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Biomedical subjects

M B Ranke

Publications and source records attributed to M B Ranke.

At least 55 records · Page 3Linked to original sources
PubMed2000

The somatotrophic system in patients with dilated cardiomyopathy: relation of insulin-like growth factor-1 and its alterations during growth hormone therapy to cardiac function.

OBJECTIVE: Treatment with human recombinant growth hormone has yielded conflicting results in patients with congestive heart failure. In addition, growth hormone resistance has been reported in severe heart failure. Therefore, the purpose of this study was to evaluate the somatotrophic axis and effects of growth hormone on haemodynamics in patients with heart failure due to dilated cardiomyopathy. DESIGN: Randomized, double-blind, placebo-controlled trial. PATIENTS: Fifty clinically-stable patients with moderate heart failure (mean left ventricular ejection fraction = 26 +/- 2%) due to dilated cardiomyopthy were examined. MEASUREMENTS: Patients were randomly assigned to treatment with placebo or 2 IU/d sc human recombinant growth hormone for a mean of 14 weeks. Cardiac size and function were evaluated by magnetic resonance imaging. Central haemodynamics were obtained by right heart catheterization. Measurements of plasma noradrenaline, serum insulin-like growth factor-1, and insulin-like growth factor binding protein-3 were performed by standard assays at baseline and at the end of the treatment period. RESULTS: The severity of heart failure as determined by stroke volume, left ventricular end diastolic diameter and plasma noradrenaline concentrations correlated significantly to baseline serum insulin-like growth factor-1 levels (each P < 0.05). The growth hormone-induced increase of insulin-like growth factor-1 predicted the changes in ejection fraction (P < 0.05). A significant increase in ejection fraction of 7% was observed in patients whose insulin-like growth factor-1 increased by more than the median increase in comparison to the patients with an increase below the median (+ 4.0 +/- 2.3% vs. - 3.0 +/- 1.8%; P = 0.03). CONCLUSIONS: Serum levels of insulin-like growth factor-1, reflecting growth hormone secretion, are diminished in relation to the severity of heart failure in patients with dilated cardiomyopathy. Growth hormone induced increases of insulin-like growth factor-1 of more than 77 ng/l caused significant improvement of ejection fraction.

Adult↗
PubMed2000

X-linked congenital adrenal hypoplasia: new mutations and long-term follow-up in three patients.

Mutations of the DAX-1 gene, which encodes a newly discovered member of the nuclear hormone receptor family, were reported to cause X-linked congenital adrenal hypoplasia and hypogonadotrophic hypogonadism. While genetic data on DAX-1 are accumulating, information on the clinical course of the disorder are scarce. Here we present a detailed documentation of longitudinal data relating to three cases. We retrospectively collected clinical data on three boys (6, 14 and 14.5 years old) who we examined over a period ranging between 5 and 14 years. Mutational analysis of the DAX-1 gene was performed by means of direct sequencing of PCR products. The patients presented at ages between 4 and 6 weeks with salt-wasting, but there was no evidence of hypoglycaemia. All three cases were initially erroneously diagnosed with isolated aldosterone deficiency. Glucocorticoid deficiency was established by means of ACTH stimulation tests at 4 months, 3 and 13 years of age. One boy, whose therapy was discontinued at the age of 4 months, developed normally until adrenal crisis occurred at the age of 13 years. In all three cases, congenital hypogonadism was ruled out during infancy, as penis size was normal, the testes were descended, and serum samples contained normal testosterone levels. One boy exhibited transient hypergonadotrophism at age 9 but showed no clinical signs of puberty or an increase in serum testosterone. Onset of puberty and LHRH tests proved to be normal in his case as well as in another patient studied. In two patients, genetic analysis revealed new mutations at the C-terminus of DAX-1, these being a 1-base deletion (656delG) inherited from the mother and a de-novo 2-base insertion (728insCA) of the DAX-1 gene, respectively, both causing frame shift and premature stops at codons 263 and 398. One boy was affected by a new nonsense mutation of codon 39 (W39X) inherited from his mother. Mineralocorticoid deficiency preceded glucocorticoid deficiency which could be diagnosed through ACTH stimulation after the neonatal period. Transitory functional recovery of the adrenal glands can occur in adrenal hypoplasia congenita (AHC). Transient hypergonadotrophism may be one of the first indicators of defects in the gonadal axis, although normal initiation of puberty is not rare. The definitive diagnosis was established by means of molecular analysis of the DAX-1 gene. There was no correlation between types of mutations and phenotypes. The diagnostic procedure in male children and adolescents presenting with adrenal crisis should include ACTH stimulation tests and mutational analysis of DAX-1 in the absence of another proven aetiology.

