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Unlabelled: So far in Europe, no studies have been published on the structuring of medical care for obese children and adolescents. Besides anthropometric parameters, evaluations of the cardiovascular risk factors hypertension, dyslipidaemia, impaired glucose metabolism and treatment modalities were documented in a standardised multicentre evaluation survey (APV) of 18 primarily outpatient and nine rehabilitation institutions. In total, 3837 children (aged 2-20 years) took part in the years 2000 up to March 2003, of whom 1985 were treated in outpatient institutions and 1852 in rehabilitation institutions. Of these children, 10% were overweight, 37% obese, 49% extremely obese and 4% of normal weight at initial presentation. The frequencies of diagnostic procedures performed and documented were low (measurement of blood pressure 43%, lipids 40%, glucose metabolism 21%). In the subgroup of obese children who were screened for cardiovascular risk factors, 23% suffered from hypertension, 11% displayed increased cholesterol, 9% increased low-density lipoprotein-cholesterol, 29% increased triglycerides, 11% decreased high-density lipoprotein-cholesterol and 6% had impaired glucose metabolism., Conclusion: Despite the high prevalence of cardiovascular risk factors in obese children and adolescents confirmed in this report, diagnostic procedures failed in a considerable percentage even in specialised treatment centres for obese children and adolescents. In future, the feedback based on standardised evaluation of diagnostic and treatment procedures should aim to improve the quality of medical care.

New pharmaceutical technologies had created either enthusiastic hope for major improvements in the medical treatment or major doubts on the use of research data and wrongdoing in clinical trials. Clinical investigators have to consider methodological and scientific principles, to stick to ethical rules, national law and international guidelines. With the invention of General Clinical Research Centres the necessary infrastructure in hospitals with well-trained personnel and the availability of laboratory, clinical and supporting service has been created in the US. Taking GCRC as a model to improve the clinical research in pediatrics, a formal collaboration between the Department of Pediatrics and the Institute for Biometry and Medical Informatics was established at the Otto-von-Guericke-University Magdeburg in 2001. Both nation-wide quality assurance programmes in Pediatric Endocrinology and clinical trials according to the principles of good clinical practice ('GCP') were planned and currently performed. Thus with the resources of the Medical faculty and additional project bound finances the necessary infrastructure has been developed.

Unlabelled: Erythema necrolyticum migrans (ENM) usually presents as a cutaneous paraneoplastic phenomenon which is in most cases associated with a glucagon-producing tumour. Here it is for the first time described as a side-effect of glucagon treatment in persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI). In both patients, the skin lesions disappeared after discontinuation of glucagon administration. In the first child the erythema resolved without scarring within 10 days after glucagon was substituted with other medication while in the second patient healing followed subtotal pancreatectomy which rendered glucagon infusion unnecessary. Initially the clinical resemblance to atopic dermatitis is prone to cause diagnostic errors, especially in this age group., Conclusion: erythema necrolyticum migrans should be considered as a differential diagnosis in patients who develop erythematosquamous skin lesions under glucagon treatment.

History and Clinical Findings: In a 31-year-old patient a conventional X-ray was performed due to persistent pain at the lumbar spine level after a cesarean section. It revealed compression fractures of L2 and L3. Besides very clear clinical signs of hypercortisolism, multiple hyperpigmentations and naevi in the patient's face including the lips and the conjunctiva of the right eye were visible, suggesting a Carney complex., Investigations: Insuppressible cortisol levels confirmed an adrenal origin of hypercortisolism. A selective catheterization of adrenal veins supported the presence of bilateral adrenal cortisol production. The computed tomography showed nodular lesions in the right and a hyperplasia of the left adrenal gland., Treatment and Course: A bilateral adrenalectomy was performed and a primary pigmented nodular adrenal hyperplasia was confirmed histologically. Clinical signs of hypercortisolism rapidly resolved after adrenalectomy., Conclusions: The diagnosis of Cushing's syndrome as a part of Carney complex was diagnosed at the end of a pregnancy although signs of hypercortisolism were present a long time before. The rare diagnosis of Carney complex should be considered in patients exhibiting symptoms of hypercortisolim and the typical clinical signs (hyperpigmentations).

Background: Alterations in the insulin-like growth factor (IGF) system have been reported for different tumours. They are of particular interest in the search for new prognostic and therapeutic approaches in cancer. In childhood acute lymphoblastic leukaemia (ALL) the amount of "tumour mass" at diagnosis can exceed 1 kg. To understand the endocrine, paracrine, and autocrine potential of the malignant transformed progenitor cells, the ability of these cells to express components of the IGF system needs to be investigated., Aim: To characterise the expression pattern of genes of the IGF system in malignant lymphoblasts of children suffering from ALL., Methods: Reverse transcription polymerase chain reaction of Ficoll separated mononuclear cells from 142 children with ALL, 127 cord blood samples, and 55 blood samples of age matched controls were studied., Results: The expression of IGF-I, IGF-II, IGF binding protein 5 (IGFBP-5), and CTGF (IGFBP-rP2) was seen in a higher proportion of mononuclear cells of patients with ALL than in controls. Patients with ALL who were in continuous remission had a lower percentage of IGFBP-2 and IGFBP-3 expressing mononuclear cells at diagnosis than did those who developed a relapse. Only malignant lymphoblasts of B cell origin showed expression of CTGF (IGFBP-rP2). Malignant lymphoblasts of T cell origin more often expressed IGFBP-2 and IGFBP-5, whereas IGF-II and IGFBP-3 expression was seen more often in lymphoblasts of B cell origin., Conclusions: Malignant lymphoblasts of patients with ALL express components of the IGF system and therefore promote their own growth in an autocrine, paracrine, or endocrine manner. Whether these components will be useful as prognostic factors in the stratification of ALL treatment in children needs to be evaluated.

Unlabelled: The short stature homeobox-containing gene (SHOX) on the short arm of the X and Y chromosomes is an important determining factor of stature phenotype. Absence of the SHOX gene is a main cause for short stature in patients with Turner syndrome. Mutations of the SHOX gene can also be responsible for Léri-Weill syndrome (dyschondrosteosis). The aim of this study was to determine the frequency of SHOX deletions in short stature children and to delineate indications for SHOX deletion screening. Out of 50 probands, 35 had idiopathic short stature, 12 cases showed additional anomalies of the forearms (in particular Madelung deformity) and three patients were affected by a congenital heart defect. Chromosomal investigations with fluoresence in situ hybridisation did not reveal a SHOX deletion in any patient with idiopathic short stature. In five of the 12 patients (41.7%) with anomalies of the forearms, a SHOX deletion on one sex chromosome could be detected. No deletion was observed in the three cases with additional heart defects., Conclusion: The frequency of short stature homeobox-containing gene deletions in patients with idiopathic short stature appears to be very low and does not require a fluorescence in situ hybridisation analysis. Short stature in association with anomalies of the forearms such as Madelung deformity makes a deletion more probable and therefore screening for such deletions is recommended in these cases.

We report on an 18-year-old female with de novo tandem duplication Xq23-->Xq27-28. The breakpoints of the duplication segment have been mapped by FISH using a panel of locus specific YACs. Despite selective inactivation of the aberrant X chromosome, proven by a combination of molecular and cytogenetic studies, the patient exhibits mental retardation, dysmorphic features and short stature. Possible mechanisms explaining this unexpected finding are discussed., (Copyright 2001 S. Karger AG, Basel)

Unlabelled: Endocrine dysfunction and damage of the epiphysial growth plates have been reported as late effects of antileukaemic treatment during childhood. It is a common opinion that cranial irradiation (CI) is the most important factor for blunted growth. Accordingly, recent therapeutic strategies in acute lymphoblastic leukaemia (ALL) avoid cranial irradiation. Here we analysed longitudinal data on growth and puberty of 54 children in first complete remission, who were treated with 18 Gy CI or not submitted to radiotherapy. Two chemotherapeutic protocols were compared which were similar during the induction period but differed in the intensity of maintenance therapy. In cranial irradiated patients both in males and females the pubertal growth spurt started at a mean age of 1.2 years (SD: 0.93 years) earlier than controls. Age at diagnosis and age at pubertal growth spurt were significantly correlated (r = 0.35, P = 0.017). Similarly, menarche occurred at a mean age (n = 22) of 12.1 years and was correlated with the age at start of therapy in girls who were treated with 18 Gy CI (r = 0.61, P = 0.01). Adult height was reached spontaneously in 30 patients treated during prepubertal age and in 10 treated shortly before or during puberty. In all prepubertal patients treated for 2-3 years with intensive maintenance therapy blunted growth resulted in a significant loss of -1.85 H-SDS (median, P = 0.0051) compared to height at diagnosis. However, if continuation treatment used only methotrexate and 6-mercaptopurine (i.e. BFM protocol) final height equalled projected adult height, despite 18 Gy CI., Conclusions: (1) multiagent chemotherapy is of major impact for growth and puberty; (2) 18 Gy cranial irradiation is below the critical dosage responsible for blunted growth; (3) loss in potential growth might be prevented by current CT strategies; (4) onset of puberty depends on age when antileukaemic therapy is applied.

A total of 74 children suffering from acute lymphoblastic leukaemia (ALL) or non-Hodgkin lymphoma (NHL) were involved in a retrospective analysis of their physical growth during and after the therapy. Out of this total number, 54 children were subjected to radiochemotherapy in compliance with the VII/(81) scheme, and another 20 children in compliance with the LSA2L2 scheme. At the beginning of the therapy the average height-standard deviation score (H-SDS) for both groups of patients corresponded with the population average. The patients subjected to the VII/(81) scheme showed, throughout the observation period of five years from the beginning of the therapy, a height normal for their age group. Contrary to this observation, the patients subjected to the LSA2L2 scheme experienced a significantly different growth in the period under observation and continually lost height in comparison to the normal population. The same results were experienced with a smaller group of patients whose growth was followed up for eight years from the beginning of therapy. 16 patients (VII/81 n = 4/LSA2L2 n = 12) reached their final height. For the patients of the VII/(81) scheme the final height showed an average H-SDS of 0.27 and for the patients of the LSA2L2 scheme of -1.22 (p = 0.068). Considering that the same cranial radiotherapy (max. 18 Gy for both schemes) and a comparable intensive induction therapy were applied, it must be concluded that the intensity and duration of the maintenance treatment are the critical factors initiating a different growth behaviour of the two groups subjected to radiochemotherapeutical schemes.

The IGF regulatory system has been shown to mediate mitogenic effects during normal growth and tumor proliferation. The bioavailability of both IGF-I and IGF-II is regulated by at least six specific IGF binding proteins (IGFBPs). Whereas IGFBP-3 is the main IGFBP postnatally, IGFBP-2 is the predominant IGFBP during fetal life. In addition, IGFBP-2 is expressed in a range of tumor cell lines. In order to investigate the IGF regulatory pathway in malignancies we analyzed by RIA serum samples of 49 children with leukemia, Non-Hodgkins' Lymphoma (NHL) or solid tumors at the time of diagnosis. Serum concentrations of IGF-I (mean/range: -2.4/0.3 to -9.9 SDS), IGF-II (-2.5/0.2 to -5.6 SDS) and IGFBP-3 (-1.3/2.2 to -6.8 SDS) were significantly decreased, but IGFBP-2 (3.2/-0.9 to 8.6 SDS) was elevated. Both absolute as well as SDS values of IGF-I, -II and the sum of IGF-I and IGF-II (r = -0.49, p < 0.01) were inversely correlated with IGFBP-2. Serum levels of the growth factors IGF-I and IGF-II were significantly decreased in different types of malignancies to concentrations usually seen only in patients with growth hormone deficiency or during starvation. However, the elevated levels of IGFBP-2 in 70% of our patients exceeded by far those in growth hormone deficiency. Furthermore, in this study we could demonstrate that serum levels of IGF-I and IGF-II were inversely correlated to IGFBP-2 independent on the type of malignancy, indicating a common regulatory mechanism of the IGF signaling pathway in these diseases.

The article reviews the history of hypoglycaemia in children, documenting its importance in the genesis of neurological damage while attacking conventional dogmas on postnatal changes and the definitions of hypoglycaemia. A great deal of further research needs to be performed on the levels of blood glucose leading to "functional" neurological changes, as well as further research on the effects of hypoglycaemia on NMDA receptors. Of greatest practical importance would be new and better monitoring techniques to obtain more precise biochemical data that are instantly available to the clinical staff at the bedside. Finally, modern technology can be applied in defining one particular cause of what may be regarded as "idiopathic hypoglycaemia". A knowledge of basic biochemical processes can be used to predict patterns of metabolite profiles which are pathognomonic of the underlying disease.

Occurrence of hypoglycaemia is directly connected to fuel balance. Compared to free fatty acids, glucose is rapidly exhausted. Therefore, besides disturbances in available glucose (i.e. defects in gluconeogenesis or glycogenolysis) as well as their hormonal control, defects of beta-oxidation might be possible causes. According to recent investigations they occurred with similar frequency. A blood glucose level of 2.6 mmol/l (= 47 mg%) already represents a critical concentration of brain function. Based on pathophysiological concepts concentrations of glucose, free fatty acids, ketone bodies and insulin must be determined from a single plasma sample. Together with case history and clinical symptom findings, these parameters are useful to get a reliable tentative diagnosis. Therefore, descriptions like "ketotic" or "idiopathic" hypoglycaemia can be avoided and suitable treatment can be started. Suspected diagnosis must be confirmed by means of chromatographic, enzymatic, and if necessary histological investigations. Successful treatment depends mainly on early diagnosis. This is of importance in case of surgery in organic hyperinsulinism, but likewise for advisory help to families with infants suffering from beta-oxidation defects, to avoid prolonged fasting.

A specific radioimmunoassay for human IGFBP-2 was developed using a polyclonal antiserum directed against a partial sequence (hIGFBP-2(176-190)). The tracer was prepared by radioiodination of a [Tyr]o-hIGFBP-2(176-190) derivative. The assay was used to study IGFBP-2 levels in numerous clinical and experimental situations. There was little circadian fluctuations of serum level which showed a marked age-dependence with high levels at birth and senescence and low levels during puberty. Decreased IGFBP-2 levels were present in untreated insulin-dependent diabetes mellitus (IDDM), in acromegaly and during dexamethasone suppression test. GH deficiency, fasting, IGF-I administration to patients with GH receptor deficiency, hepatic failure and insulinomas caused a moderate increase of serum IGFBP-2. Markedly elevated levels were found in chronic renal failure, non-islet cell tumour induced hypoglycemia and leukaemias. The fact that all possible relationships between insulin secretion and IGFBP-2 levels could be identified suggests that insulin is not a major regulator. In general, there was an inverse relationship with serum IGFBP-3 (except IDDM) and IGFBP-2 levels were high in situations where free IGF-II should be expected to be high. The tentative conclusion would therefore be that free IGF-II is a major regulator of circulating IGFBP-2.

The intellectual development of 105 children with congenital hypothyroidism was assessed. In 70 children the assessment was repeated in several times. Correlations between development of intelligence and influence of biological and/or psychosocial risks were verified.

57 children with congenital, clinical diagnosed hypothyroidism were assessed with the Luria-Nebraska-Neuropsychological Battery-Children's Revision. The results of the psychomotor assessment were in conformity with the mental development. Univariate correlations between begin of therapy and mental development were not found in all groups.

Changes in bone structure like chondronecrosis and osteonecrosis occurred in a group of adolescent athletes especially gymnasts. To determine the etiology calcium, inorganic phosphorus, alkaline phosphatase activity and levels of 25-OH-Vit D were investigated. Single low calcium values were present in nearly the half of the athletes. In 37% the vitamin-D-levels were depressed. Such results were found in athletes with and without changes in bone structure. A vitamin D supplementation is recommended if low vitamin D levels are found. Vitamin D deficiency is not the only reason for the disturbances of the bone. Other factors are to take in consideration like nutrition, delayed bone maturation and its consequences, and the mechanical load.

To assess effects of chemo- and radiotherapy on the endocrine system 31 children with acute leukaemia and NHL (3 AML, 24 ALL, 4 NHL) were investigated. Children were treated according to modified BFM protocols. 25 patients were before, 5 during and one after puberty (2 to 16 y.). Before treatment, during induction therapy, during cranial irradiation, 4-6 weeks later and during maintenance therapy the following hormone values were estimated: TSH and prolactin basal and 30 min. after TRH (5 micrograms/kg i.v.), LH and FSH basal. Final investigations included total T4 and T3. In conclusion, chemo- und radiotherapy lead to transient elevations of TSH and prolactin in a few patients, but without proof for permanent disorders. Due to the fact all 3 patients with hyperprolactinaemia showed high prolactin levels (700 to 770 mU/l) already before treatment it is unlikely therapy was the main cause of these observed alterations. Although basal LH and FSH values were in normal ranges for age the increasing values after cranial irradiation in prepubertal children may reflect a possible initiation of early maturation, reported by others. Furthermore a retrospective growth study was performed in children treated with 2 different protocols. Protocol LSA2L2 used in the past before 1981 resulted in a permanent reduction of the height. In contrast, the mean SDS for height in children treated with protocol VII declined only during the intensive period of treatment. A catch-up growth occured already during maintenance therapy. Prophylactic cranial irradiation with 18 Gy in our patients under protocol LSA2L2 did not affect growth during the first 5 years after diagnosis.

Adult height in 20 patients, successfully treated for childhood leukemia, led to reduced height less than 2 standard deviations (S.D.). The loss in projected final height of 0.8 S.D. was mainly due to intensity of maintenance therapy of protocol LSA2L2 (14). In contrast, less intensive maintenance therapy (6-MP and MTX) of protocol BFM 81 (13) showed a transient growth spurt. Final height equals projected target height. Neither 18-Gy nor gold-198 intrathecally compromised final height.

We report about results of growth-inhibiting treatment in Magdeburg between 1976-1986. In 57 girls closed treatment was studied. Side effects are small. The functional state of the hypothalamo-pituitary axis experienced no negative influence.

Four sporadically occurring characteristic cases of the Proteus syndrome are described. All patients show the main features of the disease, consisting of hemihypertrophy, partial gigantism of hands and/or feet with soft-tissue hypertrophy, plane naevi, subcutaneous tumours, and cranial anomalies. There is a remarkable polymorphism of the symptoms. Anamnestic, clinical and paraclinical findings are shown in tables. Based on a survey of the literature, the main aspects of genetics and of differential diagnosis are discussed.

A single neonatal insulin treatment in the male rat decreases, whereas in the female rat it increases, the number of insulin receptors detected at the age of one month. No difference could be observed in affinity. The extent of the binding of rat, porcine and human insulin is different (the binding of human insulin is the most pronounced), meanwhile the alterations evoked by neonatal treatment are basically identical.