Clinical Aspects of Heritable Connective Tissue Disorders

  • Aline VerstraetenEmail author
  • Bart Loeys


Connective tissue surrounds, supports, and connects a multitude of tissues and organs. It is composed of a cellular component (mostly fibroblasts) and extracellular matrix, with the latter consisting of fibers (collagen, elastic fibrils, etc.) and amorphous glycoproteins. Rare genetic defects in key connective tissue components lead to a heterogeneous group of diseases with multisystem involvement, called heritable connective tissue disorders.


Marfan syndrome Loeys-Dietz syndrome Aortic root aneurysm Ehlers-Danlos syndrome Arterial tortuosity syndrome Shprintzen-Goldberg syndrome 


  1. 1.
    McKusick V. The cardiovascular aspects of Marfan’s syndrome: a heritable disorder of connective tissue. Circulation. 1955;11:321–42.CrossRefGoogle Scholar
  2. 2.
    Aburawi EH, O’Sullivan J. Relation of aortic root dilatation and age in Marfan’s syndrome. Eur Heart J. 2007;28:376–9.CrossRefGoogle Scholar
  3. 3.
    Hwa J, Richards JG, Huang H, McKay D, Pressley L, Hughes CF, et al. The natural history of aortic dilatation in Marfan syndrome. Med J Aust. 1993;158:558–62.PubMedGoogle Scholar
  4. 4.
    Mimoun L, Detaint D, Hamroun D, Arnoult F, Delorme G, Gautier M, et al. Dissection in Marfan syndrome: the importance of the descending aorta. Eur Heart J. 2011;32:443–9.CrossRefGoogle Scholar
  5. 5.
    den Hartog AW, Franken R, Zwinderman AH, Timmermans J, Scholte AJ, van den Berg MP, et al. The risk for type B aortic dissection in Marfan syndrome. J Am Coll Cardiol. 2015;65:246–54.CrossRefGoogle Scholar
  6. 6.
    Kinori M, Wehrli S, Kassem IS, Azar NF, Maumenee IH, Mets MB. Biometry characteristics in adults and children with Marfan syndrome: from the Marfan eye consortium of Chicago. Am J Ophthalmol. 2017;177:144–9.CrossRefGoogle Scholar
  7. 7.
    Maumenee IH. The eye in the Marfan syndrome. Trans Am Ophthalmol Soc. 1981;79:684–733.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Chandra A, Ekwalla V, Child A, Charteris D. Prevalence of ectopia lentis and retinal detachment in Marfan syndrome. Acta Ophthalmol. 2014;92:e82–3.CrossRefGoogle Scholar
  9. 9.
    Konradsen TR, Zetterstrom C. A descriptive study of ocular characteristics in Marfan syndrome. Acta Ophthalmol. 2013;91:751–5.CrossRefGoogle Scholar
  10. 10.
    Dietz HC, Cutting GR, Pyeritz RE, Maslen CL, Sakai LY, Corson GM, et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature. 1991;352:337–9.CrossRefGoogle Scholar
  11. 11.
    Verstraeten A, Alaerts M, Van Laer L, Loeys B. Marfan syndrome and related disorders: 25 years of gene discovery. Hum Mutat. 2016;37:524–31.CrossRefGoogle Scholar
  12. 12.
    Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010;47:476–85.CrossRefGoogle Scholar
  13. 13.
    Loeys BL, Chen J, Neptune ER, Judge DP, Podowski M, Holm T, et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005;37:275–81.CrossRefGoogle Scholar
  14. 14.
    Loeys BL, Schwarze U, Holm T, Callewaert BL, Thomas GH, Pannu H, et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006;355:788–98.CrossRefGoogle Scholar
  15. 15.
    Maccarrick G, Black JH 3rd, Bowdin S, El-Hamamsy I, Frischmeyer-Guerrerio PA, Guerrerio AL, et al. Loeys-Dietz syndrome: a primer for diagnosis and management. Genet Med. 2014;16:576–87.CrossRefGoogle Scholar
  16. 16.
