Growth Impairment In Children Research Articles

Growth and growth hormone secretion after treatment for childhood non-Hodgkin's lymphoma.

The aim of this study was to evaluate the growth and growth hormone (GH) secretion, as assessed by the rate and pattern of secretion, in patients in remission from non-Hodgkin's lymphoma (NHL) who had been treated with corticosteroids and intense chemotherapy. None of the patients had received cranial irradiation. Twelve children were investigated yearly by taking 24-hour GH profiles starting 1 year from the time of diagnosis. The mean age at onset of the disease was 7.5 years. Another 12 young adults were studied in a cross-sectional manner 4.1-21.3 years (mean, 9.0 years) after diagnosis of NHL. The mean age at onset of the disease was 10.7 years. The median height velocity was significantly decreased during the 1st year following diagnosis (standard deviation scores [SDS] -0.15, P < .001), especially during the first 3 months (SDS -0.75, P < .001) when the most intense treatment was given. During the 2nd year height velocity was still somewhat reduced (SDS -0.13, P < .001). However, there was no reduction in final attained height. Spontaneous GH secretion, in terms of both secretory rate and pulsatile pattern, was evaluated by measuring integrated GH concentrations in 20-minute blood samples collected over a 24-hour period. The plasma GH concentrations were transformed into GH secretion rates by means of a deconvolution technique. Fourier time series analysis was applied to determine possible disturbances of rhythmicity of the GH secretion. The GH secretion rate and the pulsatile pattern of secretion in the NHL patients were similar to those of the reference population of pubertal matched healthy controls. There was no influence of the age at diagnosis or of the time from diagnosis of NHL on the GH secretion rate. Growth impairment in children with a malignant disease treated only with steroids and chemotherapy is therefore probably not caused by disturbed GH secretion, but rather by direct interference with bone growth of the cytotoxic drugs used. There was no significant influence on weight gain during the treatment period so an indirect effect of chemotherapy on bone growth through interference with adequate nutrition seems unlikely. However, GH secretion was not evaluated during the period of growth retardation, and therefore a transient deficiency was not excluded.

Zinc deficiency in women, infants and children.

Zinc deficiency in humans is widespread and is more prevalent in areas where the population subsists on cereal proteins. Conditioned deficiency of zinc is seen in many diseased states. A mild deficiency of zinc in pregnancy is associated with increased maternal morbidity, abnormal taste sensation, prolonged gestation, inefficient labor, atonic bleeding, and increased risks to the fetus. Among the urban poor in the US, a marginal zinc intake during pregnancy was associated with increased risk of preterm and very preterm delivery. Factors responsible for zinc deficiency in premature infants include high fecal losses of zinc, low body stores of zinc at birth, and increased zinc requirement during rapid growth. Zinc supplemented infants demonstrated improved linear growth velocity and maximum motor development scores. Marginal and moderate growth impairment in children as a consequence of inadequate zinc intake has been reported from many developed and developing countries. In one study from Japan, 21 prepubertal children were diagnosed to have zinc deficiency. The caloric intake, growth velocity, serum zinc, and plasma insulin-like growth factor-1 increased significantly in the zinc supplemented group. The clinical manifestations of zinc deficiency include growth retardation, hypogonadism in males, neurosensory disorders, cell-mediated immunological dysfunctions, and skin changes. Approximately 300 enzymes are known to require zinc for their activities. Zinc is required for DNA synthesis, cell division and protein synthesis. Several hundreds of zinc containing nucleoproteins are probably involved in gene expression of various proteins. A deficiency of zinc also affects proliferation and maturity of lymphocytes adversely.

Sodium or chloride deficiency lowers muscle intracellular pH in growing rats

Sodium deficiency and chloride deficiency are associated with a contracted extracellular (ECF) volume and impaired growth in young children and growing rats. In cell culture, lowering sodium in the medium reduces growth factor-stimulated Na+/H+ exchange activity, intracellular pH (pHi), and DNA synthesis. We studied the effect of chronic sodium deficiency and chloride deficiency upon growth, extracellular acid base status, and muscle pHi in young rats. We fed growing rats for 21 days either a control diet, or one deficient in sodium (0.005%), chloride (0.005%), or calories. Muscle pHi was measured using 31phosphorus nuclear magnetic resonance spectroscopy. Rats fed either the sodium-deficient or chloride-deficient diet developed ECF volume contraction and hyponatremia; growth in length and weight was impaired. Muscle pHi was decreased (pHi = 7.074 +/- 0.006, 7.078 +/- 0.006 vs. control 7.100 +/- 0.002; P < 0.02). In calorie-restricted rats, growth was impaired but pHi was not affected (pHi 7.103 +/- 0.008). Metabolic alkalosis developed in the chloride-deficient group; acid base status was not affected in the sodium-deficient group. Despite differences in ECF acid base status, both groups had a low muscle pHi. We speculate that the low muscle pHi was a result of the ECF volume contraction and hyponatremia; low muscle pHi may contribute to retarded cell growth.

