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Familial cerebral cavernous malformation: report of a further Italian family

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Abstract

Cerebral cavernous malformations (CCMs) are vascular abnormalities that may cause seizures, headaches, intracerebral hemorrhages, and focal neurological deficits; they can also be clinically silent and may occur as a sporadic or an autosomal dominant condition. Three genes have been identified as causing familial CCM: KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3, mapping, respectively, on chromosomes 7q, 7p, and 3q. This is a report on an Italian family affected by CCM due to a KRIT1 gene mutation on exon 13. The mother suffered from a cerebellar hematoma and was severely disabled; one son had suffered from intractable seizures and underwent surgery for removal of a cavernous angioma, while another son was asymptomatic. Brain MRI showed CCMs in all patients. This report underlines that a familial form of CCM could be suspected when a patient presents with multiple CCMs; neurologists and neurosurgeons should be aware that genetic testing for these forms is available.

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References

  1. Simard JM, Garcia-Bengochea F, Ballinger WE Jr et al (1986) Cavernous angioma: a review of 126 collected and 12 new clinical cases. Neurosurgery 18:162–172

    Article  PubMed  CAS  Google Scholar 

  2. Villani RM, Arienta C, Caroli M (1989) Cavernous angiomas of the central nervous system. J Neurosurg Sci 33:229–252

    PubMed  CAS  Google Scholar 

  3. Otten P, Pizzolato GP, Rilliet B, Berney J (1989) 131 cases of cavernous angioma (cavernomas) of the CNS discovered by retrospective analysis of 24,535 autopsies. Neurochirurgie 35:82–83, 128–131

    Google Scholar 

  4. Robinson JR, Awad IA, Little JR (1991) Natural history of the cavernous angioma. J Neurosurg 75:709–714

    PubMed  CAS  Google Scholar 

  5. Del Curling O Jr, Kelly DL Jr, Elster AD, Craven TE (1991) An analysis of the natural history of cavernous angiomas. J Neurosurg 75:702–708

    PubMed  Google Scholar 

  6. Bicknell JM, Carlow TJ, Kornfeld M et al (1978) Familial cavernous angiomas. Arch Neurol 35:746–749

    PubMed  CAS  Google Scholar 

  7. Rigamonti D, Hadley MN, Drayer BP et al (1988) Cerebral cavernous malformations. Incidence and familial occurrence. N Engl J Med 319:343–347

    PubMed  CAS  Google Scholar 

  8. Labauge P, Laberge S, Brunereau L et al (1998) Hereditary cerebral cavernous angiomas: clinical and genetic features in 57 French families. Soc Française Neurochir Lancet 352:1892–1897

    CAS  Google Scholar 

  9. Brunereau L, Labauge P, Tournier-Lasserve E et al (2000) Familial form of intracranial cavernous angioma: MR imaging findings in 51 families French Society of Neurosurgery. Radiology 214:209–216

    PubMed  CAS  Google Scholar 

  10. Hayman LA, Evans RA, Ferrell RE et al (1982) Familial cavernous angiomas: natural history and genetic study over a 5-year period. Am J Med Genet 11:147–160

    Article  PubMed  CAS  Google Scholar 

  11. Kattapong VJ, Hart BL, Davis LE (1995) Familial cerebral cavernous angiomas: clinical and radiologic studies. Neurology 45:492–497

    PubMed  CAS  Google Scholar 

  12. Revencu N, Vikkula M (2006) Cerebral cavernous malformation: new molecular and clinical insights. J Med Genet 43:716–721

    Article  PubMed  CAS  Google Scholar 

  13. Cavé-Riant F, Denier C, Labauge P et al (2002) Spectrum and expression analysis of KRIT1 mutations in 121 consecutive and unrelated patients with cerebral cavernous malformations. Eur J Hum Genet 10:733–740

    Article  PubMed  CAS  Google Scholar 

  14. Labauge P, Enjolras O, Bonerandi JJ et al (1999) An association between autosomal dominant cerebral cavernomas and a distinctive hyperkeratotic cutaneous vascular malformation in 4 families. Ann Neurol 45:250–254