Adolescent↗
PubMed2000

Energy expenditure, energy intake and prevalence of obesity after therapy for acute lymphoblastic leukemia during childhood.

OBJECTIVES: To investigate the prevalence and potential risk factors of obesity after therapy for childhood acute lymphoblastic leukemia (ALL). STUDY DESIGN: 39 ALL patients (age 10.7-20.5 years) who were in first remission for 3.4-14.6 years after standardized treatment with chemotherapy plus cranial irradiation (n = 25) or with chemotherapy alone (n = 14) were examined. After fasting overnight, the following parameters were investigated: body mass index (BMI) of patients and their parents; patients' BMI before ALL therapy; serum free thyroxin, growth hormone-dependent factors, estradiol, testosterone, cortisol, leptin and c-peptide; fat-free mass (bioelectrical impedance); resting metabolic rate (RMR, indirect calorimetry); caloric intake (24-hour recall); and physical activity (questionnaire). RMR data were applied to the fat-free mass and compared with 83 controls. RESULTS: The prevalence of obesity (criterion: BMI > 2 SDS) was significantly (p < 0.05) higher after ALL therapy (38%; irradiated patients 48%, non-irradiated patients 21%) than before therapy (3%). Compared to non-irradiated patients, irradiated patients had significantly lower RMRs (-1.07 +/- 0.24 vs. -0.32 +/- 0.21 SDS; p < 0.05), reduced physical activity levels (1.41 +/- 0.03 vs. 1.52 +/- 0.03; p < 0.05), and lower concentrations of insulin-like growth factor-binding protein-3 (-0.65 +/- 0.17 vs. 0.25 +/- 0.33 SDS; p < 0.05) and of free thyroxin (1.17 +/- 0.06 vs. 1.38 +/- 0.08 ng/dl; p < 0.05). Caloric intake was adequate. CONCLUSIONS: After ALL during childhood, patients face a higher risk of obesity. In the cranially irradiated patients, the likely causes are low physical activity, RMRs and hormonal insufficiency.

Adolescent↗
PubMed2000

Experience with growth hormone therapy in Turner syndrome in a single centre: low total height gain, no further gains after puberty onset and unchanged body proportions.

The experience gained since 1987, through observation of 85 girls with Turner syndrome under growth hormone (GH) treatment, has enabled the analysis of one of the largest cohorts. Our results show that age, karyotype and height reflect the heterogeneity of the patients examined at our growth centre. In 47 girls, followed over 4 years on GH (median dose 0.72 IU/kg/week), the median age was 9.4 years and mean height SDS was -3.55 (Prader) and -0.14 (Turner-specific), while height and other anthropometrical parameters [weight, body mass index, sitting height (SH), leg length (LL) SH/LL, head circumference, arm span] were documented and compared to normative data as well as to Turner-specific references established on the basis of a larger (n = 165) untreated cohort from Tübingen. The latter data are also documented in this article. Although there was a trend towards normalization of these parameters during the observation period, no inherent alterations in the Turner-specific anthropometric pattern occurred. In 42 girls who started GH treatment at a median age of 11.8 years, final height (bone age >15 years) was achieved at 16.7 years. The overall gain in height SDS (Turner) from start to end of GH therapy was 0.7 (+/- 0.8) SD, but 0.9 (+/- 0.6) SD from GH start to onset of puberty (spontaneous 12.2 years, induced 13.9 years) and -0.2 (+/- 0.8) from onset of puberty to end of growth. Height gain did not occur in 12 patients (29%) and a gain of > 5 cm was only observed in 16 patients (38%). Height gain correlated positively with age at puberty onset, duration, and dose of GH, and negatively with height and bone age at the time GH treatment started. Final height correlated positively with height SDS at GH start and negatively with the ratio of SH/LL (SDS). We conclude that, in the future, GH should be given at higher doses, but oestrogen substitution should be done cautiously, owing to its potentially harmful effect on growth. LL appears to determine height variation in Turner syndrome and the potential to treat short stature successfully with GH.

Adolescent↗
PubMed2000

Significance of basal IGF-I, IGFBP-3 and IGFBP-2 measurements in the diagnostics of short stature in children.

