Genetics of nephroblastoma. II. The incidence of developmental defects and dysplastic and asymmetrical traits in children with nephroblastoma

The frequency of developmental defects and displasticity characters in children with nephroblastoma was determined in two groups--with early, up to 2 years manifestation of the tumor (ENB), in 40 patients, and with advanced nephroblastoma (ANB), in 59 patients (manifestation of the disease after 2 years). The data were correlated with control groups adequate for age (130 children). The frequency of serious developmental defects was higher in ANB group (20%) than in ENB group (7%). Over a half of developmental defects were hemihypertrophy and doubling of organs. One case of a child with the combination of nephroblastoma and Smith-Lemli-Opitz syndrome was defined. In ANB group an increased frequency of asymmetry in the conjugate organs (foot, hand, middle finger, ears) was found. Its direction is correlated with tumor localization (tumor site). In ENB group no analogous effect was shown. The data obtained present phenotype characteristics of groups with early and late manifestation of the disease which are probably different in their genesis and thus, their identification is necessary for the adequate medicogenetic consultation (examination).     

Adult height distribution in subjects born small for gestational age

The aim of the study was to investigate the post-natal growth of subjects born small for gestational age (SGA) by describing adult height distribution and by testing the effects of parental, neonatal and pregnancy-related parameters on the risk for adult short stature. The study population was made of adults selected on birth data from a maternity registry and born either small (SGA, n = 734, birth weight < 10th percentile) or appropriate for gestational age (AGA, n = 886, 25th < birth weight < 75th percentile) in whom anthropometric parameters were measured at 22 years of age. The SGA group demonstrated significantly reduced body size in comparison to the AGA group with a mean loss of 0.7 standard deviation (SD) in adult height. The frequency of adult short stature (< -2 SD) was 10.3% in the SGA group vs. 2.4% in the AGA group (p = 0.0001), adult height < -2.5 SD was observed in only 3.7% of the SGA group. Maternal (OR = 0.31 (0.16-0.62), p = 0.0001) and paternal (OR = 0.45 (0.31-0.67), p = 0.0001) heights and subjects birth length (OR = 0.78 (0.62-0.99), p = 0.04) significantly influenced the risk of adult short stature. In summary, post-natal growth defect remains moderate in the majority of subjects born SGA and < 4% only will end up with severe short stature requiring GH therapy according to most current recommendations. The role of parental height and birth length suggests that adult short stature in SGA subjects results at least in some cases from a familial and likely genetic growth disorder with antenatal onset.     

Identification of novel serum biomarkers in child nephroblastoma using proteomics technology

To screen and identify serum biomarkers for nephroblastoma in children using surface-enhanced laser desorption/ionization (SELDI) and other proteomics technologies. The surface-enhanced laser desorption/ionization time of flight mass spectrometry (SELDI–TOF-MS) was used to identify biomarkers in 100 children with nephroblastoma and 30 gender and age-matched normal healthy children. There were 30 cases of pre-operative patients and 70 cases of post-operative patients. Differentially expressed serum proteins were screened. The target proteins were then separated, purified, and analyzed by multidimensional high performance liquid chromatography (HPLC). The peptide mass fingerprints (PMFs) of each protein were obtained after scanning with LC-MS/MS (LTQ). The proteins were identified using SEQUEST and the biological functions and characterizations of these proteins were analyzed with bioinformatic methods. Two differential proteins (m/z 6455.5, 9190.8) were obtained. According to SEQUEST, the molecular masses of this two proteins indicated that they were apolipoprotein C-I and haptoglobin, respectively. Expressions of the two proteins were lower in the pre-surgery group compared with the post-surgery and control group (P < 0.01). In contrast, the expression of this two proteins were higher in the early stage than in the advanced stage of nephroblastoma. Apolipoprotein C-I and haptoglobin may be used as potential biomarkers to predict the degree of malignancy, therapeutic outcomes, and prognosis of nephroblastoma in children.     

