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Aromatase, an enzyme located in the endoplasmic reticulum of estrogen-producing cells, catalyzes the rate-limiting step in the conversion of androgens to estrogens in many tissues. The clinical features of patients with defects in CYP19A1, the gene encoding aromatase, have revealed a major role for this enzyme in epiphyseal plate closure, which has promoted interest in the use of inhibitors of aromatase to improve adult height. The availability of the selective aromatase inhibitors letrozole and anastrozole--currently approved as adjuvant therapy for breast cancer--have stimulated off-label use of aromatase inhibitors in pediatrics for the following conditions: hyperestrogenism, such as aromatase excess syndrome, Peutz-Jeghers syndrome, McCune-Albright syndrome and functional follicular ovarian cysts; hyperandrogenism, for example, testotoxicosis (also known as familial male-limited precocious puberty) and congenital adrenal hyperplasia; pubertal gynecomastia; and short stature and/or pubertal delay in boys. Current data suggest that aromatase inhibitors are probably effective in the treatment of patients with aromatase excess syndrome or testotoxicosis, partially effective in Peutz-Jeghers and McCune-Albright syndrome, but probably ineffective in gynecomastia. Insufficient data are available in patients with congenital adrenal hyperplasia or functional ovarian cysts. Although aromatase inhibitors appear effective in increasing adult height of boys with short stature and/or pubertal delay, safety concerns, including vertebral deformities, a decrease in serum HDL cholesterol levels and increase of erythrocytosis, are reasons for caution. [ABSTRACT FROM AUTHOR]

Objective: In the past years, the canonical Wnt/β-catenin signaling pathway has emerged as a critical regulator of cartilage development and homeostasis. In this pathway, glycogen synthase kinase-3β (GSK3β) down-regulates transduction of the canonical Wnt signal by promoting degradation of β-catenin. In this study we wanted to further investigate the role of Gsk3β in cartilage maintenance. Design: Therefore, we have treated chondrocytes ex vivo and in vivo with GIN, a selective GSK3β inhibitor. Results: In E17.5 fetal mouse metatarsals, GIN treatment resulted in loss of expression of cartilage markers and decreased chondrocyte proliferation from day 1 onward. Late (3 days) effects of GIN included cartilage matrix degradation and increased apoptosis. Prolonged (7 days) GIN treatment resulted in resorption of the metatarsal. These changes were confirmed by microarray analysis showing a decrease in expression of typical chondrocyte markers and induction of expression of proteinases involved in cartilage matrix degradation. An intra-articular injection of GIN in rat knee joints induced nuclear accumulation of β-catenin in chondrocytes 72 h later. Three intra-articular GIN injections with a 2 days interval were associated with surface fibrillation, a decrease in glycosaminoglycan expression and chondrocyte hypocellularity 6 weeks later. Conclusions: These results suggest that, by down-regulating β-catenin, Gsk3β preserves the chondrocytic phenotype, and is involved in maintenance of the cartilage extracellular matrix. Short term β-catenin up-regulation in cartilage secondary to Gsk3β inhibition may be sufficient to induce osteoarthritis-like features in vivo. [ABSTRACT FROM AUTHOR]

