Growth hormone insensitivity syndromes: a preliminary report on changes in insulin-like growth factors and their binding proteins during treatment with recombinant insulin-like growth factor I

Serum levels of insulin-like growth factor (IGF) binding proteins (IGFBPs) 1, 2 and 3 were studied by radioimmunoassay in 29 patients with growth hormone (GH) insensitivity syndromes (GHIS) before and during treatment with IGF-I. As in normal subjects, there was a highly significant correlation between IGFs and IGFBP-3 but not between IGFs and the other binding proteins, though IGFBP-3 represented only about one-third of the total IGFBP concentration. In 6 patients with GH deficiency and in 5 patients with GHIS, the pharmacokinetic profile of IGF-I after a single injection was strongly dependent on the IGFBP-3 concentration. A slight but significant increase in IGFBP-3 was observed coincident with the IGF-I peak, whereas IGFBP-2 increased after a delay of about 10 hours. In the patients with GHIS, chronic IGF-I treatment, with twice-daily injections for 6 months, caused a significant steady decline of IGF-II and an increase in IGFBP-2, but had no effect on IGFBP-1 and IGFBP-3 levels. During IGF-I treatment, an inverse relationship between baseline IGF-I and GH levels was observed. The data suggest that total IGF-I and IGF-IL serum levels are determined mainly by IGFBP-3, even in extreme situations such as GHIS, while other IGFBPs are less important. The IGFBP-3 concentration seems to be a major regulator of the pharmacokinetics of exogenous IGF-I, which, in turn, influences IGFBP-3 levels. This effect of IGF-I on IGFBP-3 is not through induction of IGFBP-3 synthesis, but possibly by reduction of IGFBP-3 clearance. Finally, IGF-I administration suppresses GH secretion.     

Short-term increments of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 predict the growth response to growth hormone (GH) therapy in GH-sensitive children

The present study included a cohort of 42 children aged between 1.7 and 15.4 years, who presented with short stature and growth failure. Basal and generated serum levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3), measured in an IGF generation test following four or seven daily injections of growth hormone (GH), 0.1 IU/kg (0.033 mg/kg), were analysed in these patients. The growth response to 1 year of GH treatment, 0.6 IU/kg/week (0.2 mg/kg/week), was also investigated. Median height velocity of these patients increased from -1.6 SDS (range, -4.6 to -0.3 SDS) to 3.3 SDS (range, -0.2 to 7.1 SDS) after 1 year of GH treatment, and median height SDS increased by 0.7 SDS (range, 0.1 to 2.2 SDS). Strong correlations were observed between basal and generated IGF-I and IGFBP-3 levels. The increase in IGFBP-3 levels in response to GH in the generation test was a strong predictor of the growth response to GH therapy. All the patients in the present study could be differentiated from patients with GH insensitivity syndrome (GHIS) using the criteria of a diagnostic scoring system for GHIS. The most valuable parameters were the increases in IGF-I and IGFBP-3 levels in the generation test, which excluded 95.2% of the patients from a diagnosis of GHIS.     

Short-term increments of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 predict the growth response to growth hormone (GH) therapy in GH-sensitive children

Schwarze CP, Wollmann HA, Binder G, Ranke MB. Short-term increments of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 predict the growth response to growth hormone (GH) therapy in GH-sensitive children. Acta Paediatr 1999; Suppl 428:200-8. Stockholm. ISSN 0803-5326
The present study included a cohort of 42 children aged between 1.7 and 15.4 years, who presented with short stature and growth failure. Basal and generated serum levels of insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3), measured in an IGF generation test following four or seven daily injections of growth hormone (GH), 0.1 IU/kg (0.033 mg/kg), were analysed in these patients. The growth response to 1 year of GH treatment, 0.6 IU/kg/week (0.2 mg/kg/week), was also investigated. Median height velocity of these patients increased from-1.6 SDS (range, -4.6 to -0.3 SDS) to 3.3 SDS (range, -0.2 to 7.1 SDS) after 1 year of GH treatment, and median height SDS increased by 0.7 SDS (range, 0.1 to 2.2 SDS). Strong correlations were observed between basal and generated IGF-I and IGFBP-3 levels. The increase in IGEBP-3 levels in response to GH in the generation test was a strong predictor of the growth response to GH therapy. All the patients in the present study could be differentiated from patients with GH insensitivity syndrome (GHIS) using the criteria of a diagnostic scoring system for GHIS. The most valuable parameters were the increases in IGF-I and IGFBP-3 levels in the generation test, which excluded 95.2% of the patients from a diagnosis of GHIS. □ Growth hormone treatment, insulin-like growth factor I, insulin-like growth factor binding protein-3, insulin-like growth factor generation test     

