Advertisement

Hormones

, Volume 15, Issue 4, pp 551–556 | Cite as

Severe osteoporosis with multiple spontaneous vertebral fractures in a young male carrying triple polymorphisms in the vitamin D receptor, collagen type 1, and low-density lipoprotein receptor-related peptide 5 genes

  • Maria P. Yavropoulou
  • Panagoulia Kollia
  • Dimitris Chatzidimitriou
  • Stavroula Samara
  • Lemonia Skoura
  • John G. Yovos
Case report

Abstract

Osteoporosis is a common disease with a strong genetic component. Several studies have reported the vitamin D receptor (VDR), collagen type I (COL1A1), and LDL receptor-related protein 5 (LRP5) genes as the most likely candidates. However, most of the studies have been carried out in postmenopausal women and older men and show inconsistent results. CASE PRESENTATION: We report a case of a 26-year old male who presented with severe back pain of acute onset, unrelated to any kind of trauma, and diffuse myalgia. Imaging of the lumbar and the thoracic spine revealed two Grade 3, according to Genant’s semiquantitative method, vertebral fractures in T10 and T11 and multiple Grade 1 and 2 fractures from T8 to L2. Measurement of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) (Lunar Prodigy) showed severe osteoporosis of the lumbar spine (Z-score=−3.0, BMD = 0.866 gr/cm2). A complete laboratory and biochemical work-up was performed to exclude secondary causes of osteoporosis. Total genomic DNA was extracted from peripheral blood and was used as a template for genotype analysis. The patient was heterozygous for the p.V667M mutation of the LRP5 gene and for the BsmI [g.63980 G→A, rs1544410] and Sp1 polymorphisms fg.6252 G→T, rs1800012] of the VDR and COL1A1 genes, respectively. Further genotype analysis excluded types of osteogenesis imperfecta associated with mutations in the COL1A1 and COL1A2 genes. CONCLUSION: We herein show that the co-existence of three polymorphic sites in the VDR, COL1A1, and LPR-5 genes in a young male adult caused severe osteoporosis with multiple fractures, suggesting a combined effect and/or interaction between these genes.

Key words

COL1A1 polymorphism Idiopathic osteoporosis LRP-5 mutation Multiple fractures VDR polymorphism Young adult 