This study explored the effects of basic developmental care on the behaviour of very pre-term infants and parental stress at 1 and 2 years of corrected age. A randomized controlled trial was done to compare basic Developmental Care (standardized nests and incubator covers) and controls (standard care). Parents of infants born <32 weeks of gestation completed questionnaires measuring child behaviour and parental stress at 1 year (N=139) and 2 years (N=133) of the child's age. Parental stress was measured using the Nijmegen Parenting Stress Index and child behaviour was measured using the Infant-Toddler Social and Emotional Assessment (ITSEA) and the Child Behaviour Checklist 2-3. At 1 year of age, children in the basic developmental care group had significantly higher behaviour scores on the total competence domain (p=.009) and the competence subscale mastery motivation (p=.002) of the ITSEA questionnaire, meaning that the infants showed more curiosity, persistence, obedience and enjoyment with small accomplishments. No significant effects were found on problem behaviour or parenting stress. We conclude that introducing a basic form of developmental care in the neonatal intensive care unit has a positive influence on the child's competence behaviour at 1 year of age. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate psychosocial, cognitive, and motor functioning in patients clinically suspected of Sotos syndrome and to examine differences between patients with deletions or mutations of the gene encoding nuclear SET domain-containing protein 1 (NSD1; the major cause of the syndrome) and those without such alterations. Twenty-nine participants (21 males, 8 females) clinically suspected of Sotos syndrome (mean age 11y 10mo [SD 10y 11mo], range 1y 10mo-48y 5mo) were divided into an NSD1 mutation group (n=12; 8 males, 4 females) and an NSD1 non-mutation group (n=17; 13 males, 4 females). Intelligence, behaviour problems, attention-deficit-hyperactivity disorder (ADHD) symptoms, temperament, adaptive behaviour, and motor functioning were assessed with an extensive test battery. Scores were compared with those of control groups, and scores of the two subgroups were compared with each other. The mean IQ in the 21 individuals tested was 76 (SD 16; range 47-105). High rates of behaviour problems were found and patients lagged 1y 7mo to 2y 7mo behind in aspects of adaptive behaviour. In comparison with a control group of patients with a learning disability, motor functioning was better. NSD1 mutation compared with NSD1 non-mutation patients showed easier temperament, and fewer NSD1 mutation patients scored in the clinical range for 'total behaviour problems' (3/11 vs 13/17), 'internalizing behaviour' (2/11 vs 11/17), and ADHD (0/9 vs 4/15). [ABSTRACT FROM AUTHOR]

Aims: To obtain age references for sitting height (SH), leg length (LL), and SH/H ratio in the Netherlands; to evaluate how SH standard deviation score (SDS), LL SDS, SH/H SDS, and SH/LL SDS are related to height SDS; and to study the usefulness of height corrected SH/H cut-off lines to detect Marfan syndrome and hypochondroplasia.Methods: Cross-sectional data on height and sitting height were collected from 14 500 children of Dutch origin in the age range 0-21 years. Reference SD charts were constructed by the LMS method. Correlations were analysed in three age groups. SH/H data from patients with Marfan syndrome and genetically confirmed hypochondroplasia were compared with height corrected SH/H references.Results: A positive association was observed between H SDS, SH SDS, and LL SDS in all age groups. There was a negative correlation between SH/H SDS and height SDS. In short children with a height SDS <-2 SDS, a cut-off limit of +2.5 SD leads to a more acceptable percentage of false positive results. In exceptionally tall children, a cut-off limit of-2.2 SDS can be used. Alternatively, a nomogram of SH/H SDS versus H SDS can be helpful. The sensitivity of the height corrected cut-off lines for hypochondroplasia was 80% and for Marfan syndrome only 30%.Conclusions: In exceptionally short or tall children, the dependency of the SH/H ratio (SDS) on height SDS has to be taken into consideration in the evaluation of body proportions. The sensitivity of the cut-off lines for hypochondroplasia is fair. [ABSTRACT FROM AUTHOR]

BACKGROUND: Increasing evidence indicates that adult body composition is associated with prenatal and infancy weight gain, but the relative importance of different time periods has not been elucidated. OBJECTIVE: The objective was to study the association between prenatal, early postnatal, and late infancy weight gain and body mass index (BMI), fat mass, and fat distribution in young adulthood. DESIGN: We included 403 men and women aged 19 y from a Dutch national prospective follow-up study who were born at <32 wk of gestation. BMI, waist circumference, and waist-to-hip ratio SD scores and subscapular-to-triceps ratio, percentage body fat, fat mass, and fat-free mass at age 19 y were studied in relation to birth weight SD scores, weight gain from preterm birth until 3 mo postterm (early postnatal weight gain), and weight gain from 3 mo until 1 y postterm (late infancy weight gain). RESULTS: Birth weight SD scores were positively associated with weight, height, BMI SD scores, and fat-free mass at age 19 y but not with fat mass, percentage body fat, or fat distribution. Early postnatal and late infancy weight gain were positively associated with adult height, weight, BMI, waist circumference SD scores, fat mass, fat-free mass, and percentage body fat but not with waist-to-hip ratio SD scores or subscapular-to-triceps ratio. CONCLUSIONS: In infants born very preterm, weight gain before 32 wk of gestation is positively associated with adult body size but not with body composition and fat distribution. More early postnatal and, to a lesser extent, late infancy weight gain are associated with higher BMI SD scores and percentage body fat and more Copyright © 2005 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

