Connective Tissue Disorders in Domestic Animals

  • Jaroslava HalperEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 802)


Though soft tissue disorders have been recognized and described to some detail in several types of domestic animals and small mammals for some years, not much progress has been made in our understanding of the biochemical basis and pathogenesis of these diseases in animals. Ehlers-Danlos syndrome described in dogs already in 1943 and later in cats affects mainly skin in these animals. The involved skin is thin and hyperextensible with easily inflicted injuries resulting in hemorrhagic wounds and atrophic scars. Joint laxity and dislocation common in people are less frequently found in dogs. No systemic complications, such as organ rupture or cardiovascular problems which have devastating consequences in people have been described in cats and dogs. The diagnosis is based on clinical presentation and on light or electron microscopic features of disorganized and fragmented collagen fibrils. Several cases of bovine and ovine dermatosparaxis analogous to human Ehlers-Danlos syndrome type VIIC were found to be caused by mutations in the procollagen I N-proteinase (pnPI) or ADAMTS2 gene, though mutations in other sites are likely responsible for other types of dermatosparaxis. Cattle suffering from a form of Marfan syndrome were described to have aortic dilatation and aneurysm together with ocular abnormalities and skeletal involvement. As in people mutations at different sites of bovine FBN1 may be responsible for Marfan phenotype. Hereditary equine regional dermal asthenia (HERDA), or hyperelastosis cutis, has been recognized in several horse breeds as affecting primarily skin, and, occasionally, tendons. A mutation in cyclophilin B, a chaperon involved in proper folding of collagens, has been identified in some cases. Degenerative suspensory ligament desmitis (DSLD) affects primarily tendons and ligaments of certain horse breeds. New data from our laboratory showed excessive accumulation of proteoglycans in organs with high content of connective tissues. We have identified an abnormal form of decorin with altered biological activity in these proteoglycan deposits, and more recently changes in processing of aggrecan were found by us and other investigators.

The naturally occurring diseases of soft tissues in domestic animals described here have a potential to serve as good models for analogous human diseases. This is the case particularly relevant to dogs as a half out of the more than 400 naturally occurring hereditary canine diseases has the potential to serve as a model for human disease.


Ehlers-Danlos Dogs Cats Dermatosparaxis Cattle Sheep HERDA Hyperelastosis cutis Horses Degenerative suspensory ligament desmitis (DSLD) 


  1. 1.
    Minor RR (1980) Collagen metabolism. Am J Pathol 98:226–280Google Scholar
  2. 2.
    Sinke JD, van Dijk JE, Willemse T (1997) A case of Ehlers-Danlos-like syndrome in a rabbit with a review of the disease in other species. Vet Q 19:182–186PubMedCrossRefGoogle Scholar
  3. 3.
    Arlein MS (1947) Generalized acute cutaneous asthenia in a dog. J Am Vet Med Assoc 111:57Google Scholar
  4. 4.
    Tsai KL, Clark LA, Murphy KE (2007) Understanding hereditary diseases using the dog and human as companion model systems. Mamm Genome 18:444–451PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Bellini MH, Caldini ETEG, Scapinelli MP, Simŏes MJ, Machado DB, Nürmberg R (2009) Increased elastic microfibrils and thickening of fibroblastic nuclear lamina in canine cutaneous asthenia. Vet Dermatol 20:139–143PubMedCrossRefGoogle Scholar
  6. 6.
    Scott DW, Miller VH, Griffin CE (2001) Congenital and hereditary diseases. In: Muller and Kirk’s Small animal dermatology. WB Saunders, Philadelphia, pp 913–1003CrossRefGoogle Scholar
  7. 7.
    Hegreberg GA, Padgett GA, Gorham JA, Henson JB (1969) A connective tissue disease of dogs and mink resembling the Ehlers Danlos syndrome of man. II. Mode of inheritance. J Hered 60:249–254PubMedGoogle Scholar
  8. 8.
    Paciello O, Lamagna F, Lamagna B, Papparella S (2003) Ehlers-Danlos-like syndrome in 2 dogs: clinical, histologic, and ultrastructural findings. Vet Clin Pathol 32:13–18PubMedCrossRefGoogle Scholar
  9. 9.
