Growth impairment in very low birthweight children at 12 years: correlation with perinatal and outcome variables.

AIM: To compare the growth of very low birthweight (VLBW) children in early adolescence with that of their normal birthweight peers; to examine the role of factors contributing to growth-parental height, perinatal variables, bone maturity and sexual maturation; to examine the correlation between head growth and cognitive and educational outcome. METHODS: Standing and sitting heights, weight, occipito-frontal circumference (OFC), skinfold thicknesses and pubertal staging were assessed in 137 VLBW children and 160 controls at 11-13.5 years of age. Ninety six (70%) of the VLBW children had their bone age assessed using the TW2 method. Reported parental heights were obtained by questionnaire. All children had standardised tests of cognitive and educational ability. Perinatal data had been collected prospectively as part of a longitudinal study. RESULTS: VLBW children had lower heights, weight, and OFC. Skinfold thicknesses were no different. The children's short stature was not accounted for by difference in parental height, degree of pubertal development, or by retarded bone age. Indeed, the TW2 RUS score was significantly advanced in the VLBW children. Using the bone ages to predict final adult height, 17% have a predicted height below the third centile and 33% below the tenth. Weight was appropriate for height, but there was a residual deficiency in OFC measurements after taking height into account. In the VLBW group smaller head size was associated with lower IQ and mathematics and reading scores. CONCLUSIONS: Growth problems persist in VLBW children and final heights may be even more abnormal than present heights suggest. VLBW children have smaller OFCs than expected from their short stature alone and this may be associated with poorer educational and cognitive outcomes.     

Growth and development in simple obesity

It is well known that fat children tend to be taller than their peers and to present a slight acceleration of skeletal and pubertal maturation. To verify this tendency and to examine some of the points that are still controversial, auxological data were studied concerning 303 subjects (141 males and 162 females, aged 6–16 years) affected by simple obesity. Subjects were seen to be taller than average by about 1 SD from 6 to 9 years of age, becoming close to or shorter than average at later ages. Height below the 10th percentile was common in 17% of males and 8% of females, due to hereditary shortness, growth delay or late puberty. Girls had early puberty and menarche; the rate of sexual maturation was variable in boys.Abbreviations SO simple obesity - BMI body mass index - GP Greulich and Pyle method - TW2-RUS Tanner and Whitehouse method for skeletal age assessment (radius, ulna and short bones score) - GECS growth evaluation computerized system - G genital development - B breast development - PH pubic hair development - M menarche - SDS standard deviation scores     

Growth hormone therapy in short children born small for gestational age

Being born small for gestational age (SGA) is one of the most common causes of childhood short stature, and recombinant GH therapy has been recently licensed to promote growth in short SGA children from the age of 4 years old. Studies are now reporting very encouraging effects on adult height gains, especially in those children who started GH therapy early, at least 2 years prior to the onset of puberty. Compared to the age at starting treatment, the GH dose has a less significant impact on final height, and more attention needs to be paid now to identify earlier those SGA children who fail to catch-up spontaneously. The benefits are not just in terms of height, but also in body composition and possibly blood pressure and lipid levels. However the risk of side effects and long-term complications, particularly related to the expected metabolic effects of GH in inducing insulin resistance and hyperinsulinaemia, need to be carefully monitored especially in SGA children with a family history of type 2 diabetes. Recently, GH therapy was found to amplify the adrenarche of short SGA children and to induce a pro-inflammatory shift, as judged by a rise of neutrophil count and circulating interleukin-6 (IL-6), and a fall in adiponectin levels. Further progress is anticipated to assess the addition of insulin-sensitizing therapy to attenuate the GH-induced hyperinsulinemia, in order to alter the pro-inflammatory course, to avoid excessive release of adrenal androgens, and to slow down the potential rapid tempo of pubertal progression in SGA children. In the meantime, post-SGA short stature is rapidly becoming one of the prime indications for GH therapy in childhood.     