    Micha D, Guo DC, Hilhorst-Hofstee Y, van Kooten F, Atmaja D, Overwater E, et al. SMAD2 mutations are associated with arterial aneurysms and dissections. Hum Mutat. 2015;36:1145–9.CrossRefGoogle Scholar
  17. 17.
    van de Laar IM, Oldenburg RA, Pals G, Roos-Hesselink JW, de Graaf BM, Verhagen JM, et al. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet. 2011;43:121–6.CrossRefGoogle Scholar
  18. 18.
    Lindsay ME, Schepers D, Bolar NA, Doyle JJ, Gallo E, Fert-Bober J, et al. Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nat Genet. 2012;44:922–7.CrossRefGoogle Scholar
  19. 19.
    Bertoli-Avella AM, Gillis E, Morisaki H, Verhagen JM, de Graaf BM, van de Beek G, et al. Mutations in a TGF-beta ligand, TGFB3, cause syndromic aortic aneurysms and dissections. J Am Coll Cardiol. 2015;65:1324–36.CrossRefGoogle Scholar
  20. 20.
    Loeys BL, Dietz HC. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, LJH B, et al., editors. Loeys-Dietz syndrome. Seattle, WA: GeneReviews(R); 2008.Google Scholar
  21. 21.
    Wenstrup RJ, Meyer RA, Lyle JS, Hoechstetter L, Rose PS, Levy HP, et al. Prevalence of aortic root dilation in the Ehlers-Danlos syndrome. Genet Med. 2002;4:112–7.CrossRefGoogle Scholar
  22. 22.
    Beighton P, de Paepe A, Danks D, Finidori G, Gedde-Dahl T, Goodman R, et al. International nosology of heritable disorders of connective tissue, berlin, 1986. Am J Med Genet. 1988;29:581–94.CrossRefGoogle Scholar
  23. 23.
    Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Am J Med Genet. 1998;77:31–7.CrossRefGoogle Scholar
  24. 24.
    Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175:8–26.CrossRefGoogle Scholar
  25. 25.
    Superti-Furga A, Gugler E, Gitzelmann R, Steinmann B. Ehlers-Danlos syndrome type IV: a multi-exon deletion in one of the two COL3A1 alleles affecting structure, stability, and processing of type III procollagen. J Biol Chem. 1988;263:6226–32.PubMedGoogle Scholar
  26. 26.
    Pepin MG, Schwarze U, Rice KM, Liu M, Leistritz D, Byers PH. Survival is affected by mutation type and molecular mechanism in vascular Ehlers-Danlos syndrome (EDS type IV). Genet Med. 2014;16:881–8.CrossRefGoogle Scholar
  27. 27.
    Malfait F, Symoens S, De Backer J, Hermanns-Le T, Sakalihasan N, Lapiere CM, et al. Three arginine to cysteine substitutions in the pro-alpha (I)-collagen chain cause Ehlers-Danlos syndrome with a propensity to arterial rupture in early adulthood. Hum Mutat. 2007;28:387–95.CrossRefGoogle Scholar
  28. 28.
    Schwarze U, Hata R, McKusick VA, Shinkai H, Hoyme HE, Pyeritz RE, et al. Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway. Am J Hum Genet. 2004;74:917–30.CrossRefGoogle Scholar
  29. 29.
    Rohrbach M, Vandersteen A, Yis U, Serdaroglu G, Ataman E, Chopra M, et al. Phenotypic variability of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA): clinical, molecular and biochemical delineation. Orphanet J Rare Dis. 2011;6:46.CrossRefGoogle Scholar
  30. 30.
    Ha VT, Marshall MK, Elsas LJ, Pinnell SR, Yeowell HN. A patient with Ehlers-Danlos syndrome type VI is a compound heterozygote for mutations in the lysyl hydroxylase gene. J Clin Invest. 1994;93:1716–21.CrossRefGoogle Scholar
  31. 31.
    Coucke PJ, Willaert A, Wessels MW, Callewaert B, Zoppi N, De Backer J, et al. Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome. Nat Genet. 2006;38:452–7.CrossRefGoogle Scholar
  32. 32.
