24 TS adolescents (17.1 ± 3.1 years) we evaluated lumbar and femoral volumetric bone mineral density (vBMD) with dual energy X-ray absorptiometry (DXA), amplitude-dependent speed of sound (AD-SoS) and bone transmission time (BTT) with phalangeal quantitative ultrasound (QUS). RESULTS. Mean lumbar vBMD Z-score was normal, while mean femoral vBMD, ADSoS and BTT Z-score were reduced. 8/24 (33.3%) and 13/24 (54.2%) girls had AD-SoS and BTT ≤-2 Z-score, respectively, while lumbar vBMD and femoral vBMD were ≤-2 Z-score only in 2/24 (8.4%) and 1/24 (4.2%) patients. Overall, we documented 15 fractures (three pathological) in 8 girls. Patients who reported at least one fracture had lower AD-SoS and BTT Z-score values than fracture-free girls. The presence of a value of BTT ≤-2.0 Z-score was associated with a significant OR of positive history of fracture of 11.67 (χ2 = 5.906, p =0.015, C.I. 95% 1.14–119.54). Lumbar and femoral vBMD were not related to fracture risk. CONCLUSIONS. TS adolescents may have impaired bone mineral status in skeletal sites with predominant cortical bone. Phalangeal QUS represents a useful method to identify subjects with increased fracture risk.

We examined whether the polymorphism for BsmI restriction enzyme in the vitamin-D receptor (VDR) gene influenced radial (distal third) and lumbar (L2–L4) bone mineral density (BMD), phospho-calcium metabolism (calcium, phosphate, intact parathyroid hormone, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D), biochemical markers of bone formation (osteocalcin and carboxy-terminal propeptide of type-I procollagen) and bone resorption (carboxy-terminal telopeptide of type-I collagen and urinary cross-linked N-telopeptides of type I collagen), insulin-like growth factor I and insulin-like growth factor-binding protein 3, and growth in 209 healthy prepubertal children (112 males and 97 females) aged 7.1–10.0 years. Genotype frequencies were BB 19%, Bb 46%, and bb 35% in the pooled group of children. Clinical findings, dietary calcium intake, calcium density, and physical activity rate were not different (p NS) among the VDR genotypes. Radial BMD, lumbar BMDarea and lumbar BMD adjusted for the apparent bone volume (BMDvolume), and all the biochemical parameters did not differ (p NS) in relation to the VDR genotype. In conclusion, our data show that polymorphism for BsmI restriction enzyme in the VDR gene is not associated with radial and lumbar BMD, parameters of phospho-calcium metabolism and bone turnover, growth hormone-dependent growth factors, and growth in prepubertal children.

Failure to thrive is common in children with celiac disease. As alterations in the growth hormone-insulin-like growth factor I (GH-IGF-I) growth axis have been reported in these patients, we studied the behavior of growth hormone-binding proteins (GH-BPs I and II), IGF-I and its binding proteins in 14 children with celiac disease, either before or after a 6-month gluten-free diet. GH-BP II levels were significantly lower in patients during the active phase of the disease than after the diet or in comparison with control subjects, appropriate for age and sex. There was no difference in the GH-BP-I levels of patients and controls, nor did they change after the diet. Blood levels of IGF-I and IGFBP-3 were reduced before the diet in all patients while ligand blotting showed that IGFBP-2 and 1 were increased. All of these parameters normalized after the gluten-free diet. IGFBP-4 was not greatly influenced by the disease. Furthermore, we found a significant, positive correlation between GH-BP II and IGF-I or IGFBP-3 levels. The height standard deviation scores and body mass indices of the patients improved significantly after the diet. The body mass index significantly and positively correlated with GH-BP II, IGF-I or IGFBP-3 levels. In conclusion, our data show that celiac children had multiple alterations in the growth axis during the active phase of the disease which disappeared during the gluten-free diet.

Primary ciliary dyskinesia (PCD) is a congenital, clinically and ultrastructurally heterogeneous disease due to abnormal structure and/or function of cilia, with impaired mucociliary transport leading to several respiratory disorders. PCD can be diagnosed by the combination of thorough clinical examination with functional and ultrastructural analysis of the cilia. This paper shows progresses in PCD diagnosis obtained by ciliogenesis in culture evaluation of ciliated respiratory cells and by genetic analysis of mutations in candidate genes. Moreover, since to date no specific treatments are available to correct the ciliary dysfunction, the paper shows the proper therapeutical approach by the use of respiratory physiotherapy and regular exercise to favour airways clearance, by antibiotics administration to control acute airway infections. Macrolides administration as antinflammatory option is suggested.

The definition Small for Gestational Age (SGA) describes those newborns weighing and/or measuring in length-2 SD than expected for their gestational age. These subjects are at higher risk of short stature, neonatal complications, alterations of glucose, lipid metabolism, body composition, bone metabolism and puberty, neurocognitive vulnerabilities and alterations of the GH-IGF-I axis. With regards to growth, in 85-90% of the cases children born SGA experience a period of catch up growth that allows them to achieve an adult stature within normal range. In a 10-15% of the cases, the catch up growth period does not take place and this entails short stature in adulthood. In the latter group, GH treatment may be considered to achieve adult height in the range of genetical target stature. With reference to glucose and lipid metabolism, young adults born SGA and particularly those with early catch up growth are at higher risk of developing insulin resistance, type 2 diabetes mellitus, arterial hypertension, dyslipidemia, overweight, obesity and metabolic syndrome. Subjects born SGA are in need of a correct diagnostic and eventually therapeutic approach.

