Band 23, Heft 9

ABSTRACT Endocrine disrupting compounds (EDCs) alter the function of the endocrine system and consequently cause adverse health effects. Phytoestrogens, natural plant compounds abundantly found in soy and soy products, behave as weak estrogen mimics or as antiestrogens. They are considered to be EDCs, and have some beneficial effects on health, including reducing the risk of breast cancer and improving metabolic parameters. However, the supporting evidence that consumption of phytoestrogens is beneficial is indirect and inconsistent. Lifetime exposure to estrogenic substances, especially during critical periods of development, has been associated with formation of malignancies and several anomalies of the reproductive systems. Phytoestrogen consumption in infants, through soy-based formulas, is of particular concern. Prospective epidemiological studies for the evaluation of the effect of phytoestrogens alone, and in combination with other estrogenic chemicals, are lacking, yet possible adverse effects should not be taken lightly.

ABSTRACT Background : A 15 year old girl with Prader-Willi Syndrome (PWS) died of gastric rupture. Systematic literature research revealed seven case reports of PWS patients with acute gastric dilatation, two had a lethal course. The objective of this study was to determine if delayed gastric emptying in PWS patients might contribute to gastric dilatation. Methods : Gastric emptying was measured in eight patients with PWS by nucleotid scintigraphy after a standardized test meal. Results : Median age was 17.8 years (range 10.1-19.5). Median BMI of the male patients was 29.5 (range 18.4-34.8), of the female patients 28 (range 20.0-44.8). Half time of gastric emptying was delayed in five of the eight patients (median 78.5 minutes, range 59-134). Conclusion : Scintigraphic measurement of gastric emptying in eight PWS patients revealed delay in comparison to normal values. This might be a risk factor for gastric dilatation and rupture in patients with PWS.

ABSTRACT Objective : To assess fat distribution in non-obese Japanese children and adolescents. Design : 130 non-obese Japanese children (73 boys and 57 girls) from Kikugawa, Hamamatsu were included. The visceral fat area (VFA) and subcutaneous fat area (SFA) were measured by computed tomography (CT) and calculated (in cm 2 ). Subjects were divided into three groups based on age: group A (6-10 years), group B (11-15 years), and group C (16-20 years). Results : Girls had more subcutaneous fat than boys in groups B and C (P<0.01). Boys had an age-dependent increase in visceral fat, but girls did not. In group C (16-20 years), boys had more visceral fat than girls (P<0.01). Conclusions : In non-obese Japanese children, there are significant differences in visceral and subcutaneous fat amounts by age and sex. VFA seems to accumulate more in boys than in girls, and SFA is more prevalent in girls than boys.

ABSTRACT This study was conducted to understand the clinical features and natural course of Taiwanese girls with premature thelarche (PT). The medical records of 91 Taiwanese girls with PT who were diagnosed younger than six and have been regularly followed up for more than two years were reviewed. For comparison, GnRH test was also done in 25 girls with central precocious puberty (CPP) and 10 normal prepubertal girls. The age of onset of these patients was 1.5±1.6 years and 79% of them developed PT before the age of two. Girls with PT had intermediate degree of hypothalamic-pituitary-ovarian activity between prepuberty and CPP with FSH-predominant response to GnRH stimulation. 87% of patients have complete regression of breast development during 3.8±2.5 years' follow-up but 19% of them have progressed to CPP during follow-up. We conclude that Taiwanese girls with PT more often developed within the first two years of life. Activation of hypothalamic-pituitary-gonadal axis with predominant FSH activity during infancy may contribute to its development. In addition, PT is not always a benign self-limited condition, and clinicians should be cautious about pubertal development of these patients.

ABSTRACT Background : Growth hormone (GH), insulin-like growth factor-1 (IGF-1), and IGF-binding protein-3 (IGFBP-3) are used in the neonatal period for evaluation of diseases such as GH deficiency, intrauterine growth restriction, and hypoglycemia. However, GH level has been reported as a single value during the neonatal period. In this study, we attempted to determine the changes of GH, IGF-1, and IGFBP-3 in the neonatal period for each week. Methods : One hundred and two appropriate-for-gestational age (AGA) term neonates who did not have any diseases that would interfere with GH-IGF axis were included in this cross-sectional study. Blood samples were collected and serum GH, IGF-1 and IGFBP-3 levels were measured by immunoradiometric analysis (IRMA) and weekly values were obtained for the first postnatal four weeks. Results : We showed that GH level [median (1 st -3 rd quartile)] decreases from the first to the fourth postnatal week [25.1 (18.5-37.4); 17.2 (13.2-22.8); 17.6 (12.2-20.2); 14.4 (6.60-19.8) ng/mL, respectively)], IGF-1 and IGFBP-3 levels [median (1 st -3 rd quartile)] increase [41.7 (18.0-70.0); 55.9 (39.0-103); 53.0 (40.0-97.7); 71.7 (44.3-137) and 1852 (1597-2451); 2430 (1645-2838); 2841 (2280-3675); 3018 (2151-4189) ng/mL, respectively)]. Conclusions : GH, IGF-1 and IGFBP-3 values can be evaluated for each week separately instead of for the entire neonatal period.

