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Interactions between growth hormone (GH), insulin-like growth factor-1 (IGF-1), and the immune system are complex, bidirectional, but not fully explained. Current reviews based on numerous studies have indicated that chronic inflammation could suppress the GH/IGF-1 axis via several mechanisms such as relative GH and/or IGF-1 insufficiency, peripheral resistance to GH and/or IGF-1 resulting from down-regulation of GH and IGF-1 receptors, disruption in the GH/IGF-1 signalling pathways, dysregulation of IGF binding proteins (IGFBPs), reduced IGF bioavailability, and modified gene regulation due to changes in the microRNA system. It is well-known that relationships between the immune system and the GH/IGF-1 axis are mutual and GH as well as IGF-1 could modulate inflammatory response and the activity of systemic inflammation. Available data indicate that the GH/IGF-1 axis exerts both pro-inflammatory and anti-inflammatory effects. Pro-inflammatory cytokines such as interleukin-6 (IL-6), tumour necrosis factor-a (TNF-α), and interleukin-1b (IL-b) are some of the most significant factors, besides malnutrition, chronic stress, and prolonged use of glucocorticoids, which impair the activity of the GH/IGF-1 axis, and consequently lead to growth retardation in children suffering from childhood-onset chronic inflammatory diseases. In this review, we discuss the mechanisms underlying the impact of chronic inflammation on the GH/IGF-1 axis and growth processes during childhood and adolescence, based on a number of experimental and human studies.

Background Dubowitz syndrome (DS) is a complex and rare condition characterized by postnatal growth retardation, microcephaly, short stature, mild developmental delay, facial dysmorphism, skin eruption and bone marrow failure. Though approximately 200 cases have been described so far, no specific genetic analysis, laboratory tests or radiological exams are available to confirm the diagnosis which is still based on clinical and facial features. Although short stature is a major feature of the syndrome, no endocrine alterations have been reported so far and scant data are available about the efficacy and safety of GH treatment in these patients. Methods A 13‐year‐old male patient was referred to our attention for short stature. Endocrinological evaluation including GH axis, adrenal and gonadal functions were assessed. aCGH was performed. Results 14q terminal microdeletion associated with Dubowitz phenotype was found. Endocrinological investigations revealed the presence of hypopituitarism which showed a satisfactory response to short‐term growth hormone therapy. The subject also started glucocorticoid replacement therapy. Disorders in pubertal progression and gonadal function were noted. Conclusions Dubowitz syndrome (DS) includes different clinical findings variably occurring. Subjects with a Dubowitz phenotype should be carefully monitored for endocrinological anomalies. The prompt recognition of potential life‐threatening endocrinological condition for example adrenal insufficiency is mandatory in order to start an adequate and early treatment., We report the endocrinological features of a male patient with 14q microdeletion and Dubowitz phenotype who showed a good response to short‐term GH therapy.

Background The phenotypic features of SHOX deficiency (SHOX-D) are highly variable and can be very mild, especially in young children. The aim of this retrospective study was to evaluate auxological and radiological indicators that could be predictive of SHOX-D in children. Methods Molecular analysis of the SHOX gene was performed in 296 subjects with growth impairment or skeletal disproportion, without alternative diagnosis. Auxological variables and radiographs of the hand, wrist and forearm were evaluated. Results SHOX mutations (88% inherited, 12% de novo) were identified in 52 subjects. The most predictive auxological indicators of SHOX-D were an increased sitting height/height ratio and a decreased arm span/height ratio. The convexity of distal radial metaphysis at X-ray, not yet reported in literature, was also found to be predictive of SHOX-D. In young children, stratification of data by bone age also highlighted ulnar tilt, lucency of the ulnar border of the distal radius and enlarged radius as the radiological signs most related to SHOX-D . Conclusions In this study, the analysis of auxological and radiological indicators in SHOX-D children allowed to identify an additional early radiological sign and underlines the importance of family auxological evaluation.