Growth hormone normalizes pubertal onset in children with cystic fibrosis

Children with cystic fibrosis (CF) have a high incidence of delayed puberty and poor growth. We retrospectively reviewed pubertal maturation data from 105 children with CF who had participated in studies on growth hormone (GH). As part of the GH study, participants were randomized into two cohorts, one of which was treated with GH for 1 year, and then followed off GH, and the other group was first followed off GH, and then treated with GH for 1 year. Pubertal staging was obtained throughout these studies and we have retrospectively analyzed the data. RESULTS: In prepubertal females, GH treatment resulted in a normalized onset of breast development as compared to delayed onset in non-treated females. Females treated during puberty had a normal tempo of breast development. In prepubertal males, GH treatment resulted in a normalized onset of testicular volume compared to non-treated males. Testicular size progression was not accelerated in pubertal boys treated with GH. CONCLUSION: GH treatment normalizes pubertal onset in prepubertal children with CF.     

Growth of children with β-thalassemia major

Hypertransfusion and regular chelation therapy have allowed improved survival in patients with thalassemia major (TM). Despite medical advances, growth failure and hypogonadism remain significant clinical problems in these patients in adolescence. Disproportionate truncal shortening which is common especially among adolescents with thalassemia, is due to platyspondyly resulting from a combination of factors like hemosiderosis, desferrioxamine toxicity or deficiency of trace elements. Although growth hormone (GH) deficiency and GH neurosecretory dysfunction have been described in TM patients, most short TM patients have normal GH reserve. The low serum IGF-1 and IGFBP-3 concentrations in TM patients despite having normal GH reserve and serum GH binding protein levels suggest that a state of secondary GH insensitivity exists. The pubertal growth spurt may be impaired in TM patients going through spontaneous or induced puberty and may have a negative effect on final adult height. GH therapy in dosages ranging from 0.5–1.0 IU/kg/wk has resulted in a significant improvement in growth velocity in short TM children without any adverse effects on skeletal maturation, blood pressure, glucose tolerance and serum lipids. There is limited evidence that GH treatment can result in an improved final adult height in short TM children. Careful and regular clinical and biochemical monitoring should be preformed on these patients while they are treated with GH.     

Growth and pubertal development in patients with meningomyelocele: a retrospective analysis

Our retrospective analysis of growth and pubertal development includes 109 children and adults with meningomyelocele (MMC) (52 M, 57 F) aged 3.2-21.0 years (median 8.9 years). Anthropometric data, growth-retarding factors and data on pubertal development were analysed in comparison to the normal population using standards from Prader et al. (1). The results (mean ± SD) were as follows. Fifty patients (46.8%) had short stature (height SDS for chronological age (SDS CA)< -2). The supine length was influenced by the level of the lesion (height SDS CA: ≥ L2 -3.13 ± 1.62, ≤ S2 -0.46 ± 1.27), ambulatory status, skeletal deformities and pubertal stage. The mean adult height ( n = 15, age 16.1–21.0 years) measured 141.3cm for women (height SDS CA -3.83 ± 1.79) and 159.2 cm for men (height SDS CA -2.27 ± 1.81). In 82.6% of the subjects ( n = 90), arm spans were within the normal range. Reduced arm spans (SDS < -2) as found in 19 patients (17.4%) with short stature (mean height SDS CA -3.29 ± 1.29) may be caused by factors other than neurological lesions and skeletal deformities, and require further endocrinological studies. Out of 27 pubertal patients, central precocious puberty was diagnosed in five girls. The stages of puberty in MMC girls developed earlier than expected for the age-related group.     

