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Biomedical subjects

S L Drop

Publications and source records attributed to S L Drop.

At least 19 recordsLinked to original sources

A new model to predict final height in constitutionally tall children.

In order to develop new height prediction models for children with constitutionally tall stature, 55 such boys and 88 girls were recalled for measurement of adult final height (FH). Data on height (H), age (CA), and target height (TH) were collected from the hospital charts and radiographs of the left hand and wrist were retrieved and used for bone age (BA) determination [BA according to the methods of Greulich and Pyle (BAGP) and Tanner and Whitehouse (BARUS)]. Standard multiple regression techniques were used to develop prediction equations for FH. In addition to test the validity of the new equations, FH was measured in a second group of constitutionally tall children (n = 32) and compared with the predicted FH according to our models. In addition, a comparison was made with other prediction methods. Mean (SD) FH was 196.0 (4.9) cm in boys and 180.5 (3.8) cm in girls. The ultimate regression equation was FH (cm) = 216.07 + 0.75 x H + 0.25 x TH -11.09 BAGP + 0.74 x (CA x BAGP) for boys and FH = 161.42 + 0.73 x H + 0.15 x TH - 8.41 x CA -8.83 x BARUS -2.45 x M + 0.55 x (CA x BARUS) for girls. The models showed satisfying accuracy: the mean (SD) errors were -1.4(3.2) cm for boys and -0.5(3.1) cm for girls with corresponding mean (SD) absolute errors of 2.7 (2.2) cm and 2.0 (2.4) cm, respectively. Compared with the current prediction methods, the new models were quite promising. Their clinical validity has to be ascertained in larger groups of tall children.

Adult

Accuracy of final height prediction and effect of growth-reductive therapy in 362 constitutionally tall children.

Height reduction by means of treatment with high doses of sex steroids in constitutionally tall stature (CTS) is a well known, though still controversial, therapy. The establishment of the effect of such therapy is dependent on the height prediction method applied. We evaluated the reliability of various prediction methods together with the subjective clinician's judgment in 143 untreated children (55 boys and 88 girls) with CTS and the effect of height-reductive therapy in 249 tall children (60 boys and 159 girls) treated with high doses of sex hormones (cases). For this purpose, we compared the predicted adult height with the attained height at a mean adult age of 25 yr and adjusted the therapeutic effect for differences in bone age (BA), chronological age (CA), and height prediction between untreated and treated children. At the time of the height prediction, controls were significantly shorter, had more advanced estimated BAs (except for the BA according to Greulich and Pyle in boys), had lower target heights, and had smaller adult height predictions compared with the CTS patients (P < 0.05). At the time of the follow-up, CTS patients were significantly taller than controls for both boys and girls (P < 0.02). In controls, a large variability was found for the errors of prediction of the various prediction methods and in relation to CA. The prediction according to Bailey and Pinneau systematically overestimated adult height in CTS children, whereas the other prediction methods (Tanner-Whitehouse prediction and index of potential height) systematically underestimated final height. The mean (SD) absolute errors of the prediction methods varied from 2.3 (1.8) to 5.3 (4.3) cm in boys and from 2.0 (1.9) to 3.7 (3.5) cm in girls. They were significantly negatively correlated with CA (r = [minus 0.27 to -0.65; P < 0.05), except for the Tanner-Whitehouse prediction in boys, indicating that height prognosis is more reliable with increasing CA. In addition, experienced clinicians gave accurate height predictions by evaluating the growth chart of the child while taking into account various clinical parameters, such as CA, BA, and pubertal stage. The effect of sex hormone therapy was assessed by means of multiple regression analysis while adjusting for differences in height prediction, CA, and BA at the start of therapy between treated and untreated children. The mean (SD) adjusted effect varied from -0.5 (2.4) to 0.3 (1.4) cm in boys and from -0.6 (2.1) to 2.4 (1.4) cm in girls. The adjusted height reduction was dependent on the BA at the time of start of sex hormone therapy and was more pronounced when treatment was started at a younger BA. In boys, the treatment effect was significantly negative at BAs exceeding 14-15 yr. After cessation of therapy, additional mean (SD) growth of 2.4 (1.2) and 2.7 (1.1) cm was observed for boys and girls, respectively. The mean (SD) BA according to Greulich and Pyle at that time was 17.1 (0.7) yr for boys and 15.2 (0.6) yr for girls. These data demonstrate that height prediction in children with CTS is inaccurate in boys, but clinically acceptable in girls. With increasing age, height prognosis became more accurate. Overall, the height-reducing effect of high doses of sex hormones in children with CTS was limited, especially in boys. However, a significant effect of treatment was observed when treatment was started at BAs less than 14-15 yr, depending on the method of BA assessment. In boys, treatment appeared to be contraindicated at BAs older than 14-15 yr, because androgen administration caused extra growth instead of growth inhibition. It is recommended that referral should take place early, preferably before puberty, for careful monitoring of growth and height prediction. Moreover, it is recommended not to discontinue therapy before complete closure of the epiphyses of the hand has occurred to avoid considerable posttreatment growth.