References

  1. 1.
    1993 Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med 94: 646–650.Google Scholar
  2. 2.
    Seeman E, 2002 Pathogenesis of bone fragility in women and men. Lancet 359: 1841–1850.CrossRefGoogle Scholar
  3. 3.
    Seeman E, 2004 Estrogen, androgen, and the pathogenesis of bone fragility in women and men. Curr Osteoporos Rep 2: 90–96.CrossRefGoogle Scholar
  4. 4.
    Seeman E, 2004 The growth and age-related origins of bone fragility in men. Calcif Tissue Int 75: 100–109.CrossRefGoogle Scholar
  5. 5.
    Baim S, Binkley N, Bilezikian JP, et al, 2008 Official Positions of the International Society for Clinical Densitometry and executive summary of the 2007 ISCD Position Development Conference. J Clin Densitom 11: 75–91.CrossRefGoogle Scholar
  6. 6.
    Bonjour JP, Chevalley T, Rizzoli R, Ferrari S, 2007 Gene-environment interactions in the skeletal response to nutrition and exercise during growth. Med Sport Sci 51: 64–80.CrossRefGoogle Scholar
  7. 7.
    Chevalley T, Rizzoli R, Hans D, Ferrari S, Bonjour JP, 2005 Interaction between calcium intake and menarcheal age on bone mass gain: an eight-year follow-up study from prepuberty to postmenarche. J Clin Endocrinol Metab 90: 44–51.CrossRefGoogle Scholar
  8. 8.
    Ferrari S, Bianchi ML, Eisman JA, et al, 2012 Osteoporosis in young adults: pathophysiology, diagnosis, and management. Osteoporos Int 23: 2735–2748.CrossRefGoogle Scholar
  9. 9.
    Estrada K, Styrkarsdottir U, Evangelou E, et al, 2012 Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet 44: 491–501.CrossRefGoogle Scholar
  10. 10.
    Richards JB, Kavvoura FK, Rivadeneira F, et al, 2009 Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture. Ann Intern Med 151: 528–537.CrossRefGoogle Scholar
  11. 11.
    Richards JB, Zheng HF, Spector TD, 2012 Genetics of osteoporosis from genome-wide association studies: advances and challenges. Nat Rev Genet 13: 576–588.CrossRefGoogle Scholar
  12. 12.
    Morrison NA, Qi JC, Tokita A, et al, 1994 Prediction of bone density from vitamin D receptor alleles. Nature 367: 284–287.CrossRefGoogle Scholar
  13. 13.
    Christakos S, Dhawan P, Liu Y, Peng X, Porta A, 2003 New insights into the mechanisms of vitamin D action. J Cell Biochem 88: 695–705.CrossRefGoogle Scholar
  14. 14.
    Wong HL, Seow A, Arakawa K, Lee HP, Yu MC, Ingles SA, 2003 Vitamin D receptor start codon polymorphism and colorectal cancer risk: effect modification by dietary calcium and fat in Singapore Chinese. Carcinogenesis 24: 1091–1095.CrossRefGoogle Scholar
  15. 15.
    Thomas T, Briot K, 2016 Vitamin D, bone metabolism and fracture risk. Geriatr Psychol Neuropsychiatr Vieil 14: 122–126.PubMedGoogle Scholar
  16. 16.
    Liu YZ, Liu YJ, Recker RR, Deng HW, 2003 Molecular studies of identification of genes for osteoporosis: the 2002 update. J Endocrinol 177: 147–196.CrossRefGoogle Scholar
  17. 17.
    Arai H, Miyamoto KI, Yoshida M, et al, 2001 The polymorphism in the caudal-related homeodomain protein Cdx-2 binding element in the human vitamin D receptor gene. J Bone Miner Res 16: 1256–1264.CrossRefGoogle Scholar
  18. 18.
    Fang Y, van Meurs JB, Bergink AP, et al, 2003 Cdx-2 polymorphism in the promoter region of the human vitamin D receptor gene determines susceptibility to fracture in the elderly. J Bone Miner Res 18: 1632–1641.CrossRefGoogle Scholar
  19. 19.
    Riggs BL, Nguyen TV, Melton LJ 3rd, et al, 1995 The contribution of vitamin D receptor gene alleles to the determination of bone mineral density in normal and osteoporotic women. J Bone Miner Res 10: 991–996.CrossRefGoogle Scholar
  20. 20.
    Masi L, Cimaz R, Simonini G, et al, 2002 Association of low bone mass with vitamin d receptor gene and calcitonin receptor gene polymorphisms in juvenile idiopathic arthritis. J Rheumatol 29: 2225–2231.PubMedGoogle Scholar
  21. 21.
    Sainz J, Van Tornout JM, Loro ML, Sayre J, Roe TF, Gilsanz V, 1997 Vitamin D-receptor gene polymorphisms and bone density in prepubertal American girls of Mexican descent. N Engl J Med 337: 77–82.CrossRefGoogle Scholar
  22. 22.