    Willaert A, Khatri S, Callewaert BL, Coucke PJ, Crosby SD, Lee JG, et al. GLUT10 is required for the development of the cardiovascular system and the notochord and connects mitochondrial function to TGFbeta signaling. Hum Mol Genet. 2012;21:1248–59.CrossRefGoogle Scholar
  33. 33.
    Zoppi N, Chiarelli N, Cinquina V, Ritelli M, Colombi M. GLUT10 deficiency leads to oxidative stress and non-canonical alphavbeta3 integrin-mediated TGFbeta signalling associated with extracellular matrix disarray in arterial tortuosity syndrome skin fibroblasts. Hum Mol Genet. 2015;24:6769–87.CrossRefGoogle Scholar
  34. 34.
    Szabo Z, Crepeau MW, Mitchell AL, Stephan MJ, Puntel RA, Yin Loke K, et al. Aortic aneurysmal disease and cutis laxa caused by defects in the elastin gene. J Med Genet. 2006;43:255–8.CrossRefGoogle Scholar
  35. 35.
    Guemann AS, Andrieux J, Petit F, Halimi E, Bouquillon S, Manouvrier-Hanu S, et al. ELN gene triplication responsible for familial supravalvular aortic aneurysm. Cardiol Young. 2015;25:712–7.CrossRefGoogle Scholar
  36. 36.
    Zhang MC, He L, Giro M, Yong SL, Tiller GE, Davidson JM. Cutis laxa arising from frameshift mutations in exon 30 of the elastin gene (ELN). J Biol Chem. 1999;274:981–6.CrossRefGoogle Scholar
  37. 37.
    Hucthagowder V, Sausgruber N, Kim KH, Angle B, Marmorstein LY, Urban Z. Fibulin-4: a novel gene for an autosomal recessive cutis laxa syndrome. Am J Hum Genet. 2006;78:1075–80.CrossRefGoogle Scholar
  38. 38.
    Hebson C, Coleman K, Clabby M, Sallee D, Shankar S, Loeys B, et al. Severe aortopathy due to fibulin-4 deficiency: molecular insights, surgical strategy, and a review of the literature. Eur J Pediatr. 2014;173:671–5.PubMedGoogle Scholar
  39. 39.
    Gupta PA, Putnam EA, Carmical SG, Kaitila I, Steinmann B, Child A, et al. Ten novel FBN2 mutations in congenital contractural arachnodactyly: delineation of the molecular pathogenesis and clinical phenotype. Hum Mutat. 2002;19:39–48.CrossRefGoogle Scholar
  40. 40.
    Meester JA, Vandeweyer G, Pintelon I, Lammens M, Van Hoorick L, De Belder S, et al. Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections. Genet Med. 2017;19:386–95.CrossRefGoogle Scholar
  41. 41.
    Moutton S, Fergelot P, Naudion S, Cordier MP, Sole G, Guerineau E, et al. Otopalatodigital spectrum disorders: refinement of the phenotypic and mutational spectrum. J Hum Genet. 2016;61:693–9.CrossRefGoogle Scholar
  42. 42.
    Sheen VL, Jansen A, Chen MH, Parrini E, Morgan T, Ravenscroft R, et al. Filamin A mutations cause periventricular heterotopia with Ehlers-Danlos syndrome. Neurology. 2005;64:254–62.CrossRefGoogle Scholar
  43. 43.
    Kyndt F, Gueffet JP, Probst V, Jaafar P, Legendre A, Le Bouffant F, et al. Mutations in the gene encoding filamin A as a cause for familial cardiac valvular dystrophy. Circulation. 2007;115:40–9.CrossRefGoogle Scholar
  44. 44.
    Doyle AJ, Doyle JJ, Bessling SL, Maragh S, Lindsay ME, Schepers D, et al. Mutations in the TGF-beta repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm. Nat Genet. 2012;44:1249–54.CrossRefGoogle Scholar
  45. 45.
    Carmignac V, Thevenon J, Ades L, Callewaert B, Julia S, Thauvin-Robinet C, et al. In-frame mutations in exon 1 of SKI cause dominant Shprintzen-Goldberg syndrome. Am J Hum Genet. 2012;91:950–7.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Center for Medical GeneticsAntwerp University Hospital and University of AntwerpAntwerpBelgium

Personalised recommendations