Growth in children with X-linked hypophosphataemic rickets

Currently, X-linked hypophosphataemic rickets (XLHR) is most commonly treated with a combination of phosphate and vitamin D, but there is conflicting evidence about the effects of this treatment on linear growth. In all, 25 patients with XLHR (current age range, 4.1–22.1 years; median, 8.2 years) were studied to determine whether there was any improvement in height SDS during treatment. The duration of therapy was 2.9–15.0 years (median, 5.7 years). Measurements before the age of 2 years or after the onset of puberty were excluded to remove the effects of measurement difficulties in small infants and of variation in pubertal timing. The growth of these patients was compared with a similar group of untreated historical controls. Patients treated with calcitriol and phosphate for at least 2 years before the onset of puberty (n = 22) had a significantly better mean height SDS than the historical controls (-1.23 compared with —2.05 for the historical controls; p = 0.02). Among patients treated with calcitriol and phosphate for at least 2 years (n = 21), the change in height SDS had a positive correlation with the duration of therapy ( r = 0.51; p = 0.02). The growth of children with XLHR treated with combination therapy was thus significantly better than that of historical controls.     

Growth hormone secretion in children and adolescents with familial tall stature

Sixty-five patients (22 boys and 43 girls) presenting with familial tall stature were investigated with regard to growth hormone (GH) secretion, both physiological and after stimulation with thyrotropin releasing hormone (TRH) and growth hormone relasing hormone (GHRH). Plasma insulin-like growth factor-I (IGF-I) was also measured. Two groups of patients were distinguished according to their physiological secretion of GH: a high secretory group (n=49) with a mean 24 h integrated concentration of GH (IC-GH) of 5.4±2.3 g/l per minute and a large number of peaks (5.1±1.6 in 24 h), and a low secretory group (n=16) with a mean 24 h IC-GH of 2.1±0.5 g/l per minute and few peaks (3.3±1.3 in 24h). Plasma IGF-I levels and GH peak values after the TRH test were significantly higher in the high secretory group. These results indicate that familial tall stature is the consequence either of hypersecretion of GH or of hypersensivity to this hormone (IGF-I levels being normal in spite of low GH levels).     

Growth hormone deficiency in HIV-infected children following successful treatment with highly active antiretroviral therapy

Growth failure is common in children with untreated HIV, although growth hormone (GH) deficiency is rare. Treatment with highly active antiretroviral therapy usually results in resumption of normal growth. We report the cases of 2 children with growth failure despite stable full suppression of viremia who were found to be GH deficient.     

Calcium metabolism and growth during early treatment of children with X-linked hypophosphataemic rickets

To evaluate the effect of early treatment on calcium metabolism and growth of infants with X-linked hypophosphataemic rickets (XLH), we enrolled eight infants (one boy) with XLH in a prospective study before and during combined treatment with 40–60 mg/kg per day phosphate and 20–40 ng/kg per day 1,25(OH)₂D₃ (calcitriol). The duration of treatment ranged from 12 to 68 months (median 27 months). We measured the height and several indices of calcium and bone metabolism before and at intervals of 6 weeks to 3 months thereafter during treatment. The diagnosis XLH was established between the age of 3 to 12 weeks by the detection of elevated alkaline phosphatase activities (n=8) and urinary hydroxyproline (n=7), whereas only five patients had also hypophosphataemia. Six of seven untreated patients had decreased 1,25(OH)₂ vitamin D levels in serum. During treatment alkaline phosphatase and hydroxyproline decreased to normal or slightly elevated levels, whereas serum phosphate remained below the normal range. Several patients treated with more than 40–50 mg/kg per day phosphate developed secondary hyperparathyroidism. One patient receiving a low dose of 20 ng/kg per day calcitriol had prolonged radiological and biochemical signs of rickets and growth delay. The other patients presented with no or only slightly transient signs of rickets. Three patients developed moderate nephrocalcinosis. The statural growth rate decreased slightly below 2 SDs without a further decrease in two patients and remained within the normal range in the other patients. Only four patients developed moderate leg deformities. Conclusions Early treatment with calcitriol at a daily dose of at least 30–40 ng/kg and phosphate at a daily dose of maximal 40–50 mg/kg improves mineral metabolism and seems to obviate severe growth delay and leg deformities. Received: 11 February 1998 / Accepted in revised form: 31 May 1998     

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).     

