Advertisement

Neuroradiology

, Volume 47, Issue 10, pp 711–720 | Cite as

Neurovascular phenotypes in hereditary haemorrhagic telangiectasia patients according to age

Review of 50 consecutive patients aged 1 day–60 years
  • T. KringsEmail author
  • A. Ozanne
  • S. M. Chng
  • H. Alvarez
  • G. Rodesch
  • P. L. Lasjaunias
Diagnostic Neuroradiology

Abstract

Hereditary haemorrhagic telangiectasia (HHT) is inherited as an autosomal dominant trait with varying penetrance and expressivity. Some of the most devastating consequences of this disease result from cerebral vascular malformations that manifest themselves in either arteriovenous fistulae (AVF), small nidus-type arteriovenous malformations (AVM) or micro-AVMs with a nidus less than 1 cm in size. The purpose of this study was to compare the phenotypes of CNS-manifestations of HHT with the age of the patient. The charts and angiographic films of 50 patients diagnosed with HHT according to the Curaçao criteria were retrospectively evaluated concerning age of onset of symptoms, or, if not applicable of first consultation. The files were reviewed for clinical presentation, family and personal history, while the patients’ angiograms were analysed with respect to the number of lesions (single and multiple), the location (superficial supratentorial, deep supratentorial, infratentorial, and spinal), and type of lesion (fistulous AVM, nidus-type AVM, and micro-AVM). A total of 75 central nervous system manifestations of HHT were found. Lesions included seven spinal cord AVFs that were all present in the paediatric age group (mean age: 2.2 years), 34 cerebral AV fistulae, all but two affected patients were less than 6 years (mean age 3.0). Sixteen nidus type AVMs (mean age: 23.1 years) and 18 micro-AVMs (mean age: 31.8 years) were found. HHT displays an age-related penetrance of clinical manifestations. Since members of the same family can present with completely different phenotypes of this disease there seems to be no relationship between the type of mutation and the phenotype of the disease. Since there seems to be a continuum of vascular abnormalities (from large fistulous areas to small AVMs and micro-AVMs) associated with HHT, the most likely determinating factor of the HHT phenotype is the timing of the revealing event in relation to the maturity of the vessel. Presumably, the trigger of the quiescent genetical abnormality transforms a “dormant” disease into a morphologically and therefore clinically detectable one by impairing a specific vessel segment at a specific (more or less vulnerable) period of time. The nature of this triggering event is, however, as of yet unclear.

Keywords

Hereditary haemorrhagic telangiectasia Rendu Osler Weber disease Cerebral arteriovenous malformations Cerebral arteriovenous fistulae 