Synthetic standards for body weight

Growth charts represent body stature, body weight, and body mass index (BMI) from birth to maturity. Due to secular changes in these parameters, growth charts tend to become outdated, and must be revised from time to time. Recently, we developed alternative strategies that facilitate developing and renewing growth charts, and suggested synthetic standards for body stature. The increasing prevalence of obesity has made it necessary to develop similar techniques also for monitoring body weight and BMI. Two-hundred-and-forty historic and modern growth studies (108 studies of male growth, 132 studies of female growth) were selected from 22 European, 6 American, 3 African, and 6 Asian nations, published between 1831 and 2001. The studies contained annual information on weight and stature, either between birth and 6 years, or between 6 years and maturity, or information on the whole age range between birth and maturity. Since historic studies up to the mid-20th century usually ignore the fact that body weight (in contrast to body stature) is not normally distributed, a group of 92 more recent studies (45 male, 47 female), published between 1943 and 2001, presenting centiles for weight, was chosen for additional analysis. Furthermore, the skewness of body weight distributions, was investigated in original raw data of body weight obtained from five well reputed longitudinal growth studies, performed at Jena, Germany, Lublin, Poland, Paris, France, Prague, Czech Republic, and Zürich, Switzerland. Average body stature and average weight differ markedly between different populations. But within the same population, both parameters are closely interrelated. In males, birth length and weight correlated with r = 0.503, stature and weight correlated with r = 0.873 at the age of 2 years; with r = 0.882 at the age of 6 years; with r = 0.935 at the age of 14 years, and with r = 0.891 at the age of 18 years. Similar results were obtained in females. At birth, length and weight correlated with r = 0.619. Stature and weight correlated with r = 0.863 at the age of 2; with r = 0.912 at the age of 6; with r = 0.935 at the age of 12; and with r = 0.918 at the age of 15 years. Tables of linear regression coefficients for relative stature and weight at all ages enable the reversal of the process of the meta-analysis and allow the generation of synthetic growth references for stature and weight. Synthetic reference charts help in the revision of current growth charts without much additional effort, and may be used for populations for which autochthonous growth standards are not available.     

Lack of an association between ABO and Rh blood group polymorphisms and stature, body weight, and BMI in a cohort of British women

Analysis of variance shows no significant associations between stature, weight, or body mass index (BMI) and ABO or Rh blood group phenotypes among a sample of mothers in England, Scotland, and Wales whose children were born during March 3-9, 1958. Social factors are significantly associated with stature and weight; the effects of social class of the women's fathers, regions of birth of the women, their ages, whether their education continued beyond age 16 or not, and the total number of births were separated out by regression analysis. The adjusted residual regression of ABO and Rh phenotypes were not significantly related to reported stature, weight, or BMI.     

The influence of some socio-demographic factors on body weight and stature of 6-18 years old boys from Cairo, Egypt

Body weight and stature have been studied in a cross-sectional sample of 926 Egyptian boys aged 6-18 in relation to age, level of education of parents, sibship size and order of birth. The results show that education of either parent has obvious influence on body weight and to a lesser extent on stature. The impact of parental level of education on both characters is particularly significant, if the two parents are equally educated or not. The boys of smaller sibship size (3 or less) have heavier weight and taller stature than those of bigger sibship size (4 or more sibs). There is no consistancy in the relationship between birth order and either weight or stature. Body weight, however, is heavier for the first and second child than for the later children. Nevertheless, boys of any of the four studied categories (first, second, third, and fourth or more child) might be the tallest in one age group and the shortest in another.     