Background: The 56-item TNO AZL Child Quality Of Life (TACQOL) questionnaire was developed to meet the need for a reliable and valid instrument for measuring health-related quality of life (HRQoL) in children. HRQoL was defined as health status in seven domains plus emotional responses to problems in health status. The TACQOL explicitly offers respondents the possibility of differentiating between their functioning and the way they feel about it. The aims of the study were threefold: to evaluate psychometric performance of the TACQOL in the general population, to evaluate the relationship between Parent Forms and Child Forms and to obtain additional information about validity. Methods: A random sample of 1,789 parents of 6-11 year olds completed the TACQOL (response rate 71%), as well as 1,159 8-11 year olds themselves (response rate 69%). Results: Multiple correspondence analyses showed that item response categories were ordinal and that the TACQOL scales may be regarded as metric. Cronbach's alpha ranged from 0.65 to 0.84. Only 57% of reported health status problems were associated with negative emotions. Intraclass correlation coefficients between Parents Forms and Child Forms ranged from 0.44 tot 0.61. Pearson's correlation coefficients between TACQOL and KINDL ranged from 0.24 to 0.60. Univariate analyses of variance showed that children with chronic diseases and children receiving medical treatment had lower TACQOL scores than healthy children. Conclusions: The study showed that with the TACQOL, children's HRQoL can be measured in a reliable and valid way. [ABSTRACT FROM AUTHOR]

The comparative effect and safety of 2 IU compared with 4 IU/m2/day of recombinant human growth hormone (rhGH) was studied in 38 growth hormone deficient children regarding the impact of several factors on short term (one year) and long term (three year) growth response. In 21 newly diagnosed patients, three years of rhGH treatment resulted in a significant increase of height velocity SD score, height SD score, and predicted adult height SD score, irrespective of rhGH dose. In 17 transfer patients (previously treated with 12 IU rhGH/m2/week) 4 IU/m2/day resulted in a significantly higher height velocity SD score and height SD score for chronological age than 2 IU/m2/day, while more of them reached their target range or showed a substantial height SD score increment. Height SD score for bone age and predicted adult height SD score only increased significantly with 4 IU rhGH. After one year of rhGH treatment, new patients showed significant negative correlation between delta height SD score with age and baseline insulin-like growth factor I (IGF-I) SD score, and positive correlation with rhGH dose. After three years of treatment, delta height SD score for chronological age was significantly, negatively correlated with age and baseline 'corrected' height SD score (height SD score for chronological age minus target height SD score). There was no significant correlation with rhGH dose. Prolonged treatment with either dose had no adverse effect on IGF-I concentrations, carbohydrate or lipid metabolism. As early age and divergence between height SD score and target height SD score seem more important for growth response than rhGH dose, it is recommended that treatment starts early with 2 IU rhGH/m(2)/day and the dose is doubled if growth is insufficient after several years of treatment. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To examine the effect of intrauterine and neonatal growth, prematurity and personal and environmental risk factors on intelligence in adulthood in survivors of the early neonatal intensive care era. METHODS: A large geographically based cohort comprised 94% of all babies born alive in the Netherlands in 1983 with a gestational age below 32 weeks and/or a birth weight >1500 g (POPS study). Intelligence was assessed in 596 participants at 19 years of age. Intrauterine and neonatal growth were assessed at birth and 3 months of corrected age. Environmental and personal risk factors were maternal age, education of the parent, sex and origin. RESULTS: The mean (SD) IQ of the cohort was 97.8 (15.6). In multiple regression analysis, participants with highly educated parents had a 14.2-point higher IQ than those with less well-educated parents. A 1 SD increase in birth weight was associated with a 2.6-point higher IQ, and a 1-week increase in gestational age was associated with a 1.3-point higher IQ. Participants born to young mothers (<25 years) had a 2.7-point lower IQ, and men had a 2.1-point higher IQ than women. The effect on intelligence after early (symmetric) intrauterine growth retardation was more pronounced than after later (asymmetric) intrauterine or neonatal growth retardation. These differences in mean IQ remained when participants with overt handicaps were excluded. CONCLUSIONS: Prematurity as well as the timing of growth retardation are important for later intelligence. Parental education, however, best predicted later intelligence in very preterm or very low birthweight infants. [ABSTRACT FROM AUTHOR]