Incomplete Kawasaki disease represents a diagnostic challenge for pediatricians. In the absence of classical presentation, the laboratoristic evaluation of systemic inflammation can help in placing the correct diagnosis to promptly start adequate therapy. Erythema multiforme is an acute, self-limiting condition considered to be a hypersensitivity reaction commonly associated with various infections or medications. This aspecific skin condition has been rarely described as a sign of Kawasaki disease. We report on the case of a 4 years old boy presenting high-grade fever associated with erythema multiforme and evidence of systemic inflammation who showed a good response to prompt treatment with intravenous immunoglobulins.

Hypovitaminosis D affects children and adolescents all around the world. Italian data on vitamin D status and risk factors for hypovitaminosis D during pediatric age are lacking. Six hundred fifty-two children and adolescents (range 2.0-21.0 years) living in the northwestern area of Tuscany were recruited at the Department of Pediatrics, University Hospital Pisa. None of them had received vitamin D supplementation in the previous 12 months. 25-hydroxyvitamin D (25-OH-D) and parathyroid hormone (PTH) levels were analyzed in all subjects. Severe vitamin D deficiency was defined as serum levels of 25-OH-D < 25.0 nmol/L (10.0 ng/mL) and vitamin D deficiency as < 50.0 nmol/L (20.0 ng/mL). Serum 25-OH-D levels of 50.0-74.9 nmol/L (20.0-29.9 ng/mL) indicated vitamin D insufficiency, whereas 25-OH-D levels a parts per thousand yenaEuro parts per thousand 75.0 nmol/L (30.0 ng/mL) were considered sufficient. Hypovitaminosis D was defined as 25-OH-D levels < 75.0 nmol/L (30.0 ng/mL). The median serum 25-OH-D level was 51.8 nmol/L, range 6.7-174.7 (20.7 ng/mL, range 2.7-70.0), with a prevalence of vitamin D deficiency, insufficiency, and sufficiency of 45.9, 33.6, and 20.5 %, respectively. The prevalence of severe vitamin D deficiency was 9.5 %. Adolescents had lower median 25-OH-D levels (49.8 nmol/L, range 8.1-174.7; 20.0 ng/mL, range 3.2-70.0) than children (55.6 nmol/L, range 6.8-154.6; 22.3 ng/mL, range 2.7-61.9, p = 0.006). Non-white individuals (n = 37) had median serum 25-OH-D levels in the range of deficiency (28.2 nmol/L, range 8.1-86.2; 11.3 ng/mL, range 3.2-34.5), with 36/37 having hypovitaminosis D. Logistic regression showed significant increased risk of hypovitaminosis D in the following: blood samples taken in winter (odds ratio (OR) 27.20), spring (OR 26.44), and fall (OR 8.27) compared to summer; overweight (OR 5.02) and obese (OR 5.36) subjects compared to individuals with normal BMI; low sun exposure (OR 8.64) compared to good exposure, and regular use of sunscreens (OR 7.06) compared to non-regular use. Gender and place of residence were not associated with vitamin D status. The 25-OH-D levels were inversely related to the PTH levels (r = -0.395, p < 0.0001). Sixty-three out of the 652 (9.7 %) subjects showed secondary hyperparathyroidism. Conclusion Italian children and adolescents who were not receiving vitamin D supplementation had high prevalence of hypovitaminosis D. Careful identification of factors affecting vitamin D status is advisable to promptly start vitamin D supplementation in children and adolescents.

To evaluate the effects of treatment with recombinant human growth hormone (rhGH) on growth, mineral metabolism, and bone density in children with renal hypophosphatemic rickets (RHR).Long-term rhGH treatment combined with conventional therapy with 1,25-dihydroxyvitamin D3 plus inorganic phosphate salts.Endocrine unit, department of pediatrics, university hospital.Twelve patients (5 boys; age range 4.6 to 12.5 years, median 7.0 years) were subdivided into two groups of six patients on the basis of the median of height z score (-2.41) and the median bone age/statural age (BA/SA) ratio (1.23). Group A included patients with a severe degree of short stature (height z score -3.4 +/- 0.5) (mean +/- SD) and altered BA/SA ratio (1.26 +/- 0.08); group B included patients with a lesser degree of short stature (height z score -2.1 +/- 0.6, p0.001 vs group A) and more normal BA/SA ratio (1.04 +/- 0.15, p0.01 vs group A).Group A received rhGH treatment (0.6 IU/kg per week subcutaneously) combined with conventional therapy; group B received conventional therapy alone.Height, growth velocity, predicted adult height, serum values of calcium, phosphate, bone alkaline phosphatase isoenzyme, osteocalcin, propeptides of type I and type III procollagen, intact parathyroid hormone, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and urinary calcium/urinary creatinine ratio and tubular maximum for phosphate reabsorption normalized to the glomerular filtration rate (TmP/GFR), as well as radial bone density, were measured at baseline and for 3 years.Height z score, growth velocity z score, predicted adult height, serum values of phosphate, bone alkaline phosphatase isoenzyme, osteocalcin, propeptides of type I and type III procollagen, intact parathyroid hormone 1,25-dihydroxyvitamin D, and TmP/GFR, as well as radial bone density, improved significantly only in group A. Serum calcium and 25-hydroxyvitamin D, and urinary calcium/urinary creatinine ratio did not change in either group.Long-term rhGH administration may benefit growth, phosphate retention, and bone density in patients with RHR, without evidence of side effects.