    Article  PubMed  CAS  Google Scholar 

  15. Labauge P, Krivosic V, Denier C et al (2006) Frequency of retinal cavernomas in 60 patients with familial cerebral cavernomas: a clinical and genetic study. Arch Ophthalmol 124:885–886

    Article  PubMed  Google Scholar 

  16. Santoro A, Piccirilli M, Brunetto GM et al (2007) Intramedullary cavernous angioma of the spinal cord in a pediatric patient, with multiple cavernomas, familial occurrence and partial spontaneous regression: case report and review of the literature. Childs Nerv Syst 23:1319–1326

    Article  PubMed  Google Scholar 

  17. Ardeshiri A, Ardeshiri A, Beiras-Fernandez A et al (2008) Multiple cerebral cavernous malformations associated with extracranial mesenchymal anomalies. Neurosurg Rev 31:11–17

    Article  PubMed  Google Scholar 

  18. Toldo I, Drigo P, Mammi I et al (2009) Vertebral and spinal cavernous angiomas associated with familial cerebral cavernous malformation. Surg Neurol 71:167–171

    Article  PubMed  Google Scholar 

  19. Gangemi M, Longatti P, Maiuri F et al (1989) Cerebral cavernous angiomas in the first year of life. Neurosurgery 25:465–468

    Article  PubMed  CAS  Google Scholar 

  20. Zabramski JM, Wascher TM, Spetzler RF et al (1994) The natural history of familial cavernous malformations: results of an ongoing study. J Neurosurg 80:422–432

    PubMed  CAS  Google Scholar 

  21. Labauge P, Denier C, Bergametti F, Tournier-Lasserve E (2007) Genetics of cavernous angiomas. Lancet Neurol 6:237–244

    Article  PubMed  CAS  Google Scholar 

  22. Rigamonti D, Drayer BP, Johnson PC et al (1987) The MRI appearance of cavernous malformations (angiomas). J Neurosurg 67:518–524

    Article  PubMed  CAS  Google Scholar 

  23. Johnson EW, Iyer LM, Rich SS et al (1995) Refined localization of the cerebral cavernous malformation gene (CCM1) to a 4-cM interval of chromosome 7q contained in a well-defined YAC contig. Genome Res 5:368–380

    Article  PubMed  CAS  Google Scholar 

  24. Sahoo T, Johnson EW, Thomas JW et al (1999) Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations (CCM1). Hum Mol Genet 8:2325–2333

    Article  PubMed  CAS  Google Scholar 

  25. Liquori CL, Berg MJ, Siegel AM et al (2003) Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations. Am J Hum Genet 73:1459–1464

    Article  PubMed  CAS  Google Scholar 

  26. Denier C, Goutagny S, Labauge P et al (2004) Mutations within the MGC4607 gene cause cerebral cavernous malformations. Am J Hum Genet 74:326–337

    Article  PubMed  CAS  Google Scholar 

  27. Bergametti F, Denier C, Labauge P et al (2005) Mutations within the programmed cell death 10 gene cause cerebral cavernous malformations. Am J Hum Genet 76:42–51

    Article  PubMed  CAS  Google Scholar 

  28. Marchuk DA, Gallione CJ, Morrison LA et al (1995) A locus for cerebral cavernous malformations maps to chromosome 7q in two families. Genomics 28:311–314

    Article  PubMed  CAS  Google Scholar 

  29. Günel M, Awad IA, Anson J, Lifton RP (1995) Mapping a gene causing cerebral cavernous malformation to 7q11.2-q21. Proc Natl Acad Sci USA 92:6620–6624

    Article  PubMed  Google Scholar 

  30. Gil-Nagel A, Dubovsky J, Wilcox KJ et al (1996) Familial cerebral cavernous angioma: a gene localized to a 15-cM interval on chromosome 7q. Ann Neurol 39:807–810

    Article  PubMed  CAS  Google Scholar 

  31. Craig HD, Günel M, Cepeda O et al (1998) Multilocus linkage identifies two new loci for a mendelian form of stroke, cerebral cavernous malformation, at 7p15-13 and 3q25.2-27. Hum Mol Genet 7:1851–1858