References

  1. 1.
    Bideau A, Plauchu H, Brunet G, Robert J (1989) Epidemiological investigation of Rendu-Osler disease in France: its geographical distribution and prevalence. Population 44:3–22PubMedGoogle Scholar
  2. 2.
    Kjeldsen AD, Vase P, Green A (1999) Hereditary haemorrhagic telangiectasia: a population-based study of prevalence and mortality in Danish patients. J Intern Med 245:31–39CrossRefPubMedGoogle Scholar
  3. 3.
    Dakeishi M, Shioya T, Wada Y et al. (2002) Genetic epidemiology of hereditary hemorrhagic telangiectasia in a local community in the northern part of Japan. Hum Mutat 19:140–148CrossRefPubMedGoogle Scholar
  4. 4.
    Haitjema T, Disch F, Overtoom TT, Westermann CJ, Lammers JW (1995) Screening family members of patients with hereditary hemorrhagic telangiectasia. Am J Med 99:519–524CrossRefPubMedGoogle Scholar
  5. 5.
    McDonald JE, Miller FJ, Hallam SE, Nelson L, Marchuk DA, Ward KJ (2000) Clinical manifestations in a large hereditary hemorrhagic telangiectasia (HHT) type 2 kindred. Am J Med Genet 93:320–327CrossRefPubMedGoogle Scholar
  6. 6.
    Fulbright RK, Chaloupka JC, Putman CM et al. (1998) MR of hereditary hemorrhagic telangiectasia: prevalence and spectrum of cerebrovascular malformations. Am J Neuroradiol 19:477–484PubMedGoogle Scholar
  7. 7.
    Marchuk DA, Srinivasan S, Squire TL, Zawistowski JS (2003) Vascular morphogenesis: tales of two syndromes. Hum Mol Genet 12(1):R97–R112CrossRefPubMedGoogle Scholar
  8. 8.
    Guttmacher AE, Marchuk DA, White RI Jr (1995) Hereditary hemorrhagic telangiectasia. N Engl J Med 333:918–924PubMedGoogle Scholar
  9. 9.
    Shovlin CL, Hughes JM, Tuddenham EG et al. (1994) A gene for hereditary haemorrhagic telangiectasia maps to chromosome 9q3. Nat Genet 6:205–209CrossRefPubMedGoogle Scholar
  10. 10.
    McAllister KA, Baldwin MA, Thukkani AK et al. (1995) Six novel mutations in the endoglin gene in hereditary hemorrhagic telangiectasia type 1 suggest a dominant-negative effect of receptor function. Hum Mol Genet 4:1983–1985PubMedGoogle Scholar
  11. 11.
    McAllister KA, Grogg KM, Johnson DW et al. (1994) Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet 8:345–351CrossRefPubMedGoogle Scholar
  12. 12.
    Pepper MS (1997) Transforming growth factor-beta: vasculogenesis, angiogenesis, and vessel wall integrity. Cytokine Growth Factor Rev 8:21–43CrossRefPubMedGoogle Scholar
  13. 13.
    Attisano L, Carcamo J, Ventura F, Weis FM, Massague J, Wrana JL (1993) Identification of human activin and TGF beta type I receptors that form heteromeric kinase complexes with type II receptors. Cell 75:671–680CrossRefPubMedGoogle Scholar
  14. 14.
    Shovlin CL, Hughes JM (1996) Hereditary hemorrhagic telangiectasia. N Engl J Med 334:330–331; author reply 331–332CrossRefGoogle Scholar
  15. 15.
    Shovlin CL, Guttmacher AE, Buscarini E et al. (2000) Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet 91:66–67CrossRefPubMedGoogle Scholar
  16. 16.
    Begbie ME, Wallace GM, Shovlin CL (2003) Hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): a view from the 21st century. Postgrad Med J 79:18–24CrossRefPubMedGoogle Scholar
  17. 17.
    Shovlin CL, Letarte M (1999) Hereditary haemorrhagic telangiectasia and pulmonary arteriovenous malformations: issues in clinical management and review of pathogenic mechanisms. Thorax 54:714–729PubMedGoogle Scholar
  18. 18.
    Garcia-Tsao G, Korzenik JR, Young L et al. (2000) Liver disease in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 343:931–936CrossRefPubMedGoogle Scholar
  19. 19.
    Matsubara S, Mandzia JL, ter Brugge K, Willinsky RA, Faughnan ME, Manzia JL (2000) Angiographic and clinical characteristics of patients with cerebral arteriovenous malformations associated with hereditary hemorrhagic telangiectasia. Am J Neuroradiol 21:1016–1020PubMedGoogle Scholar
