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PubMed1992

[Measurement IGF-I in human blood by immunoenzymometric assay].

Insulin-like growth factor-I (IGF-I) is the growth factor which binds to its specific binding proteins in plasma and mediates most of the actions of growth hormone (GH). In terms of this, measurement of IGF-I concentrations is considered to be important in the diagnosis and treatment of growth abnormalities. In the present report we describe a modified immunoenzymometric assay (IEMA) for IGF-I using monoclonal antibody and peroxidase conjugated polyclonal antibody, which was originally developed by Tamura et al. The minimum detection level was 3ng/ml and good linearity was obtained at a range of 3-50ng/ml. The recovery of added IGF-I was nearly quantitative, and cross reaction with human IGF-II was less than 1%. There was a significant positive correlation between the IGF-I values determined by IEMA and by RIA. We measured the levels of IGF-I by this IEMA in normal subjects and children with short stature. Serum or plasma samples were extracted by acid-ethanol method. In normal children IGF-I level was observed age-dependently. IGF-I values gradually increased and reached peak levels (101.2-473.2ng/ml) in pubertal period and thereafter decreased to adult levels (67.3-329.6ng/ml). In subjects with short stature older than 5 yrs, the percentages falling below the normal mean for chronological age by at least 2SD were 100% for complete GH deficiency (n = 5), 80.0% for partial GH deficiency (n = 15), 25.0% for GH neurosecretory dysfunction (n = 4), 40.0% for non-endocrine short stature (n = 60) and 25.0% for Turner syndrome (n = 4). In children younger than 4 yrs, it may be difficult to use IGF-I for diagnosis of GH deficiency because there was an overlap in IGF-I values with normal children. IEMA for IGF-I is shown to be a reliable method for measurement of IGF-I in blood and is appropriate for diagnosis of growth disorders with short stature in subjects older than 5 yrs.

Adolescent↗

PubMed1994

Physiologic and clinical relevance of the insulin-like growth factor binding proteins.

The insulin-like growht factors (IGFs) are potent mitogenic agents that have been recognized for three decades. Recently, however, the complex milieu in which they operate has begun to be unraveled. Endocrine and autocrine patterns of IGF secretion have been identified and specific receptors that bind IGFs and mediate their biologic actions have been characterized. A family of six peptides, which bind IGFs with high affinity, the IGF binding proteins (IGFBPs), have been recognized as a new class of growth modulators. The IGFBPs can inhibit IGF actions, enhance IGF actions, or function as independent cell regulatory factors, possibly by interacting with their own receptors on the cell membrane. The IGFBPs, in turn, are regulated by a group of proteolytic enzymes, which are capable of cleaving IGFBPs into smaller fragments with lower affinity for the IGFs, thus enhancing IGF action. The size IGFBPs, although similar, have unique biologic properties, and appear to have specific patterns of expression and function. Radioimmunoassays for IGFBP-1, -2, and -3 are currently commercially available and information is accumulating on their diagnostic usefulness. This includes several clinical situations, such as growth disorders, where serum IGFBP-3 is a highly specific screening tool for growth hormone deficiency, various malignancies in which serum IGFBP-2 levels are elevated, and disorders of carbohydrate metabolism that display an inverse relationship between serum IGFBP-1 and insulin secretion. Current clinical practice may include the judicious use of these tests for the diagnosis and for monitoring the therapeutic response, of such disorders.

Carrier Proteins↗

PubMedDate not supplied

Hormonal effects of zinc on growth in children.

Zinc deficiency impairs the metabolism of thyroid hormones, androgens, and above all growth hormones. In view of their important role in growth, it is not surprising to find growth disorders associated with zinc deficiency. Stunted growth linked to zinc deficiency is found during gestation, and also in the newborn and children up to adolescence. Depending on the country, 5-30% of children suffer from moderate zinc deficiency, responsible for small-for-age height. Zinc supplementation has proven effective in many studies, mainly in children where zinc deficiency has first been found. Finally, zinc supplementation makes it possible in certain cases to overcome resistance to growth hormone treatment.

Adolescent↗

PubMed1997

No evidence for uniparental disomy as a common cause of Sotos syndrome.