We report on a de novo interstitial deletion of chromosome 21q in a patient presenting with characteristic facial features, intellectual disability, and epilepsy. The deletion extent was about 4.9 Mb from position 37713441 bp (21q22.13) to position 42665162 bp (21q22.3) (NCBI36/hg18 map). Patients with partial monosomy 21 are quite rare; this anomaly has been associated with a wide spectrum of clinical signs, ranging from very mild to quite severe phenotypes. This variability results from variability in the deleted regions, thus accurate molecular definition of the chromosomal breakpoints is necessary to make better genotype-phenotype correlations. We compared our patient's phenotype with the few other patients reported in the literature and found to have similar deletion when analyzed by array CGH. The minimal overlapping region contains only two genes, DYRK1A and KCNJ6 , which may play a major role in these patients' phenotype.

We evaluated growth hormone (GH) secretion and baseline serum free insulin-like growth factor-I (IGF-I) levels in 12 poorly growing patients (5 males and 7 females; age 1.6-12.5 years, median 6.4) with renal hypophosphataemic rickets treated with 1,25-dihydroxy-vitamin D3 plus inorganic oral phosphate salts. Eleven healthy normally growing children (6 males and 5 females; age 3.1-10.8 years, median 6.6) were studied as control group. All patients had a normal GH response (GH peakor = 10 micrograms/l) to at least one provocative pharmacological stimulus (levodopa or insulin tolerance test), as well as all the controls. Mean growth hormone concentrations (MGHC), mean pulse amplitude, number of GH peaks above 5 micrograms/l, and IGF-I values overlapped between patients and controls, even though four patients had MGHC below the lower limit of MGHC of controls. In these patients, however, height-SDS, serum calcium, phosphate, alkaline phosphatase, intact parathyroid hormone, 1,25-dihydroxyvitamin D concentrations and maximum tubular phosphate reabsorption/glomerular filtration rate ratio did not differ in respect to the patients who showed MGHC in the range of controls (n = 6). MGHC IGF-I and biochemical parameters of phospho-calcium metabolism did not differ when the patients were subdivided in two groups on the basis of the median (-2.4) of height-SDS. No relationship was found between MGHC or IGF-I and height-SDS or growth velocity-SDS. Height-SDS and years of treatment or age at which therapy was started were not related.(ABSTRACT TRUNCATED AT 250 WORDS)

In 1990, the Italian Study Group for Turner's Syndrome (ISGTS) undertook a nationwide survey, involving the retrospective collection of cross-sectional data and longitudinal growth profiles of 772 girls with Turner's syndrome born between 1950 and 1990. The study was carried out in 29 pediatric endocrinological centers. In this first report, the familial characteristics and neonatal data of Turner girls are described, compared to those of the general population, and related to postnatal somatic development. Furthermore, charts for birth weight and growth standards for height and weight from infancy to adulthood are presented (these are the first charts based on a large sample from the Mediterranean area). The main findings were: (1) incidence of Turner births increases with parental age or parity; (2) most of the neonates are small for dates; (3) girls with normal birth weight tend to be both taller and heavier than girls with low birth weight during the whole growth period; and (4) a 10-cm difference in midparental height leads to a 6.5-cm difference in adult stature.

Background Carotid intima-media thickness (IMT), indices of large artery stiffness and measures of endothelium function may be used as markers of early atherosclerosis in type 1 diabetes mellitus (T1DM). The aim of the present study was to compare the indices of large artery structure and function as well as endothelial function and regenerating capacity between adolescents with T1DM and healthy control of similar age. In addition, the associations of different vascular measures with endothelial progenitor cells (EPCs), glyco-metabolic control and serum levels of advanced glycation endproducts (AGEs), soluble receptors for AGEs (sRAGE) and adiponectin were evaluated. Methods Sixteen uncomplicated young T1DM patients (mean age 18 ± 2 years, history of disease 11 ± 5 years, HbA1c 7.7 ± 1.1%) and 26 controls (mean age 19 ± 2 years) were studied. A radiofrequency-based ultrasound system (Esaote MyLab 70) was used to measure carotid IMT and wave speed (WS, index of local stiffness), applanation tonometry (PulsePen) was applied to obtain central pulse pressure (PP) and augmentation index (AIx), and carotid-femoral pulse wave velocity (PWV, Complior) was used as index of aortic stiffness. Peripheral endothelium-dependent vasodilation was determined as reactive hyperemia index (RHI, EndoPAT). Circulating EPCs, glycometabolic profile, AGEs (autofluorescence method), sRAGE and adiponectin were also measured. Results After adjusting for age, sex and blood pressure, T1DM adolescents had significantly higher carotid IMT (456 ± 7 vs. 395 ± 63 μm, p < 0.005), carotid WS (p < 0.005), PWV (p = 0.01), AIx (p < 0.0001) and central PP (p < 0.01) and lower EPCs (p = 0.02) as compared to controls. RHI was reduced only in diabetic patients with HbA1c ≥7.5% (p < 0.05). In the overall population, EPCs were an independent determinant of carotid IMT (together with adiponectin), while fasting plasma glucose was an independent determinant of carotid WS, AIx and central PP. Conclusions Our findings suggest that young subjects with relatively long-lasting T1DM have a generalized preclinical involvement of large artery structure and function, as well as a blunted endothelium regenerating capacity. Hyperglycemia and suboptimal chronic glycemic control seem to deteriorate the functional arterial characteristics, such as large arteries stiffness, wave reflection and peripheral endothelium-dependent vasodilation, whereas an impaired endothelium regenerating capacity and adiponectin levels seem to influence arterial structure.