537 Growth impairment in children subjected to cranial irradiation

Growth was assessed retrospectively in 11 children (age range 2–14 years) diagnosed having brain tumors who underwent treatment with chemotherapy, surgery and cranial irradiation with a mean total dosage of 50 Gy. In these patients GH was the first hormone to have a decreased production. The average time from the radiotherapy to the significant decrease in growth rate was 17 months (range 6–27) and to the GH deficiency ( Hormonal replacement therapy with rh-GH at dose of 0.6 Ul/kg/week given by daily induced a significant increase the average height in SD after 6 months of treatment. These results suggest that GH replacement at 18 months after radiotherapy should be considered in the treatment of these patients.

Chemotherapy‐induced growth hormone deficiency in children with cancer

Chemotherapy (CT) may produce growth impairment, however, the pathogenesis is still unclear. A series of 25 patients mean age 13.3 years (6.3-19.8), previously treated for malignant solid tumours with only CT and surgery were studied. Growth hormone (GH) reserve was assessed by two different provocative stimuli (Clonidine and L-Dopa). Mean time between completion of treatment and GH evaluation was 18.5 months (2-74 months). At that time, all patients were in complete remission. GH deficiency (GHD), defined by an impaired GH response to both provocative tests was observed in 11 out of 25 patients (44%). At diagnosis, mean standing height was +0.23 +/- 1.42 SDS in the GHD group (GHD-g) and +0.18 +/- 1.23 SDS in the non-GHD group (n-GHD-g). At the end of therapy, the mean standing height in the GHD-g was -0.31 +/- 1.22 SDS and -0.17 +/- 1.41 in the n-GHD-g, differing from the former group (P = 0.05). For a mean follow-up of 30 months from the end of treatment, the mean standing height was -0.48 +/- 1.23 SDS in the GHD-g and -0.24 +/- 1.51 SDS for the n-GHD-g (P = 0.03). Growth rate at the end of treatment was +0.13 +/- 1.54 in the GHD-g and +0.21 +/- 1.75 in the n-GHD-g. For a mean follow-up of 30 months from the end of treatment, the growth rate was different between GHD-g and n-GHD-g (-0.31 +/- 2.72 vs. -0.21 +/- 1.93, P < 0.05). 1) Growth impairment in children treated because of malignant diseases has a multifactorial etiology, but CT-induced GH deficiency is one potential adverse factor. 2) An endocrine follow-up should be introduced in order to detect and treat hormonal deficiencies as early as possible.

The new paradigm of public health nutrition.

Poor food habits that result in nutritional deficiencies and excesses along with smoking infections and toxic environmental factors are the major determinants of the health and longevity of individuals. Fetal malnutrition reflects the nutritional status and health of the mother. Iodine deficiency marasmus kwashiorkor and lesser degrees of protein-energy deficiency can also have lasting functional consequences. Stunting associated with clinical malnutrition also exerts a lasting effect on learning and behavior. Nutritional supplementation of young children beneficially affects cognitive development and performance. Two well-designed studies in the late 1960s in Guatemala and Mexico demonstrated that supplementary feeding up to 2 years of age benefited rural breast-fed children who were taller had fewer infections and performed better on cognitive tests. In Guatemala over 2000 of these children performed better on comprehensive achievement tests and had completed more years of schooling when reexamined as adolescents and young adults. In a study of infants born between 1935 and 1943 blood pressure of adult men and women was strongly predicted by high placental weight combined with birth weight. Increased insulin tolerance and adult onset diabetes are also more common among individuals 45 to 54 years old with low weight at birth and at 1 year of age. Iron deficiency anemia in developing countries amounts to 26% for men and nearly 50% for women and children. The adverse consequences of anemia include weakness decreased physical capacity and impaired cognitive performance and growth of children. Osteoporosis is strongly influenced by diets low in calcium at an early age. Cancers are greatly influenced by environmental factors including diet. The 1989 US National Research Council Report on diet and health estimated the 35% to 40% of cancers in the United States were diet related. In summary fulfillment of the genetic potential of individuals is impaired by malnutrition and other environmental factors throughout life.