The role of IGF-I and IGFBP-3 measurements in the diagnostic work-up of short children is established but remains controversial. Little information exists on the value of IGFBP-2 measurements. Based on reference data established in 388 children we have reinvestigated the issue, using data from 392 short children who underwent the same diagnostic procedures between 1987 and 1998 (GHD, n = 187; non-GHD, n = 205, including patients with ISS, n = 76; IUGR, n = 46; and TS, n = 83). In comparing IGF-I, IGFBP-3 and IGFBP-2 serum levels of GHD and ISS children with reference data, we calculated the sensitivity, specificity, efficiency and positive predictive value for the diagnosis of GHD. The overall sensitivity of the parameters was high, the rank order being as follows: IGF-I >IGFBP-3 >IGFBP-2 (75, 67 and 62%, respectively). In contrast, the specificity was relatively low: IGFBP-3 >IGFBP-2 >IGF-I (50, 50 and 32%, respectively). The efficiency and positive predictive value of parameters was in the order of 40, 60 and 70--80%, respectively. In repeated measurements, the recorded basal levels of IGF-I and IGFBP-3 showed an overall narrow range of variation. We conclude that the determination of basal IGF parameters is, together with anthropometry and imaging techniques, an indispensable tool for differentiating between GHD and ISS; and that IGFBP-2 plays an additional role in this process.

Adolescent↗
PubMed2000

Transient pseudohypoaldosteronism with complex malformation of internal genitalia. A case report.

At the age of 3 weeks, a girl presenting with acute dehydration was admitted to our hospital. Clinical and laboratory findings revealed malformations of the genitourinary tract, an acute urinary infection and electrolyte disturbances (severe hyponatremia at 115 mmol/l and mild hyperkalemia at 5.6 mmol/l). According to anamnestic data, the child was born to healthy, nonconsanguineous parents. Vaccum extraction was done in the 38th gestational week due to pathological cardiotocography (CTG) findings. Auxological parameters were within the normal range for gestational age. Normal values for 17-OH progesterone and ACTH ruled out congenital adrenal hyperplasia (CAH). Pathologically high aldosterone and plasma renin activity (PRA) confirmed the diagnosis of pseudohypoaldosteronism with salt-wasting crisis which proved to be transient.

17-alpha-Hydroxyprogesterone↗
PubMed2000

Plasma concentrations of the carboxyterminal propeptide of type I procollagen (PICP) in preterm neonates from birth to term.

Carboxyterminal propeptide of type I procollagen (PICP), a marker of bone formation, has not yet been studied in preterm infants. In this study, PICP concentrations were measured longitudinally for 12 wk after birth using the ELISA technique in 43 preterm infants with a gestational age (GA) ranging from 24-29 wk and in 35 preterm infants with a GA ranging from 30-34 wk. PICP values in these preterm infants were higher than in children and adults. In cord plasma of preterm infants there was a significant gender difference, with higher PICP concentrations in male infants. A characteristic longitudinal pattern with an initial decrease during the first 3 postnatal days followed by a rapid increase from d 7 to d 28 was seen in both groups. Regarding the individual gestational ages, all preterm infants attained maximum PICP concentrations around 36 wk postmenstrual age. Multiple regression analysis revealed cord plasma PICP concentrations were significantly associated with GA, birth weight, sex, and IGF-I. A significant correlation between PICP concentrations and GA was seen at wk 1-4 and between PICP concentrations and protein intake at wk 1. Body weight and energy intake were shown to exert a significant effect on the PICP concentrations at 2 wk. The collected data in preterm infants may serve further studies evaluating PICP as a marker for bone formation and growth in very low birth weight premature infants.

Adult↗
PubMed2000

Bone turnover and growth during and after continuing chemotherapy in children with acute lymphoblastic leukemia.