Management of Growth Hormone Deficiency Through Puberty

ABSTRACT. As a model of the growth hormone (GH) dependence of growth in prepuberty and puberty, the growth of 182 children (93 boys, 89 girls) who survived in first remission for treatment of acute lymphoblastic leukaemia was examined. Chemotherapy regimens, including intrathecal methotrexate, were similar in all patients, but CNS treatment differed, in that one group received 2400 cGy cranial irradiation, while the other received 1800 cGy. There was a significant decrease in height SDS during prepuberty, which was equivalent in both sexes, whereas there was a much greater decrease in pubertal growth in girls than in boys. Girls treated with the lower dose regimen of cranial irradiation had their onset of pubertal maturation significantly advanced, to a mean of 9.9 years ( p < 0.001). Previous studies have indicated that the duration of puberty is shortened by GH treatment in patients with idiopathic multiple pituitary hormone deficiency or isolated GH deficiency (GHD). To determine whether an increase in the dose of GH administered during the adolescent growth spurt would improve final height, a prospective randomized trial was performed in 32 children (25 boys, 7 girls) with isolated GHD treated with a GH dose regimen of 15 IU/m²/week as daily s.c. injections. At the onset of the pubertal growth spurt, the patients were randomized either to an unchanged dose or to 30 IU/m²/week. There was no significant change in height velocity with the doubled dose of GH, but there was a trend in the advancement of pubertal maturation which was considered to be dose related. It is suggested that these findings are of relevance to the treatment of GHD in puberty, especially in girls with early or precocious puberty occurring as a consequence of low-dose cranial irradiation. It is concluded that optimum final heights may not be achieved in these patients without the therapeutic manipulation of the onset and/or duration of puberty.     

Growth acceleration and final height after treatment for delayed diagnosis of celiac disease

The only presenting clinical feature of diagnosing celiac disease (CD) late may be short stature. At the start of treatment with a gluten-free diet (GFD), celiac children show an accelerated growth rate. The real duration of catch-up growth and influence of diet on the final stature has not yet been defined. In order to evaluate the effect of a GFD on growth parameters, 24 children diagnosed late with CD were studied at our center. During the period of diagnosis, weight, height standard deviation score (HSDS), weight and height velocities (WV and HV), bone age (BA), and pubertal stage were recorded. Predicted height (PH) according to the Tanner method, parental height, and target height (TH) were also evaluated at diagnosis. All patients initially presented because of short stature or retarded growth (100% of patients with height less than 5th percentile). Patients showed an increased HV and WV during the first 3 years on a GFD, with maximum growth velocity occurring during the first year, but the catch-up growth was incomplete over 3 years (mean HSDS +/- SD, -1.77 +/- 0.6). Puberty began in all patients at a normal age. The 12 patients who completed pubertal development reached their target height, whatever the duration of the GFD. The final height (between the 1st and 25th percentile) seemed influenced mainly by familial characteristics; height was below the 3rd percentile in 31% of parents examined.     

Growth in Crohn's disease

Abnormal linear growth is frequent in children and adolescents with Crohn's disease. The typical pattern is of growth retardation associated with delayed skeletal maturation. Puberty is also frequently delayed. Over 50% of patients may have a subnormal height velocity, and approximately 25% will have short stature. The endocrine status is characterized by normal growth hormone secretion and a slightly subnormal serum level of insulin-like growth factor I, which is related to nutritional status. Principal therapeutic options are intestinal resection for localized disease, and enteral nutrition--using a polymeric diet--for more widespread disease, particularly involving the small intestine. Growth responses to both modalities are often excellent and produce considerable psychological benefit. Optimum therapy is achieved by close collaboration between gastroenterologists and endocrinologists, and by the use of auxological methods to document pre- and post-therapeutic management.     

Frequent growth disorders in puberty and adolescence

About 50% of our patients with concern about their actual or final height are adolescents (girls greater than 11 years, boys greater than 13 years). Growth data of 103 adolescent patients (70 boys, 33 girls) seen in 1988/89 are analysed. 85% of the patients (90% of the boys) complained of short stature (length less than 3rd centile) whereas tall stature (height greater than 97th centile) was more frequently concerning girls (9 out of 16 patients). Genetic short stature and constitutional delay of growth and adolescence (CDGA) were most often diagnosed in short stature patients. When retardation of physical maturation is a major concern in patients with CDGA, treatment with a low dose of sex steroids leads to an acceleration of growth and pubertal development. This advancement of maturation is important for reducing the psychosocial difficulties of the concerned adolescents. Constitutional tall stature was the most frequent diagnosis in our tall adolescent patients. If predicted final height is above 185 cm for girls or 200 cm for boys the administration of height dose sex steroids (ethinylo-estraidol or conjugated oestrogen for girls, testosteron for boys) for height reduction can be tried, since a reduction in height between 3.5 cm and 7.9 cm has been reported for girls and similar data exists for boys. Nevertheless a cautious approach must be advocated for the administration of oestrogens because possible long term hazards can not yet be excluded.     

