2006 - UZ Leuven

Background & aims: Intestinal neurofibromatosis (Online Mendelianinheritance in Man database number 162220) is an alternate form ofneurofibromatosis. Patients present with neurofibromas limited to theintestine in the absence of any other typical features of NF1 and NF2.At present, the molecular basis of intestinal neurofibromatosis remainselusive. The aim of the present study was to find the gene responsiblefor intestinal neurofibromatosis and to characterize functionally themutation.Methods: Three candidate genes (NF1, KIT, and PDGFRA) werescreened for mutations in 3 sisters diagnosed with intestinalneurofibromatosis. Five tumors were available for pathologicexamination. Activation (phosphorylation) of PDGFRalpha wassubsequently tested by Western blot analysis on a transfected 293Tand Ba/F3 cell line.Results: We found an inherited mutation (Y555C) in thejuxtamembrane domain of PDGFRA in the affected individuals. TheY555C mutation leads to autophosphorylation and thus activation ofPDGFRalpha. These observations confirm that PDGFRalpha(Y555C)is an oncogenic kinase. The clinical phenotype in the reported familyresembles the syndrome of familial gastrointestinal stromal tumors(familial GIST). Somatic activating mutations in KIT and PDGFRA arefrequent in sporadic GISTs, and mutations in both genes have alsobeen described in familial GISTs. The tumors in the reported familyare morphologically identical to intestinal neurofibromas, but,immunohistochemically, they do not express S100 or any of theknown GIST markers.Conclusions: The inherited PDGFRA mutation in the reported familyshows that intestinal neurofibromatosis is allelic to familial GISTcaused by PDGRA mutations. We therefore propose that thesetumors be classified as familial KIT-negative gastrointestinal stromaltumors.DERAEDT K., VANDER POORTEN V., VAN GEET C., RENARD M., DEWEVER I., SCIOT R.: Multifocal kaposiform haemangioendothelioma.Virchows Arch 2006; 448: 843-846.Kaposiform haemangioendothelioma (KHE) is a rare, locallyaggressive vascular spindle cell proliferation, with resemblance toKaposi's sarcoma. This tumour usually occurs in skin andretroperitoneum of infants and young children and is oftencomplicated by the Kasabach-Merritt phenomenon (KMP). A 3-yearoldboy presented with a right submandibular swelling due tolymphadenopathies, a violaceous skin lesion at the left commissure ofthe lips and an ill-defined lesion in the right thyroid lobe. There weresome signs of KMP. Histological examination revealed a typical45