Impaired growth in children with asthma during treatment with conventional doses of inhaled corticosteroids.

We describe 6 (4F, 2M) prepubertal children with moderate asthma diagnosed at a mean age of 2.8 years. All patients were treated with inhaled corticosteroids in a dose of between 300 and 800 mcg of beclomethasone dipropionate (becotide) daily, given either as an aerosol or rotahaler. Mean height velocity SDS decreased from -0.8 (range +0.5 to -2.0) to -3.2 (range -1.3 to -4.8) when the dose was increased. Alternatively, when the dose was reduced or stopped, mean height velocity SDS increased from -3.2 (range -2.0 to -4.8) to +0.8 (range -1.2 to +2.7). Careful assessment of height velocity is indicated in all children receiving treatment with inhaled corticosteroids.

Regulation of osteoblastic gene expression by lead.

Although it is well recognized that lead accumulates in bone, skeletal tissue is considered primarily a sequestering compartment and not a site of toxic action for lead. However, exposure to lead is associated with impaired skeletal growth in children and reductions in indices of bone formation in laboratory animals. Osteoblastic ROS 17/2.8 cells were used in an effort to better understand the consequences of lead exposure on skeletal homeostasis. Studies on confluent cultures of ROS 17/2.8 cells revealed that lead (2-200 microM) had no effect on cell number or DNA and protein synthesis. However, alkaline phosphatase activity was reduced by lead in a dose- and time-dependent manner. Reductions in steady state alkaline phosphatase mRNA levels paralleled the lead-induced inhibition of enzyme activity. Moreover, lead exposure resulted in similar dose-dependent reductions in steady state type 1 procollagen and bone Gla protein mRNA levels. The effect of lead on osteoblastic gene expression in ROS 17/2.8 cultures, however, was selective in nature, as similar lead exposures resulted in no alterations in beta-actin or glyceraldehyde-3-phosphate dehydrogenase mRNA levels. These data demonstrate that lead, in the absence of over toxicity, specifically restricts the expression of certain aspects of the differentiated osteoblast phenotype. Such alterations in osteoblast function may contribute to the skeletal abnormalities observed in settings of lead intoxication.

Regulation of osteoblastic gene expression by lead

Although it is well recognized that lead accumulates in bone, skeletal tissue is considered primarily a sequestering compartment and not a site of toxic action for lead. However, exposure to lead is associated with impaired skeletal growth in children and reductions in indices of bone formation in laboratory animals. Osteoblastic ROS 17/2.8 cells were used in an effort to better understand the consequences of lead exposure on skeletal homeostasis. Studies on confluent cultures of ROS 17/2.8 cells revealed that lead (2-200 microM) had no effect on cell number or DNA and protein synthesis. However, alkaline phosphatase activity was reduced by lead in a dose- and time-dependent manner. Reductions in steady state alkaline phosphatase mRNA levels paralleled the lead-induced inhibition of enzyme activity. Moreover, lead exposure resulted in similar dose-dependent reductions in steady state type 1 procollagen and bone Gla protein mRNA levels. The effect of lead on osteoblastic gene expression in ROS 17/2.8 cultures, however, was selective in nature, as similar lead exposures resulted in no alterations in beta-actin or glyceraldehyde-3-phosphate dehydrogenase mRNA levels. These data demonstrate that lead, in the absence of over toxicity, specifically restricts the expression of certain aspects of the differentiated osteoblast phenotype. Such alterations in osteoblast function may contribute to the skeletal abnormalities observed in settings of lead intoxication.

Growth after radiotherapy and chemotherapy in children with leukemia or lymphoma.

The effect of radio- and chemotherapy on auxological parameters was investigated in 30 children treated for acute lymphatic leukemia (ALL) or non-Hodgkins lymphoma (NHL). Growth velocity was decreased during the first year of treatment. Catch-up growth was insufficient during the following years. Thus, the whole group experienced a loss of height of 0.49 +/- 1.1 SD at 6.8 +/- 2.6 years after diagnosis. Height and growth velocity were not different between children who received 18 or 24 Gy cranial irradiation; however, growth velocity was significantly lower in children who were treated for more than 2 years or who had the more intensive chemotherapeutic protocol. Evaluation of the growth hormone (GH) response to pharmacological stimulation revealed reduced GH peaks in 47% of the patients, but there was no correlation of GH peak with growth or treatment parameters. In conclusion, the impairment of growth in children after treatment for ALL or NHL might be related to the intensity and duration of chemotherapy.