Pubertal growth and sexual maturation for adolescents with chronic illness or disability.

In adolescents with chronic illness or disability, the progress of puberty may be abnormal. Growth or sexual maturation may be delayed. In some cases, adulthood may be characterized by short stature or sexual immaturity. Genetic endowment, nutritional deficiency, or concomitants of treatment all may contribute to disordered growth; frequently the basis of abnormal physical development in adolescence is multifactorial. This paper reviews the major mechanisms by which chronic conditions may interfere with puberty and discusses the effects of common chronic conditions on the pubertal process.     

Growth restriction in children with type B Niemann-Pick disease

OBJECTIVES: To compare growth of children with type B Niemann-Pick disease (NPD) with disease variables including genotype, organomegaly, bone age, and serum insulin-like growth factor-1 (IGF-1). STUDY DESIGN: A cross-sectional analysis of growth was performed in 23 children and adolescents with enzymatically and genotypically confirmed NPD. Liver and spleen volumes were measured by quantitative computed tomography and skeletal age by a wrist radiograph. RESULTS: The mean Z scores for height and weight were -1.24 (29th percentile) and -0.75 (34th percentile). The mean liver and spleen volumes were 2.06 and 13.46 times normal for weight, respectively. Skeletal age was delayed by an average of 2.5 years, and serum IGF-1 level was at or below the 2nd percentile in 8 of 12 patients. Short stature and low weight were significantly correlated with large organ volumes, delayed bone age, and low IGF-1 levels. In contrast to patients with other mutations, individuals homozygous for the DeltaR608 mutation had normal height and weight, markedly less hepatosplenomegaly and bone age delay, and normal IGF-1 levels. CONCLUSIONS: Abnormal linear growth and delayed skeletal maturation are common in children and adolescents with type B NPD; however, homozygosity for DeltaR608 is associated with normal growth.     

The relationship between osteocalcin levels and sexual stages of puberty in male children

Osteocalcin is a specific and reliable marker which increases with rapid bone turnover and gives data about bone metabolism. The pubertal growth spurt is also known as a good example of rapid bone turnover. The aim of this study was to determine whether osteocalcin is a useful marker for the pubertal growth spurt period. In this study, osteocalcin levels in male adolescents were examined in relation to their sexual maturation stage and age. The osteocalcin levels and alkaline phosphatase levels were compared during the pubertal growth spurt. Serum osteocalcin and alkaline phosphatase levels were evaluated in 100 eligible healthy male children and adolescents (aged 10 to 17 years). Five groups (n: 20 each) of children and adolescents were formed according to their sexual maturation stages. Finally, the subjects were divided into three main groups in relation to the pubertal growth spurt and sexual maturation stages. Data were evaluated and compared among these three groups: First group = Stage 1 (prepuberty) + Stage 2 (early puberty) consisted of 40 (20 + 20) children and adolescents. Their mean osteocalcin value was 17.2 +/- 6.3 ng/ml and alkaline phosphatase 573.8 +/- 143.9 IU/L. Second group: Stage 3 + Stage 4 consisted of 40 (20 + 20) children and adolescents. These groups were known as the pubertal growth spurt groups. Their mean osteocalcin value was 29.4 +/- 10.6 ng/ml and alkaline phosphatase 728.4 +/- 233.9 IU/L. Third group: In this group, there were 20 children and adolescents who reached Stage 5 of sexual maturation and whose pubertal growth spurt was slowing. Their mean osteocalcin value was 15.3 +/- 5.8 ng/ml and alkaline phosphatase 435.8 +/- 184.8 IU/L. During the pubertal growth spurt, there is a relationship between bone remodelling and increasing osteocalcin and alkaline phosphatase levels. When sexual maturation reaches Stage 4 at 14 years old, osteocalcin and alkaline phosphatase levels make a peak, associated with the rapid growth in height. As sexual maturation reaches Stage 5, osteocalcin and alkaline phosphatase levels gradually decrease with growth maturation and their levels decline to the level of adults at the completion of this period. Our study showed that osteocalcin and alkaline phosphatase levels can be used as markers for evaluation of the growth spurt period.     