Adolescent

A placebo-controlled, double-blind trial of growth hormone treatment in prepubertal children after renal transplant.

Sustained growth retardation in spite of a successful renal transplantation (RTx) is a serious problem for many pediatric allograft recipients. Biosynthetic growth hormone (GH) was given to 11 prepubertal children with severe growth retardation after RTx in a placebo-controlled double-blind study, assessing its effect on height velocity (HV), bone maturation, renal function, plasma IGF-I and IGF-II, serum IGF-binding proteins (IGFBP), and lipid and carbohydrate metabolism. Six months of GH (4 IU/m2/day s.c.) was either preceded or followed by six months of placebo. The patients underwent a full examination every three months. All children completed the study. Mean HV improved significantly with GH therapy (P < 0.0001), but there was also some improvement with placebo (P = 0.06). The GH-induced HV increment exceeded that of placebo by 2.9 cm/six months. Bone maturation was not accelerated. Acute renal graft rejection did not occur in any of the patients. 125I-thalamate and 131I-hippuran tests showed that mean glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) did not change significantly during GH therapy. GH caused a significant increase in IGF-I (P < 0.0001), which was far greater than the insignificant increase in serum IGFBP-3 levels (P = 0.16). Mean serum levels of total cholesterol, low density lipoprotein, apolipoprotein-A1 and -B, which are elevated at the start of the study compared with that of controls, did not change significantly during GH therapy. GH induced a significant increase in mean integrated plasma insulin levels during oral glucose tolerance test, without changing plasma glucose levels. Serum fructosamine and parathyroid hormone levels remained constant. Impressive HV increment can be achieved with GH therapy in children with growth retardation after RTx, without significant changes in renal function. Bone maturation appears unaffected, suggesting an improve final height.

Adolescent

High dose testosterone therapy for reduction of final height in constitutionally tall boys: does it influence testicular function in adulthood?

