Catch-Up of Bone Mineral Density in Osteoporosis-Pseudoglioma Syndrome

  • Régis Levasseur


Skeletal fragility during childhood induces fractures due mainly to a decrease in bone quantity and also an alteration of bone quality. Osteoporosis-pseudoglioma syndrome (OPPG, MIM 259770) was discovered in the last century and is a very rare genetic disorder with an autosomal recessive mode of inheritance, characterized by congenital or infancy-onset visual loss and skeletal fragility diagnosed during childhood due to a severe defect of bone accrual during growth. More than 50 cases have now been described. This syndrome can lead to severe disability and chronic bone pain. The gene mutated and inactivated in OPPG is LRP5 (LDL receptor-related protein 5), a Wnt membrane co-receptor expressed in osteoblasts and many other cell types. LRP5 plays a pivotal role in bone accrual and skeletal remodelling by controlling bone formation through activators such as Wnt proteins or inhibitors such as DKK1. The lack of a functional LRP5 leads to a severe defect of bone formation by osteoblasts, very early in the process of bone growth and bone accrual. The main differential diagnoses of OPPG are osteogenesis imperfecta and child abuse; these should be known to clinicians. Eye examination, coupled to bone phenotype and research of LRP5 mutation, is key to diagnose OPPG. Chronic pains with severe functional disability due to repeated fractures are the main problems to manage. Clinicians should normalize the serum level of 25(OH) vitamin D and calcium diet in parallel to giving bisphosphonates during childhood. Bisphosphonates (the main studies have been done with pamidronate) allow fracture prevention, catch-up of bone mineral density, and improvement in mobility in children with OPPG. New drugs favouring osteoblast function and osteoclast inhibition are potential candidates to treat OPPG.


Bone Mineral Density Vertebral Fracture Osteogenesis Imperfecta Strontium Ranelate Physical Child Abuse 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Bone mineral density