    Barrera R, Maňe C, Duran E, Vives MA, Zaragoza C (2004) Ehlers-Danlos in a dog. Can Vet J 45:355–356PubMedPubMedCentralGoogle Scholar
  10. 10.
    Patterson DF, Minor RR (1977) Hereditary fragility and hyperextensibility of the skin of cats. Lab Invest 37:170–179PubMedGoogle Scholar
  11. 11.
    Fitchie P (1972) The Ehlers-Danlos syndrome (in a cat). Vet Res 90:165Google Scholar
  12. 12.
    Butler WF (1975) Fragility of the skin in a cat. Res Vet Sci 19:213PubMedGoogle Scholar
  13. 13.
    Scott DV (1974) Cutaneous asthenia in a cat resembling Ehler-Danlos syndrome in man. Vet Med Small Anim Clin 69:1256PubMedGoogle Scholar
  14. 14.
    Hanset R, Ansay M (1967) Dermatosparaxie (peau dechiree) ceha la veau un degaut general de tissu conjonctef, de nature hereditaire. Ann Med Vet 11:451Google Scholar
  15. 15.
    Fjølstad M, Helle O (1974) A hereditary dysplasia of collagen tissues in sheep. J Pathol 112:183–188PubMedCrossRefGoogle Scholar
  16. 16.
    Van Halderen A, Green JR (1988) Dermatosparaxis in White Dorper sheep. J S Afr Vet Assoc 59:45–46PubMedGoogle Scholar
  17. 17.
    Vaatstra BL, Halliday WD, Waropastrakul S (2011) Dermatosparaxis in two white Dorper lambs. N Z Vet J 59:258–260PubMedCrossRefGoogle Scholar
  18. 18.
    Zhou H, Hickford JG, Fang Q (2012) A premature stop codon in the ADAMTS2 gene is likely to be responsible for dermatosparaxis in Dorper sheep. Anim Genet 43:471–473PubMedCrossRefGoogle Scholar
  19. 19.
    Wang WM, Ge G, Nagase H, Greenspan DS (2006) TIMP-3 inhibits the procollagen N-proteinase ADAMTS-2. Biochem J 398:515–519PubMedCrossRefGoogle Scholar
  20. 20.
    Tang BL (2001) ADAMTS: a novel family of extracellular matrix proteases. Int J Biochem Cell Biol 33:33–44PubMedCrossRefGoogle Scholar
  21. 21.
    Colige A, Sieron AL, Li SW, Schwarze U, Petty E, Wertelecki W, Wilcox W, Krakow D, Cohn DH, Reardon W, Byers PH, Prockop DJ, Nusgens BV (1999) Human Ehlers-Danlos syndrome type VII C and bovine dermatosparaxis are caused by mutations in the procollagen I N-proteinase gene. Am J Hum Genet 65:308–317PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Holm DE, van Wilpe E, Harper CK, Duncan NM (2008) The occurrence of dermatosparaxis in a commercial Drakensberger cattle herd in South Africa. J S Afr Vet Assoc 79:19–24PubMedCrossRefGoogle Scholar
  23. 23.
    Singleton AC, Mitchell AL, Byers PH, Kathleen A, Potter KA, Pace JM (2005) Bovine model of Marfan syndrome Results from an amino acid change (c.3598G4A, p.E1200K) in a calcium-binding epidermal growth factor-like domain of fibrillin-1. Hum Mutat 25:348–352PubMedCrossRefGoogle Scholar
  24. 24.
    Hirano T, Matsuhashi T, Kobayashi N, Watanabe T, Sugimoto Y (2012) Identification of an FBN1 mutation in bovine Marfan syndrome-like disease. Anim Genet 43:11–17PubMedCrossRefGoogle Scholar
  25. 25.
    Besser TE, Potter KA, Bryan GM, Knowlen GG (1990) An animal model of Marfan syndrome. Am J Med Genet 29:581–594Google Scholar
  26. 26.