Growth hormone treatment in children with preterminal chronic renal failure: No adverse effect on glomerular filtration rate

Impaired growth and stunting remains a major therapeutic problem in children with chronic renal failure (CRF). Recombinant human growth hormone (rhGH) treatment may be beneficial, but concern has been raised about possible side-effects, i.e. deterioration of renal function and glucose intolerance. We have treated 10 prepubertal children with CRF (median age 7.5 [1.7–10.0] years) with 4 IU rhGH/m² per day s.c. over a period of 1 year. Height velocity increased significantly (P<0.03) from basal 4.6 (2.0–14.0) cm/year to 9.7 (6.8–17.6) cm/year. Height velocity SDS for chronological age and for bone age increased in all children from basal median –2.3 to +3.8 (P<0.005). Median glomerular filtration rate (GFR) measured by single injection inulin clearance at onset was 18 (11–66) ml/min per 1.73 m² and did not change significantly during the treatment year. The loss of GFR as estimated by creatinine clearance was similar during the treatment year (median loss 1.3 ml/min per 1.73 m²) compared to the year before treatment (median loss 3.7 ml/min per 1.73 m²). Serum glucose levels during an oral glucose tolerance test did not change, but fasting as well as stimulated insulin levels increased significantly with time during the study period. It is concluded that the rhGH regimen employed was remarkably effective in improving growth velocity in children with CRF without adversely affecting GFR. Glucose homeostasis remained stable, but at the expense of increased serum insulin levels.     

Changes in growth, growth hormone, and insulin-like growth factor-I (IGF-I) after orthotopic liver transplantation

Growth failure is an important consequence of chronic liver disease in childhood. Insulin-like growth factor-I (IGF-I), which is synthesized and released by the liver, plays an important role as a growth regulator in humans. We examined the growth hormone (GH)/IGF-I axis before and after orthotopic liver transplantation (LT) in 14 children aged between 2 and 11 years (mean 5.6 ± 1.1 years). Pre-transplantation serum GH levels (7.5 ± 1.2 ng/ml) were significantly higher (P < 0.001) compared with controls (5 ± 0.5 ng/ml). However, post-transplantation levels (1.8 ± 0.8 ng/ml) did not differ from those in the control group. Serum IGF-I levels showed a statistically significant increase after LT (20.1 ± 9.4 vs 190 ± 66.2 ng/ml; P < 0.001) and became indistinguishable from the levels in the control group (180 ± 96 ng/ml). In comparison with pre-transplantation data (z− 2.70), there was an increase in height 4 years postoperatively (z− 1.68). Catch-up growth was highly significant, in particular during the 1st year after LT (z−1.58 ± 1.63 vs 2.59 ± 5.29; P < 0.01). We conclude that a GH resistance state found in patients with severe chronic liver disease reverted following LT. Given that IGF-1 depends upon liver function, this could be one of the main factors in the significant catch-up growth in pediatric LT recipients.     

Growth hormone secretion in diabetic children

The postinsulin secretion pattern of the human growth hormone (HGH) was examined in 14 healthy and 27 diabetic children. Significantly higher HGH levels were found in diabetic than in healthy subjects before insulin injection as well as in the early phase of the test. This abnormality in HGH secretion increased with the duration of diabetes. No sex-related differences in HGH secretion were found in healthy or diabetic children.     

