INCREASED IMMUNOREACTIVE PLASMA AND URINARY GROWTH HORMONE IN GROWTH RETARDATION WITH DEFECTIVE GENERATION OF SOMATOMEDIN A (LARON'S SYNDROME)

ABSTRACT: Kastrup, K. W., Andersen, H. and Hanssen, K. F. (Childrens Hospital, Fuglebakken, and Steno Memorial Hospital, Copenhagen, Denmark). Increased immunoreac-tive plasma and urinary growth hormone in growth retardation with defective somatomedin A generation (Laron's syndrome). Acta Paediatr Scand 64: 613, 1975.–In a boy 4 years old with clinical hypopituitary dwarfism, high plasma and urinary levels of immunoreactive growth hormone were found. Somatomedin A levels in serum were low and failed to respond after short-term treatment with human growth hormone. The parents were first cousins. In the arginine and insulin tolerance tests the initially high immunoreactive growth hormone levels were later followed by a decrease to high normal values. Insulinopenic response was present during the arginine and glucose tolerance tests. As a growth hormone molecule defect is not found in these patients and no growth or other metabolic response to exogenous HGH can be demonstrated, it is concluded that a defective somatomedin generation may be present, probably in conjunction with a generalized receptor defect and deficient feedback system with abnormal release of HGH. The lack of somatomedin A is responsible for the severe growth retardation and the disturbance in carbohydrate metabolism is probably caused by sustained high growth hormone levels.     

Increased immunoreactive plasma and urinary growth hormone in growth retardation with defective generation of somatomedin a (Laron's Syndrome).

In a boy 4 years old with clinical hypopituitary dwarfism, high plasma and urinary levels of immunoreactive growth hormone were found. Somatomedin A levels in serum were low and failed to respond after short-term treatment with human growth hormone. The parents were first cousins. In the arginine and insulin tolerance tests the initially high immunoreactive growth hormone levels were later followed by a decrease to high normal values. Insulinopenic response was present during the arginine and glucose tolerance tests. As a growth hormone molecule defect is not found in these patients and no growth or other metabolic response to exogenous HGH can be demonstrated, it is concluded that a defective somatomedin generation may be present, probably in conjunction with a generalized receptor defect and deficient feedback system with abnormal release of HGH. The lack of somatomedin A is responsible for the severe growth retardation and the disturbance in carbohydrate metabolism is probably caused by sustained high growth hormone levels.     

Growth hormone response in fetal alcohol syndrome.

In the fetal alcohol syndrome (FAS) there is severe physical growth retardation both prenatally and postnatally. Secretion of growth hormone (GH) after insulin-induced hypoglycaemia and arginine infusion was analysed in 5 cases of FAS to find out whether changes in GH secretion might account for the abnormal growth pattern. Results showed a normal or slight hyper-response of GH up to 150 ng/ml, and normal somatomedin activity in those blood samples with high GH level. It was concluded that the growth retardation in FAS is not caused by GH or somatomedin deficiencies.     

Plasma somatomedin activity in an infant with Beckwith—Wiedemann syndrome

Plasma growth hormone levels and somatomedin activity were determined in a child with Beckwith-Wiedemann syndrome at birth and at 8 mth of age. Birthweight and length were above the 97th centile. Somatomedin activity in the cord plasma was elevated (2.8 U/ml) compared with controls (0.15-1.3 U/ml; n=15). Growth hormone was also high (76 ng/ml compared with control group range of 5.5–42.1 ng/ml, n=26). At 8 mth of age both somatomedin activity and plasma growth hormone had fallen to normal levels and weight and length were on the 75th centile. It is suggested that the high somatomedin activity may have been a contributing factor in the excessive fetal growth of this child.     

Lack of effect of chronic hyperinsulinaemia on growth and body composition in the fetal pig