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 (IGFBP-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 immunoreactive 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.

Influence of growth hormone on the immunosuppressive effect of prednisolone in mice

Growth hormone can be used to counteract some catabolic effects of long-term administration of glucocorticoids, such as impairment of growth in children and osteoporosis. However, owing to its immunostimulatory properties the hormone may counteract the effect of glucocorticoids on the immune system. To investigate this question we administered different doses of hGH (4, 8, 40 IU/kg) to C57/Bl/6J mice treated for two days with prednisolone, and evaluated thymus and spleen parameters and natural killer activity. Growth hormone at the dose of 4 and 8 IU/kg reversed prednisolone-induced reduction of spleen and thymus weight and cellularity, whereas the highest dose showed to be immunosuppressive in itself. Two days after treatment withdrawal, a recovery of spleen parameters was evident, whereas the thymus was still suppressed by preceding prednisolone or hGH (40 IU/kg) treatments. The pattern of natural killer activity displayed by the splenocytes resembled that present under treatment. In a second experiment prednisolone, administered for 10 days, drastically reduced the number of viable spleen and thymus cells as well as the relative spleen and thymus weights, an effect reversed by concomitant administration of hGH (0.8, 4, 8 IU/kg). Natural killer activity, which was significantly depressed by prednisolone, was restored by the intermediate GH dose only. The 8 IU/kg GH dose was immunosuppressive in itself.

Growth of remote Australian aborigines from birth to two years.

Lengths and weights have been measured every month from birth to two years of age in 48 Aboriginal children born into six remote communities in the Kimberley region in the far north of Western Australia. Birthweights, on average, were slightly less than international reference values but growth rates in the first 3 months of life exceeded those reference values. However, between 3 and 6 months of age rates of weight gain and linear growth fell below those expected at that age and after 9 months of age Aboriginal infants were lighter than reference values and remained so throughout the first two years of life. By 2 years of age the Kimberley children were more than 1 kg lighter and 4.5 cm (boys) and 3.6 cm (girls) shorter than the international reference values. Monthly means and standard deviations for weight and length velocities are given. Environmental factors, particularly infections and inadequate nutrition, are important contributors to impaired growth in Aboriginal infants and young children.

104 IGF-1 AND IMPAIRED GRWOTH IN CROWH'S DISEASE

Growth retardation in juvenile patients with Crohn's disease usually is only diagnosed retrospectively by growth rate measurements. However, on time therapy requires early detection. Other authors have claimed that serial IGF-1 measurements may be a useful marker of reversibility of impaired growth in children with chronic inflammatory bowel disease. In order to evaluate parameters useful to predict growth retardation we followed 26 juvenile patients by estimation of growth velocity, weight gain, Best activity index (AI) and serum levels of α-1-glycoprotein (GP), albumin and IGF-1 over periods of 6-12 months. RIA-IGF-1 was measured in serum after acid-ethanol extraction using an antiserum supplied by the NHPP, Baltimore, Md.Age corrected IGF-1 levels at the end of, but not before an observation period of 6 months were correlated to growth velocity (r= 0.57; p<0.01) and weight gain (r= 0.44; p<0.05). % weight gain also was correlated to % change of IGF-1 levels (r= 0.50; p<0.01). In contrast, there was no relation of IGF-1 to AI, GP and albumin levels, which again did not correlate to clinical parameters of growth.In conclusion: IGF-1 appears to be a better index of growth retardation compared to other parameters tested, but its value for the long-term follow-up of patients with chronic inflammatory bowel disease in limited.

Factors contributing to the impairment of growth in children with acute lymphoblastic leukemia.

Growth was studied in 88 long-term survivors of acute lymphoblastic leukemia who had been treated with three different regimens of therapy. The following time periods were evaluated: (1) during therapy; (2) between the end of therapy and the onset of puberty, and (3) between the onset of puberty and the most recent observation. We found: (1) a reduction of height SDS during therapy, related to the irradiation dose used; no significant effect of the duration of the therapy could be established; (2) a normal growth rate during the second time period studied for the total group, but a further decrease in height SDS for those found to be growth hormone deficient after therapy (47%), and (3) a further decrease in height SDS during puberty. The timing of puberty in the female patients was normal. We conclude that in patients treated for acute lymphoblastic leukemia, growth impairment has several components, different in timing and mechanism.