OBJECTIVE: We have studied the effect of treatment with high doses of androgens during puberty on testicular function in adult men with constitutionally tall stature, taking into account confounding factors interfering with sperm quality, since existing published data do not include whether testicular function is impaired by such treatment. DESIGN: Historical cohort study. PATIENTS: Forty-three previously androgen treated tall men (cases) and 30 non-treated tall men (controls). MEASUREMENTS: Physical examination, semen analysis and plasma levels of LH, FSH, testosterone (T), sex hormone binding globulin (SHBG) and inhibin. RESULTS: Sperm quality and testis volume were comparable between cases and controls. Mean sperm concentration was 66.4 x 10(6)/ml in cases and 66.2 x 10(6)/ml in controls. A left-sided varicocele was found in 45% of the cases and 37% of the controls. In cases we observed a significant effect of the age at start of androgen therapy on sperm motility (regr. coeff. (SE): 4.92 (2.41)%, P = 0.048). In addition, testicular size at start of therapy had a significant effect on sperm concentration (regr. coeff. (SE): 5.57 (1.54) x 10(6)/ml, P = 0.0012) and on total sperm count (regr. coeff. (SE): 43.1 (7.73) x 10(6), P = 0.0001). Plasma levels of T, SHBG and inhibin were not statistically different between the groups. Cases had significantly higher FSH levels (mean (SD) 3.3 (2.2) vs 2.1 (0.8) IU/I, P = 0.004) and significantly lower LH levels (mean (SD) 2.3 (0.9) vs 3.1 (1.4) IU/I, P = 0.019). We found a significant effect of age at start of therapy on plasma FSH level in the treated men (regr. coeff. (SE): -0.73 (0.18) IU/I, P = 0.0003). CONCLUSIONS: Treatment with high doses of androgens for reduction of final height in constitutionally tall stature has no long-term side-effect on sperm quality, testicular volume or plasma testosterone levels. However, treated men had significantly higher plasma levels of FSH compared with controls. The meaning of this difference remains to be established. Varicocele was present in 42% of the adult tall men.

Adult

Long term sequelae of sex steroid treatment in the management of constitutionally tall stature.

AIM: To evaluate possible long term side effects of high doses of sex steroids in the management of constitutionally tall stature, with special attention to hypothalamic-gonadal function. METHODS: Sixty four tall adult men and 180 tall adult women, who received supraphysiological doses of sex hormones during puberty, were interviewed in a standardised way at a mean follow up period of 10 years after cessation of treatment. Sixty one untreated tall adult men and 94 untreated tall adult women served as controls. RESULTS: The majority of the subjects were satisfied with their decision regarding hormone treatment. Seventy seven per cent of the women and 78% of the men reported one or more side effects during treatment. Most side effects were mild. In women, only 3% stopped treatment because of an adverse event; in men, the reported side effects never stopped treatment. The frequency of reported side effects in women was higher during treatment with high doses of oestrogens than during oral contraceptive use, indicating a dose dependent relationship. Amenorrhoea of longer than six months after cessation of therapy was found in 5%. Menstrual cycle characteristics of previously treated women were comparable with controls. Malignancy was not reported. Information about a total of 127 pregnancies was obtained and revealed no distinct differences in details and outcome between previously treated women and men, and controls. CONCLUSIONS: At a mean follow up of 10 years there is no evidence that pharmacological doses of sex hormones have a long term effect on reproductive function. However, this period is still too short to draw definite conclusions.

Adult

Children born small for gestational age: do they catch up?

Postnatal growth of 724 (423 premature, 301 full-term) small for gestational age infants (SGA, birth length less than the third length percentile (P3) for gestational age) was studied for the first 2 y of life. The study group consisted of all SGA infants who had been admitted over a period of 8 y at the Departments of Neonatology of three University Hospitals in The Netherlands with exclusion of infants with well defined causes for growth retardation, such as chromosomal disorders, syndromes, severe malformations, or complications during the neonatal period or later on. The aim of the study was to describe postnatal growth of SGA infants and to find predictive factors for catch-up growth > or = P3 during the first 2 y of life. The majority (around 85%) of the healthy SGA infants showed catch-up growth to a height > or = P3 during the first 2 y of life. The percentage of premature SGA infants with catch-up growth > or = P3 at 2 y of age (82.5%) was not significantly different from that of full-term SGA infants (87.5%). Birth length SDS was more sensitive than birth weight SDS in predicting catch-up > or = P3 in premature SGA infants. In contrast, birth weight SDS was the best predictor for catch-up > or = P3 in full-term SGA infants. Gestational age, multiple birth, and sex were not significantly associated with catch-up in height > or = P3.(ABSTRACT TRUNCATED AT 250 WORDS)

Birth Weight

Idiopathic isosexual central precocious puberty: magnetic resonance findings in 30 patients.