Extremely short stature: influence of each parent's height on clinical-biological features

Idiopathic extremely short stature probably has several causes. OBJECTIVE: To evaluate the influence of each parent's height on clinical-biological features. METHODS: 57 patients without intrauterine growth retardation seen at 7.9 +/- 0.4 years for height < or = -3 SD were classified according to the difference between their target height and actual height: < 2 SD in familial short stature (FSS, n = 28) and >2 SD in non-FSS (n = 29). RESULTS: Height decreased from -0.5 +/- 0.1 SD at birth to -2 +/- 0.2 SD at 1 year and -2.7 +/- 0.1 SD at 3 years, but the changes in the two groups were similar. FSS children were shorter than non-FSS children both at birth (p = 0.03) and as adults after growth hormone (GH) treatment (p < 0.05), but their plasma insulin-like growth factor I concentrations and GH peaks were similar. The FSS children fathers' heights were more frequently below -2 SD (64%) than the mothers' heights (35%) and were correlated with height at first evaluation (p < 0.05). For the whole population, the mothers' heights were correlated with birth weight (p < 0.05) and with height at first evaluation (p < 0.03). CONCLUSION: This study confirms the influence of the mother's height on birth weight and shows how of the father's height influences idiopathic extremely short stature.     

Relationships between some maternal factors and pregnancy outcome

This study, carried out on mother-infant pairs in obstetric hospitals in Istanbul, was designed to investigate the impact of some maternal parameters on pregnancy outcome as well as to provide information on birth weight, and incidence of low birth weight, preterm birth, and small for gestational age birth. Low birth weight, preterm birth, and fetal malnutrition are among major risk factors influencing perinatal, neonatal, and postneonatal mortality and morbidity. Reported values for prepregnancy body weight and postpartum measurements of stature, weight, mid-upper arm circumference showed that the women in this series did not have caloric undernutrition, while nearly 9% were of low stature. Maternal stature, postpartum body weight, and postpartum weight and height values were found to be important determinants of birth weight. The frequency of preterm births in this series corresponds fairly well with that found in another group of Turkish mother-infant pairs in which gestational age was determined by Dubowitz scoring. In agreement with many previous studies, maternal stature and body weight stood out as important influences on the outcome of pregnancy in this series. Overall, the nutritional state of the mother prior to pregnancy is the most important determinant of birth weight.     

Decreasing Birth Weight Is Associated with Adverse Metabolic Profile and Lower Stature in Childhood and Adolescence

Objective

We aimed to evaluate the association of birth weight SDS with insulin resistance, blood pressure, and auxology in children and adolescents born 23–42 weeks of gestation.

Methods

We studied 143 singleton children and adolescents aged 9.3 ± 3.3 years (range 2.0–17.9 years). Clinical assessments included insulin resistance measured by HOMA2-IR, auxology, and blood pressure from sphygmomanometer measurements. Continuous associations were examined, and stratified analyses carried out. For the latter, participants were divided into those of below-average birth weight (BABW, <0 SDS) and above-average birth weight (AABW, ≥0 SDS).

Results

Irrespective of gestational age, lower birth weight SDS was associated with progressively greater HOMA2-IR (p<0.0001) and higher fasting insulin concentrations (p<0.0001). Decreasing birth weight SDS was associated with higher systolic (p = 0.011) and diastolic (p = 0.006) blood pressure. Lower birth weight SDS was also associated with decreasing stature (p<0.010). The BABW group was ~40% more insulin resistant than AABW participants (p = 0.004), with the former also displaying fasting insulin concentrations 37% higher (p = 0.004). BABW participants were 0.54 SDS shorter than those of higher birth weight (p = 0.002). On average, BABW participants had not met their genetic potential, tending to be shorter than their parents (p = 0.065). As a result, when corrected for parents'' heights, BABW participants were 0.62 SDS shorter than those born of higher birth weight (p = 0.001). Sub-group analyses on participants born appropriate-for-gestational-age (n = 128) showed that associations of birth weight SDS with both insulin resistance and stature remained (although attenuated).

Conclusion

Decreasing birth weight SDS (even within the normal range) is associated with adverse metabolic profile and lower stature in children and adolescents.     