BACKGROUND & AIMS: A better understanding of prognostic factors within the heterogeneous spectrum of pediatric Crohn's disease (CD) should improve patient management and reduce complications. We aimed to identify evidence-based predictors of outcomes with the goal of optimizing individual patient management. METHODS: A survey of 202 experts in pediatric CD identified and prioritized adverse outcomes to be avoided. A systematic review of the literature with meta-analysis, when possible, was performed to identify clinical studies that investigated predictors of these outcomes. Multiple national and international face-to-face meetings were held to draft consensus statements based on the published evidence. RESULTS: Consensus was reached on 27 statements regarding prognostic factors for surgery, complications, chronically active pediatric CD, and hospitalization. Prognostic factors for surgery included CD diagnosis during adolescence, growth impairment, NOD2/CARD15 polymorphisms, disease behavior, and positive anti-Saccharomyces cerevisiae antibody status. Isolated colonic disease was associated with fewer surgeries. Older age at presentation, small bowel disease, serology (anti-Saccharomyces cerevisiae antibody, antiflagellin, and OmpC), NOD2/CARD15 polymorphisms, perianal disease, and ethnicity were risk factors for penetrating (B3) and/or stenotic disease (B2). Male sex, young age at onset, small bowel disease, more active disease, and diagnostic delay may be associated with growth impairment. Malnutrition and higher disease activity were associated with reduced bone density. CONCLUSIONS: These evidence-based consensus statements offer insight into predictors of poor outcomes in pediatric CD and are valuable when developing treatment algorithms and planning future studies. Targeted longitudinal studies are needed to further characterize prognostic factors in pediatric CD and to evaluate the impact of treatment algorithms tailored to individual patient risk.

In recent years, an aberrant gastrointestinal colonization has been found to be associated with an higher risk for postnatal sepsis, necrotizing enterocolitis (NEC) and growth impairment in preterm infants. As a consequence, the reasons of intestinal dysbiosis in this population of newborns have increasingly become an object of interest. The presence of a link between the gut and lung microbiome's development (gut-lung axis) is emerging, and more data show as a gut-brain cross talking mediated by an inflammatory milieu, may affect the immunity system and influence neonatal outcomes. A revision of the studies which examined gut and lung microbiota in preterm infants and a qualitative analysis of data about characteristic patterns and related outcomes in terms of risk of growing impairment, Necrotizing Enterocolitis (NEC), Bronchopulmonary Dysplasia (BPD), and sepsis have been performed. Microbiota take part in the establishment of the gut barrier and many data suggest its immune-modulator role. Furthermore, the development of the gut and lung microbiome (gut-lung axis) appear to be connected and able to lead to abnormal inflammatory responses which have a key role in the pathogenesis of BPD. Dysbiosis and the gut predominance of facultative anaerobes appear to be crucial to the pathogenesis and subsequently to the prevention of such diseases.

Growth impairment together with bone and joint involvement is common to most patients with mucopolysaccharidosis (MPS) disorders. The genetic basis for these metabolic disorders involves various enzyme deficiencies responsible for the catabolism of glycosaminoglycans (GAGs). The incomplete degradation and subsequent accumulation of GAGs result in progressive tissue damage throughout the body. Bone ossification is particularly affected, with the consequent onset of dysostosis multiplex which is the underlying cause of short stature. Joint manifestations, whether joint contractures (MPS I, II, VI, VII) or hyperlaxity (MPS IV), affect fine motor skills and quality of life. Subtle decreases in growth velocity can begin as early as 2–4 years of age. Pediatricians are in the front line to recognize or suspect MPS. However, given the rarity of the disorders and variable ages of symptom onset depending on disease severity, recognition and diagnostic delays remain a challenge, especially for the attenuated forms. Prompt diagnosis and treatment can prevent irreversible disease outcomes. Conclusion: We present a diagnostic algorithm based on growth velocity decline and bone and joint involvement designed to help pediatricians recognize early manifestations of attenuated forms of MPS. We illustrate the paper with examples of abnormal growth curves and subtle radiographic nuances. What is Known: • As mucopolysaccharidoses (MPSs) are rare genetic disorders infrequently seen in clinical practice, there can be a lag between symptom onset and diagnosis, especially of attenuated forms of the disease. • This highlights the need for increased disease awareness to recognize early clinical signs and subsequently initiate early treatment to improve outcomes (normal height potential) and possibly prevent or delay the development of irreversible disease manifestations. What is New: • Growth impairment co-presenting with limited range of joint motion and radiographic anomalies in children should raise suspicions of possible attenuated MPS (AMPS). • Experts present a diagnostic algorithm with detailed focus on the decline in growth velocity, delayed puberty and limitation in joint mobility seen in children with AMPS, to shorten time-to-diagnosis and treatment and potentially improve patient outcome.