ABSTRACT Diabetes mellitus type 1 might interfere with pubertal development. Particularly, longterm metabolic control and intensity of insulin treatment have been reported to contribute to a delay in pubertal onset. Data on somatic development in diabetic children are conflicting; therefore we studied bone age in 1788 children from Germany and Austria with type 1 diabetes. Bone age was retarded by -0.27 ± 1.1 years in the whole group, but particularly in the adolescents at the end of puberty (>16 years; -0.76±1.29y). Bone age delay was more pronounced in boys, and in children with longterm median HbA1c levels of 7.5 – 9.0%. No associations were found with current HbA1c levels or the intensity of insulin treatment. Bone age determinations in diabetic children should only be performed when clinical signs of impaired somatic development are present. In addition, the potential influence of diabetes on bone development needs to be considered in the interpretation of carpograms.

ABSTRACT Background : Fetal thyroid function and the hypothalamopituitary-thyroid axis continue to mature throughout pregnancy. Therefore, thyroid hormone levels of premature infants differ from those of mature ones. Our primary objective was to evaluate the reference values of serum thyroid hormones in preterm infants born before 33 wk gestation. The second objective was to define a cut-off value for transient hypothyroxinemia of prematurity (THOP) according to gestational age and association of THOP with postnatal characteristics in these infants. Subjects and methods: We recruited a cohort of 200 infants (26–32 wk gestation) admitted to neonatal intensive care units (NICU) between March 2008 and February 2009. We assessed serum levels of thyroid hormones and thyrotropin (TSH), at 1 st , 2 nd , and 3 rd -4 th wk of life. Thyroid-binding globulin (TBG), thyroglobulin (Tg), and urinary iodine values were also measured at the 1 st wk of life. The infants were divided into two groups according to gestational ages; group 1: 26-29 wk and group 2: 30-32 wk. Association of THOP with postnatal characteristics of these infants were evaluated. Results : TT4 and TT3 values steadily increased from 1 st wk to 3rd-4 th wk while FT4 value did not significantly changed. FT3 value slightly decreased from 1 st wk to 2 nd wk and not significantly changed after this period. TSH value steadily decreased from 1 st wk to 3rd-4 th wk. For all postnatal ages, TT4, TT3, and FT3 values were lower in the lower gestational age group, while there was no significant difference for FT4 and TSH values between two gestational age groups. THOP rate decreased from first wk (24.0%, n=47) to 3 rd -4 th (14.0%, n=24) in all infants. When adjusted for age, THOP was associated with need for mechanical ventilation (P=0.03, OR:0.65, CI 95% 0.4-0.9) and for having respiratory distress syndrome (RDS) (P=0.02, OR:0.61 CI95%: 0.4-0.9). Longer hospital stay (P=0.006, OR:0.96, CI 95% 0.94-0.99) was also found to be associated with THOP. Conclusions : In preterm infants below 30 wk, thyroid hormones were lower and urinary iodine values were higher compared to infants with older gestational age. THOP at the first wk of life may convey important prognostic information about neonatal morbidity and length of hospitalization stay.

ABSTRACT Background : Adiponectin has been shown to be inversely related to birth weight in schoolchildren and adolescents. However, the available information regarding a relation between birth size and adiponectin in infants and preschoolers is limited. Methods : A longitudinal study was conducted among healthy Japanese children, and serum adiponectin levels were measured at consecutive visits. The effect of sex, gestational age, birth length, birth weight, or placental weight on adiponectin was analyzed by using a linear mixed model for repeated measures. Results : Eighty-three children were evaluated. The age range at the first visit was 0.07–5.3 years. A total number of 227 measurements were made, 1–12 per subject (median, 3) and the duration of follow-up ranged from 1 day to 2.3 years (median, 1.0 years). The subjects were divided into four groups according to the age at the first visit: (1) 0–2 months (n = 29), (2) 3 months to 1 year (n = 17), (3) 2–3 years (n = 19) and (4) 4–5 years (n = 18). In the multivariate model, birth length (coefficient = 3.94, 95% CI, 0.23–7.65) was an independent predictor of serum adiponectin levels in subjects aged 0–2 months. Gestational age (3.53, 1.14–5.92), birth length (–2.71, –4.90 to –0.53) and placental weight (2.58, 0.86–4.29) were independent predictors of serum adiponectin levels in subjects aged 4–5 years. Conclusion : Birth length, not birth weight, is an independent predictor of serum adiponectin levels in Japanese young children.

ABSTRACT Steroid 21-hydroxylase deficiency is a most frequent cause of congenital adrenal hyperplasia (CAH), due to mutations in the CYP21A2 gene. Approximately 75% of patients with classical form of CAH have severe impairment of 21-hydroxylase activity. Methods: We have performed direct molecular diagnosis of the nine common CYP21A2 point mutations in 24 Macedonian CAH patients from 20 unrelated families, using differential PCR and ACRS. Results: Five of the analysed mutations were detected in 23 patients: 15 patients were homozygous for one mutation, four patients were compound heterozygotes and four patients were heterozygotes. The most common was IVS2-13A/C mutation found in 60.4% of the alleles, followed by Q318X (22.9%), R356W (4.2%), V281L (2.1%) and P30L (2.1%). The concordance of genotype to phenotype in the patients was 83.3% with complete concordance in the genotypes predicting the SW and SV phenotype. Conclusion: The distribution of the detected mutations in the Macedonian CAH patients was similar with those described in other European populations. The genotype-phenotype correlation observed in our patients strengthens the fact that the genotype cannot be completely predictive of phenotype.

ABSTRACT Benign transient hyperphosphatasemia of infancy (BTH) is a condition characterized by disproportionately high levels of serum alkaline phosphatase (SAP). We report 4 cases of healthy patients with an elevated SAP. The mean age of the patients was 33 (14-52) months, with three females and one male. All children had a normal physical exam and anthropometric measures. The maximum values of serum alkaline phosphatase recorded in the 4 patients were: 11900, 6500, 9700 and 7600 UI/L respectively, with the rest of the laboratory exams and diagnostic images being normal. The clinical course of all the patients was favourable and no patient presented signs of symptoms of illness. Blood was drawn on 6 occasions in patients 1 and 5 occasions in the rest. Benign transient hyperphosphatasemia of infancy was diagnosed. It is important to know the characteristics of this condition to order the necessary amount of complementary studies.

ABSTRACT Infantile malignant osteopetrosis is a rare and genetically autosomal recessive disease characterized by osteoclast malfunction. Decreased osteoclast-mediated bone resorption may be inadequate to maintain a normal serum calcium-phosphorus balance in the extracellular fluid. Consequently, despite markedly positive total body calcium balance, patients with osteopetrosis paradoxically could develop rickets. The concurrence of osteopetrosis and rickets has been termed “osteopetrorickets”. We report here a 3-month-old boy who was diagnosed with osteopetrorickets with clinical features. Although osteopetrorickets is defined as a rare paradoxical feature of infantile malignant osteopetrosis in some studies, it seems to be more common than was previously known. Coexistence of rickets and osteopetrosis may have adverse effects on clinical response to stem cell transplantation. Therefore, a diagnosis of rickets must be considered in patients with osteopetrosis and then for better results, prior to the SCT, the rickets should be completely treated.

ABSTRACT To assess the effect of human growth hormone (hGH) therapy and other factors on tumor recurrence after treatment of pediatric brain tumors (BTs), we retrospectively analyzed data from 108 craniopharyngioma, medulloblastoma, and ependymoma patients. Risk factors were identified using multifactorial univariate regression analysis. Recurrences occurred in 41 and second malignant neoplasms in 4 patients. There were significant correlations for completeness of tumor removal and recurrence-free survival (RFS). 13/44 hGH-treated and 28/59 non-hGH-treated children relapsed. This difference was found only for medulloblastomas and accounted for by higher rates of incomplete tumor removal in non-hGH patients. Craniopharyngioma recurrence correlated only with RFS. Malignant BT recurrence correlated with completeness of tumor removal, chemotherapy, and RFS. 4 children developed SMNs, 3/4 after hGH therapy. Our regression model yielded accurate within-sample prediction of recurrence for 90% of the study population. We conclude that hGH therapy after treatment of pediatric BTs does not increase tumor recurrence risk.

ABSTRACT Objective : The aim of this study was to describe insulin resistance and the metabolic syndrome in obese children and adolescents. Subjects : The cohort consisted of 518 patients, 250 boys, 268 girls, age ± sd: 11.8 ± 3.2 years, BMIsds ± sd: 2.94 ± 0.5. A standard OGTT was performed. Results : Impaired glucose tolerance was found in 9.4% of the boys and 5.5% of the girls. Impaired fasting glucose was found in 12.4% of the boys and 11.6% of the girls. The metabolic syndrome was present in 13.9% of children of 10 years or older. The proportion in which the metabolic syndrome was diagnosed was essentially not altered when pubertal groups were used instead of age groups. Conclusion : Both impaired fasting glucose and impaired glucose tolerance as well as the metabolic syndrome are highly prevalent among obese children and adolescents.

ABSTRACT Background : Acquired primary hypothyroidism in neonates and infants under 3 years of age is very rare. Herein we report the case of an infant female affected by acquired autoimmune hypothyroidism. Patient report : The infant was transferred to the Pediatric Clinic, University of Catania, Italy for evaluation of dysmorphic features, growth and motor retardation, and hypothyroidism on laboratory testing. Neonatal screening test for TSH and PKU was negative. An ultrasound scan showed a non-homogeneous thyroid gland which was increased in volume. Based on the laboratory results, the diagnosis of autoimmune hypothyroidism was made and L-thyroxine treatment was initiated at 50 μg/day. Conclusions : Autoimmune hypothyroidism in infancy is rare, but early recognition and therapy are essential to prevent neurologic damage and growth deficits. In this patient we would like to underline the early age of appearance of autoimmune thyroid disease and the possible onset of pathologic events before birth.

ABSTRACT Chronic administration of antiepileptic agents such as phenytoin can increase clearance rates of cortisol and synthetic glucocorticoids through hepatic microsomal enzyme induction. However, data concerning an adverse interaction between antiepileptic and steroid drugs are scarce. We herein report an adolescent boy with primary adrenal insufficiency that developed glucocorticoid deficiency after added phenytoin treatment. The patient had an increased requirement for hydrocortisone replacement, and two episodes of vomiting, hyponatremia and mild hypoglycemia. His ACTH levels were markedly elevated. Fifteen days after stopping phenytoin, his serum ACTH concentration returned to normal range. Even though the hydrocortisone dose was gradually decreased, hyponatremia and vomiting have not recurred. In conclusion, we suggest that drugs such as phenytoin affecting hepatic clearance of synthetic glucocorticoids and mineralocorticoids should not be preferred for therapy in patients with adrenal insufficiency. If their use is vital, one should be aware of increased replacement requirements for steroid drugs, and patients should be closely monitored.

ABSTRACT Background : Acquired von Willebrand Syndrome (AvWS) is a rare bleeding disorder associated with various underlying conditions. Many case reports have been published so far on bleeding tendency in hypothyroidism resembling AvWS. Objective : This study was designed to define the relationship between hypothyroidism and AvWS and to investigate the effects of L-thyroxine treatment. Subjects : Twenty four hypothyroid patients were included in the study. Nineteen patients were evaluated during treatment, 5 patients were evaluated before hormone replacement. Methods : Complete coagulation screening tests including levels of von Willebrand Factor antigen (vWF:Ag) and functional activity (vWF:RCo) were measured by thrombocyte aggregometer. Results : We demonstrated low vWF:Ag and vWF:RCo in 13 patients. Two of the 13 patients were diagnosed as AvWS, while another 2 patients were diagnosed as hereditary vWD Type 1. The remaining patients are still being followed-up. Conclusion : We would like to attract the attention of paediatricians to the possibility of bleeding due to decreased activity of vWF in hypothyroid children.

ABSTRACT Background : Familial hypocalciuric hypercalcemia (FHH) results from a mutation of the calcium sensing receptor ( CASR ) gene and typically presents as asymptomatic hypercalcemia with inappropriately low urinary calcium excretion and normal or mildly elevated levels of parathyroid hormone. Objective : To describe a case of FHH associated with Kabuki syndrome and Crohn disease. Method : Genomic DNA was screened for CASR mutations and a retrospective chart review was performed. Results : Heterozygosity was observed in exon 3, which encodes a portion of the extra-cellular domain. Sequencing revealed a n.476T>G nucleotide transversion, predicting a non-conservative substitution of arginine for leucine at codon 159 (p.L159R). Conclusion : An association between Kabuki syndrome and autoimmune disease has been described in the literature, which may explain the connection between Kabuki syndrome and Crohn disease. However, it remains unclear if there is a link between FHH, Kabuki syndrome and Crohn disease in this case.