A number of rare diseases (including Sotos syndrome) of unknown aetiology, which occur mainly sporadically and with features of growth disorder and developmental delay, may be caused by imprinted genes and therefore be associated with UPD. Using 112 dinucleotide repeat DNA polymorphisms, we have examined parental inheritance of all autosome pairs, except chromosome 15, in 29 patients with Sotos syndrome. All informative cases showed biparental inheritance and no cases of UPD were found. We conclude that Sotos syndrome is either not caused by an imprinted gene or that UPD is rare or of a segmental form in its aetiology.

Chromosome Aberrations↗

PubMed1992

Cellular proliferation markers in the evaluation of human cancer.

Our knowledge of normal growth regulatory mechanisms, and of the disordered growth that occurs during tumorigenesis, has greatly increased during the past decade. In particular, these studies have emphasized the importance of chromosomal alterations, genetic heterogeneity, and cell proliferation in tumorigenesis and metastasis. As a result, the early diagnosis and treatment of malignancy appear to be even more important than previously recognized. Clinical studies of tumor proliferative activity were first conducted by thymidine-labeling techniques and more recently by flow cytometric analysis of DNA content. This information appears to provide important information that directly relates to tumor behavior and is of great prognostic significance in many tumors. In contrast, total nuclear DNA content, as measured by flow cytometry or image analysis, appears to be an "epi-phenomenon," and its clinical significance varies in different tumors. The potential clinical value of this research is enormous, because a rapid, accurate nonradioisotopic flow cytometric determination of tumor kinetic parameters, simultaneously with DNA content and surface antigen expression, would provide information of great importance for determining patient prognosis and making therapeutic decisions. Under these circumstances, analysis of DNA content and proliferative activity should be applied cautiously to patient care. Stringent quality control should be exercised, and the potential significance and limitations of these data should be clearly provided to the requesting physician. Most importantly, additional research during the next few years will provide answers to the many questions that remain about the appropriate clinical role of this information. As Stanbridge and Nowell stated at the conclusion of a recent Cold Spring Harbor meeting on the Origins of Human Cancer, "We have come a long way. . . and we have a very long way to go."

Biomarkers, Tumor↗

PubMed1991

[Are short boys disadvantaged as adults? Follow-up of 77 men with constitutional growth delay and (or) familial short stature].

Out of a total of 119 adult males seen in our clinic for short stature in childhood, but not treated (no organic cause for short stature and no endocrine failure), 77 (mean age 24.5 [20-30] years) were re-evaluated. At initial presentation (mean age 13.7 years) their heights were 2.4 (1.5-4.0) SDs below the mean height for age. The mean final height attained was 167.4 (158.3-181.2) cm, or -1.5 (-2.85 to +0.45) SDs from the population mean. Objective parameters (marital status, number of children, school leaving qualifications, career development) and subjective attitudes of the former patients to their height were assessed. The proportion of subjects who were married (15.6%) and the number of children (a total of 16) did not differ significantly from the population mean (18.1% married, expected number of children = 12. There was a trend towards higher educational achievement (23.4% vs. 19.5% "Abitur" [academic school leaving examination] or "Fachabitur" [technical school leaving examination]). Between 80 and 95% of the former patients reported that their height presented no handicap in daily life, in seeking a partner or in their careers. On the hypothetical question of treatment with a growth accelerator, enthusiasm was negatively correlated with height in childhood and the final height attained (Spearman rank correlation, P less than 0.01). The explanations concerning disordered growth given at the time were seen as useful by only about half of the former patients.

Adolescent↗

PubMed2006

Efficacy and safety of mecasermin rinfabate.

There has been interest in using recombinant human (rh) insulin-like growth factor (IGF)-I (rhIGF-I) to treat short stature, either alone or in combination with its binding protein (insulin-like growth factor binding protein [IGFBP]-3). IGF-I has been shown to increase growth velocity in children with IGF deficiency, either as a result of growth hormone insensitivity syndrome (GHIS) or IGF gene deletion. However, there have been adverse events, particularly hypoglycaemia, reported with administration of unbound rhIGF-I. In addition, the serum half-life of unbound rhIGF-I is shorter when administered to patients with GHIS, who have low serum concentrations of its binding proteins IGFBP-3 and acid-labile subunit (ALS), than when administered to normal volunteers or to the patient with an IGF-I gene deletion (who had normal levels of IGFBP-3). iPlex (mecasermin rinfabate), an equimolar mixture of IGF-I and its binding protein IGFBP-3, was developed to prolong the half-life and to counteract acute adverse events (particularly hypoglycaemia) associated with administration of IGF-I. Although there are no published data on the efficacy of mecasermin rinfabate in treating growth disorders, it does appear that mecasermin rinfabate has a longer half-life in patients with GHIS than unbound IGF-I, and fewer reports of adverse events (including hypoglycaemia) when administered to patients with diabetes.