Basic multicellular unit


Dickkopf 1


Dual-energy X-ray absorptiometry




LDL receptor-related protein 5


Nuclear factor kappa B


Osteoporosis-pseudoglioma syndrome




Receptor activator for nuclear factor kappa B ligand


Selective oestrogen receptor modulators




  1. Ai M, Heeger S, Bartels CF, Schelling DK. Clinical and molecular findings in osteoporosis-pseudoglioma syndrome. Am J Hum Genet. 2005;77:741–53.PubMedCrossRefGoogle Scholar
  2. Barros ER, Dias da Silva MR, Kunii IS, Hauache OM, Lazaretti-Castro M. A novel mutation in the LRP5 gene is associated with osteoporosis-pseudoglioma syndrome. Osteoporos Int. 2007;18:1017–8.PubMedCrossRefGoogle Scholar
  3. Bass S, Delmas PD, Pearce G, Hendrich E, Tabensky A, Seeman E. The differing tempo of growth in bone size, mass, and density in girls is region-specific. J Clin Invest. 1999;104:795–804.PubMedCrossRefGoogle Scholar
  4. Bayram F, Tanriverdi F, Kurtoglu S, Atabek ME, Kula M, Kaynar L, Keleştimur F. Effects of 3 years of intravenous pamidronate treatment on bone markers and bone mineral density in a patient with osteoporosis-pseudoglioma syndrome (OPPG). J Pediatr Endocrinol Metab. 2006;19:275–9.PubMedCrossRefGoogle Scholar
  5. Cheung WM, Jin LY, Smith DK, Cheung PT, Kwan EY, Low L, Kung AW. A family with osteoporosis pseudoglioma syndrome due to compound heterozygosity of two novel mutations in the LRP5 gene. Bone. 2006;39:470–6.PubMedCrossRefGoogle Scholar
  6. Chung BD, Kayserili H, Ai M, Freudenberg J, Uzümcü A, Uyguner O, Bartels CF, Höning S, Ramirez A, Hanisch FG, Nürnberg G, Nürnberg P, Warman ML, Wollnik B, Kubisch C, Netzer C. A mutation in the signal sequence of LRP5 in a family with an osteoporosis-pseudoglioma syndrome (OPPG)-like phenotype indicates a novel disease mechanism for trinucleotide repeats. Hum Mutat. 2009;30:641–8.PubMedCrossRefGoogle Scholar
  7. De Paepe A, Leroy JG, Nuytinck L, Meire F, Capoen J. Osteoporosis-pseudoglioma syndrome. Am J Med Genet. 1993;45:30–7.PubMedCrossRefGoogle Scholar
  8. Di Iorgi N, Maghnie M. Motor function improvement after intravenous pamidronate in osteoporosis pseudoglioma syndrome. J Pediatr. 2006;149:734.PubMedCrossRefGoogle Scholar
  9. Ferrari SL, Deutsch S, Choudhury U, Chevalley T, Bonjour JP, Dermitzakis ET, Rizzoli R, Antonarakis SE. Polymorphisms in the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with variation in vertebral bone mass, vertebral bone size, and stature in whites. Am J Hum Genet. 2004;74:866–75.PubMedCrossRefGoogle Scholar
  10. Frontali M, Stomeo C, Dallapiccola B. Osteoporosis-pseudoglioma syndrome: report of three affected sibs and an overview. Am J Med Genet. 1985;22:35–47.PubMedCrossRefGoogle Scholar
  11. Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T, Glorieux FH, Lev D, Zacharin M, Oexle K, Marcelino J, Suwairi W, Heeger S, Sabatakos G, Apte S, Adkins WN, Allgrove J, Arslan-Kirchner M, Batch JA, Beighton P, Black GC, Boles RG, Boon LM, Borrone C, Brunner HG, Carle GF, Dallapiccola B, De Paepe A, Floege B, Halfhide ML, Hall B, Hennekam RC, Hirose T, Jans A, Jüppner H, Kim CA, Keppler-Noreuil K, Kohlschuetter A, LaCombe D, Lambert M, Lemyre E, Letteboer T, Peltonen L, Ramesar RS, Romanengo M, Somer H, Steichen-Gersdorf E, Steinmann B, Sullivan B, Superti-Furga A, Swoboda W, van den Boogaard MJ, Van Hul W, Vikkula M, Votruba M, Zabel B, Garcia T, Baron R, Olsen BR, Warman ML. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001;107:513–23.PubMedCrossRefGoogle Scholar
  12. Hartikka H, Mäkitie O, Männikkö M, Doria AS, Daneman A, Cole WG, Ala-Kokko L, Sochett EB. Heterozygous mutations in the LDL receptor-related protein 5 (LRP5) gene are associated with primary osteoporosis in children. J Bone Miner Res. 2005;20:783–9.PubMedCrossRefGoogle Scholar
  13. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266–81.PubMedCrossRefGoogle Scholar
