Buuren, S. van

Efficacy and safety of oxandrolone in growth hormone-treated girls with turner syndrome (Article)

2010-03-01T00:00:00Z

Context and Objective: GH therapy increases growth and adult height in Turner syndrome (TS). The benefit to risk ratio of adding the weak androgen oxandrolone (Ox) to GH is unclear. Design and Participants: A randomized, placebo-controlled, double-blind, dose-response study was performed in 10 centers in The Netherlands. One hundred thirty-three patients with TS were included in age group 1 (2-7.99 yr), 2 (8-11.99 yr), or 3 (12-15.99 yr). Patients were treated with GH (1.33 mg/m2· d) from baseline, combined with placebo (Pl) or Ox in low(0.03mg/kg · d) or conventional (0.06 mg/kg · d) dose from the age of 8yr and estrogens from the age of 12 yr. Adult height gain (adult height minus predicted adult height) and safety parameters were systematically assessed. Results: Compared with GH+Pl, GH+Ox 0.03 increased adult height gain in the intention-to-treat analysis (mean ± SD, 9.5 ± 4.7 vs. 7.2 ± 4.0 cm, P = 0.02) and per-protocol analysis (9.8 ± 4.9 vs. 6.8 ± 4.4 cm, P = 0.02). Partly due to accelerated bone maturation (P < 0.001), adult height gain on GH + Ox 0.06 was not significantly different from that on GH+Pl (8.3 ± 4.7 vs. 7.2 ± 4.0 cm, P=0.3). Breast development was slower on GH+Ox (GH+Ox 0.03, P = 0.02; GH+Ox 0.06, P = 0.05), and more girls reported virilization on GH+Ox 0.06 than on GH+Pl (P = 0.001). Conclusions: In GH-treated girls with TS, we discourage the use of the conventional Oxdosage (0.06 mg/kg · d) because of its low benefit to risk ratio. The addition of Ox 0.03 mg/kg · d modestly increases adult height gain and has a fairly good safety profile, except for some deceleration of breast development. Copyright

Growth monitoring to detect children with cystic fibrosis (Article)

2009-10-13T00:00:00Z

Background/Aims: Cystic fibrosis (CF) in infancy and childhood is often associated with failure to thrive (FTT). This would suggest that in countries without a newborn screening program for CF, FTT could be used as a clinical screening tool. The aim of this study is to assess the diagnostic performance of FTT for identifying children with CF. Methods: Longitudinal length and weight measurements up to 2.5 years of age were used from CF patients (n = 123) and a reference group (n = 2,151) in The Netherlands. Growth measurements after diagnosis were excluded. We developed five potential screening rules based upon length, weight and body mass index (BMI) standardized by age and gender (SDS). Outcome measures were sensitivity, specificity and positive predictive value (PPV). Results: BMI SDS had the highest sensitivity at low false-positive rates. An efficient scenario is a BMI SDS below -2.5 SD in combination with a decrease in BMI SDS of at least 0.5 SD. This scenario had a sensitivity of 32%, a specificity of 98.3% and a PPV of 0.75%. Conclusion: In the absence of a newborn screening program, young children with FTT for BMI are candidates to consider testing for CF.

Intelligence of very preterm or very low birthweight infants in young adulthood (Article)

2009-05-01T00:00:00Z

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.

Puberty induction in Turner syndrome: Results of oestrogen treatment on development of secondary sexual characteristics, uterine dimensions and serum hormone levels (Article)

2009-02-01T00:00:00Z

Background: Besides short stature, gonadal dysgenesis leading to a lack of oestrogen is one of the main characteristics of Turner syndrome (TS). In most TS girls, puberty is induced with exogenous oestrogens. Objective: To describe the pubertal development and uterine dimensions achieved by low-dose 17β-oestradiol (17β-E2) orally started at an appropriate age. Additionally, to determine whether serum hormone levels aid evaluation of pubertal progression. Design: In 56 TS girls, we prospectively studied pubertal stage, serum E2, LH, FSH, SHBG and oestrone (E1), starting oestrogen treatment with a low-dose 17β-E2 (5 μg/kg/day) during GH treatment at mean (SD) age 12.7 (0.7) years. Hormone levels were measured at start, 3 months after start and after increasing 17β-E2 dosage. Uterine dimensions were measured in 39 TS women at age 19.9 (2.2) years. Results: Although breast and pubic hair development were similar to that in normal Dutch girls up to Tanner stage B5 and P5, respectively, breast development was 2 years later. Before oestrogen therapy, E2 levels were comparable to those in prepubertal girls. With a 17β-E2 dose of 5 μg/kg/day, these levels increased significantly, becoming comparable to normal late pubertal or adult concentrations, whereas SHBG levels were unchanged. At the adult 17β-E2 dose, SHBG had increased significantly. Uterus shape was juvenile in four (10.2%), cylindrical in four and mature-adult shaped in 31 (79.5%) of TS patients. Conclusions: During GH treatment in TS girls, normal breast development up to B5 can be mimicked, with just a 2-year delay. In a clinical setting, serum hormone levels provide no additional information for evaluating pubertal progression. After age-appropriate pubertal induction, uterine dimensions in women aged nearly 20 years were subnormal. It remains unclear whether this was related to E2 dosage, timing or duration, or factors related to TS.