Changes with growth hormone treatment in growth hormone deficient children

A total of 54 previously untreated patients (15 girls, 39 boys) with poor growth due to idiopathic growth hormone deficiency (IGHD) were treated with human growth hormone (hGH), continuously up to 4 years. All of the patients had a peak hGH level which was below 10 ng/mL after at least two pharmacological tests and/or blunted physiologic hGH secretion, and their height was below ?2.5 s.d. for age and gender. After the 1st year of therapy, height velocity (HV) increased significantly when compared with baseline (from 3.18 ±0.76 cm/year to 9.17±1.03 cm/year; P <0.001), declined during the 2nd year and then remained significantly higher than pretreatment HV. When considering improvement in height expressed by height standard deviation score (SDS), during the therapy all of the patients showed a significant gain ± 1.72±1.09 (from ?4.11±0.61 to ?2.21±0.48). The height values were significantly higher than pretreatment, but remained below ?2 s.d. after 4 years of hGH therapy in our patients. Increased height velocity has been sustained, but height improvement after therapy was inversely correlated to height SDS for chronological age of patients at the start of therapy. In conclusion post-treatment height has been shown to be related to height deficit at the beginning of therapy. Therapy was well tolerated with no local or systemic adverse effects or acceleration of bone age.     

Growth in X-linked hypophosphatemic rickets

Growth failure appears frequently in children with X-linked hypophosphatemic rickets (XLHR) due to hypophosphatemia, disease severity, body disproportion, and primary bone abnormality. Recombinant human growth hormone (rhGH) increases phosphate tubular reabsorption and phosphate level in blood and, thus, constitutes an attractive but controversial therapy in short children with XLHR, those efficacy was demonstrated in small uncontrolled series. Our aim was to report our experience regarding growth in XLHR. Twenty-seven children with XLHR—20 girls, seven boys—diagnosed at a median (md) of 1.46 years of age, (range 0.39–8.5 years), were studied at 10.12 years of age (1.58–18.56), md (range). All received oral treatment with phosphate and calcitriol. At the first visit, grouped Z-height was −1; (−4.58; 0.54) md (range). After 5 years’ follow-up (0.92–15.6), Z-height was −0.91 (− 4.56; 0.17), not different from that at baseline (P = 0.465). In 16 children entirely controlled in our program upon presentation, a “catch up” phenomenon after the rickets had healed (P = 0.823) or throughout the long-term was not observed (P = 0.995). Eight patients had a Z-height ≤ −2SD at the last visit, and impaired linear growth was associated with age >2 years at diagnosis, male gender and non-adherence to treatment. Four children, all boys, received rhGH, and in two cases with sufficient follow up stature normalized. No rhGH side effects were observed, and phosphate and calcitriol doses remained stable. Linear growth failure appeared in a third of XLHR children. Efforts need to be made to reduce the age of diagnosis and to improve adherence to treatment. Treatment with rhGH should be considered early, after the rickets has been controlled, in those patients with impaired growth or delayed diagnosis.     

The pattern of growth and growth retardation of patients with hypophosphataemic vitamin D-resistant rickets: A longitudinal study

Growth in height of 16 patients (5 boys and 11 girls) with hypophosphataemic rickets (HR) was studied in a longitudinal survey. The data shortly before and during puberty were analysed on the basis of Preece Baines curves, fitted to the original data; for the analysis at the age of 5 years, the original data were used. It appeared that the overall shape of the individual and average growth pattern could be adequately described by the Preece Baines method. The results further showed that from the age of 5 years onwards, average height was approximately two standard deviations below the normal mean for Dutch children. The patients showed a normal pubertal growth spurt which was, in general, insufficient to restore the growth retardation already established before adolescence. The four children who did show catchup growth between the age of 5 years and adulthood had minimal rachitic lesions. The greater impact of the disease on growth in early childhood than on adolescent growth could be explained by the fact that HR mainly affects the growth of the legs, the major contributor to body size in early childhood. Finally, it was found that the difference between bone age, as determined by the Tanner Whitehouse (TW₂)-method, and chronological age was not significant and the adult height in all patients except two could be adequatcly predicted from bone age and height.     