  14. Kasten P, Bastian L, Schmid H, Coull R, Wippermann BW, Krettek C. Failure of operative treatment in a child with osteoporosis-pseudoglioma syndrome. Clin Orthop Relat Res. 2003;410:262–6.PubMedCrossRefGoogle Scholar
  15. Kato M, Patel MS, Levasseur R, Lobov I, Chang BH, Glass DA 2nd, Hartmann C, Li L, Hwang TH, Brayton CF, Lang RA, Karsenty G, Chan L. Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J Cell Biol. 2002;157:303–14.PubMedCrossRefGoogle Scholar
  16. Levasseur R. Treatment and management of osteoporosis-pseudoglioma syndrome. Exp Rev Endocrinol Metab. 2008;3:337–48.CrossRefGoogle Scholar
  17. Levasseur R, Lacombe D, de Vernejoul MC. LRP5 mutations in osteoporosis-pseudoglioma syndrome and high-bone-mass disorders. Joint Bone Spine. 2005;72:207–14.PubMedCrossRefGoogle Scholar
  18. Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem. 2005;280:19883–7.PubMedCrossRefGoogle Scholar
  19. Lobov IB, Rao S, Carroll TJ, Vallance JE, Ito M, Ondr JK, Kurup S, Glass DA, Patel MS, Shu W, Morrisey EE, McMahon AP, Karsenty G, Lang RA. WNT7b mediates macrophage-induced programmed cell death in patterning of the vasculature. Nature. 2005;437:417–21.PubMedCrossRefGoogle Scholar
  20. Mao B, Wu W, Davidson G, Marhold J, Li M, Mechler BM, Delius H, Hoppe D, Stannek P, Walter C, Glinka A, Niehrs C. Kremen proteins are Dickkopf receptors that regulate Wnt/beta-catenin signalling. Nature. 2002;417:664–7.PubMedCrossRefGoogle Scholar
  21. Marques-Pinheiro A, Levasseur R, Cormier C, Bonneau J, Boileau C, Varret M, Abifadel M, Allanore Y. Novel LRP5 gene mutation in a patient with osteoporosis-pseudoglioma syndrome. Joint Bone Spine. 2010;77:151–3.PubMedCrossRefGoogle Scholar
  22. Narumi S, Numakura C, Shiihara T, Seiwa C, Nozaki Y, Yamagata T, Momoi MY, Watanabe Y, Yoshino M, Matsuishi T, Nishi E, Kawame H, Akahane T, Nishimura G, Emi M, Hasegawa T. Various types of LRP5 mutations in four patients with osteoporosis-pseudoglioma syndrome: identification of a 7.2-kb microdeletion using oligonucleotide tiling microarray. Am J Med Genet A. 2010;152A:133–40.PubMedCrossRefGoogle Scholar
  23. Neuhauser G, Kaveggia EG, Opitz JM. Autosomal recessive syndrome of pseudogliomantous blindness, osteoporosis and mild mental retardation. Clin Genet. 1976;9:324–32.PubMedCrossRefGoogle Scholar
  24. Pellathy BV. Ablatio retinae und uveitis congenita bei drei Geschwistern. Z Augenheilkd. 1931;73:249–54.Google Scholar
  25. Rauch F, Glorieux FH. Osteogenesis imperfecta. Lancet. 2004;363:1377–85.PubMedCrossRefGoogle Scholar
  26. Steichen-Gersdorf E, Gassner I, Unsinn K, Sperl W. Persistent hyperplastic primary vitreous in a family with osteoporosis-pseudoglioma syndrome. Clin Dysmorphol. 1997;6:171–6.PubMedCrossRefGoogle Scholar
  27. Straub DA. Calcium supplementation in clinical practice: a review of forms, doses, and indications. Nutr Clin Pract. 2007;22:286–96.PubMedCrossRefGoogle Scholar
  28. Streeten EA, McBride D, Puffenberger E, Hoffman ME, Pollin TI, Donnelly P, Sack P, Morton H. Osteoporosis-pseudoglioma syndrome: description of 9 new cases and beneficial response to bisphosphonates. Bone. 2008;43:584–90.PubMedCrossRefGoogle Scholar
  29. Teebi AS, Al-Awadi SA, Marafie MJ, Bushnaq RA, Satyanath S. Osteoporosis-pseudoglioma syndrome with congenital heart disease: a new association. J Med Genet. 1988;25:32–6.PubMedCrossRefGoogle Scholar
  30. Zacharin M, Cundy T. Osteoporosis-pseudoglioma syndrome: treatment of spinal osteoporosis with intravenous bisphosphonates. J Pediatr. 2000;137:410–5.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of RheumatologyAngers Teaching HospitalAngersFrance
  2. 2.Service de Rhumatologie et Pôle ostéo-articulaire, Faculté de Médecine d’AngersCHU d’Angers, Inserm U922AngersFrance

Personalised recommendations