Screening rules for growth to detect celiac disease: A case-control simulation study (Article)

2008-09-11T00:00:00Z

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.

The diagnostic work up of growth failure in secondary health care; An evaluation of consensus guidelines (Article)

2008-05-13T00:00:00Z

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 (Δ HSDS < -0.25/yr or Δ 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.

Developing evidence-based guidelines for referral for short stature (Article)

2008-03-01T00:00:00Z

Objective: To establish evidence based guidelines for growth monitoring on a population basis. Study design: Several auxological referral criteria were formulated and applied to longitudinal growth data from four different patient groups, as well as three samples from the general population. Results: Almost 30% of pathology can be detected by height standard deviation score (HSDS) below -3 or at least two observations of HSDS below -2.5 at a low false-positive rate (<1%) in 0-3-year-old infants. For 3-10-year olds, a rule concerning distance to target height of >2 SD in combination with HSDS <-2.0 has the best predictive value. In combination with a rule on severe short stature (<-2.5 SDS) and a minor contribution from a rule on "height deflection", 85.7% of children with Turner syndrome and 76.5% of children who are short because of various disorders are detected at a false-positive rate of 1.5-2%.Conclusions: The proposed guidelines for growth monitoring show high sensitivity at an acceptably low false-positive rate in 3-10-year-old children. Distance to target height is the most important criterion. Below the age of 3 years, the sensitivity is considerably lower. The resulting algorithm appears to be suitable for industrialised countries, but requires further testing in other populations.

Referral patterns of children with poor growth in primary health care (Article)

2007-06-07T00:00:00Z

Background. To promote early diagnosis and treatment of short stature, consensus meetings were held in the mid nineteen nineties in the Netherlands and the UK. This resulted in guidelines for referral. In this study we evaluate the referral pattern of short stature in primary health care using these guidelines, comparing it with cut-off values mentioned by the WHO. Methods. Three sets of referral rules were tested on the growth data of a random sample (n = 400) of all children born between 01-01-1985 and 31-12-1988, attending school doctors between 1998 and 2000 in Leiden and Alphen aan den Rijn (the Netherlands): the screening criteria mentioned in the Dutch Consensus Guideline (DCG), those of the UK Consensus Guideline (UKCG) and the cut-off values mentioned in the WHO Global Database on Child growth and Malnutrition. Results. Application of the DCG would lead to the referral of too many children (almost 80%). The largest part of the referrals is due to the deflection of height, followed by distance to target height and takes primarily place during the first 3 years. The deflection away from the parental height would also lead to too many referrals. In contrast, the UKCG only leads to 0.3% referrals and the WHO-criteria to approximately 10%. Conclusion. The current Dutch consensus guideline leads to too many referrals, mainly due to the deflection of length during the first 3 years of life. The UKCG leads to far less referrals, but may be relatively insensitive to detect clinically relevant growth disorders like Turner syndrome. New guidelines for growth monitoring are needed, which combine a low percentage of false positive results with a good sensitivity.

Pubertal development in The Netherlands 1965-1997 (Article)

2001-01-01T00:00:00Z

We investigated pubertal development of 4019 boys and 3562 girls >8 y of age participating in a cross-sectional survey in The Netherlands and compared the results with those of two previous surveys. Reference curves for all pubertal stages were constructed. The 50th percentile of Tanner breast stage 2 was 10.7 y, and 50% of the boys had reached a testicular volume of 4 mL at 11.5 y of age. Median age at menarche was 13.15 y. The median age at which the various stages of pubertal development were observed has stabilized since 1980. The increase of the age at stage G2 between 1965 and 1997 is probably owing to different interpretations of its definition. The current age limits for the definition of precocious are close to the third percentile of these references. A high agreement was found between the pubic hair stages and stages of pubertal (genital and breast) development, but slightly more in boys than in girls. Menarcheal age was dependent on height, weight, and body mass index. At a given age tall or heavy girls have a higher probability of having menarche compared with short or thin girls. A body weight exceeding 60 kg (+1 SDS), or a body mass index of >20 (+1 SDS), has no or little effect on the chance of having menarche, whereas for height such a ceiling effect was not observed. In conclusion, in The Netherlands the age at onset of puberty or menarche has stabilized since 1980. Height, weight, and body mass index have a strong influence on the chance of menarche.