Chronic hyperinsulinaemia in the presence of euglycaemia was obtained in pig fetuses using implanted osmotic minipumps to deliver 3 U of insulin per day over 14 days (90-104 days gestational age); term is 114 days. Total body growth (length and weight) was unaffected by insulin administration, although some changes in organ weights were observed. There was a significant retardation of lung growth (apparently as a result of operative stress) and, in the insulin-treated fetuses, an increase in liver weight which was attributable to enhanced glycogen deposition. Two of the insulin-treated fetuses appeared to have an increase in subcutaneous fat at delivery, but overall there was no statistically significant change in body fat, water, or protein content of the carcases. Growth hormone levels in all the fetuses were high, but there were no differences between treatment groups. Bioassayable plasma somatomedin activity was increased in the insulin-treated fetuses. It is proposed that this increase may be a result of insulin-induced enhancement of liver growth hormone receptors. From these data we conclude that a 14-day period of hyperinsulinaemia towards the end of gestation does not stimulate growth of the pig fetus despite producing an increase in somatomedin activity. The growth enhancement seen in offspring from diabetic mothers is probably due to increased nutrient availability rather than a direct effect of fetal insulin. Insulin does, however, significantly increase glycogen deposition in the fetus.     

SOMATOMEDIN ACTIVITY AND GROWTH HORMONE SECRETION

Abstract. Rappaport, R., Prevot, C. and Czernichow, P. (Department of Paediatrics. Hopital des Enfants Malades, Paris, France). Somatomedin activity and growth hormone secretion. I. Changes related to body weight in anorexia nervosa. Acta Paediatr Scand 69:37, 1980.—Anorexia nervosa in childhood and adolescence, associated with impaired growth can be considered as a form of chronic malnutrition. Twelve patients aged 11 to 17 years were investigated. In spite of increased GH secretion, plasma somatomedin activities were diminished in 8 cases. Plasma T₄ T₃ and arginine stimulated insulin secretion were also decreased. In six patients who gained weight a significant negative correlation was found between weight deficit and plasma somatomedin activity. Prolonged administration of growth hormone in one case did not stimulate the generation of somatomedin activity. Nutrition and increased insulin secretion could play a role in changes observed during recovery     

Growth and somatomedin responses to growth hormone in Down's syndrome.

Five growth retarded children with Down''s syndrome, three girls and two boys aged between 3 1/2 and 6 1/2 years with trisomy 21, were treated with human growth hormone for six months. Before treatment the growth hormone response to sleep and insulin-arginine load, as well as serum concentrations of insulin, thyroid hormones, and cortisol was found to be in the normal range. During the treatment with human growth hormone the growth velocity increased in all the children with Down''s syndrome from 2.3-2.8 cm to 3.3-5.8 cm per six months. The serum concentrations of immunoreactive insulin like growth factor 1 (IGF-1) were low before treatment and increased during the treatment with human growth hormone. The serum concentrations of immunoreactive insulin like growth factor 2 (IGF-2), which were within the normal range, however, increased during treatment with human growth hormone. Children with Down''s syndrome respond to treatment with human growth hormone, with an increase in both growth velocity and serum somatomedin concentrations.     

Wiedemann-beckwith syndrome

The Wiedemann-Beckwith syndrome (WBS) comprises an accumulation of multiple congenital anomalies. Exomphalos, macroglossia and gigantism are considered the most common manifestations, hence the alternative designation EMG-syndrome. The syndrome carries with it an increased risk of developing specific tumours. One of the more frequent metabolic changes is transient neonatal hypoglycaemia, the result of increased insulin secretion. Inheritance of the syndrome remains uncertain. Most cases are sporadic, but a number of familial cases have been reported. Present evidence suggests that WBS is an autosomal dominant trait with variable expressivity. This review summarizes the abundant literature on the subject and discusses recent molecular genetic developments that may explain the interrelationship between the clinical abnormalities, metabolic disturbances and development of tumours.Abbreviations WBS Wiedemann-Beckwith syndrome - IGF insulin-like growth factors - LH lutemizing hormone - LHRH luteinizing hormone releasing hormone - TRH thyrotrophin releasing hormone - ACTH adrenocorticotrophic hormone - GH growth hormone     