    Potter KA, Hoffman Y, Sakai LY, Byers PH, Besser TE, Milewicz DM (1993) Abnormal fibrillin metabolism in bovine Marfan syndrome. Am J Pathol 142:803–810PubMedGoogle Scholar
  27. 27.
    Potter KA, Besser TE (1994) Cardiovascular lesions in bovine Marfan syndrome. Vet Pathol 31:501–509PubMedCrossRefGoogle Scholar
  28. 28.
    Gigante A, Chillemi C, Potter KA, Bertoni-Freddari C, Greco F (1999) Elastic fibers of musculoskeletal tissues in bovine Marfan syndrome: a morphometric study. J Orthop Res 17:624–628PubMedCrossRefGoogle Scholar
  29. 29.
    Downing AK, Knott V, Werner JM, Cardy CM, Campbell ID, P.A H (1996) Solution structure of a pair of calcium-binding epidermal growth factor-like domains: implications for the Marfan syndrome and other genetic disorders. Cell 85:597–605PubMedCrossRefGoogle Scholar
  30. 30.
    Reinhardt DP, Ono RN, Sakai LY (1997) Calcium stabilizes fibrillin-1 against proteolytic degradation. J Biol Chem 272:1231–1236PubMedCrossRefGoogle Scholar
  31. 31.
    Lopez A, Spracklin D, McConkey S, Hanna P (1999) Cutaneous mucinosis and mastocytosis in a shar-pei. Can Vet J 40:881–883PubMedPubMedCentralGoogle Scholar
  32. 32.
    Zanna G, Fondevila D, Bardagi M, Docampo MJ, Bassols A, Ferrer L (2008) Cutaneous mucinosis in shar-pei dogs is due to hyaluronic acid deposition and is associated with high levels of hyaluronic acid in serum. Vet Dermatol 18:314–318CrossRefGoogle Scholar
  33. 33.
    Zanna G, Docampo MJ, Fondevila D, Bardagi M, Bassols A, Ferrer L (2009) Hereditary cutaneous mucinosis in shar pei dogs is associated with increased hyaluronan synthase-2 mRNA transcription by cultured dermal fibroblasts. Vet Dermatol 20:377–382PubMedCrossRefGoogle Scholar
  34. 34.
    Farias GHG, Johnson GS, Taylor JF, Giuliano E, Katz ML, Sanders DN, Schnabel RD, McKay SD, Khan S, Gharahkani P, O’Leary CA, Pettitt L, Forman OP, Boursnell M, McLaughlin B, Ahonen S, Lohi H, Hernandez-Merino E, Gould DJ, Sargan DR, Mellersh C (2010) An ADAMTS17 splice donor siten mutation in dogs with primary lens luxation. Invest Ophthalmol 51:4716–4721CrossRefGoogle Scholar
  35. 35.
    Morales J, Al-Sharif L, Khalil DS, Shinwari JM, Bavi P, Al-Mahrouqi RA, Al-Rahji A, Alkuraya FS, Meyer BF, Al Tassan N (2009) Homozygous mutations in ADAMTS10 and ADAMTS17 cause lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature. Am J Hum Genet 85:558–568PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Plaas A, Sandy JD, Liu H, Diaz MA, Schenkman D, Magnus RP, Bolam-Bretl C, Kopesky PW, Wang VM, Galante JO (2011) Biochemical identification and immunolocalization of aggrecan, ADAMTS5 and inter-alpha-trypsin-inhibitor in equine degenerative suspensory ligament desmitis. J Orthop Res 29:900–906PubMedCrossRefGoogle Scholar
  37. 37.
    Hardy MH, Fisher KR, Vrablic OE, Yager JA, Nimmo-Wilkie JS, Parker W, Keeley FW (1988) An inherited connective tissue disease in the horse. Lab Invest 59:253–262PubMedGoogle Scholar
  38. 38.
    Gunson DE, Halliwell RE, Minor RR (1984) Dermal collagen degradation and phagocytosis. Occurrence in a horse with hyperextensible fragile skin. Arch Dermatol 120:599–604PubMedCrossRefGoogle Scholar
  39. 39.