血清Ghrelin、p21 waf/cip1以及IGF-1与儿童特发性矮小症相关性分析

摘要 目的：研究特发性矮小症（ISS）儿童血清生长激素释放肽（Ghrelin）、p21 waf/cip1以及胰岛素生长因子-1（IGF-1）水平及其临床意义。方法：选择2017年1月到2020年12月在我院接受治疗的特发性矮小症儿童60例（ISS组）,选择同期体检健康儿童60例作为对照（对照组）,比较两组儿童一般资料,检测并比较两组儿童血清Ghrelin、p21 waf/cip1以及IGF-1水平。分析ISS儿童血清Ghrelin、p21 waf/cip1以及IGF-1水平与生长指标的相关性,同时分析治疗对其影响。结果：（1）ISS组患儿性别、年龄和体质指数与对照组比较无显著差异（P>0.05）,但身高、体重以及生长速度显著低于对照组儿童（P<0.05）;（2）ISS组患儿血清Ghrelin和p21 waf/cip1均显著高于对照组,而血清IGF-1显著低于对照组（P<0.05）;（3）ISS组患儿血清Ghrelin和p21 waf/cip1均与身高、体重和生长速度呈负相关,而血清IGF-1与身高、体重和生长速度呈正相关（P<0.05）;（4）治疗显著提高ISS组患儿身高、体重、生长速度以及血清IGF-1水平,而显著降低ISS组患儿血清Ghrelin和p21 waf/cip1水平（P<0.05）。结论：Ghrelin、p21 waf/cip1和IGF-1在特发性矮小症患儿血清中表达异常,共同调控儿童生长发育,是评价儿童生长发育的良好指标。     

Growth disorders in children with type 1 diabetes mellitus

The aim of the research was to analyze anthropometric variables in children with type 1 diabetes mellitus (DM) in relation with the stage of pubertal development at onset of disease and quality of metabolic control over five-year long observation. Diagnosed children were taller than their peers. This especially referred to age group between 4 and 9.5 years. On the whole, weight of the patients and healthy controls did not differ. However, the diagnosed children had substantially lower weight in puberty than healthy controls. Body mass index was significantly lower in the group of diagnosed children on the whole and in puberty. During a five-year long observation patients have had a significant retardation of growth. However, that retardation referred primarily to patients in prepuberty. Growth retardation was more pronounced with bad metabolic control. Growth was satisfactory if onset of disease had been in puberty. A significant weight gain was observed in patients in puberty whereas in those in prepuberty there was no significant change of body weight at the end of five-year long observation. Metabolic control did not affect observed changes. There were significant differences of anthropometric variables between those suffering from type 1 DM and their peers. The differences depended on the age at onset. The disease had a negative effect on growth with onset in prepuberty, whereas in puberty growth was satisfactory. However, puberty was a period in which patients increased their weight excessively. Prepuberty was a period in which growth had been significantly affected by metabolic control.     

Growth curves of children with Down syndrome.

Growth curves of 105 children with Down syndrome (50 boys and 55 girls) were established. At birth height, weight and head circumference of Down syndrome children were lower than these parameters in controls. This delay remained stable until puberty. For weight there was no clear-cut pubertal growth spurt. For stature, the prepubertal growth spurt occurred earlier (at the age of 11 years in boys and 9 1/2 years in girls) than in controls but was less marked. As a result, Down syndrome patients had a short stature with a quite normal weight. These reference curves, available since prenatal diagnosis of Down syndrome is performed routinely, are helpful for monitoring normal and abnormal development in Down syndrome patients.     

Physiological growth hormone secretion in children with short stature and intra-uterine growth retardation

31 prepubertal children with short stature [mean height standard deviation score (SDS) -2.84] and low birth weight (mean -2.82 SDS) were studied. Mean age was 6.0 years and mean height velocity SDS was -0.76. Patients were classified as having either the clinical characteristics of Russell-Silver syndrome (RSS) (4 F, 13 M) or not (4 F, 10 M). All children had an overnight profile of spontaneous growth hormone (GH) secretion. 4 children achieved a maximum GH concentration of less than 20 mU/l. 9 children with RSS secreted only one large GH peak during the night. Most of the non-RSS group had normal GH pulse frequency but 3 boys had a fast-frequency pattern. Abnormal GH secretion may contribute towards growth failure in children with low birth weight/RSS.     