Diagnostic procedures in pediatric hypoglycemias

Depending on its etiology hypoglycemia appears after short or prolonged periods of fasting and shows different metabolite and hormonal patterns. In children it is caused by a disturbed homoeostasis of blood glucose (hormonal disorders, decreased activity of glycogenolysis or gluconeogenesis), by a primarily decreased ketogenic activity, or by a deranged adjustment of ketogenesis and carbohydrate metabolism. For the diagnostic procedure the age at manifestation, periods of fasting as well as signs and symptoms (f.e. hepatomegaly, growth retardation, somnolence) have to be carefully evaluated. Based on the extent of ketonemia the hypoglycemic syndromes can be classified into ketotic and hypoketotic forms. Hyperinsulinism, defects in fatty acid oxydation, glycogen storage disease I and postprandial hypoglycemias belong to the second category. In diagnosing hypoglycemia analysis of metabolite (glucose, lactate, beta-hydroxybutyrate, free fatty acids, carnitine) and hormonal (insulin, cortisol, growth hormone) patterns during hypoglycemic episodes is of outstanding importance. Urine has to be analysed for abnormal organic acids in order to demonstrate disturbed fatty acid oxydation. Rarely, loading tests with intermediates of carbohydrate metabolism are necessary. Suspected enzyme deficiencies have to be demonstrated in appropriate tissues (liver biopsy, erythrocytes, fibroblasts).     

Hypoglykämien mit neurologischen Komplikationen bei Kindern mit Typ-1-Diabetes im Vorschulalter

Rationale. Preschool children with type 1 diabetes have a high incidence of severe hypoglycemia with convulsions or loss of consciousness. Prevention of severe hypoglycemias is a preeminent goal in the long-term care of diabetic children. Methods. Twenty-four preschool children with diabetes (age ≤6 yrs) were prospectively studied for 12 months. Incidence of severe hypoglycemic episodes and neurologic symptoms were registered and related to diabetes control and therapy. Severe hypoglycemia was defined as blood glucose below 60 mg/dl and severe neurologic signs (convulsions, loss of consciousness, paresis). Results. Five episodes of severe hypoglycemia occurred in 5 out of 24 preschool children (incidence 0.21/yr). Major signs were generalized convulsions (2 patients), focal convulsion without loss of consciousness (2 patients) and isolated transient hemiparesis in 1 patient. All episodes occurred at night between 11.30 p. m. and 4.20 a. m.. Causes identified in retrospect were an inadequately high basal insulin dose at bedtime in 4 children and an insufficient reduction of insulin after increased physical activity in one child. In the 5 children with severe hypoglycemia BMI was significantly (p = 0.015) higher in the 5 children with severe hypoglycemia compared with those without severe hypoglycemias. Age, duration of diabetes, average HbA1c levels, daily insulin dose, number of insulin injections and number of blood glucose tests were not different. Conclusions. All episodes of severe hypoglycemias in preschool children occurred at night between 11.30 p. m. and 4.20 a. m. The most likely cause was too much basal insulin at bedtime. Families with young diabetic children should be alert to the danger of high insulin doses at bedtime and the necessity of early dose reductions. A high body mass index was associated with the occurrence of severe hypoglycemia, while a low HbA1c value by itself was not.     

Somatomedin activity in human cord plasma and relationship to birth size,insulin, growth hormone,and prolactin

Somatomedin activity was determined by a rabbit chondrocyte bioassay in cord plasma from babies of between 37 and 41 wk gestation. A positive correlation (P<0.001) was found between plasma somatomedin activity and birthweight. The mean somatomedin activity in infants whose birthweights were within 1 SD of the mean (3293 g) was 0.76 ± 0.27 U/ml. Mean somatomedin activity in infants whose weight was (a) greater than the mean weight ± 1 SD was 1.3 ± 0.17 U/ml, and (b) less than the mean weight ? 1 SD was 0.48 ± 0.15 U/ml. Plasma somatomedin activity was also correlated with placental weight, P< 0.02 and gestational age, P<0.05. No correlation was found between plasma somatomedin activity and birth length, OFC, most measurements of skinfold thickness, cord plasma, growth hormone, prolactin or insulin.     

Laron dwarfism: growth and immunoreactive insulin following treatment with human growth hormone.

A 13 1/2-year-old boy with features of growth hormone deficiency had elevated fasting plasma GH levels (5.7 to 66 ng/ml). Serum somatomedin values remained low despite treatment with human growth hormone. Plasma GH values were suppressed following oral administration of glucose and increased following insulin-induced hypoglycemia, L-dopa, and arginine. Chlorpromazine suppressed GH, both fasting and during IIH. These results suggest that the neuroendocrine mechanisms mediating GH secretion seemed to be intact. Peak plasma insulin levels increased in response to glucose administration after HGH suggesting that GH has a direct effect on the pancreatic beta cell which is not mediated by Sm. Plasma testosterone values increased to adult male levels, but there was inadequate secondary sexual response. Growth was enhanced by HGH and may have been due to testosterone and/or insulin. Although Laron dwarfism may result from a receptor defect, an abnormality in GH structure is also possible.     

