Ashraf T. Soliman

Serum insulin-like growth factors I and II concentrations and growth hormone and insulin responses to arginine infusion in children with protein-energy malnutrition before and after nutritional rehabilitation.

ABSTRACT: Serum insulin, growth hormone (GH), insulin-like growth factors (IGFs) I and II, cortisol, and albumin concentrations were measured in 15 children with kwashiorkor, 15 with marasmic-kwashiorkor, and 21 with marasmus, before and in the survivors, after nutritional rehabilitation, as well as in 10 underweight and eight normal Egyptian children. We also evaluated arginine-induced insulin and GH secretion. IGF-I concentrations were reduced in the three severely malnourished groups (0.07 ± 0.03, 0.05 ± 0.03, and 0.09 ± 0.09 U/ml, respectively) but returned to normal after refeeding. IGF-II concentrations were low in the kwashiorkor (175 ± 79 ng/ml), marasmic-kwashiorkor (111 ± 57 ng/ml), and marasmic children (128 ± 70.9 ng/ml) and returned to normal after nutritional rehabilitation. Basal GH levels were high in the three severely malnourished groups (21.9, 28.8, and 16.6 ng/ml, respectively) and returned to normal after refeeding (8.1, 6.5, and 6.0 ng/ml, respectively). GH responses to arginine were depressed in the three malnourished groups and improved significantly in marasmic-kwashiorkor and marasmic children after nutritional rehabilitation. Insulin responses to arginine were impaired in kwashiorkor, and marasmic-kwashiorkor children and improved significantly after refeeding. IGF-I levels correlated significantly with percent of expected weight (r=0.52, p<0.001), percent of expected height (r=0.42, p<0.001), and weight/ (height)2 index (r=0.34, p<0.01). IGF-I levels correlated positively with insulin levels (r=0.421, p<0.001) and negatively with cortisol concentrations (r=—0.400, p<0.001). It is suggested that effective lipolysis mediated by high GH and possibly low IGF levels, is an important adaptive mechanism to assure fuel (fatty acids) supply for metabolism of brain and peripheral tissues during nutritional deprivation.

Bone mineral density in prepubertal children with β-thalassemia: Correlation with growth and hormonal data

Patients with beta-thalassemia major (beta-thalassemia) frequently have bone disorders of multifactorial etiology. We attempted to analyze the relationship between the bone mineral density ([BMD] measured by dual-photon absorptiometry) and auxanologic parameters, degree of siderosis, function of the growth hormone (GH)/insulin-like growth factor-I (IGF-I)/IGF-binding protein-3 (IGFBP3) axis, calcium-phosphate balance, parathyroid hormone (PTH), and cytokines (interleukin-1beta [IL-1] and tumor necrosis factor-alpha [TNF-alpha]) in 30 prepubertal children with beta-thalassemia major and 15 age-matched children with constitutional short stature (CSS), who have normal glucose tolerance and thyroid function. Children with beta-thalassemia had a significantly decreased BMD and mean BMD% for age and sex (0.75+/-0.24 g/cm2 and 71%+/-10%, respectively) versus children with CSS (1.06+/-0.3 g/cm2 and 92%+/-7%, respectively). Thalassemic patients had significantly lower circulating concentrations of IGF-I and IGFBP3 (49+/-21 ng/mL and 1.2+/-0.25 mg/L, respectively) compared with control children (153+/-42 ng/mL and 2.1+/-0.37 mg/L, respectively). The GH response to provocation by clonidine and glucagon was defective (peak GH < 7 microg/L) in 12 of the 30 thalassemic children. Serum concentrations of IL-1beta and TNF-alpha did not differ among the two study groups. Hypocalcemia was detected in five of the 30 thalassemic patients: hypoparathyroidism was diagnosed in two of the five and rickets in the other three. BMD was highly correlated with the circulating concentrations of IGF-I and IGFBP3, as well as with the auxanologic parameters (age, weight, height, height standard deviation score [HSDS], and body mass index [BMI]). It is suggested that increasing the circulating IGF-I concentration through aggressive nutritional therapy and/or GH/IGF-I therapy with supplementation with vitamin D and/or calcium might improve bone growth and mineralization and prevent the development of osteoporosis and consequent fractures in these patients. Such therapy requires blinded controlled trials.

Growth and pubertal development in transfusion-dependent children and adolescents with thalassaemia major and sickle cell disease: a comparative study.

