Alterations in Bone Mineral Density in Marfan Syndrome and Homocystinuria

  • Philip F. Giampietro
  • Margaret Peterson
  • Cathy L. Raggio
Original Paper


Homocystinuria and Marfan syndrome represent distinct genetic conditions that share phenotypically similar skeletal features. An overview of the current understanding of genetic and physiologic contributing to the etiology of these conditions is summarized. The focus of this review is to explore the present understanding of the pathophysiology of Marfan syndrome and homocystinuria relative to the occurrence of osteoporosis in both conditions. Osteoporosis has been reported in association with homocystinuria. However, evidence supporting an association of osteoporosis with Marfan syndrome is equivocal and sources of ambiguity are critically reviewed. Advisability and approaches to bone mineral density monitoring in patients with Marfan syndrome or homocystinuria to inform clinical management are discussed. Finally, future research foci are proposed which will improve understanding of association of osteoporosis with Marfan syndrome or homocystinuria.


Homocystinuria Marfan syndrome Osteoporosis Bone mineral density 


  1. 1.
    Dietz HC, Cutting GR, Pyeritz RE, et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature. 1991;352:337–9.PubMedCrossRefGoogle Scholar
  2. 2.
    Pyeritz RE, McKusick VA. The Marfan syndrome: diagnosis and management. N Engl J Med. 1979;300(14):772–7.PubMedGoogle Scholar
  3. 3.
    De Paepe A, Devereux RB, Dietz HC, Hennekam RC, Pyeritz RE. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet. 1996;62:417–26.PubMedCrossRefGoogle Scholar
  4. 4.
    Shores J, Berger KR, Murphy EA, Pyeritz RE. Progression of aortic dilatation and the benefit of long-term beta-adrenergic blockade in Marfan’s syndrome. N Engl J Med. 1994;330:1335–41.PubMedCrossRefGoogle Scholar
  5. 5.
    Neptune ER, Frischmeyer PA, Arking DE, et al. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet. 2003;33:407–11.PubMedCrossRefGoogle Scholar
  6. 6.
    Carter N, Duncan E, Wordsworth P. Bone mineral density in adults with Marfan syndrome. Rheumatology (Oxford). 2000;39:307–9.CrossRefGoogle Scholar
  7. 7.
    Giampietro PF, Peterson M, Schneider R, et al. Assessment of bone mineral density in adults and children with Marfan syndrome. Osteoporos Int. 2003;14:559–63.PubMedCrossRefGoogle Scholar
  8. 8.
    Gray JR, Bridges AB, Mole PA, Pringle T, Boxer M, Paterson CR. Osteoporosis and the Marfan syndrome. Postgrad Med J. 1993;69:373–5.PubMedGoogle Scholar
  9. 9.
    Kohlmeier L, Gasner C, Bachrach LK, Marcus R. The bone mineral status of patients with Marfan syndrome. J Bone Miner Res. 1995;10:1550–5.PubMedCrossRefGoogle Scholar
  10. 10.
    Kohlmeier L, Gasner C, Marcus R. Bone mineral status of women with Marfan syndrome. Am J Med. 1993;95:568–72.PubMedCrossRefGoogle Scholar
  11. 11.
    Le Parc JM, Plantin P, Jondeau G, Goldschild M, Albert M, Boileau C. Bone mineral density in sixty adult patients with Marfan syndrome. Osteoporos Int. 1999;10:475–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Moura B, Tubach F, Sulpice M, et al. Bone mineral density in Marfan syndrome. A large case-control study. Joint Bone Spine. 2006;73:733–5.PubMedCrossRefGoogle Scholar
  13. 13.
    Tobias JH, Dalzell N, Child AH. Assessment of bone mineral density in women with Marfan syndrome. Br J Rheumatol. 1995;34:516–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Carson N, Raine D. Inherited disorders of sulfur metabolism. Edinburgh: Churchill Livingstone; 1971.Google Scholar
  15. 15.
    Giampietro PF, Peterson MGE, Schneider R, et al. Bone mineral density determinations by dual-energy X-ray absorptiometry-some factors which affect the measurement. HSSJ. 2007;3:89–92.CrossRefGoogle Scholar
  16. 16.
    Green MC, Sweet HO, Bunker LE. Tight-skin, a new mutation of the mouse causing excessive growth of connective tissue and skeleton. Am J Pathol. 1976;82:493–512.PubMedGoogle Scholar
  17. 17.
    Siracusa LD, McGrath R, Ma Q, et al. A tandem duplication within the fibrillin 1 gene is associated with the mouse tight skin mutation. Genome Res. 1996;6:300–13.PubMedCrossRefGoogle Scholar
  18. 18.
    Barisic-Dujmovic T, Boban I, Adams DJ, Clark SH. Marfan-like skeletal phenotype in the tight skin (Tsk) mouse. Calcif Tissue Int. 2007;81:305–15.PubMedCrossRefGoogle Scholar
  19. 19.
    Mudd S, Levy H, Skovby F (1989) Disorders of trans-sulfuration. In: Scriver C, Beaudet A, Sly W, editors. The metabolic basis of inherited disease. 6th ed. New York: McGraw-Hill; 1989. 693 p.Google Scholar
  20. 20.
    Tada K, Tateda H, Arashima S, et al. Follow-up study of a nation-wide neonatal metabolic screening program in Japan. A collaborative study group of neonatal screening for inborn errors of metabolism in Japan. Eur J Pediatr. 1984;142:204–7.PubMedCrossRefGoogle Scholar