Lead and Growth

Lead is highly toxic to the human body and children are much more vulnerable to lead toxicity than adults. Many studies have revealed that relatively low levels of blood lead can adversely affect human health, especially childhood growth and development. Blood lead levels (BLL) of children and adults have been decreasing recently almost all over the world, but a safety level for blood lead does not exist, and lead exposure is still a serious health problem especially for fetuses and children. Maternal lead burden causes fetal lead exposure and increases the risk of abortions, prematurity, low birth weight, and some minor anomalies. Infant BLL are inversely associated with weight gain. A negative relationship between somatic growth and BLL in children has been revealed. It has been suggested that lead exposure causes decrease of gonadotropin secretion of adolescents and delay of pubertal development. Several studies have revealed that children who are exposed to cigarette smoke have higher BLL than children who are not. Children should be protected from cigarette smoke for the purpose of avoiding the risk of increased BLL which might adversely affect their intellectual development and physical growth.     

中枢性性早熟对儿童体格及性发育的影响

中枢性性早熟（CPP）是一种青春期发育异常,表现为第二性征提前、骨格成熟和体格提前发育,最终影响儿童的成年身高,甚至可能会产生如恐惧、不安等心理行为问题。目前国际上公认治疗最好的药物为促性腺激素释放激素类似物（GnRHa）,其主要目的是改善儿童的最终成年身高;但与此同时,其对患儿的生长发育也存在一些不良反应。该文就CPP及GnRHa治疗对儿童体格及性发育的影响作一综述,以引起临床医师对此疾病及其安全用药的关注。     

Assessment of bone ages: Is the Greulich‐Pyle method sufficient for Turkish boys?

BACKGROUND: The Greulich-Pyle (GP) Atlas of skeletal maturation has been prepared in white children who born between 1917 and 1942 in the USA, and is frequently used for assessment of skeletal maturity. In this study, we investigated whether or not the GP method is sufficient for Turkish children for the determination of the skeletal age. METHODS: Plain radiographies of left hands and wrists of 225 healthy boys between 7 and 17 years of age were taken. Pubic hair (PH) stages of boys were determined by using the Tanner criteria. Mean chronological ages and mean skeletal ages according to GP Atlas were compared for each age groups and each PH stage. RESULTS: Mean skeletal ages were delayed 0.61, 0.72, 0.54, 0.39, 0.25, 0.39, and 0.32 years than the mean chronological ages in the 7-13 years age groups, respectively, and advanced 0.13, 0.01, 0.89, and 0.52 years in the 14-17 years age groups. In PH stages 1, 2, and 3, mean skeletal ages were delayed 0.67, 0.51 and 0.40 years than the mean chronological ages, respectively. In PH stages 4 and 5, mean skeletal ages were advanced 0.66 and 0.76 years than mean chronological ages. CONCLUSION: The results suggest that Turkish boys may have a different tempo of skeletal maturation during pubertal development from that of American children which GP standards were derived. Therefore, GP Atlas is not completely applicable to Turkish boys but can be used with some modification.     

Constitutional delay of growth and pubertal development: growth hormone secretory pattern and possible therapy

Constitutional delay of growth and pubertal development is a frequent cause of short stature. These children have a significant retardation of skeletal age and delayed sexual development. They generally maintain a normal growth curve and tend to attain normal adult height. Although children with constitutional delay of growth are believed to have no medical or endocrine abnormality to explain their short stature, some controversy regarding their growth hormone secretory status has recently surfaced; some authors have reported low growth hormone levels to provocative stimuli and decreased growth hormone secretion during sleep, as well as low somatomedin C values in some children with constitutional delay of growth. Others, however, have found the growth hormone secretory status to be normal and similar to that of a control population. The implications of these findings, particularly in regard to possible forms of therapy, are discussed in some detail.     