Burns↗

PubMed2000

Growth and endocrine disorders in multisystem Langerhans' cell histiocytosis.

INTRODUCTION: Langerhans' cell histiocytosis is a rare disorder, with diabetes insipidus occurring in up to half of patients. Causes of growth failure include the illness itself, treatments used and growth hormone insufficiency. PATIENTS AND METHODS: We identified all patients with an endocrinopathy secondary to Langerhans' cell histiocytosis (LCH). Growth data were analysed from all patients with multisystem involvement. RESULTS: Of 144 patients with multisystem LCH, 50 had an endocrinopathy, 49 of whom had diabetes insipidus. Growth hormone insufficiency (GHI) was present in 21 patients, seven of whom had other anterior pituitary deficiencies as well (gonadotrophin deficiency + GHI n = 2, gonadotrophin deficiency + TSH deficiency + GHI n = 2, panhypopituitarism n = 3). GH insufficiency, the development of which appeared to be independent of pituitary radiation, occurred at a median age of 8.3 years (4.7-18 years) and at a median interval of 3.5 years (0-11.8 years) after diagnosis of LCH. The median height SDS at diagnosis of growth hormone insufficiency was -2.9. Thirteen of the patients with growth hormone insufficiency attained final height with a median height SDS of -1.2. The final height SDS of 15 patients without GH insufficiency was closer to target height SDS, but not statistically different from that of the GH insufficient group. CONCLUSIONS: GH therapy significantly improves growth in GH insufficient patients with Langerhans' cell histiocytosis. Early institution of GH therapy may further improve height outcome. However, most children with Langerhans' cell histiocytosis regardless of endocrine function, failed to reach target height.

Adolescent↗

PubMed2000

MR imaging of pituitary hyperplasia in a child with growth arrest and primary hypothyroidism.

Magnetic resonance imaging of pituitary hyperplasia has been rarely described in children with primary hypothyroidism. We report a case of pituitary hyperplasia in a child presented with significant growth arrest and laboratory evidence of hypothyroidism. Magnetic resonance imaging revealed symmetrical pituitary enlargement simulating macroadenoma. After thyroid hormone replacement therapy, the child's height increased and pituitary enlargement regressed to normal. Awareness of MRI appearance of pituitary hyperplasia in children with laboratory evidence of hypothyroidism might avoid misdiagnosis for pituitary tumor, which may also manifest as growth disorder, obviating unnecessary surgery.

Child↗

PubMed2001

[Magnetic resonance imaging of pituitary hyperplasia in a child with growth arrest and primary hypothyroidism].

We report a case of pituitary hyperplasia in a child presented with significant growth arrest and laboratory evidence of hypothyroidism. Magnetic resonance imaging (MRI) revealed symmetrical pituitary enlargement seemed to be macroadenoma. After thyroid hormone replacement therapy, the child's height increased and pituitary enlargement regressed. Awareness of MRI appearance of pituitary hyperplasia in children with laboratory evidence of hypothyoidism might avoid misdiagnosis for pituitary tumor, which may also manifest as growth disorder, obviating unnecessary surgery.

Child↗

PubMed1986

[Growth curves as a screening instrument--possibilities and limits].

The application of growth charts as screening tools for children is a commonplace. Growth charts published during the past 15 years in Germany are now under debate with respect to their validity. An analysis of the problems related to growth curves gave the following results: A clear, sharp boundary between normal and non-normal permitting reliable grouping of children does not exist. Due to the heterogeneity of the population of children coming for screening, the call for an allround optimal and representative growth-curve remains wishful thinking. The growth charts so far published, show marked differences in the course of the percentile lines. The discrepancies can be explained by different sample sizes and algorithms of calculation. In the example of the longitudinal Zurich growth study on normal children it can be demonstrated, that the change between percentile ranges during the initial 4 years of life often considered to be pathological occurs in almost 50% of the probands. By conservative interpretation all growth charts can be used, because only with rare exceptions the diagnosis of growth disorders will be solely based on the measurement of tallness and its comparison to percentile values. As a rule: The grouping of a child as having non-normal growth is the result of multiparametric medical considerations.