Since the 1970s, there has been a worldwide scientific discussion on the potential health consequences of human exposure to endocrine disrupters: many environmentally persistent compounds are oestrogen agonists and/or androgen antagonists. Thus, they can dysregulate the hypothalamic-pituitary-gonadal axis potentially affecting human puberty timing. Zearalenone (ZEA) is a non-steroidal mycotoxin produced by Fusarium species on several grains. Despite its low acute toxicity and carcinogenicity, ZEA exhibits oestrogenic and anabolic properties in several animal species. ZEA food contamination is caused either by direct contamination of grains, fruits and their based-products or by 'carry-over' of mycotoxins in animal tissues, milk and eggs after intake of contaminated feedstuff. In addition, zeranol (alpha-ZAL), a resorcyl lactone derived from ZEA, has been widely used in the USA as a growth promoter to improve fattening rates in cattle. From 1978 to 1984, a great epidemic of premature thelarche and precocious puberty occurred in Puerto Rico. To explain this condition, it was suggested that dairy and meat products could be contaminated with anabolic oestrogens such as ZEA or alpha-ZAL. Subsequently, worldwide other groups have also reported causative associations between oestrogenic mycotoxins and development of early thelarche and/or precocious puberty in exposed children. In addition to animal data, epidemiological studies strongly support the hypothesis that human pubertal development may be induced by foetal/early or prepubertal exposure to oestrogenic compounds. Indeed, ZEA and its metabolites are able to adopt molecular conformation, which sufficiently resembles 17beta-oestradiol to allow it to bind to oestrogen receptors (ERs) in target cells exerting oestrogenic (agonist) actions. In this view, oestrogenic mycotoxins are suspected as triggering factor for precocious pubertal development at least in prepubertal exposed girls.

In subjects with an isolated GH deficiency the inhibition of puberty by GnRH-analogue administration may be attempted to delay the onset, or to prolong the duration, of pubertal maturation in order to improve final height. We report our experience on the matter in 10 subjects (6M, 4F) suffering from isolated GH deficiency with a chronological age ranging from 6.5 to 10.6 years at diagnosis. After a period of 1–5.1 years of GH treatment, GnRH-analogues (long-acting D-Trp-6-GnRH) were added to GH for 12 months, when six subjects were still prepubertal and four in early puberty. During combined therapy, a regression in pubertal development was shown in three out of four children in early puberty, while serum testosterone or estradiol decreased. Height velocity decreased (from 5.23±1.49 (mean±sd) to 4.12±0.67 cm/year; psd scores for bone age increased (from −0.75±0.42 to −0.47±0.55; p

We examined intact PTH and 1,25-dihydroxyvitamin D [1,25-(OH)2D] in both baseline and dynamic conditions (low calcium diet) in 14 patients with Turner's syndrome (mean age, 12.6 +/- 5.9 yr; range, 4.2-21.0 yr) and bone demineralization as well as in a control group of 15 healthy girls (mean age, 12.8 +/- 5.6 yr; range, 3.8-22.7 yr). In both groups we also measured osteocalcin serum levels in response to oral 1,25-(OH)2D3 administration (1.8 micrograms/m2/daily for 6 days) to assess osteoblast function. The low calcium diet decreased ionized calcium (Ca2+) levels and elevated PTH values to the same extent in both patients (Ca2+, -8.40 +/- 3.78%; intact PTH, +47.88 +/- 13.24%) and controls (Ca2+, -9.09 +/- 3.25%; intact PTH, +52.77 +/- 10.52%; P = NS vs. patients). While controls showed an increment in their serum 1,25-(OH)2D levels (+52.15 +/- 8.95%), patients did not (+10.93 +/- 4.71%; P = NS vs. baseline; P0.001 vs. controls). 1,25-(OH)2D3 administration caused a rise in the serum osteocalcin levels in a similar fashion in both groups (peak values: patients, +35.38 +/- 7.20%; controls, +34.09 +/- 7.98%; P = NS). We conclude that in patients with Turner's syndrome there is an altered renal vitamin D metabolism in response to physiological stimulus, while osteoblast function in response to 1,25-(OH)2D3 administration is not affected.

Osteoporosis is a common finding in Turner's syndrome. To test the hypothesis that calcitonin deficiency may contribute to bone mineral loss in Turner's syndrome, we studied basal and calcium-stimulated (2 mg/kg body weight in 5 min) levels of total calcitonin, extractable calcitonin and katacalcin in 15 girls with Turner's syndrome and osteoporosis. Fifteen age-matched healthy girls were studied as controls. Both basal calcitonin (total and extractable) and katacalcin values were not significantly different in patients with Turner's syndrome in comparison with those of the controls. The calcium stimulation test showed a similar "C" cell secretory reserve in both groups. The calculation of delta CT/delta iCa of total and extractable calcitonin and delta KC/delta iCa, which accounts for individual variations in serum ionized calcium increases, did not show any significant difference between girls with Turner's syndrome and controls. We conclude that calcitonin deficiency is not a causative factor of osteoporosis in girls with Turner's syndrome and that in this syndrome long-life estrogen deficiency does not impair "C" cell secretory activity.