Growth impairment in children with atopic eczema.

Growth was studied in 89 children with atopic eczema aged 1-16 years. Nine (10%) had a standing height below the 3rd centile. Both boys and girls had significantly reduced sitting height but normal subischial leg length, and both sexes had significantly delayed skeletal maturity scores. Impaired growth was particularly associated with widespread eczema, but also with the presence of asthma and the potency of topical corticosteroid. Six of the 15 patients with a corrected height centile below the 10th centile had been receiving potent (British National Formulary category I or II) topical corticosteroids. This study suggests that impaired linear growth is a feature of atopic eczema. While the causes of the growth impairment are unclear, there is a need for caution in the use of potent topical corticosteroids in children.

Somatomedin-C levels in growth-impaired children and adolescents with chronic inflammatory bowel disease

The relationship between caloric insufficiency and impaired growth in children with chronic inflammatory bowel disease has been increasingly recognized in recent years. The mechanism by which nutritional insufficiency leads to decreased growth in these children is unclear. Our study suggests that chronic undernutrition lowers circulating somatomedin-C, which is known to exert anabolic effects on peripheral tissues. Therapeutic intervention that increases caloric intake results in improved somatomedin-C levels and growth velocity. Monitoring somatomedin-C levels in growth-impaired children with inflammatory bowel disease provides an important marker of nutritional sufficiency and reversibility of growth retardation.

Methylphenidate and Growth: Demonstration of a Growth Impairment and a Growth-Rebound Phenomenon

Methylphenidate (MPH), the drug of choice in the treatment of attention deficit disorder with hyperactivity (ADD/H), has been shown to reduce the body stature of some patients. The present study was undertaken to determine if MPH suppresses growth in rats, and whether the clinical observation of a growth rebound phenomenon could be experimentally demonstrated. Our results demonstrate that neonatal rats treated with MPH show a reduction in femur length and a reduction in thyroid, pituitary, testis, adrenal gland, and brain weights immediately following drug cessation. However, a growth-rebound phenomenon occurs such that there are no differences between treated and control groups within 30 days of the last drug exposure. These data, along with those from the clinical literature, suggest that growth impairment is most likely a result of the acute effects of the drug. Further, these data suggest that when administered at therapeutic doses which avoid significant weight loss in the patient, MPH is not likely to cause growth impairment in children.

SODIUM DEPLETION IN INFANTS AND CHILDREN WITH BILIARY DRAINAGE PROCEDURES (BDP)

Sodium excretion from the biliary tract has not been well studied in children but could lead to hyponatremia and growth impairment in children with BDP. Salt homeostasis was studied in 17 infant outpatients with BDP for biliary atresia (BA). Bile(B) serum (S), and urine (U) were collected simultaneously and analyzed for Na+ and CL− at 1-3 month intervals during the post operative period for 1-12 months; 49 analyses of B,S, and U each were performed. Mean B Na+ remained high (122±15 mEq/1) even though mean S Na+ was low (132±7). Since bile volume was sometimes as high as 1000 ml/day, biliary NA+ losses could easily lead to depletion in spite of maximal renal Na+ conservation. (U Na+ fell to 0 when S Na+ was 132 mEq/1). B Cl− (115±21 mEq/1) consistently exceeded that of S Cl− (95±12). Data from 3 additional patients with BDP who became ill from Na depletion presented below. Symptoms resolved in all with saline supplements and bile refeeding. Conclusion: Children with BDP are at risk for NA+ depletion and should be monitored and treated accordingly.

Evaluation of the chronic hepatic toxicity of 6-mercaptopurine in the wistar rat.

The ability of choline (C) to prevent hepatic toxicity due to chronic administration of 6-mercaptopurine (6-MP) was evaluated in male Wistar rats. Two dose levels of 6-MP and two dose levels of C were used. Choline did not prevent or diminish the hepatic accumulation of triglyceride when administered in combination with 6-MP. The 6-MP did impair the growth of the experimental animals, and this effect was antagonized by C administration. The data provided experimental support for the clinical observation of growth impairment in children treated with chronic antimetabolite therapy for acute lymphoblastic leukemia.