RESUMO
Cavernous malformations (CMs) of the central nervous system can occur in a sporadic condition or as a familial form with an autosomal-dominant inherited pattern. Apart from a family history, some clinical features may help to identify familial CMs. We demonstrate clinical, neuroradiological, pathological, and genetic data of a patient with cerebral and spinal CMs. The presence of multiple cerebral CMs and distinct cutaneous vascular lesions, including hyperkeratotic cutaneous capillary-venous malformations, in this patient suggested familial CMs. A genetic study confirmed a nonsense mutation (c.1708A>T) in the KRIT1 gene.
Assuntos
Neoplasias Encefálicas/genética , Malformações Vasculares do Sistema Nervoso Central/genética , Hemangioma/genética , Proteínas Associadas aos Microtúbulos/genética , Proteínas Proto-Oncogênicas/genética , Dermatopatias Vasculares/genética , Neoplasias Cutâneas/genética , Doenças Vasculares da Medula Espinal/genética , Adolescente , Adulto , Neoplasias Encefálicas/complicações , Capilares/anormalidades , Malformações Vasculares do Sistema Nervoso Central/complicações , Códon sem Sentido , Feminino , Hemangioma/complicações , Humanos , Proteína KRIT1 , Linhagem , Dermatopatias Vasculares/complicações , Neoplasias Cutâneas/complicações , Doenças Vasculares da Medula Espinal/complicações , Adulto JovemRESUMO
BACKGROUND: Cerebral cavernous malformations (CCM) are vascular brain anomalies which can result in a variety of neurological symptoms. Familial CCM is inherited as an autosomal-dominant trait. There is one study in the literature which reports statistical evidence for anticipation in familial CCM. METHODS: We reevaluated the clinical course of the disease and performed molecular analyses in a previously described three-generation CCM family with apparent anticipation. RESULTS: Disease started at a younger age in each generation, strongly suggesting anticipation. The patient in generation I showed no clinical symptoms by the age of 68, whereas his son became wheelchair-bound at the age of 43 due to an intramedullary cavernous malformation at the thoracolumbar transition of the spinal cord. The patient in generation III had a pons hemorrhage at the age of 11 due to a large brainstem cavernoma. The hemorrhage caused facial palsy and hemiparesis, persisting as Millard-Gubler syndrome. Sequencing of KRIT1 identified a novel frameshift mutation in exon 15 (c.1561delC or p.Leu551X) which cosegregated with the phenotype. Flow-FISH analysis of granulocyte and lymphocyte telomere length showed that telomeres were longest in the youngest affected family member. CONCLUSIONS: We could not find any evidence for either of the two currently known molecular mechanisms for genetic anticipation (i.e., expansion of repetitive DNA elements or progressive telomere shortening) in this family. However, the family presented here raises the important question whether surveillance of CCM families with gradient-echo MRI should not only include the cerebrum, but the spinal cord as well.