Despite regular blood transfusion and desferrioxamine treatment, growth impairment and pubertal delay are commonly seen in children and adolescents with transfusion-dependent thalassaemia and sickle cell disease (SCD). We evaluated growth parameters and sexual maturation in a large cohort of children and adolescents with SCD (n = 110) and thalassaemia (n = 72) receiving nearly the same protocol of transfusion and chelation, and compared them with those for 200 normal age-matched children, 30 children with constitutional delay of growth (CSS), and 25 children with growth hormone deficiency (GHD). Before transfusion, haemoglobin concentration had not been less than 9 g/dl in the past 7 years; desferrioxamine was administered for 7-10 years, including by the intramuscular and subcutaneous routes, three times or more per week. The height standard deviation score (HtSDS), growth velocity (GV) (cm/yr), and growth velocity standard deviation score (GVDSD) of children and adolescents with thalassaemia and SCD were significantly decreased compared to normal children (p < 0.01). Forty-nine per cent of thalassaemic patients and 27 per cent of patients with SCD had HtSDS less than -2, and 83 per cent of thalassaemic patients and 67 per cent of SCD patients had HtSDS less than -1. Fifty-six per cent of thalassaemic children and 51 per cent of children with SCD had GVSDS less than -1. The GV of thalassaemic children was significantly slower than that for children with SCD. Children with thalassaemia and SCD had HtSDS and GVSDS comparable to those for children with CSS but higher than those for patients with GHD. Serum ferritin concentration was correlated significantly with the linear GV in all patients (r = 0.45, p < 0.001). The bone age delay did not differ among the three groups with thalassaemia, SCD and CSS, but the delay was significant in the group with GHD. The mid-arm circumference was significantly smaller in children with thalassaemia and SCD than in normal children. The triceps skin-fold thickness of patients with SCD was significantly decreased compared to thalassaemic and normal children. The upper/lower segment ratio was significantly lower in thalassaemic and SCD patients than in normal children. In thalassaemic patients between the ages of 13 and 21 years a complete lack of pubescent changes was present in 73 per cent of boys and 42 per cent of girls. Seventy-four per cent of the thalassaemic girls had primary amenorrhoea. Girls with SCD aged between 13 and 21 years had markedly delayed breast development and menarche. Twenty-five per cent of boys with SCD above the age of 14 years had absence of testicular development. Males with thalassaemia and SCD who had spontaneous testicular development had significantly smaller testicular volume than did normal controls. Short children with thalassaemia and SCD had significantly decreased serum insulin-like growth factor 1 (IGF-1) concentrations compared to children with CSS. Collectively, these data confirm the high prevalence of impaired growth and pubertal delay/failure in children and adolescents with thalassaemia and SCD. The aetiology of impaired growth includes the contributions of lack of pubertal growth spurt due to delayed/absent puberty, decreased synthesis of IGF-1 which might be secondary to a disturbed GH-IGF-1 axis and/or under nutrition, probably due to the hypermetabolic status of these children. It is suggested that newer protocols of treatment, in addition to optimization of transfusion and chelation requirements, should increase the caloric intake of these patients and properly manage their pubertal delay-failure in order to improve their adult height.

Congenital adrenal hyperplasia complicated by central precocious puberty: Linear growth during infancy and treatment with gonadotropin-releasing hormone analog

Some children with congenital adrenal hyperplasia (CAH) develop true precocious puberty with early maturation of the hypothalamic-pituitary-gonadal axis. We have seen six such children who had the diagnosis of CAH with late initiation of corticosteroid treatment and/or poor compliance who developed central precocious puberty (CPP). These patients were treated with standard-dose hydrocortisone and fludrocortisone. Administration of depot leuprorelin (3.75 mg subcutaneously every 28 days) for 2 years or longer was effective in arresting the manifestations of puberty, decelerating the pretreatment growth velocity ([GV] 10.8 +/- 1.5 v3.65 +/- 0.95 cm/yr), increasing the predicted adult height ([PAHT] 147.5 +/- 7.8 v 153.4 +/- 8.3 cm), and decreasing the bone age to statural age ratio (1.26 +/- 0.13 v 1.16 +/- 0.09). Analysis of auxanological data during the first 2 years of life showed that linear growth was significantly accelerated and bone age was advanced in patients who developed CPP compared with 11 age-matched patients. It appears that proper glucocorticoid replacement to achieve adequate control of hyperandrogenemia during early life might prevent development of CPP in these patients. Gonadotropin-releasing hormone agonist (GnRHa) therapy can improve the final adult height, bringing it closer to that expected from the genetic potential.

Testosterone treatment in adolescent boys with constitutional delay of growth and development.