  21. 21.
    Whiteman PD, Clayton BE, Ersser RS, Lilly P, Seakins JW. Changing incidence of neonatal hypermethioninaemia: implications for the detection of homocystinuria. Arch Dis Child. 1979;54:593–8.PubMedGoogle Scholar
  22. 22.
    Doherty LB, Rohr FJ, Levy HL. Detection of phenylketonuria in the very early newborn blood specimen. Pediatrics. 1991;87:240–4.PubMedGoogle Scholar
  23. 23.
    Naughten ER, Yap S, Mayne PD. Newborn screening for homocystinuria: Irish and world experience. Eur J Pediatr. 1998;157(Suppl 2):S84–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Walter JH, Wraith JE, White FJ, Bridge C, Till J. Strategies for the treatment of cystathionine beta-synthase deficiency: the experience of the Willink Biochemical Genetics Unit over the past 30 years. Eur J Pediatr. 1998;157(Suppl 2):S71–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Yap S, Naughten E. Homocystinuria due to cystathionine beta-synthase deficiency in Ireland: 25 years’ experience of a newborn screened and treated population with reference to clinical outcome and biochemical control. J Inherit Metab Dis. 1998;21:738–47.PubMedCrossRefGoogle Scholar
  26. 26.
    Barber G, Spaeth G. Pyridoxine therapy in homocystinuria. Lancet. 1967;1:337.CrossRefGoogle Scholar
  27. 27.
    Kraus JP, Janosik M, Kozich V, et al. Cystathionine beta-synthase mutations in homocystinuria. Hum Mutat. 1999;13:362–75.PubMedCrossRefGoogle Scholar
  28. 28.
    Wilcken DE, Wilcken B, Dudman NP, Tyrrell PA. Homocystinuria—the effects of betaine in the treatment of patients not responsive to pyridoxine. N Engl J Med. 1983;309:448–53.PubMedGoogle Scholar
  29. 29.
    Brenton DP. Skeletal abnormalities in homocystinuria. Postgrad Med J. 1977;53:488–96.PubMedCrossRefGoogle Scholar
  30. 30.
    McKusick V. Heritable disorders of connective tissue. St. Louis: C V. Mosby; 1966.Google Scholar
  31. 31.
    Schedewie H, Willich E, Grobe H, Schmidt H, Muller KM. Skeletal findings in homocystinuria: a collaborative study. Pediatr Radiol. 1973;1:12–23.PubMedCrossRefGoogle Scholar
  32. 32.
    Parrot F, Redonnet-Vernhet I, Lacombe D, Gin H. Osteoporosis in late-diagnosed adult homocystinuric patients. J Inherit Metab Dis. 2000;23:338–40.PubMedCrossRefGoogle Scholar
  33. 33.
    Mudd SH, Skovby F, Levy HL, et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. Am J Hum Genet. 1985;37:1–31.PubMedGoogle Scholar
  34. 34.
    Lubec B, Fang-Kircher S, Lubec T, Blom HJ, Boers GH. Evidence for McKusick’s hypothesis of deficient collagen cross-linking in patients with homocystinuria. Biochim Biophys Acta. 1996;1315:159–62.PubMedGoogle Scholar
  35. 35.
    McLean RR, Jacques PF, Selhub J, et al. Homocysteine as a predictive factor for hip fracture in older persons. N Engl J Med. 2004;350:2042–9.PubMedCrossRefGoogle Scholar
  36. 36.
    van Meurs JB, Dhonukshe-Rutten RA, Pluijm SM, et al. Homocysteine levels and the risk of osteoporotic fracture. N Engl J Med. 2004;350:2033–41.PubMedCrossRefGoogle Scholar
  37. 37.
    Herrmann M, Kraenzlin M, Pape G, Sand-Hill M, Herrmann W. Relation between homocysteine and biochemical bone turnover markers and bone mineral density in peri- and post-menopausal women. Clin Chem Lab Med. 2005;43:1118–23.PubMedCrossRefGoogle Scholar
  38. 38.
    Lumbers M, New SA, Gibson S, Murphy MC. Nutritional status in elderly female hip fracture patients: comparison with an age-matched home living group attending day centres. Br J Nutr. 2001;85:733–40.PubMedCrossRefGoogle Scholar
  39. 39.
    Reynolds TM, Marshall PD, Brain AM. Hip fracture patients may be vitamin B6 deficient. Controlled study of serum pyridoxal-5′-phosphate. Acta Orthop Scand. 1992;63:635–8.PubMedGoogle Scholar
  40. 40.
    Villadsen MM, Bunger MH, Carstens M, Stenkjaer L, Langdahl BL. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is associated with osteoporotic vertebral fractures, but is a weak predictor of BMD. Osteoporos Int. 2005;16:411–6.PubMedCrossRefGoogle Scholar
  41. 41.
    Dodds RA, Catterall A, Bitensky L, Chayen J. Abnormalities in fracture healing induced by vitamin B6-deficiency in rats. Bone. 1986;7:489–95.PubMedCrossRefGoogle Scholar
  42. 42.
    Rauch F, Plotkin H, Dimeglio L, et al. Fracture prediction and the definition of osteoporosis in children and adolescents: the ISCD 2007 pediatric official positions. J Clin Densitom. 2008;11:22–8.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2008

Authors and Affiliations

  • Philip F. Giampietro
    • 1
  • Margaret Peterson
    • 2
  • Cathy L. Raggio
    • 3
  1. 1.Department of Genetic ServicesMarshfield ClinicMarshfieldUSA
  2. 2.Hospital for Special SurgeryNew YorkUSA
  3. 3.Department of Pediatric OrthopedicsHospital for Special SurgeryNew YorkUSA

Personalised recommendations