The purpose of this prospective study was to define the incidence of magnetic resonance imaging (MRI) abnormalities in the brain in patients with idiopathic central precocious puberty without any additional neurological signs and symptoms, and to evaluate the routine use of gadolinium contrast in these patients. 30 patients (29 girls, one boy; age range 1.9-11.9 years) with idiopathic central precocious puberty were studied. MRI of the brain in axial, coronal and sagittal planes was performed before and after administration of gadopentetate dimeglumine, with special attention to the region of the third ventricle. There are three major findings: (1) the height of the pituitary gland is increased up to adult size compared with normal individuals; (2) in four patients (13%) major structural abnormalities were found; three hamartomas of the tuber cinereum and one gliomatous process extending from the chiasm to the optic tract; and (3) the routine use of gadopentetate dimeglumine did not reveal new abnormalities although the lack of enhancement made a positive contribution to diagnostic certainty. We conclude that contrast enhanced MR examination is a safe and reliable method for the exclusion of abnormalities in children with precocious puberty and for the follow-up of those patients in whom abnormalities are present.

Adolescent

IGF, type I IGF receptor and IGF-binding protein mRNA expression in the developing mouse lung.

The IGFs are important mitogens involved in lung growth and development. The regulation of IGF action depends not only on the expression of IGFs and IGF receptors, but also on the modulation of IGF activity by IGF-binding proteins (IGFBPs). In this study, we describe the mRNA expression of IGF-I, IGF-II, type I IGF receptor, IGFBP-2, IGFBP-4 and IGFBP-5 during mouse lung development as studied by in situ hybridization techniques. The IGF, type I IGF receptor and IGFBP-2, -4 and -5 genes were expressed in developing lung as early as embryonal day 12.5. Expression of IGFBPs-1, -3 and -6 was below detection. IGF and IGFBP-2 mRNAs were expressed both in mesenchymal and epithelial cells. Type I IGF receptor transcripts were also observed throughout the developing lung, with the exception of the epithelial cells of the bronchi after embryonal day 15. Furthermore, mRNA expression of IGFBPs-4 and -5 was noted in neighbouring cell types, and after embryonal day 15, co-expression of the type I IGF receptor and IGFBP-4 transcripts was detected. The observed expression patterns imply that the IGFBP-2, -4 and -5 genes are differentially regulated during embryonic development and suggest that each may have a discrete function. A possible role for IGFBPs-2, -4 and -5 is to participate in the regulation of cell-specific IGF responses during mouse lung development.

Animals

Stimulation of hepatic insulin-like growth factor-binding protein-1 and -3 gene expression by octreotide in rats.

It has recently been demonstrated in various clinical experiments that native somatostatin and its long-acting analogues increase circulating levels of insulin-like growth factor-binding protein-1 (IGFBP-1) within 1-2 h, independent of effects on circulating insulin or glucose levels. Using human hepatoma cells in vitro the somatostatin analogue, octreotide, has been shown to increase IGFBP-1 mRNA within 24 h indicative of a direct stimulatory effect of octreotide on IGFBP-1 synthesis. In order to ascertain whether octreotide acutely stimulates IGFBP-1 mRNA in vivo, placebo or two doses of octreotide were injected subcutaneously into three groups of rats. One hour after saline or octreotide administration, liver, kidney and serum were obtained for the measurement of IGFBPs-1 to -6 mRNA in tissue and IGFBPs and IGF-I in serum. Octreotide increased liver IGFBP-1 (562%) and IGFBP-3 (23%) mRNA expression with a concomitant rise in the circulating 30 kDa (106%) and 38-42 kDa (23%) IGFBPs. No detectable changes were seen in other liver IGFBP transcripts, other circulating IGFBPs or in any of the kidney IGFBP transcripts. Serum IGF-I increased by 37% in the animals receiving the high octreotide dose. No concomitant changes were observed in glucose or insulin levels. These data show that octreotide acutely stimulates hepatic IGFBP-1 and -3 mRNA in vivo in rats. The stimulating effect on IGFBP-3 presents a possible hitherto unknown form of regulation of IGFBP-3 whilst the effect on IGFBP-1 indicates that the stimulatory effect of octreotide on circulating IGFBP-1 described in clinical trials may be due to increased hepatic production. The present findings may be of importance in the clinical use of octreotide.