Infrequent involvement of c-fos in avian leukosis virus-induced nephroblastoma.

To determine whether c-fos is involved in avian leukosis virus-induced nephroblastoma, 28 tumors from chickens were analyzed for novel fos fragments. DNA from 1 of 16 clonal outgrowths (in chicken 6561) contained novel fos-related EcoRI and KpnI fragments which hybridized to both v-fos and viral probes. Oncogenicity tests using filtered 6561 tumor cell homogenates did not reveal a tumor-inducing transduction of c-fos. We conclude that c-fos is only an occasional target for proviral insertions or new transductions in avian leukosis virus-induced nephroblastoma. The results also identify a polymorphism in c-fos in K28 chickens and demonstrate that unintegrated viral DNA is not a general characteristic of avian leukosis virus-induced nephroblastoma.     

Adult outcome of normal children who are short or underweight at age 7 years.

OBJECTIVES--To evaluate the adult growth outcome (at age 23) of children who are short or underweight at age 7 years in whom no identifiable pathological cause exists for their poor growth. DESIGN--Longitudinal follow up of a birth cohort. SETTING--The national child development study (1958 birth cohort) of Great Britain. SUBJECTS--523 children with a height or a weight below the fifth centile at age 7. Of these, 70 (13.4%) were excluded because they had a longstanding illness that could account for their poor growth. The remaining 453 subjects, who were followed to age 23, provided the base group from which those with additional data, such as parental height, were obtained. RESULTS--55/174 (31.6%) boys who were short at age 7 became short men; 60/211 (28.4%) girls who were short at age 7 became short women. Among boys who were underweight at age 7, 46/160 (28.7%) were still underweight at age 23, while 61/200 (30.5%) girls underweight at age 7 became underweight women. Having short parents did not increase the probability of being small as an adult. Children with delayed puberty were as likely to remain small as those in whom puberty was not delayed. CONCLUSIONS--One in three normal children who was short or underweight at age 7 became a short or underweight adult. This informs the management of short children and may be valuable when prolonged growth hormone treatment for short stature is being considered.     

Babies born small for gestational age: insulin sensitivity and growth hormone treatment

Epidemiological studies have identified an association between size at birth and adult risk for type 2 diabetes mellitus and cardiovascular disease. In contemporary populations, children who are relatively small at birth and show rapid infancy weight gain are at greatest risk for the development of childhood obesity, increased visceral fat and insulin resistance: possible early markers of adult disease risk. Individuals presenting to growth clinics with short stature and a history of low birthweight will not have shown post-natal catch-up growth and may be a very heterogeneous group. Nevertheless, there are some data to suggest that as a group they are insulin resistant with decreased lean mass. Growth hormone treatment leads to reversible worsening of the insulin resistance, and short-term data do not indicate an increased risk for type 2 diabetes. However, further long-term follow-up is required, and particular care should be taken in monitoring children with a strong family history of type 2 diabetes and those from ethnic groups in which there is a high background prevalence of the disease.     

Early influences on the tempo of puberty

Fetal growth retardation appears to be associated with an increased risk of premature adrenarche, early puberty, polycystic ovary syndrome and associated fertility problems. In a rat model of intrauterine growth retardation, based on ligation of the uterine arteries, the onset of puberty was delayed in female pups, with anovulation during the first cycle. The ovaries showed a lower number of follicles. The onset of puberty was also delayed in male pups. Testosterone production was lower in these growth-retarded rats compared with controls. The relationship between birth weight and the onset of puberty and pubertal progression in different cohorts of healthy children has been examined. In girls, no differences were observed in timing and progression of puberty, including age of menarche, between groups of different birth weights. In boys, a relatively delayed onset of puberty was observed in those with low birth weight, with a normally timed progression. In children with low birth weight, particularly boys, higher dehydroepiandrosterone levels were found compared with children with a normal birth weight, indicating an overactive adrenal gland in children with low birth weight. These data indicate that impaired fetal growth may have long-lasting effects on pubertal development. The fact that results of human studies on the relationship between fetal growth and the onset of puberty are often controversial may be explained by the heterogeneity of children born small for gestational age with respect to the intrauterine insult that they experience. From rat studies, it is clear that a serious intrauterine insult associated with growth failure can lead to dysregulation of puberty and gonadal function.     