A reduced GH secretion has often been shown in prepubertal children with delays in pubertal development. In order to study the mechanism underlying this finding, we evaluated peripheral circulating levels of GH, GHRH, and somatostatin (SRIH) before and after the onset of sexual development in a group of eight late maturing children (six boys, two girls), comparing the results with those obtained in two groups of five prepubertal and four pubertal short children with familial short stature. GH was measured by a two-site immunoradiometric assay. Both GHRH and SRIH were assayed by specific RIAs after an acetone-petrolether extraction from plasma. Our data showed a significant increase (P less than 0.001) in GH, GHRH, and SRIH levels (peak vs. basal values) in response to L-dopa administration in all groups. In pubertal children with delays in pubertal development GH and GHRH peak values (15.8 +/- 2.2 micrograms/L and 120 +/- 18 pg/mL, respectively) were significantly greater (P less than 0.001) than in the same subjects before puberty (8.2 +/- 0.9 micrograms/L and 79 +/- 9 pg/mL, respectively), whereas SRIH peak values did not significantly change (41 +/- 6 vs. 41 +/- 5 pg/mL; P = NS). Furthermore, prepubertal subjects with delays in pubertal development showed GH and GHRH peak values lower (P less than 0.001) than those of prepubertal subjects with FSS (13.3 +/- 1.8 micrograms/L and 120 +/- 13 pg/mL, respectively), whereas no statistical difference was present between the two groups of subjects after pubertal development (18.2 +/- 2.9 micrograms/L and 128 +/- 11 pg/mL, respectively). In conclusion, these findings support the assumption that in late maturing subjects during prepubertal period the decreased GH secretion may be ascribed to a reduced GHRH secretion, reversible with the onset of puberty, without change in circulating SRIH levels.

Cryptorchidism, the most common congenital abnormality in newborn boys, is a major risk factor for male infertility and testicular malignancy in adulthood. This disorder appears as an isolated form or as part of impaired male sex development or a congenital malformation syndrome. Based mainly on the laboratory studies of the rodent models, sex steroidal signaling pathways have been shown to be involved in testicular descent; however, data on the human genetic susceptibility are less compelling. Mutations in the human genes encoding androgen receptor (AR), estrogen receptor alpha (ERalpha) and beta (ERbeta), and steroidogenic factor-1 (SF-1) have occasionally been identified but do not seem to be a frequent cause of this genital malformation. On the other hand, common polymorphisms in these genes have recently been investigated as possible contributing risk factors for idiopathic isolated (nonsyndromic) cryptorchidism, alone or by influencing susceptibility to other causal factors such as environmental endocrine disruptors.Androgen Receptor (AR); DNA-Binding Domain (DBD) ;Environmental Estrogen Disruptors (EEDs); Estrogen Receptor Alpha (ERalpha); Estrogen Receptor Beta (ERbeta); Ligand-Binding Domain (LBD); Linkage Disequilibrium (LD); Odds Ratio (OR); Restriction Fragment Length Polymorphism (RFLP); Single Nucleotide Polymorphism (SNP); Steroidogenic Factor-1 (SF-1); Transactivation Domain (TAD); Testicular Dysgenesis Syndrome (TDS); Wild Type (WT).

Spontaneous growth hormone (GH) secretion in 116 short children was studied by sampling blood for GH measurement every 20 min over 24 h. We calculated 24-h mean GH concentration (MGHC), diurnal 12-h MGHC (dMGHC) and nocturnal 12-h MGHC (nMGHC). The children were subdivided into four groups: prepubertal children with 'classical' GH deficiency (group 1, n = 12, low responses to two provocative stimuli tests and MGHC less than 3 ng/ml), prepubertal children with 'nonclassical' GH deficiency (group 2, n = 36, normal GH responses to two provocative tests and MGHC less than 3 ng/ml), short normal children (normal GH responses to two provocative tests and MGHC greater than 3 ng/ml) at stage P1 of puberty (group 3, n = 41) and at stage P2 of puberty (group 4, n = 27). The values of MGHC, dMGHC and nMGHC were significantly higher in groups 3 and 4 than in groups 1 and 2, and in group 4 than in group 3. The values of MGHC and nMGHC were significantly higher in group 2 than in group 1. MGHC correlated highly with nMGHC and dMGHC (r = 0.97 and 0.94, respectively; p less than 0.001). On the basis of regression equations between MGHC and nMGHC or dMGHC, the study of the diagnostic accuracy showed values higher for nMGHC than for dMGHC: 94.1 vs. 89.6% for sensitivity, and 93.7 vs. 89.7% for specificity, respectively.