Animals

Growth hormone treatment in growth-retarded adolescents after renal transplant.

Growth failure is a psychosocial problem for many patients who have undergone renal transplantation. 18 adolescents (mean age 15.6, range 11.3-19.5) with severe growth retardation after renal transplantation were treated with biosynthetic growth hormone (GH) for 2 years. All received prednisone, administered daily or on alternate days, with azathioprine and/or cyclosporin A. 16 were blindly assigned to one of two GH doses (4 vs 8 IU per m2 per day). Growth, bone maturation, renal graft function, plasma insulin-like growth factors, serum binding proteins, and other biochemical parameters were checked regularly. Glomerular filtration rate and effective renal plasma flow were tested with 125I-Thalamate and 131I-Hippuran. Data on growth and glomerular filtration rate during GH treatment were also compared with those of matched non-GH-treated controls. Mean (standard deviation) increment in height after 2 years of GH was 15.7 (5.1) cm, significantly greater (p < 0.0001) than in matched controls, 5.8 (3.4) cm. Results were similar for the two GH dosage groups. Bone maturation was not accelerated. Glomerular filtration rate and effective renal plasma flow did not change significantly. The incidence of a > 25% reduction in glomerular filtration rate over 2 years was not significantly higher in GH-treated patients than in non-GH-treated controls (39% vs 32%, p = 0.97). Although a few patients had deterioration of graft function, we could not find a relation with GH treatment. Our results show that sustained improvement of height can be achieved with GH in severely growth-retarded adolescents after renal transplantation.

Adolescent

cDNA cloning and mRNA expression of the six mouse insulin-like growth factor binding proteins.

The insulin-like growth factor binding proteins (IGFBPs) comprise a family of six distinct proteins which modulate insulin-like growth factor action. We have isolated cDNAs encoding the six mouse IGFBPs (mIGFBPs). In addition, we studied the mRNA expression of the six mIGFBPs during development and in various adult tissues. Our results show that each of the six mIGFBPs is highly homologous to their human and rat counterparts, whereas only the N and C terminal ends are conserved between the six mIGFBPs. Northern blotting revealed that mIGFBP-2, -3, -4 and -5 genes are already expressed at gestational day 11.5, suggesting a role for these mIGFBPs in embryonal development. In liver, a peak of mIGFBP-1 mRNA expression was found around birth, suggesting a function for mIGFBP-1 in the newborn mouse. Finally, tissue-specific expression of the six mouse IGFBP genes was observed in adult tissues suggesting different roles or modes of actions in adult life.

Amino Acid Sequence

Endogenous and stimulated GH secretion, urinary GH excretion, and plasma IGF-I and IGF-II levels in prepubertal children with short stature after intrauterine growth retardation. The Dutch Working Group on Growth Hormone.