    Article  PubMed  CAS  Google Scholar 

  32. Zhang J, Clatterbuck RE, Rigamonti D et al (2001) Interaction between krit1 and icap1alpha infers perturbation of integrin beta1-mediated angiogenesis in the pathogenesis of cerebral cavernous malformation. Hum Mol Genet 10:2953–2960

    Article  PubMed  CAS  Google Scholar 

  33. Zawistowski JS, Serebriiskii IG, Lee MF et al (2002) KRIT1 association with the integrin-binding protein ICAP-1: a new direction in the elucidation of cerebral cavernous malformations (CCM1) pathogenesis. Hum Mol Genet 11:389–396

    Article  PubMed  CAS  Google Scholar 

  34. Zawistowski JS, Stalheim L, Uhlik MT et al (2005) CCM1 and CCM2 protein interactions in cell signaling: implications for cerebral cavernous malformations pathogenesis. Hum Mol Genet 14:2521–2531

    Article  PubMed  CAS  Google Scholar 

  35. Squitieri F, Maglione V, Buzzi MG et al (2000) Cavernous angiomas of the nervous system in Italy: clinical and genetic study. Neurol Sci 21:129–134

    Article  PubMed  CAS  Google Scholar 

  36. Marini V, Ferrera L, Dorcaratto A et al (2003) Identification of a novel KRIT1 mutation in an Italian family with cerebral cavernous malformation by the protein truncation test. J Neurol Sci 212:75–78

    Article  PubMed  CAS  Google Scholar 

  37. Gianfrancesco F, Cannella M, Martino T et al (2007) Highly variable penetrance in subjects affected with cavernous cerebral angiomas (CCM) carrying novel CCM1 and CCM2 mutations. Am J Med Genet B Neuropsychiatr Genet 144B:691–695

    Article  PubMed  CAS  Google Scholar 

  38. Battistini S, Rocchi R, Cerase A et al (2007) Clinical, magnetic resonance imaging, and genetic study of 5 Italian families with cerebral cavernous malformation. Arch Neurol 64:843–848

    Article  PubMed  Google Scholar 

  39. Guarnieri V, Muscarella LA, Amoroso R et al (2007) Identification of two novel mutations and of a novel critical region in the KRIT1 gene. Neurogenetics 8:29–37

    Article  PubMed  CAS  Google Scholar 

  40. Liquori CL, Penco S, Gault J et al (2008) Different spectra of genomic deletions within the CCM genes between Italian and American CCM patient cohorts. Neurogenetics 9:25–31

    Article  PubMed  CAS  Google Scholar 

  41. Liquori CL, Berg MJ, Squitieri F et al (2006) Low frequency of PDCD10 mutations in a panel of CCM3 probands: potential for a fourth CCM locus. Hum Mutat 27:118

    Article  PubMed  Google Scholar 

  42. Labauge P, Brunereau L, Lévy C et al (2000) The natural history of familial cerebral cavernomas: a retrospective MRI study of 40 patients. Neuroradiology 42:327–332

    Article  PubMed  CAS  Google Scholar 

  43. Reich P, Winkler J, Straube A et al (2003) Molecular genetic investigations in the CCM1 gene in sporadic cerebral cavernomas. Neurology 60:1135–1138

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Neurological and Psychiatric Sciences, University of Florence, Viale Morgagni 85, 50134, Florence, Italy

    Serena Nannucci, Francesca Pescini, Anna Poggesi, Laura Ciolli, Domenico Inzitari & Leonardo Pantoni

  2. S.S. Laboratorio di Genetica Medica, A.O. Niguarda Ca’ Granda, Milan, Italy

    Maria Cristina Patrosso, Alessandro Marocchi & Silvana Penco

Authors
  1. Serena Nannucci
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  2. Francesca Pescini
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  3. Anna Poggesi
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  4. Laura Ciolli
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  5. Maria Cristina Patrosso
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  7. Domenico Inzitari
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  8. Silvana Penco
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  9. Leonardo Pantoni
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Correspondence to Leonardo Pantoni.

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Nannucci, S., Pescini, F., Poggesi, A. et al. Familial cerebral cavernous malformation: report of a further Italian family. Neurol Sci 30, 143–147 (2009). https://doi.org/10.1007/s10072-009-0020-3

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  • DOI: https://doi.org/10.1007/s10072-009-0020-3

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