Children treated for acute lymphoblastic leukemia may develop reduced bone mineral density during treatment, but there is little information on the mechanisms involved. In a prospective, longitudinal study on 15 children with ALL, we undertook serial measurements of markers of bone and collagen turnover, insulin-like growth factor (IGF)-I and its binding proteins (IGFBPs)-3 and -2 during the second year of continuing chemotherapy. In eight patients we also measured lower leg length by knemometry. Height SD scores, lower leg length velocity, IGF-I, and markers of bone collagen turnover did not differ significantly from healthy children. However, bone alkaline phosphatase, a marker of the differentiated osteoblast, was lower (mean SD score, -0.64; p < 0.0001), whereas procollagen type III N-terminal propeptide (P3NP, a marker of soft tissue collagen turnover; mean SD score, +0.93, p < 0.05), IGFBP-3 (mean SD score, +0.76; p < 0.01), and IGFBP-2 (mean SD score, +1.24, p = 0.01) were all higher than in healthy children. IGFBP-3 decreased during episodes of afebrile neutropenia (p < 0.05). Within 3 mo after completion of treatment, bone ALP increased in all eight patients, but collagen markers showed little change. IGFBP-2 returned to normal posttreatment, but P3NP and IGFBP-3 remained significantly elevated compared with healthy children (mean SD scores, +1.51 and +1.36, respectively; p < 0.01). We conclude that continuing chemotherapy was associated with normal growth and bone collagen turnover but enhanced soft tissue collagen turnover. Bone bone alkaline phosphatase was low throughout treatment, which suggests impaired osteoblast differentiation resulting from a direct effect of chemotherapy on bone. Although the effect was reversible, the long-term implications for bone health in survivors remain uncertain.

Adolescent↗
PubMed2000

Identification of short stature caused by SHOX defects and therapeutic effect of recombinant human growth hormone.

Point mutations or complete deletions of SHOX, the short-stature homeobox-containing gene on the pseudoautosomal region of the sex chromosomes (Xp22 and Yp11.3), were recently reported in one family with idiopathic short stature and in several families with Leri-Weill syndrome (dyschondrosteosis). The missing SHOX is also thought to attribute to the growth failure in Turner syndrome. For testing the frequency of defects of SHOX in unexplained growth failure and recombinant human GH (rhGH) as a possible growth-promoting agent, we selected 68 children with idiopathic short stature. These probands had heights below -2.0 SD score for age, normal target heights, no significant bone age retardations, no endocrine abnormalities, no skeletal diseases, and no other organic diseases. No mutations were detected by single-strand conformational polymorphism analysis of the PCR-amplified SHOX. The analysis of three microsatellite DNA markers of the pseudoautosomal region, including one located on the 5' untranslated region of SHOX-exon 1, identified a 15-yr-old girl who carried a mutation in the form of a complete SHOX deletion. This girl who had a normal karyotype presented with mild mesomelic shortening of the forearms and lower legs. We treated two children with short stature on the basis of a SHOX point mutation (C674T) with rhGH at a dose of 1.0 IU/kg body weight-week in accordance with the regimen used in Turner syndrome. During the first 12 months of treatment, these two children (5.9- and 8.4-yr-old) showed an excellent growth spurt with a growth rate of 9.5 and 9.4 cm/yr, respectively. Growth of the lower extremities was weaker than in the trunk and arms. Our data suggest that short stature due to SHOX deletions is not a rare entity. Growth-promoting therapy with rhGH was effective with regard to height gain, but a tendency to disproportionate growth was apparent. In cases of unexplained growth failure, especially if associated with any mild skeletal disproportions, genetic analysis of SHOX should be considered.

Adolescent↗
PubMed2000

Prediction of long-term response to recombinant human growth hormone in Turner syndrome: development and validation of mathematical models. KIGS International Board. Kabi International Growth Study.

It has become common practice to apply GH treatment in short Turner syndrome patients with the objective of promoting growth. The variability in response and the high costs of this treatment demand the individualization and optimization of therapy. Based on 686 prepubertal Turner patients from the Kabi International Growth Study (KIGS; Pharmacia & Upjohn, Inc. International Growth Database), we undertook a multiple regression analysis of height velocity (centimeters per yr) by using various parameters of potential relevance. Derived prediction models for the first 4 yr of GH treatment were validated with 76 additional KIGS patients and 81 patients from Tuebingen, Germany. Among the 6 predictors identified, the most influential variable for first year growth response was the natural log (ln) of the weekly GH dose. The first year growth response was also correlated with age and distance between height and target height (SD score; both negative) and body weight SD, number of GH injections per week, and oxandrolone treatment given additionally (positive). The first year model explains 46% of the variability, with 1 SD of 1.26 cm. For the second to fourth years, 5 predictors were identified: height velocity during previous years, weekly GH dose (ln), weight SD, oxandrolone therapy (all positive), and age (negative). These models explained 32%, 29%, and 30% of the variability, respectively, with SD scores of 1.1, 1.0, and 1.0 cm, respectively. When the models were applied to the other cohorts, no significant difference was noted between observed and predicted responses. Although the parameters used in our models do not entirely explain the variability in the growth response in Turner syndrome, the parameters themselves were clinically relevant to our present understanding and proved to be of high precision. Some of the tested markers, such as karyotype, do not contribute to the growth response. These variables make the models practical and suitable for planning beneficial and cost-effective therapy.