Administration of androgens to adolescent boys with constitutional delay in growth has been highly controversial. One hundred forty-eight adolescent boys with constitutional delay of growth and puberty with a mean age of 14.3 +/- 0.7 years were treated with testosterone enanthate 100 mg intramuscularly each month for 6 months. Growth parameters, sexual maturation, and circulating concentrations of testosterone and insulin-like growth factor-I (IGF-I) were compared with those for 50 age-matched adolescent boys with constitutional delay of growth and puberty with a mean age of 14.1 +/- 0.9 years who did not receive any treatment. The mean height growth velocity, height standard deviation score, weight gain, and IGF-I concentration were significantly greater in the treatment group after 1 year of follow-up evaluation. The advancement in bone age equaled that in chronologic age in the treatment group, with no significant change in the bone age to chronologic age ratio (BA/CA) before versus after therapy. All subjects in the treatment group had clearly entered puberty by the end of 1 year. Testicular size increased significantly in the treatment group and they had significantly higher serum testosterone concentrations 6 months after the end of testosterone therapy as compared with the control group, denoting activation of the hypothalamic-pituitary testicular axis. All subjects in the treatment group were psychologically satisfied with the enhanced growth and increased muscle mass, versus only 40% of those in the control group. In conclusion, our regimen appears to be efficacious and safe for treatment of boys with constitutional delay of growth and puberty and has no deleterious effect on skeletal age.

Maternal and Neonatal Prevalence of Toxoplasma and Cytomegalovirus (CMV) Antibodies and Hepatitis-B Antigens in an Egyptian Rural Area

To determine the seroprevalence of maternal and neonatal toxoplasmosis and cytomegalovirus (CMV) antibodies and hepatitis-B (HB) antigenaemia in a rural Egyptian area, a prospective serological study was done on a randomly selected sample of pregnant women (n = 150) and their newborn infants (n = 150). Sera were collected from the mothers during the first antenatal visit, and at the time of delivery and cord blood specimens (paired samples) taken from their infants to be tested for toxoplasma-IgG and IgM antibodies, CMV-IgG and IgM antibodies surface antigen (HBsAg) and HBe antigen (HBeAg). Maternal infection was indicated in cases where specific IgM antibody was present or where an initial maternal specimen gave negative result for IgG antibody, but the second blood specimen gave positive result. Specific IgM antibody in a cord blood specimen indicated fetal infection. Out of the 150 pregnant women, 64 (43 percent) were toxoplasma immune at their first antenatal visit and their newborns were toxoplasma IgG positive. Toxoplasma specific IgM antibody was detected in only three mothers at the time of deliver. The rate of maternal infection in susceptible pregnancies was 4 percent and the maternal-fetal transmission rate was estimated to be 33 percent, as only one newborn infant had toxoplasma-IgM antibody at birth. This denoted a prevalence of congenital toxoplasma infection = < 1.0 percent to non-immune mothers. There were no clinical features of congenital infection in the infant with toxoplasma-IgM antibody, but he will require long-term follow-up. All the mothers infected during pregnancy had known risk factors for toxoplasma infection. One-hundred-and-forty-three (96 percent) of the pregnant women were CMV-IgG seropositive at their first antenatal visit. At the time of delivery 143 (96 percent) of the mothers and their newborn infants were CMV-IgG seropositive. None of the mothers or their infants was CMV-IgM seropositive. HBsAg was detected in 8 per cent of pregnant mothers (n = 12) and in two (17 percent) of their newborn infants. None of the mothers was HBeAg positive. In conclusion, the prevalence of toxoplasma infection during pregnancy and its transplacental transmission rate in a rural Egyptian area are high compared to other countries. A toxoplasmosis antenatal screening and public education programmes for pregnant mothers is justifiable in rural Egypt. However, it appears that an antenatal screening programme for CMV is, at present, not warranted.

Prevalence of Hepatitis-C Antibody Seropositivity in Healthy Egyptian Children and Four High Risk Groups

We studied the prevalence of HCV antibody seropositivity and serum alanine concentrations in a random sample of healthy Egyptian children (n = 110) as well as in four high risk groups of children. Group 1 included 18 children with thalassemia major, group 2 included 17 children with insulin-dependent diabetes mellitus (IDDM), group 3 included 21 children with schistosomal hepatic fibrosis (SHF), and group 4 included 20 children with chronic rheumatic heart disease (RHD). The prevalence rate of HCV seropositivity was 12 per cent in normal children, 44 per cent in thalassemic children, 29 per cent in children with IDDM, 38 per cent in children with SHF and 0 per cent in patients with RHD. The liver size was significantly larger in HCV seropositive normal children as well as in HCV seropositive children with thalassemia and SHF compared to the seronegative children in each group respectively (P < 0.05). In all groups serum alanine transferase concentrations were significantly higher in HCV seropositive v. seronegative children. This pointed out to the high risk of continuous parenchymal hepatic damage in these children following acute HCV infection. In summary, our data revealed a relatively high prevalence of HCV antibody seropositivity in healthy Egyptian children compared to reports from other countries, and a significantly high prevalence of HCV seropositivity in children with thalassemia, IDDM, and SHF which carries a considerably high risk for development of chronic liver disease in these patients.