Juvenile diabetics and sport. Aims, possibilities and limits (author's transl)]

The advantageous effects of muscular exercise for the Juvenile diabetic in physiologic and psychologic terms are accentuated. Participation in school sport, club sport, and high performance sport is favoured. To avoid hypoglycemias, protocols are recommended to establish the reduction of insulin dosage and/or carbohydrate addition individually required for a given amount of muscular exercise. Limits of sport activities of the diabetic are mentionend.     

Growth in children with acute lymphocytic leukemia: A pediatric oncology group study

We have studied 127 children from 5 participating institutions as to the effect of acute lymphoblastic leukemia (ALL) or the therapy used in the treatment of ALL on growth, growth hormone concentrations, and somatomedin activity. The study (SWOG No. 7581) was initiated in December 1975 and was closed to new entry in September 1979 and to data collection in February 1981. Heights, weights, and blood samples for growth hormone and somatomedin activity were obtained at the time of initial diagnosis and at intervals during the 55 months of observation. The percentage of boys <4 years of age below the 50th percentile is significantly greater than the expected 50% for both initial and final height (P<0.01). Girls <4 years appeared to have significantly different percentile height distribution from the normal for their final height measurement (P<0.05) but not for their initial height measurement. No other significant differences in the percentile height distribution were found. When growth rate, since time of diagnosis of ALL, is compared to the expected growth of normal children of the same age by linear regression analysis, there is a difference in the slope of the lines. Children with ALL are significantly shorter. The mean initial growth hormone and somatomedin concentration, 6.2 ng/ml and 1.3 μg/ml, respectively, vs mean remission growth hormone and somatomedin of 2.5 ng/ml and 1.1 μg/ml, respectively, were different. This was significant at P<0.01. The slope of the computed regression lines for multiple analysis of growth hormone and somatomedin were negative for more than 60% of the patients when compared to the initial concentration. These data suggest that a significant number of the children <4 years of age are short prior to the onset of therapy, and this persists throughout the course of their disease. Second, there is a reduction in growth rate during intensive therapy or the first year of the disease, with a normal growth rate thereafter. Third, growth hormone and somatomedin concentrations appear to be higher at the time of onset of the disease and decrease while on therapy.     

Regulation of growth in children with chronic illness. Therapeutic implications for the year 2000

Children with chronic illness often have poor growth and short stature. The causes are multiple and are related to the organ systems involved, malnutrition, superimposed infections, and the effects of specific therapy, eg, steroids. The impairment of growth contributes to poor body image in these children and may result in problems complying with the treatment regimen and poorer long-term outcome, eg, in diabetes. The somatomedin system or net circulating somatomedin activity in the blood has been shown to mediate growth in children. In addition, many authors have now documented reduced somatomedin generation by the liver and an increase in plasma factors that inhibit the effects of somatomedin on growth in children with chronic illness. Recognition of these phenomena may lead to the use of somatomedin to promote growth in certain of these children in the future.     

HYPERBILIRUBINAEMIA AND IDIOPATHIC HYPOPITUITARISM IN THE NEWBORN PERIOD

Abstract. Two infants with idiopathic panhypopituitarism presented with severe neonatal hypoglycaemia, hepatomegaly and hyperbilirubinaemia (direct and indirect). Abnormal liver function tests returned to normal over a 5–8 month period. The growth rate in the absence of detectable growth hormone was 50% of normal during the first 6 months. The effect of growth hormone on somatomedin levels and growth rate during the first year of life in one of the infants is described.     

Hyperbilirubinaemia and idiopathic hypopituitarism in the newborn period.

Two infants with idiopathic panhypopituitarism presented with severe neonatal hypoglycaemia, hepatomegaly and hyperbilirubinaemia (direct and indirect). Abnormal liver function tests returned to normal over a 5--8 month period. The growth rate in the absence of detectable growth hormone was 50% of normal during the first 6 months. The effect of growth hormone on somatomedin levels and growth rate during the first year of life in one of the infants is described.     

Pituitary gigantism.

A case of pituitary gigantism resulting from a pituitary adenoma which secreted growth hormone is described. The patient was successfully treated by surgery, which led to the normalisation of endogenous growth hormone secretion. An acceptable final height was achieved with high dose intramuscular testosterone treatment.