中枢性性早熟患儿5种骨龄测定方法的比较研究

目的探讨CHN法、TW2法中日英3种标准、TW3法5种骨龄测定方法对中枢性性早熟(CPP)患儿的诊断价值及正常值临界点的确定。方法由两名医师采用盲法回顾性分析CPP患儿61例(病例组),与每一个CPP患儿性别相同,年龄、身高、体质量基本一致的同期体检者61例、8岁以后出现乳房发育的女童6例(均为对照组)治疗前左手腕部X线片,用CHN法、TW2法中英日3种标准和TW3法进行骨龄判定,计算骨龄与年龄的差值,用SPSS13.0统计软件进行受试者工作特征(ROC)分析。结果 (1)两名医师骨龄测定结果的Kappa值为0.776(u=16.128,P<0.05);(2)5种骨龄测定方法的ROC曲线下面积分别为:CHN法0.921±0.024,95%可信区间为0.875～0.967;TW2法中国南方人标准为0.947±0.019(0.910～0.983);TW2法日本人标准为0.937±0.023(0.892～0.982);TW2法英国人标准为0.931±0.022(0.888～0.975);TW3骨龄测定法为0.924±0.023(0.879～0.969);5种方法的诊断价值差异无统计学意义(Z=0.85,P>0.05...     

Growth and sexual maturation in thalassemia major

Growth and sexual development were evaluated in 250 adolescents with beta-thalassemia major. Before transfusion hemoglobin concentration had not been less than 9.5 gm/dl in the last 5 years; desferrioxamine had been administered for 7 to 10 years, including by the subcutaneous route for 3 years. Thirty-seven percent of patients were found to be 2 SD below the mean for normal height; after age 14 years the percentage was 62% for males and 35% for females. Eighty-three percent of males and 75% of females had delayed skeletal maturation. Complete lack of pubescent changes was present in 38% of females and 67% of males aged 12 to 18 years. Only 19% of females had experienced menarche; secondary amenorrhea intervened in a third of them. A multiple regression analysis of indicators of pubertal development with age, age at first transfusion, age at splenectomy, number of transfusions, serum transaminase and ferritin, and duration and intensity of chelation therapy failed to identify the factors responsible for the variation observed in sexual maturation among patients with thalassemia.     

Influence of growth hormone treatment on pubertal timing and pubertal growth in children with idiopathic short stature. Dutch Growth Hormone Working Group

We studied the influence of recombinant human growth hormone (rhGH) on pubertal timing and pubertal growth in children with idiopathic short stature (ISS), and evaluated whether this was different between children with and without intra-uterine growth retardation (IUGR). Twenty-six (18 M, 6 IUGR; 'treated') subjects were treated with rhGH (6-7 days/week, dosage: 14-28 IU/m2 per week [i.e. 0.2-0.3 mg/kg per week]). Fifty-eight subjects (31 M, 9 IUGR; 'controls') were not treated. All subjects attained final height. Prepubertal height gain was significantly larger in the treated children compared to control children (M: 0.66 SDS, 95% confidence interval [CI] 0.41 to 0.92; F. 0.92 SDS, CI 0.58 to 1.26). Pubertal height gain, peak height velocity and duration of puberty were similar for the treated and control subjects. rhGH advanced the age at peak height velocity by 0.7 years (CI 0.3 to 1.0) in boys, and the age at onset of puberty by 1.1 years (CI 0.3 to 1.9) in girls. The gain in final height was 2-3 cm. Age and height SDS at start were the most important predictors for pubertal height gain, total height gain and final height in a multivariate regression analysis. Total height gain of treated subjects with IUGR was less than that of treated subjects without IUGR. In conclusion, rhGH did not affect pubertal growth in children with ISS, and slightly improved their final height. rhGH treatment should be started early to improve height as much as possible before the onset of puberty.