    Mencej-Bedrac S, Prezelj J, Kocjan T, et al, 2009 The combinations of polymorphisms in vitamin D receptor, osteoprotegerin and tumour necrosis factor superfamily member 11 genes are associated with bone mineral density. J Mol Endocrinol 42: 239–247.CrossRefGoogle Scholar
  23. 23.
    Gong G, Stern HS, Cheng SC, et al, 1999 The association of bone mineral density with vitamin D receptor gene polymorphisms. Osteoporos Int 9: 55–64.CrossRefGoogle Scholar
  24. 24.
    Zintzaras E, Rodopoulou P, Koukoulis GN, 2006 BsmI, TaqI, ApaI and FokI polymorphisms in the vitamin D receptor (VDR) gene and the risk of osteoporosis: a meta-analysis. Dis Markers 22: 317–326.CrossRefGoogle Scholar
  25. 25.
    Qin G, Dong Z, Zeng P, Liu M, Liao X, 2013 Association of vitamin D receptor BsmI gene polymorphism with risk of osteoporosis: a meta-analysis of 41 studies. Mol Biol Rep 40: 497–506.CrossRefGoogle Scholar
  26. 26.
    Uitterlinden AG, Ralston SH, Brandi ML, et al, 2006 The association between common vitamin D receptor gene variations and osteoporosis: a participant-level meta-analysis. Ann Intern Med 145: 255–264.CrossRefGoogle Scholar
  27. 27.
    Ji GR, Yao M, Sun CY, Li ZH, Han Z, 2010 BsmI, TaqI, ApaI and FokI polymorphisms in the vitamin D receptor (VDR) gene and risk of fracture in Caucasians: a meta-analysis. Bone 47: 681–686.CrossRefGoogle Scholar
  28. 28.
    Fang Y, Rivadeneira F, van Meurs JB, Pols HA, Ioannidis JP, Uitterlinden AG, 2006 Vitamin D receptor gene BsmI and TaqI polymorphisms and fracture risk: a meta-analysis. Bone 39: 938–945.CrossRefGoogle Scholar
  29. 29.
    Valadares ER, Carneiro TB, Santos PM, Oliveira AC, Zabel B, 2014 What is new in genetics and osteogenesis imperfecta classification? J Pediatr (Rio J) 90: 536–541.CrossRefGoogle Scholar
  30. 30.
    O’Sullivan ES, van der Kamp S, Kilbane M, McKenna M, 2014 Osteogenesis imperfecta in adults: phenotypic characteristics and response to treatment in an Irish cohort. Ir J Med Sci 183: 225–230.PubMedGoogle Scholar
  31. 31.
    Van Dijk FS, Sillence DO 2014 Osteogenesis imperfecta: clinical diagnosis, nomenclature and severity assessment. Am J Med Genet A 164A: 1470–1481.CrossRefGoogle Scholar
  32. 32.
    Uitterlinden AG, Pols HA, Burger H, et al, 1996 A large-scale population-based study of the association of vitamin D receptor gene polymorphisms with bone mineral density. J Bone Miner Res 11: 1241–1248.CrossRefGoogle Scholar
  33. 33.
    Ralston SH, Uitterlinden AG, Brandi ML, et al, 2006 Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes: the GENOMOS study. PLoS Med 3: e90.CrossRefGoogle Scholar
  34. 34.
    Jin H, van’t Hof RJ, Albagha OM, Ralston SH, 2009 Promoter and intron 1 polymorphisms of COL1A1 interact to regulate transcription and susceptibility to osteoporosis. Hum Mol Genet 18: 2729–2738.CrossRefGoogle Scholar
  35. 35.
    Yavropoulou MP, Yovos JG, 2007 The role of the Wnt signaling pathway in osteoblast commitment and differentiation. Hormones (Athens) 6: 279–294.CrossRefGoogle Scholar
  36. 36.
    Gong Y, Slee RB, Fukai N, et al, 2001 LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107: 513–523.CrossRefGoogle Scholar
  37. 37.
    Gong Y, Vikkula M, Boon L, et al, (1996) Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13. Am J Hum Genet 59: 146–151.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Little RD, Carulli JP, Del Mastro RG, et al, 2002 A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet 70: 11–19.CrossRefGoogle Scholar
  39. 39.
    van Meurs JB, Trikalinos TA, Ralston SH, et al, 2008 Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis. JAMA 299: 1277–1290.CrossRefGoogle Scholar

Copyright information

© Hellenic Endocrine Society 2016

Authors and Affiliations

  • Maria P. Yavropoulou
    • 1
  • Panagoulia Kollia
    • 2
  • Dimitris Chatzidimitriou
    • 3
  • Stavroula Samara
    • 2
  • Lemonia Skoura
    • 3
  • John G. Yovos
    • 1
  1. 1.Division of Endocrinology and Metabolism, 1st Department of Internal Medicine, AHEPA University hospitalAristotle University of ThessalonikiThessalonikiGreece
  2. 2.Department of Genetics and Biotechnology, Faculty of Biology, School of Physical SciencesUniversity of AthensAthensGreece
  3. 3.Department of Microbiology, Medical SchoolAristotle University of ThessalonikiThessalonikiGreece

Personalised recommendations