Anabolic Agents↗
PubMed2000

17alpha-hydroxylase/17,20-lyase deficiency as a model to study enzymatic activity regulation: role of phosphorylation.

Cytochrome P450 17alpha-hydroxylase (CYP17) is a single gene-encoded protein with two activities: 17alpha-hydroxylase and 17,20-lyase. The two catalytic activities are differentially regulated in health and disease. We took advantage of naturally occurring human mutations to understand the molecular bases of this differential regulation. We identified eight novel mutations in the CYP17 gene, different in nature and spread throughout the gene. As posttranslational modifications appear to be important for activity control, we investigated the phosphorylation state of wild-type and mutant CYP17 proteins. Although phospholabeled protein was seen when the wild-type and most mutant proteins were expressed, no phosphorylation was detected for the F417C mutant. F417C is the only 17,20-lyase deficiency case confirmed at the molecular level and represents the first phosphorylation CYP17-deficient mutant. In search of the physiological agents involved in this process, the effect of cAMP was tested on activity and phosphorylation state of our mutant CYP17 proteins. cAMP stimulates activity and phosphorylation in all cases, except in the F417C and R35L mutants. The lack of response to the physiological second messenger might explain the different phenotypes. The F417C mutant protein, which is already shown to be associated with the lack of electron transfer, provides for the first time a link between the electron transfer system and the phosphorylation state of the CYP17 enzyme in the control of 17,20-lyase activity.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2000

New paradigms for growth hormone treatment in the 21st century: prediction models.

Inconsistent and sometimes disappointing final height outcomes in studies in which exogenous growth hormone (GH) was given to children with short stature resulting from various causes have led to attempts to determine the factors that influence responsiveness to GH. Many such factors have been identified, including the genetically determined height potential of the child, the height deficit, current and perinatal auxological and biological factors, and, importantly, GH treatment modalities. These factors vary depending on the cause of the growth failure and during the course of childhood and treatment with GH. Data from well-defined large cohorts can be entered into multiple regression analyses to derive algorithms describing the variation in growth response during a defined period and the influence on this of various factors. Pharmacoepidemiologic surveys have been particularly useful in this regard. Algorithms with low-error SD values, which have included the dose of GH as a variable, can be used to predict the response to a putative GH dose in a similar cohort or in an individual over an equivalent period. A sequential series of such algorithms can be integrated to form a predictive model. Such a model can be used for planning a course of treatment, but the patient data required for entry into the model should be easily obtainable if the model is to have widespread utility. The development of such models will allow GH treatment to be better individualized and optimized for growth and cost outcomes. Growth prediction models will facilitate realistic expectations and will permit stepwise goals to be set and monitored.

Adolescent↗
PubMed2000

Symptomatic versus substitution growth hormone therapy in short children: from auxology towards a comprehensive multidimensional assessment of short stature and related interventions.

There is an ongoing debate as to whether symptomatic growth hormone treatment (GHT) in short children without growth hormone deficiency (GHD) is justified, since there is no substitutional indication. The increasing evidence that final height cannot be normalized in these patients (e.g. in Ullrich-Turner syndrome) reinforces this controversy. We have focused on the empirical evidence on the psychosocial and physical meaning of being short in childhood as well as on the underlying assumptions of the different GHT indications. The indication for GHT in patients with non-GHD may be seen as a pharmacotherapeutic intervention in order to prevent the developmental, physical and psychosocial risks associated with short stature. This requires a qualitative shift in methodological assessment with respect to the psychosocial and physical impact of being short as well as of the potential benefit of new treatment indications in terms of a more comprehensive evaluation including health-related quality of life for these patients.

Body Height↗
PubMed1999

Correlation of type I insulin-like growth factor receptor (IGF-I-R) and insulin receptor-related receptor (IRR) messenger RNA levels in tumor cell lines from pediatric tumors of neuronal origin.