OBJECTIVE: The pathophysiological mechanisms underlying the failure of catch up-growth in children with short stature after intrauterine growth retardation (IUGR) remain obscure. Since GH secretion disturbances might play a role in the growth retardation of these children we have investigated various aspects of the GH/IGF axis. DESIGN: Cross-sectional study in one group of patients. PATIENTS: Forty prepubertal children (15 girls/25 boys; mean age (range) 7.5 years (3.4-10.8)) with short stature (height below the third centile) after IUGR, defined as a birth length below the third centile for gestational age, were studied. MEASUREMENTS: GH secretion was determined by a 24-hour plasma GH profile (sampling every 20 minutes) and, on a separate occasion, by a standard arginine provocation test (ATT). Plasma IGF-I and IGF-II levels were measured at the start of the GH profile. Urine was collected to measure urinary GH levels. Plasma and urinary GH were determined by double antibody RIA. IGF-I and IGF-II were determined by specific RIA after acid chromatography. The 24-hour GH profiles were analysed using Pulsar. RESULTS: Endogenous GH secretion was similar for boys and girls. Boys had significantly lower mean GH levels compared to healthy controls. Forty per cent of the children met our criteria for a normal 24-hour GH profile (group A; n = 16) and 60% (n = 24) did not. We subdivided these 24 children into two groups: group B (n = 14) (children with either mean GH levels less than controls but with at least one spontaneous GH peak above 20 mU/l and children with normal mean GH levels but with no GH peak above 20 mU/l (subnormal 24-hour GH profile)) and group C (n = 10) (children with mean GH levels less than controls and no GH peak above 20 mU/l (low 24-hour GH profile)). The GH secretory abnormalities were due to a decrease in pulse amplitude, not in pulse frequency. Mean (SD) maximal GH response during ATT was 22.3 (12.1) mU/l. Nineteen children (47.5%) had a maximal GH value < 20 mU/l. Moderate, but significant, correlations were found between several 24-hour GH profile characteristics and the maximal GH response during ATT (r = 0.31-0.35; P < 0.05). Mean (SD) overnight urinary GH excretion was 3.8 (2.1) and 4.4 (3.5) microU/night for boys and girls, respectively. Compared to healthy schoolchildren, overnight urinary GH was lower in boys, but not in girls. Mean (SD) IGF-I and IGF-II SDS levels for chronological age were -0.88 (1.40) and -0.64 (1.48), respectively. Plasma IGF-I and IGF-II levels were significantly reduced compared to controls. Height SDSCA or height velocity SDSCA did not correlate with either spontaneous or stimulated GH secretion, urinary GH excretion or plasma IGF-I or IGF-II levels. CONCLUSIONS: Our study indicates that 50-60% of children with short stature after intrauterine growth retardation have 24-hour GH profile abnormalities and/or subnormal responses to arginine provocation, while mean plasma IGF-I and IGF-II levels are significantly reduced, indicating GH insufficiency. Urinary GH excretion is lower in boys, but not in girls. The precise mechanism of the failure to catch up growth needs further elucidation. It seems justified to start clinical trials in order to investigate whether treatment with exogenous GH might be beneficial for these children.

Arginine

De novo deletion (2) (p11.2p13): clinical, cytogenetic, and immunological data.

We report a case of a boy with a de novo interstitial deletion of chromosome (2) (p11.2p13). Clinical features included dysmorphism of the face, genital region, and limbs, psychomotor retardation, and vitiligo. A reduced ratio of immunoglobulin (Ig) light chain expression (kappa/lambda ratio: 0.7) was found, compatible with deletion of one Ig kappa allele on chromosome 2p12. The patient had no clinical or laboratory signs of immunodeficiency.

Abnormalities, Multiple

Growth after renal transplantation in prepubertal children: impact of various treatment modalities.

A retrospective study evaluated posttransplant growth of 70 prepubertal children during the first 2 y after renal transplantation (RTx). Immunosuppressive treatment consisted of prednisone administered either daily or on alternate days in combination with either azathioprine or cyclosporin A. The increment in height standard deviation score for chronologic age during the first 2 y after RTx was less than 0.5 SD for 70% of the study population. The predictive factors for posttransplant growth were determined by evaluating several factors and treatment modalities singly and simultaneously in a multiple regression analysis. Patients with the most severe growth retardation at RTx appeared to have the most pronounced growth spurt after RTx, but even they never had complete catch-up growth, and 2 y after RTx they were still shorter than those with less severe growth retardation at RTx. Alternate-day instead of daily prednisone administration had a significantly positive influence, whereas a high cumulative dose of prednisone, azathioprine instead of cyclosporin A therapy, and a persistently reduced GFR (GFR < 50 mL/min/1.73 m2) had a significantly negative influence on catch-up growth during the 2 y after RTx. Other factors, such as gender, chronologic and bone age at RTx, primary renal disease, duration of initial dialysis, repeat RTx, and target height SD score for chronologic age, whether evaluated singly or simultaneously with other significant factors, appeared to have no significant influence on post-RTx growth. Thus, 70% of the prepubertal children do not experience appreciable catch-up growth during the first 2 y after RTx. Optimization of pretransplant height appears very important. Immunosuppressive treatment with cyclosporin therapy in combination with a minimal dose of alternate-day prednisone would then result in optimal post-transplant growth, particularly if the GFR remains above 50 mL/min/1.73 m2).