UFU - Universidade Federal de Uberlândia A baixa estatura em crianças com doença renal crônica (DRC) tem etiologia multifatorial, altas prevalência e morbimortalidade e se torna mais frequente com a redução progressiva da taxa de filtração glomerular. O objetivo deste trabalho é analisar como os fatores de risco se associam à baixa estatura no início e no final do tratamento conservador. Este trabalho é uma coorte retrospectiva, na qual foram avaliados os prontuários dos pacientes com DRC, com idade no início do seguimento inferior a 13 anos, entre os anos de 1999 e 2015. Os pacientes (n=71) foram acompanhados durante 62,4 ± 49 meses, sendo 60,6% do sexo masculino. Foram avaliados idade, altura, presença de hipertensão arterial sistêmica (HAS), anemia, acidose metabólica, proteinúria e a TFG estimada (fórmula de Schwartz). Os pacientes foram divididos em grupos quanto à estatura inicial (normal ou baixa) e TFG inicial (menor ou maior que 30ml/min/1,73m2). Na análise estatística foram utilizados o teste do Qui-Quadrado, teste t pareado, curvas de Kaplan Meier e modelo de regressão de Cox multivariado. Vinte e cinco pacientes apresentavam baixa estatura no início do estudo. A acidose estava associada à baixa estatura no início do acompanhamento enquanto a TFG e a anemia estavam ao final. Houve redução significativa do número de pacientes hipertensos no grupo que apresentava estatura inicial normal e no grupo com TFG inicial ≥ 30ml/min/1,73m2, mas a HAS não esteve associada à baixa estatura. A dobra de creatinina, considerado marcador de progressão da doença renal, foi o fator independente mais significativo para a baixa estatura (r=10,3; P0,05). Conclui-se que, mesmo com o controle clínico das crianças com DRC no tratamento conservador, houve uma progressão do número de casos de baixa estatura durante o acompanhamento, provavelmente devido à referência tardia ao nosso serviço e à redução progressiva da função renal nestes pacientes. Os fatores de risco estudados estão diferentemente associados à baixa estatura no início e no final do acompanhamento das crianças com DRC em tratamento conservador. Short stature in children with chronic kidney disease (CKD) has a multifactorial etiology, high prevalence, and high morbidity and mortality, which becomes more frequent with the progressive reduction of the glomerular filtration rate (GFR). The objective of this study was to analyze risk factors associated with short stature at both the beginning and end of conservative treatment. This is a retrospective cohort study, in which the medical records of patients with CKD, aged less than 13 years at the beginning of follow-up, were evaluated between 1999 and 2015. Of the 71 patients examined, 60.6% were male and the average follow-up duration was 62.4 ± 49 months. Age, height, presence of systemic blood hypertension (SBH), anemia, metabolic acidosis, proteinuria, and estimated GFR were evaluated (Schwartz's formula). Patients were divided into groups based on initial stature (normal or low) and initial GFR (< or ≥30 mL/min/1.73m2). The Chi-square test, paired t-test, Kaplan-Meier curves, and multivariate Cox regression models were used in the statistical analysis. Twenty-five patients displayed short stature at the beginning of the study. Acidosis was associated with short stature at the start of follow-up, while GFR and anemia were associated with short stature at the end of follow-up. There was a significant reduction in the number of hypertensive patients in the GRF initial ≥ 30ml/min/1,73m2 and normal initial stature groups, but SBH was not associated with short stature. Creatinine doubling, considered a marker of progression of renal disease, was the most significant independent factor for short stature (r = 10.3; P

Objectives: Connective tissue diseases (CTD) are a heterogeneous group of chronic inflammatory conditions. One of their complications in children is the inhibition of growth velocity. Due to direct inflammation within the musculoskeletal system as well as glucocorticoid therapy, this feature is the most essential and is mainly expressed in the course of juvenile spondyloarthropathies and juvenile idiopathic arthritis (JIA). Duration of the disease, but predominantly the activity of the inflammatory process, seems to have a significant impact on the abnormal growth profile in children. Effective biological therapy leads to improvement of the patient’s clinical condition and also, through the extinction of disease activity and reduction of daily doses of glucocorticosteroids (GCS), it gradually accelerates and normalizes the growth rate in children with CTD. Our objective was to evaluate the impact of biological therapy on growth in children with chronic inflammatory CTD. Material and methods: Data from 24 patients with CTD treated with tumor necrosis factor--blockers (etanercept, adalimumab, golimumab) and an interleukin-6 receptor blocker (tocilizumab) were reviewed at the time of disease onset, biological treatment initiation and at least 12 up to 24 months onwards. The rate of growth was correlated with the daily doses of GCS, and the type and duration of biological therapy. Results: Patient median height, measured as the change in height standard deviation score, was 0.36 ±1.07 at disease onset and –0.13 ±1.02 at biologic therapy initiation. The growth velocity accelerated in 17 patients (70.1%) during the biological treatment. Mean height-SDS improvement between biological treatment initiation up to two years was 0.51 ±0.58. In 47% of patients daily doses of GCS were reduced to 0 mg/kg/day. Conclusions: In the treatment of CTD, biological agents restore growth velocity not only by inflammation inhibition, but also through limiting GCS daily doses.