Background: It is generally assumed that most patients with celiac disease (CD) have a slowed growth in terms of length (or height) and weight. However, the effectiveness of slowed growth as a tool for identifying children with CD is unknown. Our aim is to study the diagnostic efficiency of several growth criteria used to detect CD children.Methods: A case-control simulation study was carried out. Longitudinal length and weight measurements from birth to 2.5 years of age were used from three groups of CD patients (n = 134) (one group diagnosed by screening, two groups with clinical manifestations), and a reference group obtained from the Social Medical Survey of Children Attending Child Health Clinics (SMOCC) cohort (n = 2,151) in The Netherlands. The main outcome measures were sensitivity, specificity and positive predictive value (PPV) for each criterion.Results: Body mass index (BMI) performed best for the groups with clinical manifestations. Thirty percent of the CD children with clinical manifestations and two percent of the reference children had a BMI Standard Deviation Score (SDS) less than -1.5 and a decrease in BMI SDS of at least -2.5 (PPV = 0.85%). The growth criteria did not discriminate between the screened CD group and the reference group.Conclusion: For the CD children with clinical manifestations, the most sensitive growth parameter is a decrease in BMI SDS. BMI is a better predictor than weight, and much better than length or height. Toddlers with CD detected by screening grow normally at this stage of the disease. [ABSTRACT FROM AUTHOR]

Background: As abnormal growth might be the first manifestation of undetected diseases, it is important to have accurate referral criteria and a proper diagnostic work-up. In the present paper we evaluate the diagnostic work-up in secondary health care according to existing consensus guidelines and study the frequency of underlying medical disorders.Methods: Data on growth and additional diagnostic procedures were collected from medical records of new patients referred for short stature to the outpatient clinics of the general paediatric departments of two hospitals (Erasmus MC - Sophia Children's Hospital, Rotterdam and Spaarne Hospital, Haarlem) between January 1998 and December 2002. As the Dutch Consensus Guideline (DCG) is the only guideline addressing referral criteria as well as diagnostic work-up, the analyses were based on its seven auxological referral criteria to determine the characteristics of children who are incorrectly referred and the adequacy of workup of those who are referred.Results: Twenty four percent of children older than 3 years were inappropriately referred (NCR). Of the correctly referred children 74-88% were short corrected for parental height, 40-61% had a height SDS <-2.5 and 21% showed height deflection (Delta HSDS < -0.25/yr or Delta HSDS < -1). In none of the children a complete detailed routine diagnostic work up was performed and in more than 30% no routine laboratory examination was done at all. Pathologic causes of short stature were found in 27 children (5%).Conclusion: Existing guidelines for workup of children with suspected growth failure are poorly implemented. Although poorly implemented the DCG detects at least 5% pathologic causes of growth failure in children referred for short stature. New guidelines for referral are required with a better sensitivity and specificity, wherein distance to target height should get more attention. The general diagnostic work up for short stature should include testing for celiac disease in all children and for Turner syndrome in girls. [ABSTRACT FROM AUTHOR]