Body Height↗

PubMed1999

[Primary care population screening for growth].

OBJECTIVE: To find the effectiveness of growth screening of 6 and 7-year olds in primary care and the characteristics of slow growth found. DESIGN: Crossover, observational study. PATIENTS: 6 to 7-year old population attended at 8 health centres in the province of Barcelona. INTERVENTIONS: Exploration of height and weight. The population with height=percentile 3 was referred to the paediatric endocrinologist for diagnosis. RESULTS: 2306 children (45% of the population attended) were screened. 73 had low height (3.5%). Of these, 8.2% did not attend the appointment with the endocrinologist; 5.5% had been wrongly measured, and for 19% no definite diagnosis could be reached. 49 cases were classified as cases of slow growth: 11 organic and 38 non-organic. The effectiveness of the screening was one unidentified case of slow growth in every 80 children screened. CONCLUSIONS: It would seem advisable to maintain the practice of screening for slow growth in primary care. To improve its efficiency, it is proposed to refer to the specialist only the population with their height under the percentile 0.4. The paediatrics team should deal with non-organic growth disorders.

Child↗

PubMed2003

IGF-I and IGF-binding protein-3 measurements on filter paper blood spots in children and adolescents on GH treatment: use in monitoring and as markers of growth performance.

BACKGROUND/AIM: In childhood an appropriate response to GH treatment is achieved by titration of growth response against dose administered, with careful observation for side-effects. In order to evaluate the potential use of IGF monitoring in children treated with GH, a cross-sectional study has been carried in 215 children and adolescents (134 with GH deficiency (GHD), 54 with Turner syndrome (TS) and 27 with non-GHD growth disorders) treated with GH for 0.2-13.7 years. METHODS: IGF-I and IGF-binding protein-3 (IGFBP-3) were measured in ELISAs, using dried capillary blood collected onto filter papers. Results were expressed as the mean S.D. range (SDS). Values of either analyte < -2 or > +2 SDS were considered abnormal. RESULTS: IGF-I and IGFBP-3 SDS were higher in the TS and non-GHD groups (mean +0.01 and +0.1 respectively) than in those with GHD (mean value -0.6). Nineteen per cent of the IGF-I values (13% low, 6% high) and 12% of IGFBP-3 values were abnormal (10% low, 2% high). Abnormalities, either low or high, were most common in the GHD group. There was a weak but significant relationship between change in height SDS over the Year up to the time of sampling in the whole group and IGF-I SDS. Satisfactory growth performance (+0.5>change in height SDS> -0.5) was found in those with high (7.2%), normal (60%) and low (9.3%) IGF-I levels. Overall, it was estimated that 26% of the tests would indicate that an adjustment to GH dose (up in 18% and down in 8%) could be considered. CONCLUSIONS: From this cross-sectional study of IGF monitoring across a broad range of diagnoses and ages, it can be concluded that the majority of children on GH have normal levels of IGF-I and IGFBP-3, but 26% of tests could suggest that a change of GH dose should be considered. Regular monitoring of IGF-I and IGFBP-3 should be considered in any child on GH treatment.

Adolescent↗

PubMed2003

Imprinted methylation profiles for proximal mouse chromosomes 11 and 7 as revealed by methylation-sensitive representational difference analysis.