Intrauterine growth pattern and risk of childhood onset insulin dependent (type I) diabetes: population based case-control study.

OBJECTIVE: To investigate whether prenatal growth affects the risk of development of childhood onset insulin dependent (type I) diabetes mellitus. DESIGN: Population based case-control study. SETTING: Data from a nationwide childhood diabetes case register were linked with data from the nationwide Swedish Medical Birth Registry. SUBJECTS: Data from a total of 4584 diabetic children born after 1973 and diagnosed with diabetes from 1978 to 1992 were studied. For each child with insulin dependent diabetes three control children were randomly selected from among all infants born in the same year and at the same hospital as the proband. MAIN OUTCOME MEASURES: Birth weight, gestation, maternal age and parity, number of previous spontaneous abortions, and sex specific birth weight by gestational week expressed as multiples of the standard deviation (SD). RESULTS: There was a clear trend in the odds ratio for childhood onset diabetes according to SD of birth weight. The odds ratio (95% confidence interval) for small for gestational age after stratification for maternal age, parity, smoking habits, and maternal diabetes was 0.81 (0.65 to 0.99) and for large for gestational age after similar stratification was 1.20 (1.02 to 1.42). CONCLUSIONS: Intrauterine conditions that affect prenatal growth seem also to affect the risk of development of childhood diabetes in the way previously described for postnatal growth: a poor growth decreases and an excess growth increases the risk. The mechanism for this association is unclear.     

Variation of morphophysiological and genetic demographic traits in children with congenital cleft lip and palate

Medical records and questionnaire data have been used to analyze morphophysiological (the birth weight and length) and genetic demographic (maternal age and marriage structure) traits in a sample of children with orofacial malformations (OMs, cleft palate and/or cleft lip) living in Krasnodar Territory, Russia. The sample of children with malformations (including premature infants) differs from the control group in lower birth weight and length and a lower proportion of children with morphophysiological values close to the population average ones, as well as a higher family exogamy level estimated on the basis of marriage structure in the parental and preceding generations. The risk of congenital cleft palate and/or cleft lip is considerably increased is the maternal age is older than 35 years or, to a lower degree, if it is younger than 20 years.     

Immunology and growth faltering of Anga children,Papua New Guinea: Preliminary work

Nutrition–infection interactions among poor children of the less-developed world influence growth and development. However, the relative importance of each is difficult to determine, because the relationship is mediated by immunological status. In this analysis, relationships between immunological measures and anthropometry were sought among 41 Anga, Papua New Guinea children aged 0–7 years. These had elevated serum total leucocyte and leucocyte subset counts relative to western reference values. Although there was no correlation between anthropometric nutritional status and total leucocytes and leucocyte subsets for this group, the small group (n = 8) with very high total leucocyte count (greater than 15,000/mm²) had significantly lower mean Z score of stature for age (−3.78), and weight for stature (−1.35) than those with leucocyte counts lower than this cut-off (weight for stature Z score: −0.59; stature for age Z score: −2.68, respectively. Low stature-for-age Z score was associated with lower total lymphocyte count and increasing age, against a background of elevated lymphocyte levels relative to western reference values among the older children; low weight-for-stature Z score was associated with lower neutrophil count, against a background of normal neutrophil levels across all age groups. The pattern of weight and stature growth seen in the Anga may reflect extended nutritional deficits which result in stunting of a degree to which the most growth-compromised children die, leaving those above a threshold associated with high mortality alive. Thus, the anthropometric and immunological characteristics of the older children in this small sample may reflect the biology of survival under severe ecological conditions, where poor linear growth and elevated leucocyte status relative to normative values are characteristics of survivorship. Am J Phys Anthropol 106:515–520, 1998. © 1998 Wiley-Liss, Inc.