    White SD, Affolter VK, Bannasch DL, Schultheiss PC, Hamar DW, Chapman PL, Naydan D, Speir SJ, Rosychuk RAW, Rees C, Veneklasen GO, Martin A, Revier D, Jackson HA, Bettenay S, Matousek J, Campbell KL, Ihrke PJ (2004) Hereditary equine regional dermal asthenia (‘hyperelastosis cutis’) in 50 horses: clinical, histological, immunohistological and ultrastructural findings. Vet Dermatol 15:207–217PubMedCrossRefGoogle Scholar
  40. 40.
    Borges AS, Conceição LG, Alves ALG, Fabris VE, Pessoa MA (2005) Hereditary equine regional dermal asthenia in three related Quarter horses in Brazil. Vet Dermatol 16:125–130PubMedCrossRefGoogle Scholar
  41. 41.
    Brounts SH, Rashmir-Raven AM, Black SS (2001) Zonal dermal separation: a distinctive histopathological lesion associated with hyperelastosis cutis in a Quarter horse. Vet Dermatol 12:219–224PubMedCrossRefGoogle Scholar
  42. 42.
    Grady JJ, Elder SH, Ryan PL, Swiderski CE, Rashmir-Raven AM (2009) Biomechanical and molecular characteristics of hereditary equine regional dermal asthenia in Quarter Horses. Vet Dermatol 20:591–599PubMedCrossRefGoogle Scholar
  43. 43.
    Ishikawa Y, Vranka JA, Boudko SP, Pokidysheva E, Mizuno K, Zientek K, Keene DR, Rashmir-Raven AM, Nagata K, Winand NJ, Bächinger HP (2012) The mutation in cyclophilin B that causes hyperelastosis cutis in the American Quarter Horse does not affect peptidyl-prolyl cis-trans isomerase activity, but shows altered cyclophilin B-protein interactions and affects collagen folding. J Biol Chem 287:22253–22265Google Scholar
  44. 44.
    Tryon RC, White SD, Bannasch DL (2007) Homozygosity mapping approach identifies a missense mutation in equine cycophilin B (PPIB) associated with HERDA in the American Quarter Horse. Genomics 90:93–102PubMedCrossRefGoogle Scholar
  45. 45.
    Swiderski C, Pasquali M, Schwarz L, Boyle C, Read R, Hopper R, Ryan P, Rashmir-Raven A (2006) The ratio of urine deoxypyridinoline to pyridinoline identifies horses with hyperelastosis cutis (A.K.A. hereditary equine regional dermal asthenia or HERDA). J Vet Int Med 20:756Google Scholar
  46. 46.
    Rüfenacht S, Straub R, Steinmann B, Winand N, Bidaut A, Stoffel MH, Gerber V, Wyder M, Müller E, Roosje PJ (2010) Swiss warmblood horse with symptoms of hereditary equine regiomal asthena without mutation in the cyclophylin B gene (PPIB). Schweiz Arch Tierheilkd 152:188–192PubMedCrossRefGoogle Scholar
  47. 47.
    Mero JL, Pool R (2002) Twenty cases of degenerative suspensory ligament desmitis in Peruvian Paso horses, vol 48. Abstract for AAEP, Orlando, pp 329–334Google Scholar
  48. 48.
    Mero J, Scarlett J (2005) Diagnostic criteria for degenerative suspensory ligament desmitis in Peruvian Paso horses. J Equine Vet Sci 25:224–228CrossRefGoogle Scholar
  49. 49.
    Halper J, Kim B, Khan A, Yoon JH, Mueller POE (2006) Degenerative suspensory ligament desmitis as a systemic disorder characterized by proteoglycan accumulation. BMC Vet Res 2:12PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Halper J, Khan A, Mueller POE (2011) Degenerative suspensory ligament desmitis – a new reality. Pak Vet J 31:1–8Google Scholar
  51. 51.
    Dyson SJ, Arthur RM, Palmer SE, Richardson D (1995) Suspensory ligament desmitis. Vet Clin North Am 11:172–215Google Scholar
  52. 52.