The insulin-like growth factor I generation test in the investigation of short stature

Genotypic and phenotypic heterogeneity in patients with growth hormone (GH) insensitivity syndrome suggests that partial defects exist in the GH receptor. The insulin-like growth factor I (IGF-I) generation test was assessed as a means of identifying partial GH receptor defects in a heterogeneous group of 22 prepubertal children with short stature. In a subgroup of nine patients with peak GH levels of 63.7 ± 3.7 mU/l during a glucagon tolerance test, the response to the IGF-I generation test was no different from that for the group as a whole (peak GH, 43.3 ± 4.5 mU/l), despite the fact that this subgroup exhibited a negative relationship between height SDS and peak GH and a positive relationship between height SDS and IGF binding protein-3. This preliminary study therefore suggests that the IGF-I generation test in its present form will not be useful as a primary screening test for partial GH insensitivity. Despite this, the IGF-I generation test has been extremely useful in the confirmation of the diagnosis of GHIS and may therefore also prove useful in the confirmation of partial defects in the GH receptor. A subgroup of short children with peak GH levels above 40 mU/l had some characteristics of partial GH receptor deficiency. These children, to whom GH therapy would not normally be given, may respond better to recombinant human IGF-I.     

Insulin-Like Growth Factors (IGFs) and IGF Binding Proteins in Chronic Renal Failure: Evidence for Reduced Secretion of IGFs

To test the hypothesis that growth hormone (GH) insensitivity is responsible, amongst other mechanisms, for impaired growth in uraemic children, insulin-like growth factor I (IGF-I), IGF-II, IGF binding protein-1 (1GFBP-1), IGFBP-2 and IGFBP-3 were measured by radioimmunoassay in normal control children, in patients with end-stage renal failure (n = 51) and in patients with preterminal chronic renal failure (n = 11) and the production rate of IGF was calculated. A unique pattern of normal IGF-I and IGF-II levels and markedly increased levels of all three IGFBPs was present in uraemia. Measurement of free IGF-II binding capacity, and affinity cross-linking experiments showed that the excess immuno-reactive IGFBP was able to bind IGFs. To explain the excess of unoccupied IGF binding sites in uraemia, a mathematical model was developed which describes the production of IGFs and their interaction with IGFBP. Calculations of IGF secretion rates suggested that production of IGF is two orders of magnitude lower in uraemic children than in control children, despite normal GH secretion. It is concluded that in uraemia there is a relative GH insensitivity with respect to IGF production.     

Is there heterozygote expression of growth hormone receptor deficiency?

Expression of heterozygosity for the defect in the growth hormone (GH) receptor has been proposed to be reflected in stature, and in GH binding protein (GHBP) and insulin-like growth factor I (IGF-I) levels in parents and other relatives of patients with GH receptor deficiency (GHRD; Laron syndrome). The Ecuadorean population with GHRD, in which heterozygosity can be accurately determined in clinically unaffected relatives of probands, offers a unique opportunity to consider this issue. It has previously been demonstrated that 17 parents heterozygous for the Ecuadorean mutation of the GH receptor differed little in biochemical measures (GHBP, IGF-I, IGF-II, IGFBP-2 and IGFBP-3) from Ecuadorean controls. Mean height SDS of 24 non-carrier siblings (−1.3 ± 0.95 SD) and 41 heterozygote siblings or offspring of probands (−1.8 ± 1.15) did not differ significantly ( p = 0.08). Thus, although there may be slight heterozygote expression of the defective gene for the GH receptor, there is no rationale for counselling based on such minimal variation.     

Relationship of insulin-like growth factor-I, insulin-like growth factor binding protein-3, insulin, growth hormone in cord blood and maternal factors with birth height and birthweight

BACKGROUND: To determine whether the following factors are related to birthweight or birth height, we measured insulin-like growth factor (IGF)-I, insulin-like growth factor binding protein (IGFBP)-3, insulin and growth hormone (GH) levels in cord blood and also observed the relationship between birthweight, birth height and maternal factors. METHODS: One hundred and ninety-four cord bloods were collected, 106 from males and 88 from females. Three newborns were small for gestational age (SGA), 168 were appropriate (AGA) and 23 were large (LGA); 21 newborns were preterm and 172 were term. RESULTS: Levels of IGF-I and IGFBP-3, measured by enzyme-linked immunosorbent assay, were significantly lower in preterm babies (35.3 +/- 15.1 and 1025.6 +/- 562.8 ng/mL, respectively) than in term babies (61.6 +/- 39.5 and 1252.6 +/- 403.2 ng/mL, respectively; P < 0.01), but neither insulin nor GH levels, measured by radioimmunoassay, showed any significant difference between the two groups (P > 0.05). Among term babies, IGF-I and IGFBP-3 levels were significantly higher in the LGA group (96.1 +/- 34.1 and 1544.7 +/- 418.1 ng/mL, respectively) than in the AGA group (56.4 +/- 37.6 and 1212.8 +/- 383.4 ng/mL, respectively; P < 0.01). Levels of IGF-I and IGFBP-3 showed significant correlation with birthweight and length, respectively (P < 0.01), although GH and insulin levels did not (P > 0.05). There was a significant correlation between IGF-I and IGFBP-3 levels (P < 0.01, r = 0.64), but IGF-I and IGFBP-3 levels showed no relationship with GH or insulin levels. Birthweight correlated significantly with prepartum maternal weight, maternal weight gain and maternal height (P < 0.05), but birth length correlated significantly only with maternal height (P < 0.05). CONCLUSIONS: Our results suggest that fetal growth depends on fetal levels of IGF-I and IGFBP-3 and maternal factors, not on insulin or GH. Levels of IGF-I and IGFBP-3 may not be regulated by insulin alone, but by the complex interactions between several factors, such as insulin, GH and maternal factors.     

Effects of insulin-like growth factor I treatment on the molecular distribution of insulin-like growth factors among different binding proteins

The molecular distribution of insulin-like growth factor I (IGF-I) and IGF-II among the IGF binding proteins (IGFBPs) was studied before and during IGF-I therapy in Ecuadorean adults with growth hormone receptor deficiency (GHRD). Of the total circulating IGF-I and IGF-II, 70% was carried by the 150 kDa complex in normal subjects, while in patients with GHRD, 50% of serum IGF-I, but only 30–35% of serum IGF-II, was measured within the 150 kDa IGFBP-3 region. Administration of IGF-I altered the concentration of IGF-I and IGF-II, although the percentage of total IGF measured within each IGFBP region was not affected, as the increase in IGF-I and the decrease in IGF-II were proportional. Similarly, serum concentrations of IGFBP-3 and the acid-labile subunit, measured by radioimmunoassay, were unaltered. Thus, administration of IGF-I to patients with GHRD was unable to correct the aberrant distribution of IGFs among the IGFBPs.     

Insulin-like growth factor binding protein-3 proteolysis and growth of athyreotic infants in the first weeks of life

To gain a better understanding of the growth of athyreotic newborns in the first weeks of life, we evaluated auxological parameters and determined the serum levels of growth hormone (GH), insulin-like growth factor I (IGF-I) and free IGF-I, and IGF-binding protein-3 (IGFBP-3) in 15 hypothyroid infants (10 females) at a mean age of 25 d of life, immediately before the beginning of L-thyroxine therapy, and at 3 and 6 mo of life. Fourteen normal infants (9 females) of the same age were studied as controls. IGFBP-3 proteolytic activity was evaluated in 8 patients and in 8 controls at 25 d and 6 mo of life. There was no significant difference concerning weight and length between the patients and controls at birth, 25 d, 3 and 6 mo of life. The blood GH, IGF-I and IGFBP-3 levels were significantly lower in patients at diagnosis than in controls of the same age (p < 0.01 for all parameters), as well as IGFBP-3 studied by Western blotting. At diagnosis, the patients' free IGF-I level was within the control range, but the free IGF-I percentage of total IGF-I was higher than in the controls (p < 0.01). IGFBP-3 proteolytic activity was found to be greater in the patients (p < 0.01). At 6 mo of life, after therapy, none of these parameters was different from those of the controls. CONCLUSION: Increased IGFBP-3 proteolytic activity in our patients at diagnosis, favouring IGF-I bioavailability, could account for normal free IGF-I levels and in turn for their normal growth pattern during the first weeks of life and before the start of treatment.     

Relationship between phenotype and genotype in growth hormone insensitivity syndrome

Woods KA, Clark AJL, Amselem S, Savage MO. Relationship between phenotype and genotype in growth hormone insensitivity syndrome. Acta Pædiatr 1999; Suppl 428: 158–62. Stockholm. ISSN 0803–5326
Growth hormone insensitivity syndrome (GHIS) of genetic origin is associated with many different mutations of the growth hormone receptor (GHR) gene and a recently described genetic defect of the insulin-like growth factor I (IGF-I) gene. Phenotypic and biochemical features were examined in a cohort of 82 patients with GHIS from 23 countries. The mean age of these patients was 8.3 years, their mean height SDS was -6.09 and their median IGF-binding protein-3 (IGFBP-3) SDS was -8.5. In total, 19 of the 82 patients (23%) were growth hormone-binding protein (GHBP)-positive (> 10%). The mean heights in GHBP-negative and GHBP-positive patients were -6.45 SDS and -4.89 SDS, respectively ( p < 0.001). Sixteen different GHR gene mutations were identified in 27 patients with GHIS. All of these patients had homozygous mutations, except one who had a compound heterozygous mutation. There was no relationship between the type or site within the GHR gene of the mutation and the height SDS or IGFBP-3 SDS of the patients. GHIS is associated with a wide variation in the severity of clinical and biochemical phenotypes. This variation cannot clearly be accounted for by defects in the GHR gene alone. Other genes or environmental factors must contribute to the control of growth in patients with GHIS. □ Growth hormone, growth hormone insensitivity, growth hormone receptor gene     

Relationship between phenotype and genotype in growth hormone insensitivity syndrome

Growth hormone insensitivity syndrome (GHIS) of genetic origin is associated with many different mutations of the growth hormone receptor (GHR) gene and a recently described genetic defect of the insulin-like growth factor I (IGF-I) gene. Phenotypic and biochemical features were examined in a cohort of 82 patients with GHIS from 23 countries. The mean age of these patients was 8.3 years, their mean height SDS was -6.09 and their median IGF-binding protein-3 (IGFBP-3) SDS was -8.5. In total, 19 of the 82 patients (23%) were growth hormone-binding protein (GHBP)-positive (> 10%). The mean heights in GHBP-negative and GHBP-positive patients were -6.45 SDS and -4.89 SDS, respectively (p < 0.001). Sixteen different GHR gene mutations were identified in 27 patients with GHIS. All of these patients had homozygous mutations, except one who had a compound heterozygous mutation. There was no relationship between the type or site within the GHR gene of the mutation and the height SDS or IGFBP-3 SDS of the patients. GHIS is associated with a wide variation in the severity of clinical and biochemical phenotypes. This variation cannot clearly be accounted for by defects in the GHR gene alone. Other genes or environmental factors must contribute to the control of growth in patients with GHIS.     

Noonan's Syndrome: Abnormalities of the Growth Hormone/IGF-I Axis and the Response to Treatment with Human Biosynthetic Growth Hormone

ABSTRACT. Auxological and endocrine data from 6 children (3 male, 3 female) aged 8.5–12.8 years with Noonan's syndrome and the results of treatment with human biosynthetic growth hormone (hGH) are presented. All the children were short (Ht SDS -3.5 to -2.3) and height velocity SDS ranged between -1.76 and +0.03. The maximum plasma growth hormone (GH) response to standard provocation tests ranged from 17 to 52 mU/l, yet, plasma insulin-like growth factor I (IGF-I) concentrations were low or low normal. Overnight GH secretory profiles were normal in all but 2 children who had disordered pulsatility with high trough concentrations. In 5 children who have completed one year of hGH therapy mean height velocity increased from 4.8 to 7.4 cm/year and the height velocity SDS ranged from +0.2 to +3.75. This improvement was associated with an increase in plasma IGF-I in three subjects. These results suggest that a defect of the GH/IGF-I axis may be present in some children with Noonan's syndrome and hGH therapy may have a role in the management of the short stature in these children.     

Evaluation of insulin-like growth factor (IGF)-I and IGF binding protein-3 generation test in short stature

BACKGROUND: Differentiation between growth hormone deficiency (GHD) and idiopathic short stature (ISS) based on GH tests and basal IGF-I and IGFBP-3 levels may be difficult. The aim of this study was to evaluate the role of pharmacological GH tests, IGF-I and IGFBP-3 generation test and height velocity off-treatment in the evaluation of GHD and ISS. METHODS: Thirty-three (17 M, 16 F) prepubertal short (height SDS < -2) children were divided into two groups: Group 1 (n = 19) with peak GH level <10 tg/l (GHD) and Group 2 (n = 14) GH > or =10 microg/l in two sex steroid primed pharmacological GH tests. Having excluded other diagnoses, Group 2 was regarded as having ISS. The generation test was performed concomitantly (0.1 IU/kg GH s.c. for 4 days) with IGF-I and IGFBP-3 measured on the 4th day in both groups. The patients were followed for a year for height velocity (HV). RESULTS: Group 1 and 2 had comparable height SDS (-2.3 +/- 0.4 and -2.3 +/- 0.3) at comparable ages (7.8 +/- 2.8 and 7.0 +/- 2.7 yr). Although the deltaIGF-I response was low (<2.0 nmol/l 115 ng/ ml]) in seven (37%) children in the GHD group, all GHD patients with low height velocity had adequate (> or =14 nmol/I [400 ng/ml]) deltaIGFBP-3 response. deltaIGFBP-3 in the generation test showed a negative correlation with HV (p = 0.021, r = -0.570) and also with basal IGFBP-3 (p <0.001, r = -0.743) in the GHD group. In the ISS group, deltaIGF-I and deltaIGFBP-3 responses were low in 31% and 7%, respectively, and the correlation between basal IGF-I, IGFBP-3 and HV and between delta values in the generation test were significantly positive, pointing to a difference in the growth response of these children. CONCLUSION: In the GHD group, based on pharmacological tests, an adequate deltaIGFBP-3 response in the generation test predicts poor height velocity at follow up and thus strengthens the diagnosis of true GHD.     

Insulin: the other anabolic hormone of puberty

To determine the effect of puberty on isulin action, we used the euglycaemic-hyperinsulinaemic clamp technique in combination with stable isotopes and indirect calorimetry in lean preadolescents, adolescents and; adults. These studies indicated that the insulin resistance induced by normal puberty alters glucose metabolism but is insufficient to adversely affect insulin-stimulated protein metabolism or to inhibit lipolysis. Using the hyperglycaemic clamp technique, we evaluated the impact of the insulin resistance on insulin secretion in pre-adolescents, adolescents and young adults. These studies revealed that the insulin and C-peptide responses to a standardized intravenous hyperglycaemic stimulus were two-to threefold greater in adolescents than in preadolescent children and adults. As growth hormone (GH), insulin-like growth factor 1 (IGF-1) and insulin levels normally peak during puberty, we examined the influence of insulin on IGF-1 regulation by measuring basal GH, total and free IGF-I, and IGF binding protein (IGFBP) levels in lean adolescents and young adults. During the clamp studies, the adolescents exhibited low levels of IGFBP-1 and -2 as well as a reduced insulin-induced suppression of IGFBP-1, compared with lean adults. Thus, we postulate that the insulin resistance of puberty induces compensatory hyperinsulinaemia, which in turn suppresses circulating levels of IGFBP-1, which in turn leads to increased levels of free IGF-I.     

Insulin-like growth factors in childhood-onset Gaucher disease

There is a high prevalence of growth retardation in children with type 1 Gaucher disease. The cause of this poor growth is not yet known; however, studies have shown acceleration of growth with enzyme replacement therapy (ERT). IGF are recognized as important determinants of somatic growth. It has been proven that chronic diseases with liver involvement might cause IGF deficiency. The aim of this study was to assess the IGF system in patients with childhood-onset Gaucher disease, before and after ERT, and its association with other clinical and analytical parameters. Twenty-two patients with type I Gaucher disease were included. The diagnosis was established before 14 y of age in all patients. Baseline determinations of total IGF-I, free IGF-I, and IGF binding protein 3 (IGFBP-3) were obtained in 19 patients before starting ERT at a mean age of 13.8 +/- 11.2 y. A Spearman test was performed to establish the association with other clinical and analytical parameters. In a group of 13 patients receiving IGF, changes were evaluated during the initial 2 y of treatment. A Wilcoxon test was performed for the statistical analysis. Total IGF-I, free IGF-I, and IGFBP-3 were expressed as SD scores (SDS). We found low levels of IGF and its binding proteins before ERT. A significant association was found between the total IGF-I SDS before treatment and the age-adjusted severity score index: r = -0.62, p < 0.05. Total IGF-I and IGFBP-3 SDS correlated negatively with the presence of the L444P mutation (r = -0.53 and -0.5, respectively, p < 0.05). Height SDS correlated with total IGF-I and IGFBP-3 SDS in eight children (r = 0.84 and 0.78, respectively, p < 0.05). Total IGF-I SDS increased from -1.8 +/- 0.8 to -0.8 +/- 1.4 (p = 0.005) and free IGF-I increased from -1.2 +/- 1 to 1.1 +/- 2.1 after 12 +/- 6.8 mo (p = 0.011) of ERT. IGFBP-3 SDS increased from -1.3 +/- 0.6 to -0.2 +/- 1.2 (p = 0.012) after 12 +/- 4.5 mo of ERT. Type 1 Gaucher disease is associated with low levels of IGF and its binding proteins, which could be a consequence of liver involvement. Total IGF-I deficiency is associated with the severity of the illness. Growth retardation in pediatric patients with Gaucher disease is related to the alterations in IGF axis. Total IGF-I and IGFBP-3 are the two parameters that better correlate with height before treatment. ERT results in significant increase of total IGF-I, free IGF-I, and IGFBP-3 during the first year of treatment.     

Effect of zinc supplementation on growth hormone secretion, IGF-I, IGFBP-3, somatomedin generation, alkaline phosphatase, osteocalcin and growth in prepubertal children with idiopathic short stature

Controversy exists about the effect of zinc on growth and the GH-IGF system. Zinc supplementation has been shown to stimulate linear growth in zinc-deficient children. However the mechanism of this effect has not been well characterized. Furthermore, the effect of zinc supplementation on non-zinc-deficient short children is unknown. We investigated the effect of zinc supplementation on endogenous GH secretion, serum IGF-I and IGFBP-3 concentrations, IGF-I and IGFBP-3 generation in response to exogenous GH, bone formation markers, and linear growth of non-zinc-deficient children with idiopathic short stature. We analyzed prospectively serum zinc, IGF-I, IGFBP-3, alkaline phosphatase, osteocalcin, and GH response to clonidine test, and performed a somatomedin generation test before and 6 weeks after zinc supplementation in 22 (16 M, 6 F) prepubertal children with idiopathic short stature. Serum IGF-I increased from 67.4+/-70.6 to 98.2+/-77.3 ng/ml (p <0.001), IGFBP-3 from 2326+/-770 to 2758+/-826 ng/ml (p <0.001), alkaline phosphatase from 525+/-136 to 666+/-197 U/l (p <0.0001), and osteocalcin from 16.8+/-10.6 to 25.8+/-12.8 ng/ml (p <0.05) after zinc supplementation despite there being no difference in GH response to clonidine after zinc supplementation (peak GH 11.6+/-6.9 vs 13.4+/-7.8 ng/ml, GH area under the curve during clonidine test 689+/-395 vs 761+/-468, NS). Percent change in IGF-I and IGFBP-3 during the somatomedin generation test was not significantly affected by zinc supplementation (118% vs 136% and 57% vs 44%, respectively). There was no significant correlation between percentage increase in zinc levels and percentage increase in parameters tested. Height SDS or weight SDS did not improve significantly in 17 patients who continued on zinc supplementation for at least 6 months (6-12 months) (-2.59 vs -2.53 SDS and -1.80 vs -1.67 SDS, respectively). Zinc supplementation increased basal IGF-I, IGFBP-3, alkaline phosphatase and osteocalcin without changing GH response to clonidine. Zinc supplementation did not affect sensitivity to exogenous GH as tested by IGF-I and IGFBP-3 generation test. These results suggest a direct stimulatory effect of zinc on serum IGF-IGFBP-3, alkaline phosphatase and osteocalcin. Despite improvements in the above parameters, zinc supplementation to children with idiopathic short stature with normal serum zinc levels did not significantly change height or weight SDS during 6-12 months follow-up.     

一个Laron 综合征家系患者临床特点和生长激素受体基因突变分析

Laron 综合征是一种常染色体隐性遗传病,生长激素受体（GHR）基因缺陷是导致Laron 综合征的主要病因。Laron 综合征主要临床特征为生后严重的生长落后伴特殊面容,血生化特点为高生长激素(GH)、低胰岛素样生长因子- (IGF-I) 和低胰岛素样生长因子结合蛋白- (IGFBP-3)。该研究报道一家系2例Laron 综合征患者的临床特点及GHR基因突变。这两个病人为同胞姐弟。弟弟8岁,身高80.0 cm (-8.2 SDS),姐姐11岁,身高96.6 cm (-6.8 SDS)。他们出生体重和身长无特殊,自生后出现生长落后,身高明显落后于同龄正常儿童,并均呈现了典型Laron 综合征外貌特征：身材矮、肥胖、前额突出、大眼睛、塌鼻梁、头发稀软。这两个病人空腹血清GH值均明显高于正常儿童,空腹血清IGF-I明显低于同年龄同性别正常儿童,血浆IGFBP-3和生长激素结合蛋白（GHBP）低于检测线。其中1例（8岁男孩）胰岛素和可乐定刺激后GH峰值大于350 ng/mL,给予重组人生长激素治疗1年,身高由治疗前的80.0 cm 增加至83.3 cm。GHR基因序列测定结果显示2例患者均存在外显子4上第65位氨基酸的纯合突变S65H(TCA → CCA),为新发现的突变。Laron 综合征患者存在特殊的面貌特征,结合血GH、IGF-I、IGFBP-3和GHBP测定可以明确诊断。GHR基因外显子4上S65H突变可能是这两位Laron 综合征患者的致病原因。［中国当代儿科杂志,2007,9（4）：335-338］     

Children with Craniopharyngioma

ABSTRACT. Pre- and postoperative growth was analyzed in 22 children with craniopharyngioma. In 19 children a growth failure preceded the diagnosis by a mean of 4 years. Six children were obese preoperatively. During the first 3 postoperative months relative weight increased 7gt;10% in 14/21 children (there was one surgical death). One year after surgery 13/21 were obese. Neither the size of the tumor nor the mode of surgery was decisive in the development of the obesity. Serum insulin and insulin-like growth factor I (IGF-I) were assessed in four children with growth hormone deficiency (GHD) who, after surgery for craniopharyngioma, were growing normally without GH substitution. One of them was normal in weight and had normal insulin and IGF-I levels; the others were obese and had supranormal insulin and subnormal IGF-I levels. One of the four and two other children with unsubstituted GHD reached final height SDS -0.8, -2.0 and -2.4. One child with normal postoperative GH response reached final height SDS -0.7. Final height SDS ≧-2.5 was gained with GH substitution by 6/11 children. It was >2.0 SD below the height SDS expected from the heights of the parents in 7/11. An adequate monitoring of children's growth would lead to earlier diagnosis and probably better outcome.     

Evaluation of clinical and laboratory parameters during 2 years of growth hormone treatment in prepubertal children with chronic renal failure

Twelve prepubertal children with chronic renal failure (CRF) were treated with human growth hormone (GH) (1.2 IU/kg/week) for 2 years. High doses of GH clearly increased growth velocity, from 3.8±1.3 to 9.6±1.5 (P=0.0001) and 6.9 ±0.8 cm/year (P=0.0001) after the 1 st and 2nd year of treatment, respectively, leading to a mean height gain of 1.4 SD. During the 1 st year of treatment the height increment, expressed in SDS, correlated negatively with chronological age (P=0.003). Basal insulin-like growth factor 1 (IGF 1) levels were normal or elevated (7/12 patients) and correlated positively with the overnight integrated GH concentration (r=0.68,P<0.001). Basal insulin-like growth factor binding protein 3 (IGF-BP3) levels were elevated in 8/12 patients. GH induced a significant increase in IGF 1 and IGF-BP3 levels; IGF 1 peaked after 6 months (when growth velocity was optimal) and IGF-BP3 peaked after 12 months. The mean glomerular filtration rate, measured by inulin clearance and corrected for body surface area, fell after the 1st year of treatment, and significantly so at the end of the 2nd year (P=0.02).     

Novel growth hormone receptor mutation in a Chinese patient with Laron syndrome

Laron syndrome, growth hormone (GH) insensitivity syndrome, caused by a mutation of the GH receptor (GHR) gene, is extremely rare in the Chinese population. We report a Chinese girl diagnosed with Laron syndrome at age 1.9 years with height -4.9 SDS, basal GH 344 mIU/ml, IGF-I <12 ng/ml, IGFBP-3 <0.2 mg/ml, and undetectable GHBP. A novel mutation of the GHR, not previously described, was identified at the donor splice site of intron 6.