Proximal mouse Chromosome (Chr) 11 shares regions of orthology with the candidate gene region for the imprinting growth disorder Silver-Russell syndrome (SRS) on human Chr 7p. It has previously been shown that mice with two maternal or two paternal copies (duplications, Dp) of proximal Chr 11 exhibit reciprocal growth phenotypes. Those with two paternal copies show fetal and placental overgrowth, while those with two maternal copies are growth retarded. The growth retardation observed in the latter is reminiscent of the intrauterine growth restriction (IUGR) observed in SRS patients with maternal uniparental disomy for Chr 7 (mUPD7). We have carried out a methylation-sensitive representational difference analysis (Me-RDA) screen to look for regions of differential methylation (DMRs) associated with imprinted genes. For these experiments, we have used mouse embryos with uniparental duplications of Chrs 11 and 7 proximal to the breakpoint of the reciprocal translocation T(7;11)40Ad. Two previously known imprinted loci associated with paternal allele hypomethylation were recovered on proximal mouse Chr 11, U2af1-rs1 and Meg1/Grb10. These two genes map 15 cM apart, so it seems likely that they are within separate imprinted domains that do not contain additional DMRs. The known imprinted gene Peg3, located on mouse proximal Chr 7, was also detected in our screen. The finding that Peg3 was differentially methylated in embryos with uniparental inheritance of proximal Chr 7 confirms that Peg3 is located proximal to the breakpoint of T40Ad in G-band 7A2. Because GRB10 has previously been reported to be a candidate gene for SRS, we analysed 22 patients for epimutations of the GRB10 differentially methylated region that could lead to the altered expression of this gene. No such mutations were found.

Aneuploidy↗

PubMed1991

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.

Adolescent↗

PubMed2006

Clinical utility of insulin-like growth factor-I (IGF-I) and IGF binding protein-3 measurements in paediatric practice.

Measurements of serum insulin-like growth factor-I (IGF-I) and its major binding protein, IGFBP-3, are utilised in the routine clinical management of short children. In this review, the value of such measurements in the diagnosis of primary and secondary IGF-I deficiency is presented. The achievement of optimal growth while maintaining IGF-I within the normal range is the goal of GH treatment schedules used in a range of growth disorders, and thus data on IGF-I monitoring during initiation and maintenance phases of GH treatment are discussed. Comment is also made on the relationship between levels of IGF-I and IGFBP-3 in the population with regard to risks for cancer and cardiovascular disease.IGF-I and IGFBP-3 are important parameters to measure as one part of the process of managing short children. It is proposed that improving the clinical value of IGF measurement may involve measurement of specific prohormones and E-peptides, to get closer to the pool of GH dependent IGF-I.

Biomarkers↗

PubMed2006

Transforming growth factor-betas and vascular disorders.

Transforming growth factor-beta (TGF-beta) superfamily members, TGF-beta and bone morphogenetic proteins (BMPs), are potent regulatory cytokines with diverse functions on vascular cells. They signal through heteromeric type I and II receptor complexes activating Smad-dependent and Smad-independent signals, which regulate proliferation, differentiation, and survival. They are potent regulators of vascular development and vessel remodeling and play key roles in atherosclerosis and restenosis, regulating endothelial, smooth muscle cell, macrophage, T cell, and probably vascular calcifying cell responses. In atherosclerosis, TGF-beta regulates lesion phenotype by controlling T-cell responses and stimulating smooth muscle cells to produce collagen. It contributes to restenosis by augmenting neointimal cell proliferation and collagen accumulation. Defective TGF-beta signaling in endothelial cells attributable to mutations in endoglin or the type I receptor ALK-1 leads to hereditary hemorrhagic telangiectasia, whereas defective BMP signaling attributable to mutations in the BMP receptor II has been associated with development of primary pulmonary hypertension. The development of mouse models with either cell type-specific or general inactivation of TGF-beta/BMP signaling has started to reveal the importance of the regulatory network of TGF-beta/BMP pathways in vivo and their significance for atherosclerosis, hereditary hemorrhagic telangiectasia, and primary pulmonary hypertension. This review highlights recent findings that have advanced our understanding of the roles of TGF-beta superfamily members in regulating vascular cell responses and provides likely avenues for future research that may lead to novel pharmacological therapies for the treatment or prevention of vascular disorders.

Animals↗

PubMed2001

GT repeat polymorphism in the 5' flanking region of the human growth hormone receptor gene.

A polymorphic GT dinucleotide repeat sequence has been identified in the 5' flanking region of the human growth hormone receptor (hGHR) gene on chromosome 5p13.1-p12, within the promoter region of the V9 5'UTR exon. Thirteen alleles have been identified in 50 non-related individuals, with an observed heterozygosity of 52%. The major allele contains 24 repeats, although a range of 19-32 repeats has been observed. Codominant segregation was demonstrated in five two-generation and two three-generation families. This marker may be useful in analysing the role of the hGHR gene in pre- and postnatal growth disorders.

5' Untranslated Regions↗