Decreased Bone Mineral Density in Prepubertal Children with Sickle Cell Disease: Correlation with Growth Parameters, Degree of Siderosis and Secretion of Growth Factors

Patients with sickle cell disease (SCD) frequently have bone disorders of multifactorial aetiology. We attempted to analyse the relationships between bone mineral density (BMD) on the one hand and auxologic parameters, degree of siderosis, function of the growth hormone (GH)/insulin-like growth factor-I (IGF-I)/IGF-binding protein 3 (IGFBP3) axis, and calcium-phosphate balance in 28 prepubertal children with SCD and 15 age-matched children with constitutional short stature (CSS). Children with SCD had significantly decreased BMD (77.9 +/- 11.9 per cent of normal BMD for age and sex) and circulating concentrations of IGF-I (91 +/- 31 ng/ml) and IGFBP3 (1.7 +/- 0.44 mg/l) compared with the control group (BMD = 93.5 +/- 8.2 per cent of normal BMD for age and sex, IGF-I = 221 +/- 48 ng/ml, and IGFBP3 = 2.3 +/- 0.34 mg/ml). GH response to provocation was defective (peak below 10 micrograms/l) in 40 per cent of children with SCD. Those with SCD with defective GH secretion had significantly lower circulating IGF-I concentration and BMD than those with normal GH secretion. Serum calcium, phosphate and alkaline phosphatase concentrations were normal in all children with SCD. BMD was correlated significantly with height, weight, and body mass index as well as with the circulating concentrations of IGF-I and IGFBP3. It is suggested that increasing the circulating IGF-I concentration, either through increasing the caloric intake of subjects and/or via GH/IGF-I therapy, may improve growth and bone mineralization in these patients.

Recessive Robinow syndrome: With emphasis on endocrine functions

We present the characteristic features of 14 children with the recessive form of Robinow syndrome and the growth hormone (GH) response to provocation with clonidine and the serum insulin-like growth factor-I (IGF-I) concentration in 12 of these children. The gonadotropin (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) response to gonadotropin-releasing hormone (GnRH) was evaluated in early pubertal and pubertal patients, and the testosterone response to human chorionic gonadotropin (HCG) was evaluated in males. Children with Robinow syndrome, born at full-term, were short at birth (length, 41.4+/-2.1 cm) and had markedly slow growth velocity (GV) during the first year (13.1+/-2.1 cm/yr); consequently, they were significantly short at the end of the first year of life (length, 54.4+/-2.9 cm). This intrauterine and early extrauterine growth delay reflected low growth potential. During childhood, the GV standard deviation score (GVSDS) remained low (-2.17+/-0.83). Despite the presence of empty sella in all of the patients, they had an adequate GH response to clonidine provocation (peak, 19.3+/-5.8 microg/L) and a normal serum IGF-I concentration (309+/-142 ng/mL) for their age. During childhood and early adolescence, boys with Robinow syndrome had low basal testosterone and a low testosterone response to HCG stimulation (3,000 IU/m2/d intramuscularly [IM] for 3 days). However, their basal and GnRH-stimulated FSH concentrations were normal. Two girls (Tanner II breast development) had a normal serum estradiol (E2) concentration but high LH and FSH responses to GnRH stimulation. This suggested either defective feedback of E2 on the hypothalamic-pituitary axis or hyporesponsiveness of the ovaries to gonadotropin. Four weeks of HCG therapy (2,500 IU/m2 IM twice weekly) in three boys with Robinow syndrome increased the penile length and testicular volume, denoting a significant Leydig cell response to prolonged HCG stimulation and the presence of functioning androgen receptors. It is suggested that HCG and/or testosterone therapy during infancy may improve the severe micropenis in these patients.

Empty sellae, impaired testosterone secretion, and defective hypothalamic-pituitary growth and gonadal axes in children with Bardet-Biedl syndrome

We evaluated growth parameters and hypothalamic-pituitary-gonadal and growth functions in five children with Bardet-Biedl syndrome (BBS). Three of the five children had stature below the fifth percentile for age. Their growth hormone (GH) response to provocation was defective, and computed tomographic (CT) scanning revealed empty sellae in all of them. All the children were obese (body mass index [BMI] > 95th percentile for age). Three had hypercholesterolemia. Their basal serum testosterone concentration and testosterone response to 3-day human chorionic gonadotropin (HCG) stimulation were significantly lower than the levels in 12 age-matched obese normal children. Testosterone secretion failed to respond to HCG therapy for 4 weeks. Both basal gonadotropin levels (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) and gonadotropin responses to LH-releasing hormone (LHRH) stimulation were normal and did not differ among the two study groups. It appears that primary hypogonadism is a cardinal feature of BBS, and it may be accompanied by hypothalamic and pituitary abnormalities.