Azathioprine

A practical approach to the detection of androgen receptor gene mutations and pedigree analysis in families with x-linked androgen insensitivity.

Androgen insensitivity syndrome (AIS) is an X-linked disorder in which defects in the androgen receptor gene have prevented the normal development of both internal and external male structures in 46,XY individuals. This survey reports the analysis of 11 AIS subjects. The androgen receptor gene of these subjects was analyzed using polymerase chain reaction (PCR)-single-strand conformation polymorphism analysis and sequencing or sequencing of PCR-amplified androgen receptor gene fragments alone. In total, 10 single base changes and one partial gene deletion were detected. Seven single base changes resulted in an amino acid change, one resulted in the introduction of a premature stop codon, one event represented a single base insertion resulting in a frame-shift, and one single base change affected a donor splice site. The androgen receptor protein in genital skin fibroblasts from several patients was studied with respect to molecular mass after immunoprecipitation and SDS-PAGE. Two patients expressed a truncated receptor protein in agreement with the established genomic mutation. Pedigree analysis was performed to identify possible carriers for the syndrome in families of AIS patients using single-strand conformation polymorphism and restriction site analysis of PCR products. In one case, the polymorphic (CAG)n(CAA) repeat in exon 1 encoding a polyglutamine stretch was used to identify the mutant allele in a family with X-linked partial androgen insensitivity before the identification of the actual genomic mutation. PCR-single-strand conformation polymorphism analysis proved to be a fast and reliable technique to screen for androgen receptor gene mutations and to study the androgen receptor gene of family members of AIS-affected individuals.

Base Sequence

Final height and its predictive factors after renal transplantation in childhood.

A retrospective study is reported assessing final height (FH) and its predictive factors in 52 patients (31 male, 21 female) who underwent renal transplantation (RTx) before the age of 15 y. They received prednisone daily or on alternate days as well as azathioprine. The study period covered 20 y. FH remained below the third height percentile [height standard deviation score for chronologic age (hSDSCA) < -1.88] for most of these patients (77% males, 71% females). Median (range) FH was 165.0 (143.0-176.8) cm in males and 153.0 (135.0-168.4) cm in females. Median difference between FH and target height was 15.0 and 15.4 cm for males and females, respectively. For both sexes, the median hSDSCA was already below -1.88 at the start of the first hemodialysis, after which it decreased significantly until the first RTx. After RTx, there was no significant improvement of hSDSCA. The predictive factors for FH were determined by evaluating various factors simultaneous in a multiple regression analysis. This analysis provided a regression equation for predicting FH. A higher hSDSCA at the time of the first RTx and alternate-day versus daily prednisone therapy both had a significantly positive influence on FH, whereas a longer duration of reduced GFR (< 50 mL/min/1.73 m2) had a significantly negative effect on FH. Other factors such as age or bone age at first RTx, primary renal disease, duration of initial dialysis, repeat RTx, and the cumulative dose of prednisone did not influence FH significantly. In conclusion, 71-77% of patients that received their first renal transplant before the age of 15 ended up with severely short adult stature. Optimization of the hSDSCA at first RTx appears very important. Long-term administration of prednisone on alternate days would then result in optimal FH, particularly if the GFR remains above 50 mL/min/1.73 m2.