Background: Gonadotropin-releasing hormone agonists (GnRHa) represent the gold-standard treatment for central precocious puberty (CPP). In CPP children, GnRHa treatment slows bone age progression and preserves adult height (Ht) by suppressing sexual steroid secretion. In some patients, however, GnRHa induce an inappropriate growth deceleration impairing Ht outcome. Furthermore, slowly progressive CPP (spCPP) forms were reported which do not need GnRHa treatment. Methods: We evaluated the growth outcome of 26 spCPP girls treated with triptorelin (TR) and 21 with leuprorelin acetate (LA) for 36.5 ± 0.7 months. Results: GnRHa treatment induced a progressive growth deceleration in both spCPP groups. No difference in bone maturation was detected (p > 0.05; TR vs. LA group), however compared to LA, TR treatment resulted in significantly higher Ht after 24 months (p < 0.05; LA vs. TR group). Although target height (TH) standard deviation score (SDS) and predicted adult height (PAH)-SDS at diagnosis were similar in both spCPP groups (p > 0.05; LA vs. TR group), final height (FH-SDS) was lower in LA-treated subjects (p < 0.05; LA vs. TR group). In both spCPP groups, FH-SDS was significantly lower than TH-SDS (p < 0.001) but not lower than PAH-SDS at diagnosis (p > 0.05). Ht-SDS correlated with 17β-estradiol (E2) blood levels in both spCPP groups (p < 0.0001) throughout GnRHa treatment, and E2 values were higher in the TR- than in the LA-treated patients during the 12 months after GnRHa administration (p < 0.05; LA vs. TR group). GnRHa-induced E2 secretion and Ht-SDS at GnRHa withdrawal correlated positively with FH (p < 0.01 and p < 0.001, respectively). Conclusions: The effectiveness of GnRHa treatment in improving FH in spCPP girls was doubtful.

As (131)I therapy, used to achieve ablation of thyroid gland remnant, can cause chromosome damage in cultured peripheral lymphocytes especially, we investigated whether administration of radioiodine may induce early genome damage in peripheral T lymphocytes of adolescents with differentiated thyroid carcinoma (DTC).We studied 11 patients, aged 14.8 +/- 3.1 years, who assumed (131)I (range: 1.11-4.44 GBq) to ablate thyroid remnant. A blood sample for micronucleus assay and for evaluating expression of some genes involved in the DNA repair or the apoptosis pathways was obtained from each patient 1 h before (T(0)) and 24 (T(1)) and 48 h (T(2)) post-radioiodine administration.Compared to T(0), we did not find any difference in the number of micronucleated cells at both T(1) and T(2) in any subject. Nine out of 11 patients had altered expression levels in a majority of the DNA repair and apoptosis genes at T(1), which decreased at T(2).We demonstrated for the first time that peripheral cells of DTC children and adolescents who received (131)I at a mean dosage of 3.50 +/- 0.37 GBq did not show chromosome damage within 48 h from the end of radiometabolic therapy. This may be due to a prompt activation of the cell machinery that maintains the integrity of the genome to prevent harmful double-strand breaks from progressing to chromosome mutations, either by repairing the lesions or by eliminating the most seriously damaged cells via apoptosis.

Context: The Middle East has a high incidence of rickets, and it is also common in Europe-dwelling children of Middle Eastern origin. Objective: The objective of the study was to explore the mechanisms leading to rickets in children of the Middle East. Design and Setting: We conducted a prospective study in 98 rachitic and 50 controls (aged 6 months to 4 yr) from university and community outpatient hospitals in Egypt and Turkey. Main Outcome Measures: We collected epidemiological, maternal, nutritional, radiographic, and biochemical parameters; markers of bone turnover; and vitamin D receptor (VDR) gene polymorphisms. Results: Epidemiological factors had a key role in pursuit of rickets; Egyptian and Turkish patients had lower (P < 0.01) dietary calcium intake than controls and the recommended dietary intakes, and serum 25-hydroxyvitamin D levels were reduced in patients, the difference with controls being significant (P < 0.001) only in Turkey, although rickets was more severe in Egypt as determined by the x-ray score (P < 0.05). In Turkey, the F VDR allele frequency was significantly (P < 0.05) increased in patients. The BB VDR genotype was associated with lower serum 25-hydroxyvitamin D levels in both patients and controls and with severity of rickets. Conclusions: In Turkey most patients had vitamin D deficiency, whereas in Egypt they had mostly calcium insufficiency combined with vitamin D deficiency. In this environ, VDR genotypes may predispose to rickets by increased frequency of the F allele. The unique environs and genetic predisposition have to be accounted for in the design of preventive measures, rather than using European or American recommended dietary intake for calcium and vitamin D.

The quantity, type and composition of snack foods may play a role in the development and maintenance of obesity in children. A high consumption of energy-dense snacks may promote fat gain.To assess the type and number of snacks consumed weekly by a large sample of 8- to 10-year-old children, as well as to assess its relationship with body size.The children consumed on average 4 snacks per day. There was no statistical difference in the number of servings per day between obese and nonobese children. However, the mean energy density of the foods consumed was significantly higher for obese and overweight children than for normal weight children [6.8 (0.3) kJ/g, 6.8 (0.16) kJ/g, and 6.3 (0.08) kJ/g, respectively; P0.05]. Logistic regression analysis showed that the energy density of the snacks (kJ/g), their savory taste (servings/week), television viewing (hours/day) and sports activity (hours/week) independently contributed to predict obesity in children. However, when the parents' body mass index was included among the independent variables of the regression, only salty foods and sports activity showed an independent association with childhood obesity.Parents' eating habits and lifestyle influence those of their children, as suggested by the association between parents' obesity and their children's energy-dense food intake at snacktime, the savory taste of snacks and sedentary behavior. However, regardless of parents' body mass index, the preference for savory snacks seems to be associated with overweight in prepubertal children.

We studied bone mineralization and calcium homeostasis in two children with hyperthyroidism before and during 3 yr of methimazole therapy in order to evaluate the effects of thyrotoxicosis and its therapy on mineral metabolism. Case 1, female, 4.1 year old with hyperthyroidism from 6 months. Biochemical data: increased thyroid function, phosphate and osteocalcin, decreased 1,25(OH)2 D levels. X-ray: severe osteoporosis; bone mineral content (BMC) −23.0%, BMC/BW −25.1%. Case 2, female, 7.4 year old with hyperthyroidism from 9 months. Biochemical data: thyroid function, ionized calcium and osteocalcin were increased, 1,25(OH)2 D and intact PTH were decreased. X-ray: severe osteoporosis: BMC −32.8%, BMC/BW −36.0, After the patients were euthyroid, they showed an increase of 1,25(OH)2 D and intact PTH into normal values and a fall in calcium and phosphate. Osteocalcin levels returned in normal range one yr after first evaluation. Bone mineral analysis showed no variation of BMC and BMC/BW in the first 6 months of therapy and an increase in the following 6 months. In the following two years BMC and BMC/BW rose to normal range. Our study provides further evidence that in hyperthyroidism an altered mineral homeostasis is present with a reversible disturbance in vitamin D metabolism. We found that the return to euthyroidism was associated with a normalization of mineral homeostasis and with a recovery of bone mineralization. Osteocalcin assay may be an useful index to monitor bone metabolism in hyperthyroidism.

Guidelines on life or death strategies in extremely preterm infants have been formulated in various countries worldwide.1–15 The general agreement is not to initiate resuscitation in neonates when gestational age is less than or equal to 22 weeks, and intensive care is assured for infants of 25 weeks and over; in the middle there is a sort of “grey zone”. To provide helpful suggestions for initial management of threatened birth in infants at a gestational age of 25 completed weeks or less, a …

To examine the effects of long-term gonadotropin-releasing hormone agonist (GnRHa) administration on thyroid function in children affected by central precocious puberty (CPP).We retrospectively evaluated circulating thyroid hormones in 73 GnRHa-treated girls who were diagnosed with idiopathic CPP. Monthly depot injections (.1 mg/body kg) of leuprorelin acetate (LA) and of triptorelin (TR) were continuously administered for 40.4 +/- .7 months to 34 and 39 CPP patients, respectively. Serum levels of thyrotropin (TSH), free triiodothyronine (FT3), free thyroxine (FT4), and thyroid antibodies were determined at baseline and after 6, 12, 18, 24, 30, 36, and 40 months of GnRHa administration.While there was no difference in FT4 release (p.05), FT3 levels significantly declined during both LA and TR treatments from untreated baseline (p.05). Opposite to circulating FT4 and FT3 values (p.05), FT3/FT4 ratio was significantly different among LA and TR groups (p.05). Both GnRHa treatments did not affect TSH secretion (p.05); however, LA induced lower TSH values than TR (p.05).There is no evidence of thyroid dysfunction during both GnRHa treatments, though changes in TSH, FT3, and FT3/FT4 ratios were noted. Finally, monitoring of thyroid activity during GnRHa administration is not required.

X-linked hypophosphatemic rickets (XLH) is an hereditary form of rickets due to isolated renal tubular phosphate wasting and impaired production of 1,25-dihydroxyvitamin D [1,25(OH)2D]. XLH is caused by mutations in the PHEX (phosphate regulating gene with homology to endopeptidases) gene, which is located on Xp22.1. The pathogenetic mechanisms by which mutations in the PHEX gene cause XLH are not completely known. Hypophosphatemia associated with disproportionate short stature and bone deformities of the lower limbs are the main findings in XLH patients. Some studies have shown that conventional treatment with vitamin D metabolites, such as 1,25(OH)2D3 or 1 alpha-hydroxyvitamin D3, combined with inorganic phosphate salts is able to improve serum phosphate concentrations and linear growth, as well as healing rickets. However, some patients may have poor beneficial effects by this therapy. On the other hand, some important treatment complications, such as hypervitaminosis D, nephrocalcinosis and secondary/tertiary hyperparathyroidism may occur during the current therapy. Despite conventional treatment, some patients may require surgical correction of bone deformities. In the light of the recent genetic advances the mechanisms that could be involved in the pathogenesis of XLH are discussed. Furthermore, the article reviews the effects of the medical treatment providing current recommendations for the management of XLH patients.

Bone mass increases progressively during childhood, but mainly during adolescence when approximately 40% of total bone mass is accumulated. Peak bone mass is reached in late adolescence, and is a well recognised risk factor for osteoporosis later in life. Thus, increasing peak bone mass can prevent osteoporosis. The critical interpretation of bone mass measurements is a crucial factor for the diagnosis of osteopenia/osteoporosis in children and adolescents. To date, there are insufficient data to formally define osteopenia/osteoporosis in this patient group, and the guidelines used for adult patients are not applicable. In males and females aged

Smith-Lemli-Opitz syndrome (SLOS) is an inborn error of cholesterol biosynthesis characterized by developmental delay and multiple malformations. Some of the patients have skin photosensitivity and therefore tend to avoid direct exposure to sunlight.SLOS patients typically have low concentrations of cholesterol and abnormally high concentrations of its precursor 7-dehydrocholesterol (7-DHC) in biological fluids and tissues. 7-DHC is also a precursor in the cutaneous synthesis of vitamin D. Sunlight exposure plays a major role in this pathway and reactions transforming 7-DHC into vitamin D and then into 25-hydroxyvitamin D are known not to be specifically regulated. The aim of this study was to evaluate vitamin D status in SLOS patients. We measured 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D serum concentrations and markers of calcium metabolism in five SLOS patients. Despite abnormally high concentrations of 7-DHC, circulating concentrations of vitamin D metabolites were not significantly different from appropriate controls matched for sex, age and season of blood collection. The analysis of historical serum samples stored in our laboratory from the same cases plus 10 other SLOS patients further supported these findings. Our data suggest that SLOS patients have a peculiar vitamin D metabolism that protects them from vitamin D intoxication. This appears to be due in most cases to decreased transformation of 7-DHC into 25-hydroxyvitamin D, perhaps depending on reduced sunlight exposure as a consequence of photosensitivity. Possible alternative mechanisms are discussed.