The insulin receptor-related receptor (IRR) is a member of the insulin receptor family. So far no ligand has yet been discovered for this receptor type (orphan receptor). IRR, insulin receptor (IR), and insulin-like growth factor-I receptor (IGF-I-R) are all tyrosine kinases. The cellular function of the IRR is not known. The expression of IRR mRNA is restricted to a few, e.g. neuronal tissues, and has also been found in neuroblastomas. Since tyrosine kinase receptors, including the IGF-I-R, may be involved in tumor genesis, we examined the expression of IRR mRNA and IGF-I-mRNA in 18 tumor cell lines using RT-PCR and the solution hybridization/RNAse protection assay. In particular, the mRNA levels of IRR and IGF-I-R were compared by semi-quantitative RT-PCR in seven neuroblastomas and 11 soft tissue sarcomas (STS), five of which were of neuronal origin. In all of the seven neuroblastoma cell lines and in five of the 11 STS cell lines, the IRR mRNA was detected. In addition, the IRR mRNA was expressed in rhabdomyosarcoma, in leiomyosarcoma, in one of the Ewing sarcoma and in the neurofibrosarcoma cell line. The last two tumor cell types are of neuronal origin. The levels of expression of IGF-I-R and IRR mRNA of the neuroblastoma cell lines were closely related (r = 0.82, P < 0.002). Furthermore, IRR mRNA was found only in cell lines that also expressed IGF-I-R mRNA. In conclusion, cell lines from pediatric tumors of neuronal origin express IRR mRNA simultaneously with a another tyrosine kinase receptor (IGF-I-R) mRNA. The tight coupling of their mRNA expression suggests a functional association of both receptors in the tumor cells.

Base Sequence↗
PubMed1999

A rapid screening for steroid 21-hydroxylase mutations in patients with congenital adrenal hyperplasia. Mutations in brief no. 247. Online.

Steroid 21-hydroxylase deficiency is the major cause of congenital adrenal hyperplasia (CAH). CAH due to 21-hydroxylase deficiency is divided into three classes: salt-wasting (classical), non-classical and simple virilizing, reflecting different degrees of clinical severity. Using polymerase chain reaction (PCR) and allele-specific oligonucleotide hybridisation (ASO), we screened the DNA of 62 Caucasian CAH families (heterozygous parents and children) for 14 different and frequently-found CYP21-mutations (HGMD). Of the 62 patients (21 males, 41 females), 26 females and 11 males had the classical or salt-wasting form, 3 females and 1 male had the non-classical form and 14 females and 7 males had simple virilizing CAH. More than 60% of the patients were compound-heterozygous. We found the mutations on 110 alleles (out of 124 alleles). There were 30 CYP21 gene deletions/conversions, 3 substitutions (P30L) in exon 1, 30 splice mutations (c.93-13A/C>G) in intron 2, 26 point mutations (I172N) in exon 4, one cluster of mutations (I236N, V237E, M239K) in exon 6, 8 mutations (V281L and 1760-1761insT) in exon 7, and 8 nonsense (Q318X) and 4 missense (R356W) mutations in exon 8. Our study supports the case for using this rapid technique for CAH-family screening as long as alleles from both affected patients and parents are screened in parallel.

Adrenal Hyperplasia, Congenital↗
PubMed1999

Spontaneous growth and bone age development in a patient with 17alpha-hydroxylase deficiency: evidence of the role of sexual steroids in prepubertal bone maturation.

A male pseudohermaphrodite with 17alpha-hydroxylase deficiency and complete nonvirilization was monitored for excessive weight from the age of 3.5 to 11.5 years before the absence of sex steroids was detected. The retrospective analysis of growth data showed retarded bone age development despite adequate growth, which led to a remarkable increase in final height prognosis.

Adolescent↗
PubMed1999

Effects of a third intensification block of chemotherapy on bone and collagen turnover, insulin-like growth factor I, its binding proteins and short-term growth in children with acute lymphoblastic leukaemia.

Children with acute lymphoblastic leukaemia (ALL) have reduced bone turnover caused by the disease itself and early intensive chemotherapy, but the effects of later chemotherapy using different drug combinations are uncertain. We report here a longitudinal study on 9 children with ALL randomised to receive an additional third intensification block of chemotherapy, compared with 9 children receiving continuing chemotherapy over the same period. During third intensification, bone alkaline phosphatase, procollagen type I C-terminal propeptide, the carboxyterminal propeptide of type I collagen, procollagen type III N-terminal propeptide and lower leg length all decreased in response to dexamethasone, then returned to (but not beyond) baseline levels after dexamethasone was stopped and other drugs started. These changes were unrelated to circulating insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-3 or IGFBP-2. In all children, bone alkaline phosphatase remained below the population mean throughout. We conclude that dexamethasone decreased bone and soft tissue turnover, probably through direct effects on target tissues. The postdexamethasone phase of third intensification and continuing chemotherapy had no major deleterious effect on collagen turnover, but there was evidence of continuing suboptimal bone mineralisation.

Adolescent↗