Die Neurofibromatose Typ 1 (NF1) ist eine häufige, autosomal-dominant erbliche Phakomatose. Die Diagnostik, basierend auf den NIH- („National Institutes of Health-“) Kriterien, führt oftmals im Kindesalter zu einer verzögerten Krankheitserkennung.

Fragestellung: Fetale Wachstumsstörungen, welche durch maternales Rauchen in der Schwangerschaft verursacht werden, stehen möglicherweise in Zusammenhang mit der Veränderung einer Reihe endokrinologischer Parameter. Ziel der Arbeit war es, Nabelschnurkonzentrationen metabolisch wirksamer Hormone zum Geburtstermin nach Schwangerschaften ohne und mit maternalem Zigarettenkonsum zu messen.

Background: Red blood cell (RBC) transfusions are associated with the development of retinopathy of prematurity (ROP). During the period of retinal neovascularization a rise of insulin-like growth factor 1 (IGF-1) may trigger rapid growth of new blood vessels. Objectives: To study endocrine factors in RBC transfusions that might be of importance for ROP. Methods: IGF-1, IGF-2 and their binding proteins 1–3 (IGFBP-1–3) were determined by radioimmunoassays in 7 very-low-birthweight (VLBW) infants with ROP ≧ stage 2 receiving a RBC transfusion, in 10 controls (VLBW infants with ROP ≤ stage 1, no transfusion), in supernatants of 7 RBCs and of 5 washed RBCs (WRBC). Results: IGF-1 (mean ± SD) in infants with ROP was 20.0 ± 4.2 µg/l, in controls 35.9 ± 15.2 µg/l (Mann-Whitney U test, p = 0.030). IGF-1 in RBC was 12.88 ± 5.03 µg/l and in WRBC 0.45 ± 0.74 µg/l (average of the three-course washing procedure). IGF-2 in infants with ROP was 485.67 ± 158.73 µg/l, in controls 389.9 ± 102.8 µg/l (not significant), in RBC 109.50 ± 117.89 µg/l, in WRBC 61.07 ± 30.0 µg/l. Except for IGFBP-3 other IGFBPs were barely or not detectable in RBC or WRBC. Conclusions: Considering lower IGF-1 concentrations in preterm infants than in adults (factor 20), the IGF-1 in RBC transfusions is equivalent to a single dose of 1 µg/kg IGF-1 (5–10% of the adult dose with proved metabolic responses). Endocrinological relationships between the donor’s load and the acceptor’s individual features are a new aspect of potential side effects of RBC transfusions. Further research is necessary to clarify the share of the described IGF administration on the development of ROP.

Insulin-like growth factor binding protein (IGFBP)-2 has mitogenic effects in normal and neoplastic cells. The purpose of this study is to examine the diagnostic and prognostic significance of elevated IGFBP-2 levels in children with AML after hematopoietic stem cell transplantation (HSCT) at relapse and continuous complete remission (CCR). In 27 children with AML (mean age 13.6±5.3 years; patients in remission n =15 with relapse n =12) serum parameters of IGFBP-2, IGFBP-3, IGF-I and IGF-II were analyzed up to 18 months after HSCT by RIA. AML-patients with evidence of relapse demonstrated a continuous increase of IGFBP-2 levels during the follow-up. At day 100 after HSCT, IGFBP-2 concentrations were significantly higher in patients with relapse than in children without relapse (7.4±4.0 standard deviation score (SDS) vs 3.9±1.7 SDS; P =0.01). Serum IGFBP-2 was identified as an independent factor for the prediction of relapse. Furthermore, the probability of relapse-free survival (RFS) in patients with IGFBP-2 >4.5 SDS at day 100 after HSCT was 31% compared to patients with IGFBP-2 <4.5 SDS was 72% ( P =0.004). Patients with IGFBP-2 concentration up to 4.5 SDS more likely developed a relapse and had a poorer outcome. Identification of these patients allows a more individualized and aggressive adjuvant treatment and follow-up.

Fragestellung: Literaturangaben weisen auf einen möglichen Einfluss von Ghrelin auf das fetale Wachstum hin. Nach der Geburt ist die Regulation dieses vor wenigen Jahren entdeckten orexigenen Peptids weitgehend unklar. Ziel der Arbeit war es, Serumkonzentrationen von Ghrelin bei frühgeborenen Kindern während der ersten Lebensmonate zu bestimmen.

Fragestellung: Die fetale Ausprägung der insulin-ähnlichen Wachstumsfaktoren (IGF) unterscheidet sich von der Regulation der somatotropen Achse im späteren Lebensalter. Ziel der Studie war es, im Längsschnitt Konzentrationen von IGFs und IGF-Bindungsproteinen (IGFBP) von der Geburt bis zum Ende des ersten Lebensjahres zu messen.

Purpose: Determination of skeletal development in children is important. The most used evaluation method is to study left hand X-ray based on the standards depicted by Greulich & Pyle. The aim of our study was to compare the accuracy of a new sonographically based method with the standard method. Material and Methods: 160 consecutive evaluated children and adolescents (77 male, 83 female) who received a X-ray of the left hand were evaluated. Ultrasound examination of the same hand was performed on the same day using the BonAge (TM) system (Sunlight Medical Ltd., Israel). This system evaluates the relationship between the velocity of the wave (speed of sound) passing thorough the distal radial and ulna epiphysis and growth, using gender- and ethnicity-based algorithms. Three experienced investigators (U1-U3) analysed the X-ray and assigned bone age scores based on the Greulich & Pyle atlas (G&P). The investigators were blinded to the calendary age (CA) of the patient and also for the BonAge (TM) result. Correlation between BonAge system results and G&P was performed using SPSS 12.0.1. Results: In 152 patients BonAge (TM) measurement could be performed successfully. The correlation between the three investigators using the G&P method was between 0.977 and 0.980; correlation between the BonAge system and the investigators (U1-U3) was 0.902 and 0.920. The paired t-test showed no significant differences between the BonAge system and the three investigators and also for the comparison between U1 and U2. There were significant differences between U1 vs. U3 and U2 vs. U3 (p < 0.05). Discussion: The BonAge (TM) device demonstrates the ability to produce an sufficient assessment of bone age using an ultrasound method. The results are correlated with conventional skeletal age evaluation using the G&P method. Advantages of the ultrasound device are objectivity, lack of ionizing radiation, and easy accessibility. In the case of first investigation Xray is necessary to look for dissociated skeletal age, dysplasia, and mineralisation.

Fragestellung: Der Einfluss von Ghrelin auf das fetale und neonatale Wachstum wird in der Literatur kontrovers diskutiert. Ziel der Studie war es, Konzentrationen dieses orexigenen Peptids im Nabelschnurblut und im postnatalen Serum in Zusammenhang mit klinischen Daten sowie biochemischen Parametern zu messen.

PURPOSE:Determination of skeletal development in children is important. The most used evaluation method is to study left hand X-ray based on the standards depicted by Greulich and Pyle. The aim of our study was to compare the accuracy of a new sonographically based method with the standard method.MATERIAL AND METHODS:160 consecutive evaluated children and adolescents (77 male, 83 female) who received a X-ray of the left hand were evaluated. Ultrasound examination of the same hand was performed on the same day using the BonAge system (Sunlight Medical Ltd., Israel). This system evaluates the relationship between the velocity of the wave (speed of sound) passing thorough the distal radial and ulna epiphysis and growth, using gender- and ethnicity-based algorithms. Three experienced investigators (U1-U3) analysed the X-ray and assigned bone age scores based on the Greulich and Pyle atlas (G and P). The investigators were blinded to the calendary age (CA) of the patient and also for the BonAge result. Correlation between BonAge system results and G and P was performed using SPSS 12.0.1.RESULTS:In 152 patients BonAge measurement could be performed successfully. The correlation between the three investigators using the G and P method was between 0.977 and 0.980; correlation between the BonAge system and the investigators (U1-U3) was 0.902 and 0.920. The paired t-test showed no significant differences between the BonAge system and the three investigators and also for the comparison between U1 and U2. There were significant differences between U1 vs. U3 and U2 vs. U3 (p < 0.05).DISCUSSION:The BonAge device demonstrates the ability to produce an sufficient assessment of bone age using an ultrasound method. The results are correlated with conventional skeletal age evaluation using the G and P method. Advantages of the ultrasound device are objectivity, lack of ionizing radiation, and easy accessibility. In the case of first investigation X-ray is necessary to look for dissociated skeletal age, dysplasia, and mineralisation.

Background. Neurofibromatosis type I (NF1) is an frequent autosomal dominant inherited neuroectodermal disorder. The diagnosis is performed using the NIH Consensus criteria from 1987. In childhood, the diagnosis often seems to be difficult because the symptoms are age dependent.Patients and methods. A total of 28 NF1 children and adolescents aged from 6 months to 17 years were investigated over 7 years. Distinct symptoms were documented for the NIH criteria complimented by further signs such as macrocephaly, short stature, skeletal abnormalities, cerebral MRI changes, and mental development.Results. Cafe-au-lait spots and plexiform neurofibroma existed at birth in 68% and 7% of subjects, respectively. In toddler age, macrocephalus (32%) and at school age scoliosis (43%) were frequently found. Cutaneous neurofibroma (43%) often developed at the age of 10 years. Cerebral MRI revealed hyperintense structures in 85% of patients.Conclusion. In children and adolescents, NF1-criteria show an age-dependent appearance leading to further diagnostic characteristics.

Die Neurofibromatose Typ 1 (NF1) ist eine häufige autosomal-dominant erbliche neuroektodermale Erkrankung. Die Diagnose wird nach den NIH-Konsensus-Kriterien von 1987 gestellt. Bei Kindern gestaltet sie sich schwierig, da sich einzelne Merkmale erst entwickeln.

This study compared the cellular uptake of pure conjugated linoleic acid isomers (CLA(9c,11t) and CLA(9c,11c)) to linoleic acid (LA) and their effects on polyunsaturated fatty acid (PUFA) synthesis, its metabolism into conjugated long chain fatty acids (FAs) by desaturation and chain-elongation as well as cell proliferation and the associated anticarcinogenic effects on various human leukemia cell lines (K562, REH, CCRF-CEM and U937 cells). Furthermore, selective effects of this individual isomers of CLA on desaturation steps involved in the biosynthesis of PUFAs associated with cell growth were investigated. CLA isomers supplemented in the culture medium was readily incorporated and esterified into phospholipids (PLs) in the four cell lines in a concentration- and time-dependent manner. The incorporation of the specific CLA isomers in PLs was similar to LA. All four incubating leukemia cells (40 μM CLA for 48 h) showed very high cellular CLA content in PLs (range: 32–63 g FA/100 g total phospholipid fatty acid) affected by the nature of CLA and the cell type. Supplementation with CLA or LA altered also cell membrane composition by n-6 PUFA synthesis. Accordingly, CLA metabolism interferes with LA metabolism. We were able to show that CLA isomers are converted by the leukemia cells of the same metabolic pathway into conjugated diene fatty acids (CDFAs) as LA into non-conjugated PUFAs. In this view, the gas chromatography-flame ionization detector detection of major CDFAs (CD-18:3, CD-20:2 and CD-20:3) in cell membrane of CLA-treated cultures resulted from successive Δ6-desaturation, elongation and Δ5-desaturation of CLA isomers. However, in comparison to LA, relatively lower amounts of elongation and/or desaturation metabolites were detected for CLA(9c,11t), and only minor amounts or trace CDFAs were observed for CLA(9c,11c). Furthermore, CLA(9c,11t) revealed only very low levels of CD-20:4 FA and no CLA(9c,11c)-conversion could be detected. The metabolization of CLA indicated that CLA(9c,11c)60 μM) had the CLA type dependent antiproliferative effects. Thus, the 9cis,11trans- and the 9cis,11cis-CLA isomers regulate cell growth and survival in different leukemia cell types through their existence alone and/or by their inhibitory effects of desaturase activity.

Einleitung: Transfusionen mit Erythrozytenkonzentraten beeinflussen die Ausbildung einer Retinopathia prematurorum (ROP). Während der Periode der retinalen Neovaskularisation kann ein Anstieg von Insulin-like growth factor 1 (IGF-1) das Wachstum neuer Gefäße triggern. Unbekannt ist, ob der Einfluss von Bluttransfusionen auf die ROP über endokrinologische Faktoren vermittelt wird.

Summary: Insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) may play an important role in tumor proliferation. This study aimed to investigate the IGF system in children with acute leukemia prior to and after hematological stem cell transplantation (HSCT). In 51 patients (AML n =27; ALL n =24; mean age 11.2±4.8 years), serum parameters (IGF-I,-II, IGFBP-2,-3) were investigated up to 18 months after HSCT by RIA. Patients with AML showed a significant increase of IGFBP-2 up to 100 days after HSCT (mean ±s.d. prior to HSCT: 3.2±3.6 SDS vs 100 days after HSCT: 5.3°±3.4 SDS, P =0.005). Furthermore, IGF-I and IGFBP-3 were significantly decreased (IGF-I: −0.3±1.5 vs −0.7 ±1.2 SDS, P =0.001; IGFBP-3: −0.3±1.1 vs −1.0±1.1 SDS, P =0.02). Children with AML showed significantly higher IGFBP-2 ( P =0.04) and significantly lower IGF-I ( P =0.03) and IGFBP-3 ( P =0.05) levels than children with ALL at day 100 after HSCT. We conclude that children with acute leukemia show important changes in the IGF system after HSCT. In particular, IGFBP-2 was significantly elevated at day 100 after HSCT. Increased IGFBP-2 and decreased IGF-I and IGFBP-3 may be associated with the increased proliferation rate of transplanted bone marrow.

Mutations of the ATP7A gene (OMIM 300011) lead to the Menkes disease (MD, OMIM 309400) involving impaired brain development, neurological degeneration, connective tissue abnormalities, and high lethality in early infancy. Occipital horn syndrome (OHS, OMIM 304150), a milder phenotype, is also caused by ATP7A gene mutations. In MD patients, an early copper-histidine treatment may prevent the neurological impairment and prolong survival leading to an OHS phenotype. To demonstrate the genotype/phenotype correlation, two male patients are reported with different ATP7A gene mutations and several phenotypes. In the first patient with the MD phenotype, a mutation within the exon 20 (Gln1288Ter) was found producing a stop codon just prior to the highly conserved ATP binding domain. The OHS phenotype of the second patient was caused by a splice site mutation involving the position +6 of intron 6 within a copper binding domain. Small amounts of correctly spliced ATP7A transcript were sufficient to develop the milder OHS phenotype in this patient (OMIM 30001.0006). In conclusion, mutations of the copper transporting P-type ATPase ATP7A gene cause distinct human diseases showing some genotype/phenotype correlation and implications for treatment.

Mutations in the Wilson disease gene ATP7B, a P-type ATPase, are responsible for copper accumulation in the liver and other organs leading to Wilson disease (WD, OMIM 277900). Clinical manifestations of Wilson disease (WD) include chronic liver disease, acute hepatic failure or neuropsychiatric diseases. Since potent medical treatments are available to prevent disabling residual symptoms, early diagnosis is crucial. To demonstrate the clinical course and genetic findings, a male patient with a novel mutation in the ATP7B gene, a 10 base pair insertion in exon 6 (1927ins 10), and a second missense mutation in exon 13 (P992L) is reported. The patient presented with signs of chronic liver disease at the age of 10 years. Clinical findings included hepatomegaly, elevated liver enzymes and coagulopathy. A combination treatment with the copper chelating agent D-penicillamine and zinc acetate was started leading to normalization of liver function and no appearance of neurological signs or Kayser-Fleischer ring after 7 years follow-up. Truncating mutations of the ATP7B gene (insertions, deletions, nonsense mutations) leading to gross loss of C-terminal parts of the protein, thereby probably completely destroying the protein function, may correlate with a hepatic phenotype and early onset as seen in the patient presented.

This report presents changes of IGFs and IGFBPs in a female infant with partial trisomy 9q in the 12th week of life. Studying deficient growth in this hypoplastic infant (birth weight 1405 g, birth length 36 cm) with dysmorphic features, the following changes in IGFs and IGFBPs were detected (microg/l): IGF-I: 26.5 vs 48.1 in healthy infants; IGF-II: 420 vs 728; IGFBP-2: 931 vs 524; IGFBP-3: 800 vs 1070. This demonstrates that IGFs and IGFBPs may reflect individual insufficient growth even at this early age.