Winfried Barthlen

Clinical and Genetic Evaluation of Patients with KATP Channel Mutations from the German Registry for Congenital Hyperinsulinism

Congenital hyperinsulinism (CHI) causes hypoglycemia due to irregular insulin secretion. In infants, a rapid diagnosis and appropriate management to avoid severe hypoglycemia is mandatory. CHI is a heterogeneous condition at the clinical and genetic level, and disease-causing genes have been identified in about half of the patients. The majority of mutations have been identified in the ABCC8 and KCNJ11 genes encoding subunits of the KATP channel responsible for two distinct histological forms. The diffuse form is caused by autosomal recessive or dominant inherited mutations, whereas the focal form is caused by a paternally transmitted recessive mutation and a second somatic event. We report on an unselected cohort of 136 unrelated patients from the German CHI registry. Mutations in either the ABCC8 or KCNJ11 gene were identified in 61 of these patients (45%). In total, 64 different mutations including 38 novel ones were detected in this cohort. We observed biparental (recessive) inheritance in 34% of mutation-positive patients, dominant inheritance in 11% and paternal transmission of a mutation associated with a focal CHI type in 38%. In addition, we observed inheritance patterns that do not exactly follow the classical recessive or dominant mode, further adding to the genetic complexity of this disease.

Significance of heparin-binding growth factor expression on cells of solid pediatric tumors

BACKGROUND The heparin-binding growth factors pleiotrophin (PTN), midkine (MK), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) stimulate tumor cell proliferation and angiogenesis. In this study the authors wanted to know if these growth factors are expressed by cell lines and tumor tissue of solid pediatric tumors, growth factor expression is influenced by proinflammatory cytokines, and local growth factor concentration has an influence on experimental tumor growth. METHODS Growth factor mRNA expression was analyzed by reverse transcriptase polymerase chain reaction (RT-PCR) and protein secretion by enzyme-linked immunosorbent assay (ELISA). Neuroblastoma cells were suspended in solutions containing different growth factor concentrations before injection into the nude mice, which were given pentosan polysulfate (PPS) for antagonism. RESULTS The analyzed growth factors were expressed by most cells of solid malignant pediatric tumors. Their expression was not influenced by proinflammatory cytokines. The inhibition of tumor growth by PPS in the nude mouse model was dependent on the local growth factor concentration. High concentration excluded significant tumor suppression. CONCLUSIONS Because of the redundancy of growth factor expression and the abolishment of PPS efficacy by a high local growth factor concentration, the authors conclude that overall targeting of growth factors is a promising approach to cancer therapy in childhood.

Positron emission tomography/computed tomography diagnostics by means of fluorine-18-L-dihydroxyphenylalanine in congenital hyperinsulinism

The unfavorable prognosis of congenital hyperinsulinism (CHI) can be avoided if the patients are treated with high-dose glucose infusions and timely surgical intervention. Circumscribed foci used to be identified by selective percutaneous pancreatic vein catheterization and determination of the insulin level. Fluorine-18-L-dihydroxyphenylalanine-positron emission tomography (PET) was developed as a milder alternative for diagnostic localization of focal disease. The uptake of fluorine-18-L-dihydroxyphenylalanine is considerably increased in foci with high insulin synthesis rates. In Berlin, diagnosis was achieved by high definition PET/computed tomography with multiphase contrast media protocols that provided all necessary data with one investigation. We have investigated 135 patients with congenital hyperinsulinism, including 45 patients with focal disease (33.3%). All the foci were excised on the basis of PET/computed tomography images. The German data demonstrate that 87% to 91% of the operated patients could be completely healed.

Visualization of the focus in congenital hyperinsulinism by intraoperative sonography

In surgery for focal congenital hyperinsulinism (CHI), the identification and complete resection of the focus without collateral damage is of utmost importance. In a pilot study we applied intra-abdominal high-frequency sonography during surgery for focal CHI in 2 infants. The focus could be identified, its relation to the pancreatic and common bile duct could be shown, and the typical octopus-like tentacles could be demonstrated. In one case the resection was successful; in the other it was not. These preliminary results suggest that intraoperative sonography could be a valuable tool in the surgical therapy of focal CHI and warrants further evaluation in a clinical study.

Techniques in pediatric surgery: congenital hyperinsulinism.

For surgery in congenital hyperinsulinism (CHI), a distinct strategy and technique is required for focal, diffuse and atypical types. In focal CHI, a confined, localized and parenchyma-sparing resection which is guided by the PET-CT is always indicated in order to cure the patient. In diffuse CHI, however, the results of surgical therapy are unpredictable and cure is an exception. Therefore, a strong tendency exists nowadays that medical therapy should be preferred in diffuse CHI. In atypical CHI the situation is more complex: if the focal lesion or the segmental mosaic are not too extensive, cure by resection should be possible. But care must be taken in atypical cases not to resect too much of the gland in order not to induce diabetes.

Die Milz und ihre Erkrankungen

Der 8-jahrige Junge war mit dem Fahrrad gesturzt und hat sich die Lenkstange in die linke Flanke gestosen. Bei der Aufnahme in der Klinik klagt er uber Schmerzen unter dem linken Rippenbogen, besonders beim Einatmen. Blutdruck und Puls sind stabil, der Hb betragt 13,8 g/dl. Eine Hamaturie besteht nicht. In der Sonographie zeigt sich ein groses, subkapsular gelegenes Hamatom in der Milz (▶ Abb. 23.2) sowie wenig freie Flussigkeit im Douglas-Raum. Der Junge wird auf die Kinderintensivstation aufgenommen. Die Vitalparameter werden mit dem Monitor uberwacht. Alle 6 h erfolgt eine Ultraschallkontrolle. Es zeigt sich ein konstantes Bild ohne Grosenzunahme des Hamatoms. Nach einer Woche stationarem Aufenthalt stellt sich das Milzhamatom regredient dar mit beginnender Organisation, worauf der Junge entlassen wird.