重组人生长激素注射液治疗儿童生长激素缺乏症的临床评价

目的 生长激素缺乏症(GHD)有赖于生长激素替代治疗.生长激素注射液可简化注射过程,提高依从性.进一步评价中国重组人生长激素注射液治疗儿童GHD的疗效和安全性.方法 采用多中心、前瞻性、随机开放的研究方法 ,对31例[男20例,女11例,年龄(10.5±4.1)岁]确诊为完全件GHD的患儿,给予重组人生长激素注射液,0.25 mg/(kg·周)[0.107 U/(kg·d)],每晚睡前皮下注射1次,治疗3、6、9、12个月后进行随访,疗程12个月.比较治疗前后的身高增长量(△HT)、年生长速率(growth velocity,GV)、身高均值标准差积分(HT SDS)、血胰岛素样生长因子Ⅰ(IGF-1)、胰岛素样生长因子结合蛋白质3(IGFBP-3)、抗生长激素抗体和骨成熟情况的变化,并评估药物治疗的安全性.结果 (1)治疗3、6、9、12个月后△HT(cm)分别为4.0±1.3、7.0±2.0、10.3±2.6和12.9±3.3(P<0.01),显示治疗后呈良好线性生长;GV(cm/年)治疗前为2.7±0.9,治疗后分别升至16.0±5.1、14.1±4.0、13.7±3.5和12.9±3.3,显示治疗后追赶生长明显,治疗前后比较,差异有统计学意义(P<0.01);HT SDS治疗前为-4.62±1.46,治疗后分别为-3.80±1.53、-3.28±1.60、-2.86±1.75和-2.47±1.86,显示治疗后身高与同年龄同性别正常儿童差距逐步缩小,与治疗前相比差异有统计学意义(P<0.01);(2)血IGF-1(ug/L)治疗前为41±64,治疗后分别为179±155、202±141、156±155和159±167;IGFBP-3(mg/L)治疗前为1540±1325,治疗后分别为3891±1815、4051±1308、3408±1435和3533±1413,显示随着身高增长,IGF-1、IGFBP-3被药物激活到较高水平,治疗前后差异均有统计学意义(P<0.01);(3)在治疗6个月、12个月后进行骨龄评估,骨成熟程度(△BA/△CA)分别为1.01±0.57、1.07±0.75,显示骨龄无加速发展;(4)治疗期间未发生严重不良事件,与药物有关的伴随反应主要表现为甲状腺功能减低.结论重组人生长激素注射液足一种安全有效治疗儿童GHD的药物.     

Growth hormone therapy—established uses in short children

Since the first reported efficacious use of human growth hormone in 1958, numerous children have been treated with this hormone. This review discusses the five indications for use of human growth hormone in children that have been approved to date by the United States Food and Drug Administration.
Conclusion: Further, long-term studies will be needed to address the optimal use of this hormone in each of these conditions.     

Growth retardation and reduced growth hormone secretion in a boy with achalasia

A 15-year-old boy with achalasia of the oesophagus is described in whom growth retardation was the presenting and misleading symptom. Growth hormone (GH) and insulin-like growth factor-I secretion were decreased but GH therapy was unsuccessful. After pneumatic dilatation of the oesophageal sphincter catch up growth occurred.     

Growth hormone treatment enhances bone mineralisation in children with chronic renal failure