Adolescent

Double blind trial comparing the effects of two doses of growth hormone in prepubertal patients with chronic renal insufficiency.

Growth retardation is a major problem for children with chronic renal insufficiency (CRI). Recent studies have convincingly shown that recombinant human GH accelerates growth significantly, but the optimal GH dose with regard to long term growth response and safety has not yet been established. GH therapy was given to 23 prepubertal children (18 boys and 5 girls; mean +/- SD age, 7.1 +/- 3.6 yr; range, 1.6-14.1) with CRI and severe growth retardation in a double blind, dose-response trial. Patients were randomly assigned to either 2 or 4 IU GH/m2.day for 2.5 yr. During the first 6 months, there were comparable and significant increases in height velocity SD score for chronological age with both doses (P < 0.001). However, during the ensuing 2 yr, the higher GH dose induced a significantly greater improvement in height velocity SD score for chronological age than 2 IU GH. Catch-up growth was only sustained for 2.5 yr with 4 IU. In contrast, catch-up growth ceased after 6 months with 2 IU. Neither 2 nor 4 IU GH resulted in accelerated bone maturation during 2.5 yr of therapy. There was a significant increase in plasma insulin-like growth factor-I (IGF-I) levels with either dose, but significantly more so with 4 IU. Plasma IGF-II levels only increased significantly with 4 IU. The pretreatment elevation of IGF-binding protein-1 (IGFBP-1) levels decreased by 50% during the first study year with the higher GH dose, whereas there was no decrease with 2 IU. The elevated pretreatment IGFBP-3 levels increased comparably and significantly with either GH dose. Interestingly, only 4 IU resulted in a significantly greater increase in IGF-I than in IGFBP-3 levels. Regardless of GH dose, there was an insignificant decrease in fructosamine levels, whereas lipid and parathyroid concentrations remained constant. Renal function deterioration did not accelerate. GH therapy with 4 IU/m2.day induced and maintained catch-up growth during 2.5 yr in children with CRI without evidence of adverse effects. Bone maturation did not accelerate. This suggests that this higher GH dose may be beneficial for children with severe growth retardation secondary to CRI.

Adolescent

Difference in biological effects between insulin-like growth factor binding protein 1 and 3.

Insulin-like growth factor binding proteins 1 and 3 are essentially known as regulators of IGF bioactivity. However, we previously showed that IGFBP-3 was able, in chick embryo fibroblast (CEF), to 100% inhibit DNA synthesis stimulated by calf serum, while the maximal inhibition found with IGFBP-1 was 60%, suggesting a difference between the two IGFBPs in their biological functions. Results of the present work agree with this assumption: (a) Recombinant human IGFBP-3, like rat IGFBP-3, was able to 100% inhibit DNA synthesis stimulation induced by human serum, while this stimulation was 75% decreased by IGFBP-1. However, the most striking difference was observed when the effects of the two IGFBPs were compared for stimulation induced by a serum growth factor (SGF) fraction depleted in IGFs. Stimulation induced by the SFG fraction was more significantly decreased (p < 0.001) by IGFBP-3 than by IGFBP-1. The mean percent inhibition +/- SEM was 67.1 +/- 2.5 in the presence of IGFBP-3 (200 ng/ml) and 29.3 +/- 2.7 and 34.2 +/- 4 in the presence of 200 and 400 ng/ml IGFBP-1 respectively. Inhibition by 200 ng/ml IGFBP-1 and inhibition by 6 ng/ml IGFBP-3 were additive. However, inhibition by IGFBP-3 and that by IGFBP-1 were no longer additive at high concentrations of IGFBP-3, which might thus replace IGFBP-1. (b) FGF stimulation of CEF was similarly inhibition (65% and 70%) by IGFBP-1 and IGFBP-3. (c) TGF beta stimulation of CEF was more strongly decreased by IGFBP-3 (90%) than by IGFB-1 (60%).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals