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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.

'22q11 deletion syndrome' (22q11DS) is a rare genetic syndrome, in which most patients share the same deletion, but their clinical features may vary a great deal. The genetic mechanisms underlying the variable expressivity and reduced penetrance of 22q11DS still have to be fully elucidated. Epilepsy has been reported in about 15.2% of the patients, however, few studies have focused on this topic and in most cases a detailed epileptic profile is missing. Since only a minority of patients experience epileptic seizures, 22q11deletion can be considered a predisposing factor, which is not sufficient ‘per se’ to cause epilepsy; to date, no candidate gene for epilepsy has been identified in the deleted region. We report on a 6-year-old girl with 22q11DS presenting a form of epilepsy that can be classified as ‘Panayiotopoulos syndrome’. Array CGH revealed an additional microduplication of 172 kb in 2q37, harboring three genes. One of these, DGKD (diacylglycerol kinase delta), is interrupted by the distal breakpoint of the duplication. DGKD encodes a cytoplasmic enzyme that phosphorylates diacylglycerol to produce phosphatidic acid. This is an important second messenger in a pathway of lipid signaling that has been implicated in epilepsy and other neurological diseases. Disruption of DGKD by a t(X;2) has been previously reported in a patient with epilepsy. The 2q37 microduplication was inherited from her mother, who never experienced epileptic seizures, thus this imbalance is not 'per se' sufficient to cause epilepsy. It can be hypothesized that the epileptic phenotype is provoked by the simultaneous presence of 22q11.2 deletion and 2q37 duplication. It has been shown that rare additional copy number variations outside the 22q11.2 region may modulate the risk of congenital heart defects. It is possible that also for the epileptic phenotype, the additional CNVs may represent an important modifying factor underlying the variable expressivity and incomplete penetrance in the 22q11DS.

Summary Background Mannose-binding lectin (MBL) plays an important role in innate immunity and has been reported to be associated with the age-related decline in lung function in cystic fibrosis. Hypothesis MBL polymorphisms are associated with lung function decline in Primary Ciliary Dyskinesia (PCD). Methods We performed sputum microbiology, spirometry pre- and post-administration of salbutamol, ciliary motion analysis, ultrastructural assessment of cilia, ciliogenesis in culture, and chest high resolution computed tomography in children with a clinical history of respiratory tract infections and/or presence of bronchiectasis suggestive of PCD or secondary ciliary dyskinesia (SCD). All subjects were evaluated for single nucleotide polymorphisms in the gene encoding MBL-2. Results The diagnosis of PCD was established in 45 subjects, while in the remaining 53 the diagnosis was SCD. A significant bronchodilator response was observed only in PCD associated with the MBL2–3 genotype, which is known to be associated with low/undetectable MBL serum levels. Also, bronchiectasis severity was significantly greater in subjects with MBL2–3 in both PCD and SCD. No other association was found between MBL genotypes and clinical findings. Conclusions MBL plays a relatively minor role as a disease modifier in PCD. A similar finding in SCD supports the likely significance of this result. Pediatr Pulmonol. 2015; 50:179–186. © 2014 Wiley Periodicals, Inc.

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

More than six decades have elapsed since the introduction of corticosteroids into the pharmacologic armamentarium of pediatricians. Despite the widespread clinical use of these agents for many years, several questions remain concerning their appropriate therapeutic role, indications, possible regimens, and adverse effects. The discovery of corticosteroids can be considered one of the most important therapeutic revolutions of the last century. Steroids became crucial for the treatment of several inflammatory and rheumatic diseases, including diseases that occur during childhood. However, the great enthusiasm over the discovery of corticosteroids was hampered in later years by the identification of important side effects that raised concerns regarding steroid therapy. Thus, in the past years, research focused on the development of new steroid compounds with lower toxicity and higher efficacy as well as on novel therapeutic regimens. Now, 60 years later, treatment with corticosteroids has stood the test of time, and despite the well-known side effects they are still a keystone in the therapy of many disorders and can sometimes be life-saving.

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.

L’osteopenia si associa a diverse condizioni patologiche del bambino e dell’ adolescente. La diagnosi di osteopenia, oltre che su dati clinici, si basa sulla dimostrazione di ridotti valori di densita minerale ossea misurata mediante tecniche densitometriche. L’interpretazione dei risultati densitometrici deve essere effettuata da personale con esperienza nel settore poiche alcuni fattori, legati sia alla metodica utilizzata che alla sede anatomica valutata, possono influire sensibilmente sui valori dell’esame.

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.

In the recent years, some cases of 17q12 deletions and duplications have been reported, but the clinical impact of these imbalances is still to be fully elucidated. In particular, 17q12 duplications elude syndrome classification, since they are associated with a wide phenotypic spectrum, ranging from very mild to quite severe phenotypes. Here, two unrelated patients with the same 1.2 Mb microduplication of 17q12 are reported. Comparing these patients' phenotype with those previously published, it emerges that the more patients reported, the more difficult is finding common characteristics, even in presence of exactly the same genetic anomaly. The role of the genes duplicated in this region and the impact of this chromosomal imbalance are discussed.

Herein, we report mutation analysis of the LH receptor gene in 17 males with LH-independent precocious puberty, of which 8 were familial and 9 had a negative family history. A total of 7 different mutations (all previously reported) were detected in 12 patients. Among 10 European familial male-limited precocious puberty (FMPP) patients who had a LH receptor gene mutation, none had the Asp578Gly mutation, which is responsible for the vast majority of cases in the U.S. The restricted number of activating mutations of the LH receptor observed in this and other studies of FMPP strongly suggests that an activating phenotype is associated with very specific sites in the receptor protein. Clinical follow-up of the 5 patients who did not have LH receptor mutations shows that such cases most likely do not have true FMPP. LH receptor mutation analysis provides a sensitive tool for distinguishing true FMPP from other causes of early-onset LH-independent puberty in males.

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.

Resume Les donnees disponibles a ce jour montrent que les traitements par hormone de croissance recombinante (GHr) et œstrogenes ont tous deux un effet positif sur la densite minerale osseuse (DMO) dans le syndrome de Turner. Dans la mesure ou la DMO semble etre normale chez les filles atteintes de syndrome de Turner traitees par GHr, il pourrait etre utile de retarder chez elles l'administration d'oestrogenes afin de garantir un resultat optimal pour leur croissance, sans affecter pour autant la qualite de leur mineralisation osseuse.

This article summarizes the content of an international workshop on the diagnosis and treatment of growth hormone deficiency (GHD) in children and adolescents that was held in Pisa, Italy, in March 1998. The issues discussed are divided into those addressing the definition and diagnosis, and the treatment of GHD in children and adolescents, and those concerning the transition of patients with GHD from adolescence to adulthood. Recommendations are presented for improving the diagnosis and management of children and adolescents with GHD and issues are highlighted that require further studies to be undertaken before recommendations can be made.

Resume Le rachitisme hypophosphatemique familial (RHF) s'accompagne volontiers d'un retard de croissance et d'une petite taille a l'âge adulte, meme si le traitement conventionnel par phosphate et calcitriol ou 1α-hydroxyvitamine D est bien conduit. La pathogenie de ce deficit statural n'est pas eclaircie ; la secretion d'hormone de croissance (GH) est habituellement normale. Un traitement de GH recombinante (GHr) a ete entrepris pendant une duree de 6 ans chez six enfants porteurs d'un RHF (âge: 7,8 ±1,8 ans) porteurs d'un RHF avec retard de croissance important (score Z moyen: − 3,4 ± 0,5) recevant par ailleurs un traitement conventionnel. Un groupe temoin etait compose de six enfants porteurs d'un RHF (âge: 7,9 ± 2,5 ans) ne recevant que le traitement conventionnel. Le traitement de GHr a entraine une amelioration de la croissance staturale avec augmentation significative du score Z et de la prediction de taille adulte, le gain statural etant significativement plus eleve dans le groupe traite comparativement au groupe temoin. Parallelement, etait observee une augmentation de la densite minerale osseuse radiale. Le traitement par GHr apparait donc comme un complement utile au traitement conventionnel, permettant d'ameliorer la qualite de la croissance des enfants avec RHF.

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.

In the last 30 years, there is increasing concern about chemical pollutants that have the ability to act as hormone mimics. Because of structural similarity with endogenous hormones, their ability to interact with hormone transport proteins, or their ability to disrupt hormone metabolism, these environmental chemicals have the potential mimic, or in some cases block, the effects of endogenous hormones (Safe, 2000). In either case, these chemicals serve to disrupt the normal actions of endogenous hormones and thus have become known as “endocrine disruptors”. An endocrine disruptor is defined as “an exogenous agent which interferes with the synthesis, secretion, transport, binding, action or elimination of natural hormones in the body which are responsible for maintenance of homeostasis, reproduction, development or behavior” (Massart et al., 2006a). This wide definition includes all substances that can affect endocrine function via interference with estrogen, androgen or thyroid hormone (TH) signaling pathways.

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)

The relationships between spontaneous variations in serum 24-h osteocalcin (OC), carboxyterminal propeptide of type I procollagen (PICP), and aminoterminal propeptide of type III procollagen (PIIINP) concentrations and GH secretion, measured as GH response to provocative pharmacologic stimuli and spontaneous GH secretion during 24 h, were evaluated in prepubertal normal children and in GH-deficient and GH-secreting short normal children (SNC). All the subjects showed a circadian rhythm in smoothed 24-h OC and PICP mean data with higher nocturnal values in comparison with diurnal values. Conversely, serum PIINP concentrations did not vary throughout the day. In children with classic GH deficiency and nonclassic GH deficiency, mean 24-h serum levels and smoothed 24-h mean data for OC, PICP, and PIIINP were significantly reduced (p < 0.001) with respect to age-matched controls. SNC showed mean 24-h OC concentrations similar (p = NS) to those we found in age-matched controls, but they had significantly lower (p < 0.001) diurnal 12-h mean data in comparison with controls. SNC also showed both 24-h PICP and PIIINP mean data and smoothed 24-h PICP and PIIINP mean data significantly lower (from p < 0.02 to p < 0.001) at all the time points of measurement in comparison with controls. Twenty-four-hour PICP and PIIINP mean data were positively related to spontaneous 24-h GH concentrations (r = 0.77, p < 0.005 and r = 0.69, p < 0.005, respectively) and growth velocity (r = 0.85, p < 0.005, and r = 0.70, p < 0.005, respectively), whereas 24-h OC mean data were not.(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.