Dual energy X-ray absorptiometry of the whole body and the lumbar spine was performed to study bone mineralisation before and after 1 year of recombinant human growth hormone (rhGH) treatment in ten children with chronic renal failure. At the start, median age was 7.3 years (range 2.0–8.8 years) and median glomerular filtration rate 15 ml/min per 1.73 m² (range 7–41 ml/min per 1.73 m²). Total body mineral content (TBMC), lumbar spine mineral content (LBMC), total body bone mineral density (TBMD) and lumbar spine mineral density (LBMD) improved significantly (P < 0.05) after 1 year of treatment. Bone mineral data before and after treatment were compared with two groups of controls, i.e. ten healthy children matched for age and ten healthy children matched for height. Patients' TBMC, LBMC, TBMD and LBMD data before treatment were no different from those of height-matched controls; the same was true after 1 year of treatment except for the patients' significantly better LBMD (P < 0.05). When compared with age-matched controls, patients had significantly lower baseline TBMC and LBMC levels before treatment; after treatment LBMC was no longer different. However, there were no differences in TBMD or LBMD between patients and age-matched controls at baseline or after rhGH. Conclusion Recombinant human growth hormone treatment for 1 year results in a significant increase in both growth velocity and bone mineralisation. Comparison with height-matched controls shows a similar bone mineralisation at baseline and a better bone mineral density after treatment. Received: 10 August 2000 and in revised form 10 November 2000 and 5 January 2001 /  Accepted: 8 January 2001     

Growth hormone stimulation tests in chronic renal failure with metabolic acidosis

Metabolic acidosis is one of the possible causes of growth retardation in chronic renal failure (CRT³'). Data about the effect of metabolic acidosis on growth hormone (GH) secretion in CRF are limited. A study was earned out on eight CRF patients, hospitalized because of severe metabolic acidosis, and eight age-matched prepubertal healthy short children. Growth hormone stimulation tests were done with L-dopa and clonidine before or during acidosis therapy and after the correction of metabolic acidosis. The levels of GH were measured by radio-immunoassay. The mean of the peaks of both tests were used for each patient and statistical significance was tested by Mann-Whitney U and Wilcoxon tests. No difference was found between the GH peaks of the two groups during acidosis and after the correction of acidosis (Wilcoxon test, P > 0.05). In view of this data it was concluded that metabolic acidosis has little effect on GH stimulation tests.     

Growth and growth hormone secretion in children after bone marrow transplantation

Long-term sequelae of bone marrow transplantation (BMT) are a major concern among long-term survivors since the procedure has been considerably developed over the past decade. In this study, linear growth and growth hormone (GH) secretion were evaluated in 25 children (14 males and 11 females) with various neoplastic or non-neoplastic hematological disorders who had survived for more than 3 years after BMT. Impaired linear growth after BMT, as defined by a change in height standard deviation score (SDS) by more than ? 1.0 SD, was observed in 14 patients (56%). Four children showed severe growth suppression with a decrease in SD score by more than 2.0, and 10 exhibited a moderate reduction by between 1.0 and 2.0 SD. A recovery of normal height velocity was observed in those who had received BMT at a younger age. The type of disease, a difference in preconditioning regimen, the presence of chronic graft-versus-host disease or a GH secretory capacity 1 year after BMT were not contributing factors for impaired growth. A serial examination of GH secretion with insulin-induced hypoglycemia demonstrated that poor GH secretion was not necessarily a prerequisite for impaired growth. These results indicate that the secretory status of GH does not predict the future growth pattern of children who received BMT.     

Growth response to recombinant human growth hormone in short prepubertal children with chronic renal failure with or without dialysis

The growth-promoting effect of recombinant human growth hormone (GH) in children with chronic renal failure was assessed in eight clinical trials. A total of 103 prepubertal children participated in the trials, 34 of whom were undergoing dialysis. The children were treated with GH, 30 IU/m²/week (approximately 1 IU/kg/week), for up to 2 years, and various growth parameters, bone age and renal function were assessed before and during treatment. In all trials, the children showed clear catch-up growth and an improved height SDS after treatment with GH, although the increase in height was less in dialysis patients than in those not receiving dialysis. GH maintained its growth-promoting effect during the second year of treatment; the effect, however, was less marked than during the first year of treatment. Bone age appeared to advance in parallel with chronological age. Median serum creatinine increased from 204 μmol/1 to 230 and 262 μmol/l after 12 and 24 months of treatment, respectively, due to increased muscle mass and/or progression of the underlying renal disease. The loss of estimated glomerular filtration rate/year was not different before and during GH treatment.