Band 14, Heft 8

Triggered by the Olympic games in Sydney last year, many articles in the press suggested that recombinant human growth hormone (hGH) is one of the most popular performance enhancing drugs used by athletes. However, any hard facts on hGH abuse were provided by Australian customs officers - and not by laboratory assessment. The lack of an official test for hGH doping together with the widespread rumours on its tremendous beneficial effects seem to make this compound attractive for athletes. From a scientific point of view, there are two major questions about this issue: First, as there is no controlled study demonstrating a profound effect of hGH administration on workload capacity in healthy adults, why do athletes use hGH? Second, how could the application of a substance naturally occurring in the human body be detected? Both aspects are discussed in this article.

Numerous studies have reported that offspring whose mothers had type 2 diabetes mellitus (DM) are more likely to develop type 2 DM, impaired glucose tolerance, and obesity at an early age than offspring whose fathers had DM. Exposure to the diabetic intrauterine environment has been shown to be an important risk factor for all these conditions. To what extent transmission of type 2 DM from mother to offspring is the effect of genetic inheritance and to what extent it is the long-term consequence of exposure to maternal hyperglycemia is still uncertain. There are, of course, interactions between the diabetic intrauterine environment and genetics. Several data in experimental animals as well as in humans suggest, however, that exposure of the fetus to the mother’s DM confers a risk for type 2 DM and obesity that is above any genetically transmitted susceptibility. In the Pima Indian population much of the increase in childhood type 2 DM can be attributed to the diabetic intrauterine environment. This suggests that intensive glucose control during pregnancy might have extended beneficial effects, contributing to a decrease in the prevalence of childhood type 2 DM.

We present a family with X-linked adrenal hypoplasia congenita (AHC) due to a truncation mutation in the DAX1 gene. The three patient reports demonstrate variable clinical and biochemical features at presentation. They presented with adrenal crises at 3 years, 4 weeks, and 3 weeks. Mineralocorticoid deficiency preceded glucocorticoid deficiency in patient 3 and an early ultrasound indicated normal sized adrenal tissue. Genetic analysis showed that potential female carriers were unaffected.

Background: Obesity and hypotonia in children with Prader-Willi syndrome (PWS) are accompanied by abnormal body composition resembling a growth hormone (GH) deficient state. Hypothalamic dysfunction in PWS includes decreased GH secretion, suggesting a possible therapeutic role for GH treatment. While recent studies have demonstrated short-term benefits of treatment with GH, a critical question is whether beneficial changes persist or wane with prolonged therapy, and whether these effects on body composition are dose-dependent as seen in adult GH deficiency. Objectives and Methods: After 24 months of GH theapy at a dose of 1 mg/m 2 /day (“standard dose”), the effects of 12 additional months of GH treatment at varying doses (0.3-1.5 mg/m 2 /day) on growth, body composition, strength and agility, pulmonary function, resting energy expenditure (REE), and fat utilization were assessed in 46 children with PWS. Percent body fat, lean muscle mass, and bone mineral density (BMD) were measured by dual X-ray absorptiometry (DXA). Indirect calorimetry was used to determine REE and to calculate respiratory quotient (RQ). Results: During months 24-36 of GH therapy, further changes in body composition (decrease in fat mass, and increase in lean body mass), growth velocity, and REE occurred with standard and higher-dose GH therapy (1.5 mg/m2/day), but not with lower dose GH (0.3 mg/m2/day). Prior improvements in BMD, and strength and agility, which occurred during the initial 24 months, were sustained during the additional 12 months (to 36 months) regardless of dose. Conclusions: Salutary and sustained . GH- induced changes in growth, body composition, and physical function in children with PWS require GH doses of >0.3 mg/m 2 /day. Conversely, BMD increased during the additional 12 months of therapy regardless of GH dose. Lower doses of GH, effective in improving body composition in adults with GHD, do not appear to be effective in children with PWS.

Adrenarche was evaluated in five patients, aged 17.4 ± 3 years, with combined pituitary hormone deficiency (CPHD), caused by a PROP-1 gene defect. Adrenocorticotrophic hormone (ACTH), cortisol and dehydroepiandrosterone sulfate (DHEAS) were determined prior to and following the administration of corticotropinreleasing hormone (CRH) in four of the five patients, while only basal values of ACTH, cortisol and DHEAS were determined in the fifth. In the four patients in whom a CRH test was carried out, the mean basal values of cortisol, ACTH and DHEAS were 289 ±140 nmol/1, 4.5 ±1.7 μmol/1 and 0.26 ± 0.36 μmol/1, respectively. The corresponding post-CRH peak values were 584 ± 204 μmol/1, 12.7 ± 3.9 μmol/1 and 0.43 ± 0.41 μmol/1. In the fifth patient, basal ACTH, cortisol and DHEAS values? were 4 μmol/1, 411 μmol/1, and 2.33 μmol/1, respectively. Thus the basal and post CRH values of DHEAS (a marker of adrenarche) were low for age, while basal and post-CRH cortisol and ACTH values were within normal limits. For the interpretation of these findings two hypotheses can be proposed: 1) The PROP-1 gene is only expressed in the pituitary, and the role of PROP-1 is related to the maturation of the cells which synthesize the presumed adrenal androgen stimulating hormone (AASH). 2) The PROP-1 gene is also expressed in the adrenal cortex and, when defective, the zona reticularis does not function appropriately. Regardless of the interpretation involved, patients with CPHD caused by a PROP-1 gene defect also have insufficient adrenarche. This finding has possible important pathophysiological implications.

Familial glucocorticoid deficiency (FGD) or unresponsiveness to ACTH at the receptor level is a rare autosomal recessive hereditary syndrome characterized by a low cortisol level despite high serum ACTH concentration. Aldosterone levels are normal. The clinical entity generally presents in the first year of life with skin hyperpigmentation and hypoglycemic convulsions. Cortisol response to exogenous ACTH is also absent. Unresponsiveness to ACTH may be due to a mutation in the ACTH receptor; sometimes no mutation is found. We discuss the clinical and laboratory findings and genetic studies in six patients with a diagnosis of FGD. A homozygous V142L mutation was detected in three of the patients and a homozygous D103N mutation was detected in two patients.

This study was planned to investigate the relationship between birth weight and insulinlike growth factor-I (IGF-I),IGF binding protein-3 (IGFBP-3), and leptin levels in neonates with normal growth (appropriate for gestational age: AGA) and retarded growth (small for gestational age: SGA); and to evaluate these growth factors’ effects in early postnatal growth. All newborns were full-term: gestational age 38-41 weeks. Of 50 neonates, 25 were SGA. IGF-I, IGFBP-3 and leptin levels were measured in maternal serum and venous cord blood at birth and at 15 days of life of neonates using specific RIAs. Maternal serum leptin concentrations were significantly higher than cord blood leptin concentrations (p <0.001). Maternal serum IGF-I, IGFBP-3 and leptin levels did not show correlations with birth weight. In contrast, there were significantly positive correlations between birth weight and venous cord blood IGF- I, IGFBP-3 and leptin levels (p <0.001). In the SGA group, the newborns with a slow postnatal growth pattern had lower umbilical cord serum IGF-I levels compared with newborns with a normal growth pattern. A similar result was also found in the AGA group. Similar results were not found for serum leptin and IGFBP-3. In conclusion, cord blood IGF-I, IGFBP-3 and leptin levels play an important role in the regulation of fetal and neonatal growth. It is likely that IGF-I has a more important role than the other factors in early postnatal growth.

In order to evaluate the role of leptin in neonatal hematological parameters, we studied the serum concentrations of leptin in relation to blood hemoglobin, leukocyte and platelet values in 30 healthy term infants. We also studied the serum concentrations of IGF-I and IGFBP-3 in relation to leptin concentrations. The mean concentrations of leptin, IGF-I and IGFBP-3 were 1.63 ± 1.09, 24.65 ± 10.04 and 976.05 ± 214.50, respectively, at birth. A positive correlation was observed between leptin concentrations and birth weights of the infants. As no relationship could be found between concentrations of leptin and blood hemoglobin, leukocyte and platelet values, we could not determine any involvement of leptin in the regulation of physiologial hemoglobin, leukocyte and platelet concentrations at birth.

Treatment with recombinant growth hormone (rhGH), 0.6 IU/kg/week s.c., previously successfully conducted for one year, was continued in 15 (Group A) and 8 (Group B) short thalassemia major patients with reduced GH reserve, for two and three years, respectively. In Group A, height for chronological: age (Ht SDSca) increased significantly (p = 0.021) from the start of treatment, but the positive effect was only apparent because of the concomitant slight worsening of height for bone age (Ht SDSba). Median AHt SDScA/AHt SDSba was <1.0 with respect to both the start (0.87) and the end of the first year of rhGH therapy (0.89). IGF-I levels increased significantly (p = 0.043) compared with values both at the start and at the end of the first year of rhGH therapy. In Group B neither Ht SDSca : nor Ht SDSba differed statistically from starting values, the former having a positive trend and the latter a negative one. Median AHt SDScA/AHt SDSba was 0.92 with respect to the start, and 0.94 with respect to the end of the second year. IGF-I levels increased significantly (p = 0.043) with respect to starting values. Our data show that the encouraging results described from the first year of rhGH treatment did not persist during the second and third years, and we conclude that this is because increase in bone age with continued treatment is equal to, or slightly greater than the height age increase. We propose that patients with thalassemia major with short stature should receive rhGH treatment for only one year, and that more prolonged treatment should be reserved for selected adolescents who have psychological problems due to shortness; for these patients growth acceleration could represent the main goal, even if this leads to a substantially unchanged or slightly decreased final height.

Assessment of the status of iodine prophylaxis was studied in 5,523 schoolchildren randomly selected in all cantons in Bosnia and Herzegovina Federation (BHF). According to the iodine content of household salt samples, all cantons of BHF were divided into two groups: Group A: 95.5% of the salt used is produced in the Tuzla plant, in which the salt is iodized at 5-15 mg Kl/kg salt, and 4.5% of the salt used is produced in the Pag plant, in which the salt is iodized at 20-30 mg Kl/kg of salt, and Group B: 19.9% of the salt used is produced in the Tuzla plant and 80.1% in the Pag plant. In Group A the amount of iodine in salt was significantly lower than in Group B (11.4 mg/kg vs 18.9 mg/kg, P <0.001). In Group A the prevalence of goiter was significantly higher than in Group B (32.6% vs 19.7%, P <0.001). The highest prevalence of goiter was in Bosnian Podrinje Canton (51.2%) and Central Bosnian Canton (42.6%) while the lowest was in West Herzegovina Canton (12.9%). Significantly higher concentrations of urinary iodine were found in Group B than in Group A (82.6 μg/1 vs 75.2 μg/1, P <0.001). In Group A the percentage of urine samples below 50 μg/1 iodine was significantly higher than in Group B (35.6% vs 26.9%, P <0.001), but there was no difference in the percentage of urine samples with iodine values less than 100 μg/1 (70.7 μg/1 vs 68.25 μg/1, P >0.05). We conclude that FBH is an iodine deficient area and that the improvement of iodine prophylaxis is urgently required, primarily by increasing salt iodine content to 20-30 mg/kg, in order to eradicate endemic goiter.

Background: Obesity, increasingly prevalent among children, causes major morbidities, among which is earlier onset of type 2 diabetes mellitus (DM). Methods: We reviewed charts of children aged 3 to 18 years (n=106). The population was divided into four age groups. Anthropomorphic measurements, family history, diet and exercise patterns, and selected endocrine/metabolic measurements were recorded, and descriptive statistics were calculated. Results: Obesity in one or both parents correlated with a higher percent of ideal body weight (IBW) (p=0.01). Fifty-eight percent of the children had first- or second-degree relatives with a history of type 2 DM; 9% had relatives with type 1 DM. Fifty-four percent had dieted and exercised regularly. Mean onset of obesity was at 4.2 ± 0.9 years. Mean cholesterol was elevated at 176 mg/dl. Average BMI was 26.6 in the youngest children (Group 1; normal mean for this age ~15.5), and increased to 37.8 in adolescents (Group 4; normal mean ~21). Elevated TSH was present in <1% of the population. The number of patients with an abnormal insulin: glucose ratio (>1:4) increased with age. Conclusions: Childhood obesity in children is correlated with family histories of obesity and DM. Thyroid dysfunction is seldom found, although mild hypercholesterolemia and insulin insensitivity are prevalent, especially among adolescents.

A 7 year-old boy presenting with growth retardation, fasting hypoglycemia and ketoacidosis was diagnosed as having both idiopathic growth hormone (GH) deficiency and hepatic glycogen synthase (GS) deficiency caused by a homozygous mutation in exon 5 of the liver glycogen synthase gene (GYS-2). After four years of treatment with recombinant human GH, height increased from -4.9 SDS to -2.05 SDS which is near his target height of -1.6 SDS. The GH treatment, however, did not prevent the fasting hypoglycemia. Blood glucose levels were only normalized after avoiding fasting intervals of more than five hours and the frequent feeding of protein-rich meals according to the guidelines for treatment of hepatic GS deficiency.

The drugs used to treat diabetes mellitus are diverse and include several classes. One class is sulfonylureas which primarily cause serum glucose reduction by stimulating the release of preformed insulin from the pancreatic islets. Gliclazide, a second generation sulfonylurea, is used to control glycemic levels in non-insulin- dependent diabetes mellitus. We report a 14 year-old non-diabetic girl who developed hepatitis, hemiplegia and dysphasia after ingestion of an overdose of gliclazide (20 mg/kg/day) in a suicide attempt. Our purpose is to draw attention to the severity of gliclazide-induced neurological signs. To the best of our knowledge, gliclazide-induced hemiplegia and dysphasia have not been previously reported in the literature.

A female newborn was admitted with the symptoms of mild respiratory distress, protruding tongue, hypotonicity, cutis marmorata, sclerema, myxedema, abdominal distension, and feeding problems on the first day of life. She had a huge neck mass, a large anterior and posterior fontanel, and hoarse cry. She had no umbilical hernia or jaundice. A history of maternal potassium iodine (expectorant) usage without doctor’s advice was obtained; the mother had not attended a clinic throughout the pregnancy. On ultrasonographic examination, the thyroid right lobe was 53x31 mm and the left lobe was 34x31 mm. The results of thyroid hormone tests on the first day were as follows: T 3 20 ng/dl (normal: 32-216 ng/dl), T 4 0.9 μg/dl (11.8-22.6 μg/dl), TSH 120 mIU/1 (2.5-13.3 mIU/1). This patient is presented to emphasize the role of hypothyroidism in drug-induced neonatal goiter and to discuss the possibility of a life-threatening effect of congenital goiter, i.e. respiratory tract obstruction.

Background: Idiopathic hypothalamic dysfunction is a rare syndrome that has been described in young children. This syndrome is characterized by a disturbance of thirst regulation with hypernatremia, hyperosmolarity, and altered hypothalamic function. Patient report: At age 6 years the reported patients presented with precocious puberty, by age 12 years she had hypernatremia presumed secondary to central diabetes insipidus and was treated with DDAVP, and at age 14 was identified to have hyperprolactinemia. At age 19 she presented with serum sodium of 185 mg/dl, during an episode of illness associated with dehydration. After hydration, her sodium remained elevated. Arginine vasopressin was measurable but inappropriate to serum sodium, while urinary cyclic AMP response to vasopressin was appropriate. Conclusions: This is the first case of precocious puberty identified in association with the more classic features of idiopathic hypothalamic dysfunction, including later-onset hypernatremia, poor thermoregulatory function, obesity, and hyperprolactinemia.

Neonatal hyperthyroidism generally arises as a result of active maternal Graves’ disease via transplacental passage of thyroid stimulating immunoglobulins (TSI). On occasions, production of these antibodies may continue after thyroid ablation, either surgically or with radioiodine therapy. We present data concerning three patients (two of them twins) whose mothers had previously undergone near-total thyroidectomy prior to conception. Two of the neonates had neonatal hyperthyroidism due to persistence of TSI in the mother, and the third due to relapse of the maternal Graves’ disease during pregnancy. We recommend monitoring TSI during pregnancy in mothers with a history of Graves’ disease, even if they are in a state of post-surgical hypothyroidism.

A 2 month-old male infant presented with severe hypercalcemia due to parathyroid hyperplasia. A total parathyroidectomy and partial heterotopic autotransplantation were carried out. Hypercalcemia recurred two months later. Normocalcemia was re-established after removing one half of the implanted tissue. Despite two separate surgical explorations and several imaging studies, including 99m Tc-sestamibi scintigraphy, ultrasonography, and MRI, only three parathyroid glands were found. Severe pulmonary calcinosis has not previously been reported in children with PHPT. In conclusion, developmental variations of the parathyroid glands may be difficult to identify with present imaging techniques. This may pose difficulties in management of PHPT. The present report describes pulmonary calcinosis as a sequela which can cause additional morbidity in these infants.

A congenital asymmetric crying facies (ACF) is caused by congenital hypoplasia or agenesis of the depressor anguli oris muscle. Associations of this facial defect with major congenital anomalies have been reported, most commonly in the cardiovascular system and less frequently involving the genitourinary, musculoskeletal, cervicofacial, respiratory, and rarely, the endocrine system. It is also well known that congenital hypothyroidism may be associated with other congenital malformations, especially with cardiac defects. Two newborn infants who had ACF associated with congenital heart defect and congenital hypothyroidism are described. To the best of our knowledge the association of ACF and congenital hypothyroidism has not previously been published.