Background/Aim: Linear growth impairment (LGI) is one of the most important features peculiar to children with inflammatory bowel disease (IBD). The aim of this report is to define the impact of IBD on the linear growth of children in the Kingdom of Saudi Arabia (KSA). Setting and Design: Multicenter retrospective study. Patients and Methods: Data from a cohort of newly- diagnosed children with IBD from 2003 to 2012 were analyzed retrospectively. The diagnosis of IBD was confirmed in accordance with the published criteria. Length/height for age was measured at diagnosis. The World Health Organization (WHO) reference was used and LGI was defined by length/height for age

Background/Aim: Linear growth impairment (LGI) is one of the most important features peculiar to children with inflammatory bowel disease (IBD). The aim of this report is to define the impact of IBD on the linear growth of children in the Kingdom of Saudi Arabia (KSA). Setting and Design: Multicenter retrospective study. Patients and Methods: Data from a cohort of newly- diagnosed children with IBD from 2003 to 2012 were analyzed retrospectively. The diagnosis of IBD was confirmed in accordance with the published criteria. Length/height for age was measured at diagnosis. The World Health Organization (WHO) reference was used and LGI was defined by length/height for age

Aflatoxin M1 (AFM1), a human carcinogen, is found in milk products and may have potentially severe health impacts on milk consumers. We assessed the risk of cancer and stunting as a result of AFM1 consumption in Nairobi, Kenya, using worst case assumptions of toxicity and data from previous studies. Almost all (99.5%) milk was contaminated with AFM1. Cancer risk caused by AFM1 was lower among consumers purchasing from formal markets (0.003 cases per 100,000) than for low-income consumers (0.006 cases per 100,000) purchasing from informal markets. Overall cancer risk (0.004 cases per 100,000) from AFM1 alone was low. Stunting is multifactorial, but assuming only AFM1 consumption was the determinant, consumption of milk contaminated with AFM1 levels found in this study could contribute to 2.1% of children below three years in middle-income families, and 2.4% in low-income families, being stunted. Overall, 2.7% of children could hypothetically be stunted due to AFM1 exposure from milk. Based on our results AFM1 levels found in milk could contribute to an average of &minus, 0.340 height for age z-score reduction in growth. The exposure to AFM1 from milk is 46 ng/day on average, but children bear higher exposure of 3.5 ng/kg bodyweight (bw)/day compared to adults, at 0.8 ng/kg bw/day. Our paper shows that concern over aflatoxins in milk in Nairobi is disproportionate if only risk of cancer is considered, but that the effect on stunting children might be much more significant from a public health perspective, however, there is still insufficient data on the health effects of AFM1.

The diagnosis of congenital hypopituitarism is difficult and often delayed because its symptoms are nonspecific. To describe the different clinical presentations of children with congenital hypopituitarism to reduce the time for diagnosis and to begin a precocious and appropriate treatment. We analyzed a cohort of five children with congenital hypopituitarism, describing their clinical, biochemical and radiological characteristics from the birth to diagnosis. As first sign of the disease, all of five patients presented a neonatal hypoglycemia, associated in four cases with jaundice. In all these four cases, the clinicians hypothesized a metabolic disease delaying the diagnosis, which was performed in only two cases within the neonatal period. In the other three cases, the diagnosis was formulated at 2, 5 and 8 years of life because there was severe and precocious growth impairment. It is important to suspect congenital hypopituitarism in the presence of persistent neonatal hypoglycemia associated with jaundice and of a precocious and severe reduction of the growth velocity in childhood. In all these cases, it is necessary to undertake a hypothalamic–pituitary magnetic resonance imaging scan as soon as possible, and to start appropriate treatment.

Background Helicobacter pylori (H. pylori) has been recognized as one of the most common chronic bacterial infections in the world. Most children are colonized in early childhood, and the infection will last a lifetime unless the child is treated with appropriate antibiotics. Aim To evaluate whether H. pylori infection has an influence on growth and whether the severity of endoscopicfindings relates to the growth impairment. Methods We formed four groups based on the presence or absence of H. pylori infection and gastrointestinal complaints as follows: group I: RAP +/H. pylori+; group II: RAP +/H. pylori-; group III: RAP -/H. pylori+; group IV: RAP -/H. pylori-. The relationship between endoscopic appearances, histological severity of gastritis, and antral H. pylori density with growth parameters was evaluated. Results The BMI standard derivation scores of groups I and II were significantly lower than those of asymptomatic controls independent of their H. pylori status. A significant difference in height for age standard derivation scores was observed only between groups I and IV. When we compared the BMI and height for age standard derivationscores of group III and group IV combined with that of theendoscopically normal children in the recurrent abdominal pain group, there was no significant difference between the two groups. Conclusion Recurrent abdominal pain associated with gastric mucosal injury plays a role in a decrease in BMI independent of H. pylori infection. However, if recurrent abdominal pain originates from H. pylori infection, it appears that linear growth is also affected. © Springer Science+Business Media, LLC 2010. Acknowledgments This study was financially supported by Yedi-tepe University Hospital.