  20. 20.
    Mahadevan J, Ozanne A, Yoshida Y et al. (2004) Hereditary haemorrhagic telangiectasia. Cerebrospinal localization in adults and children. Review of 39 cases. Intervent Neuroradiol 10:27–35Google Scholar
  21. 21.
    Putman CM, Chaloupka JC, Fulbright RK, Awad IA, White RI Jr, Fayad PB (1996) Exceptional multiplicity of cerebral arteriovenous malformations associated with hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome). Am J Neuroradiol 17:1733–1742PubMedGoogle Scholar
  22. 22.
    Yasargil MG (1987) Pathological considerations. In: Yasargil MG (ed) Microneurosurgery, vol 3a. Thieme, Stuttgart, pp 63–64Google Scholar
  23. 23.
    Yoshida Y, Weon YC, Sachet M et al. (2004) Posterior cranial fossa single-hole arteriovenous fistulae in children: 14 consecutive cases. Neuroradiology 46:474–481Google Scholar
  24. 24.
    Garcia-Monaco R, Taylor W, Rodesch G et al. (1995) Pial arteriovenous fistula in children as presenting manifestation of Rendu-Osler-Weber disease. Neuroradiology 37:60–64Google Scholar
  25. 25.
    Willinsky R, Lasjaunias P, Comoy J, Pruvost P (1988) Cerebral micro arteriovenous malformations (mAVMs). Review of 13 cases. Acta Neurochir (Wien) 91:37–41CrossRefGoogle Scholar
  26. 26.
    Mazighi M, Porter P, Alvarez H et al. (2000) Associated cererbal and spinal AVM in infant and adult. Report of two cases treated by endovascular approach. Intervent Neuroradiol 6:321–326Google Scholar
  27. 27.
    Plauchu H, de Chadarevian JP, Bideau A, Robert JM (1989) Age-related clinical profile of hereditary hemorrhagic telangiectasia in an epidemiologically recruited population. Am J Med Genet 32:291–297CrossRefPubMedGoogle Scholar
  28. 28.
    Porteous ME, Burn J, Proctor SJ (1992) Hereditary haemorrhagic telangiectasia: a clinical analysis. J Med Genet 29:527–530PubMedGoogle Scholar
  29. 29.
    Conway EM, Collen D, Carmeliet P (2001) Molecular mechanisms of blood vessel growth. Cardiovasc Res 49:507–521CrossRefPubMedGoogle Scholar
  30. 30.
    Satomi J, Mount RJ, Toporsian M et al. (2003) Cerebral vascular abnormalities in a murine model of hereditary hemorrhagic telangiectasia. Stroke 34:783–789CrossRefPubMedGoogle Scholar
  31. 31.
    Lasjaunias P (2000) Segmental identiy and vulnerability in cerebral arteries. Intervent Neuroradiol 6:113–124Google Scholar
  32. 32.
    Bourdeau A, Cymerman U, Paquet ME et al. (2000) Endoglin expression is reduced in normal vessels but still detectable in arteriovenous malformations of patients with hereditary hemorrhagic telangiectasia type 1. Am J Pathol 156:911–923PubMedGoogle Scholar
  33. 33.
    Sanchez-Elsner T, Botella LM, Velasco B, Langa C, Bernabeu C (2002) Endoglin expression is regulated by transcriptional cooperation between the hypoxia and transforming growth factor-beta pathways. J Biol Chem 277:43799–43808CrossRefPubMedGoogle Scholar
  34. 34.
    Sanchez-Elsner T, Botella LM, Velasco B, Corbi A, Attisano L, Bernabeu C (2001) Synergistic cooperation between hypoxia and transforming growth factor-beta pathways on human vascular endothelial growth factor gene expression. J Biol Chem 276:38527–38535Google Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • T. Krings
    • 1
    • 2
    Email author
  • A. Ozanne
    • 1
  • S. M. Chng
    • 1
  • H. Alvarez
    • 1
  • G. Rodesch
    • 3
  • P. L. Lasjaunias
    • 1
  1. 1.Service de Neuroradiologie Diagnostique et ThérapeutiqueHôpital de BicetreParisFrance
  2. 2.Departments of Neuroradiology and NeurosurgeryUniversity Hospital of the Technical UniversityAachenGermany
  3. 3.Service Neuroradiologie Diagnostique et ThérapeutiqueHôpital FochSuresnes, ParisFrance

Personalised recommendations