    Dyson S (2007) Diagnosis and management of common suspensory lesions in the forelimbs and hindlimbs of sport horses. Clin Tech Equine Pract 6:179–188CrossRefGoogle Scholar
  53. 53.
    Gibson KT, Steel CM (2002) Conditions of the suspensory ligament causing lameness in horses. Equine Vet Educ 4:50–64Google Scholar
  54. 54.
    Xie L, Spencer ND, Beadle RE, Gaschen L, Buchert MR, Lopez MJ (2011) Effects of athletic conditioning on horses with degenerative suspensory ligament desmitis: a preliminary report. Vet J 189:49–57PubMedCrossRefGoogle Scholar
  55. 55.
    Miller KD, Juzwiak JS (2010) Bilateral degenerative suspensory desmitis with acute rupture in a Standardbred colt. Equine Vet Educ 22:267–270CrossRefGoogle Scholar
  56. 56.
    Schenkman D, Armien A, Pool R, Williams JM, Schultz RD, Galante JO (2009) Systemic proteoglycan deposition is not a characteristic of equine degenerative suspensory ligament desmitis (DSLD). J Equine Vet Sci 29:748–752CrossRefGoogle Scholar
  57. 57.
    Fales-Williams A, Sponseller B, Flaherty H (2008) Idiopathic arterial medial calcification of the thoracic arteries in an adult horse. J Vet Diagn Invest 20:692–697PubMedCrossRefGoogle Scholar
  58. 58.
    Holmes JR, Rezakhani A, Else RW (1973) Rupture of a dissecting aortic aneurysm into the left pulmonary artery in a horse. Equine Vet J 5:65–70PubMedCrossRefGoogle Scholar
  59. 59.
    van der Linde-Sipman JS, Kroneman J, Meulenaar H, Vos JH (1985) Necrosis and rupture of the aorta and pulmonary trunk in four horses. Vet Pathol 22:51–53PubMedGoogle Scholar
  60. 60.
    Ploeg M, Saey V, de Bruijn CM, Gröne A, Chiers K, van Loon G, Ducatelle R, van Weeren PR, Back W, Delesalle C (2013) Aortic rupture and aorto-pulmonary fistulation in the Friesian horse: characterisation of the clinical and gross post mortem findings in 24 cases. Equine Vet J 45:101–106PubMedCrossRefGoogle Scholar
  61. 61.
    Smith JD, Hamir AN, Greenlee JJ (2011) Cartilaginous metaplasia in the sclera of Suffolk sheep. Vet Pathol 48:827–829PubMedCrossRefGoogle Scholar
  62. 62.
    Kim B, Yoon JH, Zhang J, Mueller POE, Halper J (2010) Glycan profiling of a defect in decorin glycosylation in equine systemic proteoglycan accumulation, a potential model of progeroid form of Ehlers-Danlos syndrome. Arch Biochem Biophys 501:221–231PubMedCrossRefGoogle Scholar
  63. 63.
    Velasco J, Li J, DiPietro L, Stepp MA, Sandy JD, Plaas A (2011) Adamts5 deletion blocks murine dermal repair through CD44-mediated aggrecan accumulation and modulation of transforming growth factor β1 (TGFβ1) signaling. J Biol Chem 286:26016–26027PubMedCrossRefGoogle Scholar
  64. 64.
    Wang VM, Bell RM, Thakore R, Eyre DR, Galante JO, Li J, Sandy JD, Plass A (2012) Murine tendon function is adversely affected by aggrecan accumulation due to the knockout of ADAMTS5. J Orthop Res 30:620–626PubMedCrossRefGoogle Scholar
  65. 65.
    Hassing HC, Mooji H, Guo S, Monia BP, Chen K, Kulik W, Dallinga-Thie GM (2012) Inhibition of hepatic sulfatase-2 in vivo: a novel strategy to correct diabetic dyslipidemia. Hepatology 55:1746–1753PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Rowell JL, McCarthy DO, Alvarez CE (2011) Dog models of naturally occurring cancer. Trends Mol Med 17:380–388PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  1. 1.Department of Pathology, College of Veterinary Medicine and Medical PartnershipThe University of GeorgiaAthensUSA

Personalised recommendations