title: Review of familial cerebral cavernous malformations and report of seven additional families.
abstract: Cerebral cavernous malformations are vascular anomalies of the central nervous system characterized by clusters of enlarged, leaky capillaries. They are caused by loss-of-function mutations in KRIT1, CCM2, or PDCD10. The proteins encoded by these genes are involved in four partially interconnected signaling pathways that control angiogenesis and endothelial permeability. Cerebral cavernous malformations can occur sporadically, or as a familial autosomal dominant disorder (FCCM) with incomplete clinical and neuroradiological penetrance and great inter-individual variability. Although the clinical course is unpredictable, symptoms typically present during adult life and include headaches, focal neurological deficits, seizures, and potentially fatal stroke. In addition to neural lesions, extraneural cavernous malformations have been described in familial disease in several tissues, in particular the skin. We here present seven novel FCCM families with neurologic and cutaneous lesions. We review histopathological and clinical features and provide an update on the pathophysiology of cerebral cavernous malformations and associated cutaneous vascular lesions. © 2016 Wiley Periodicals, Inc.
authors: Department of Clinical Genetics, Maastricht University Medical Center+, Maastricht, The Netherlands.|School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center+, Maastricht, The Netherlands.|Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
authors: Ivo J H M
authors: IJ
authors: de Vos
authors: Department of Clinical Genetics, Maastricht University Medical Center+, Maastricht, The Netherlands.|School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center+, Maastricht, The Netherlands.
authors: Maaike
authors: M
authors: Vreeburg
authors: Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Center+, Maastricht, The Netherlands.
authors: Ger H
authors: GH
authors: Koek
authors: Institute of Medical Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.|School of Medicine and School of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors: Maurice A M
authors: MA
authors: van Steensel
mesh_terms: D001706:Biopsy; D002352:Carrier Proteins / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D005820:Genetic Testing; D005838:Genotype; D020786:Hemangioma, Cavernous, Central Nervous System / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D000075927:KRIT1 Protein; D008279:Magnetic Resonance Imaging; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics
chemical_list: C502544:CCM2 protein, human; D002352:Carrier Proteins; D000075927:KRIT1 Protein; C107928:KRIT1 protein, human; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins
keywords: CCM; cerebral cavernous malformation; cutaneous cavernous malformation