Human milk is the best natural and optimal food for neonates with several immunologic, developmental and practical advantages throughout childhood. Although the World Health Organization strongly supports breastfeeding, it recognizes the potential health risks posed by the presence of environmental toxicants in breast milk. Contamination of human milk is widespread and due to decades of inadequately controlled pollution by toxicants, persistent pesticides or chemical solvents. These chemicals tend to degrade slowly in the environment, to bioaccumulate in the food chain and to have long half-lives in humans. Many of these environmental pollutants have estrogen-like activities and, thus they are called environmental estrogen disruptors or xenoestrogens. Certain adverse health and reproductive outcomes are attributed to these chemicals in laboratory animals and in wildlife as well as in humans. Here, we review available data from breast milk monitoring studies suggesting the environmental chemicals that may affect child health through breastfeeding.

The potential health consequences of human exposure to environmental estrogen disrupters are not known. Because many chemical compounds are environmentally persistent, toxic and estrogen-active, they can dysregulate the hypothalamic-pituitary-gonadal axis, potentially inducing reproductive disorders such as central precocious puberty (CPP). We performed a multi-center analysis of CPP distribution in northwest Tuscany (NWT), an area of 5990 km2 with 1,280,895 inhabitants. Study criteria consisted of recorded CPP diagnoses and prescriptions of gonadotropin-releasing hormone analogs from January 1, 1998 to December 1, 2003. Although similar CPP prevalences were found in four major cities of NWT (Livorno, Lucca, Massa and Pisa) (mean 30.4 per 100,000 children, standard deviation 18.6; p0.05), Viareggio area (300 km2) with 19,219 child inhabitants (0-14 years of age) had the highest CPP prevalence: more than 161 CPP cases per 100,000 children. Living in Viareggio area significantly increased the risk of CPP (relative risk (RR) 5.73, 95% confidence interval (CI) 3.5-9.3; rate/risk difference 0.133%, p0.05). Annual CPP incidence in the Viareggio area was relatively constant and significantly higher than in other NWT areas (RR 5.04, 95% CI 2.3-11.2; rate/risk difference 0.03%, p0.05). Indeed, 47% of total NWT cases were distributed in the countryside (300?km2) surrounding Viareggio. Specifically, three villages - Camaiore, Pietrasanta and Stazzema - in Viareggio presented the highest CPP frequency: 216.1, 393.5 and 274.0 CPP cases per 100,000 children, respectively (RR 9.59, 95% CI 1.71-16.6; rate/risk difference 0.26%, p0.05). Owing to the definite geographic distribution of CPP and because increasing distance (km) from Pietrasanta rarefied CPP frequency, we suggest environmental factors (e.g. estrogen disrupter pollution) as major CPP determinants in NWT.

Objective To examine the effect of long-term administration of GnRH agonists (GnRHa) on PRL secretion in children affected by central precocious puberty (CPP) and growth hormone deficiency (GHD). Design Prospective analysis of blood sampling before, during, and after GnRHa treatments. Setting Pediatric endocrine center. Patient(s) One hundred nineteen and 93 children with a diagnosis of CPP and GHD, respectively. Intervention(s) Monthly depot injections of GnRHa drugs (leuprorelin acetate 3.75 mg [LA] and triptorelin 3.75 mg [TR]) administered to CPP and GHD patients for 40 and 24 months, respectively. Main Outcome Measure(s) Serum PRL levels at baseline and after 6, 12, 18, 24, 30, 36, and 40 months of treatment with GnRHa were compared between CPP and GHD groups. PRL levels at 6 and 12 months after GnRHa withdrawal were also examined. Result(s) Although serum PRL levels tended to be higher in TR- than in LA-treated patients, no significant difference in circulating PRL in basal condition and during GnRHa treatment was detected between the CPP and GHD groups. However, five children (3.8%) developed hyperprolactinemia during TR treatment. Conclusion(s) Although there are no general concerns about GnRHa treatment safety, careful PRL monitoring is required in GnRHa-treated children.

Item does not contain fulltext Bone development is one of the key processes characterizing childhood and adolescence. Understanding this process is not only important for physicians treating pediatric bone disorders, but also for clinicians and researchers dealing with postmenopausal and senile osteoporosis. Bone densitometry has great potential to enhance our understanding of bone development. The usefulness of densitometry in children and adolescents would be increased if the physiological mechanisms and structural features of bone were given more consideration in the design and interpretation of densitometric studies. This review gives an overview on the most relevant techniques of quantitative noninvasive bone analysis. Furthermore it describes the relationship between bone biology, selected surrogates describing the biological processes and the possibilities of measuring these surrogates specifically and precisely by the different devices. The overall recommendation for researchers in this field is to describe firstly the biological process to be analyzed (bone growth in length, remodeling or modeling, or all together), secondly the bone parameter which describes this process, and thirdly the reason for selecting a special device.