European Journal of Pediatrics

, Volume 178, Issue 3, pp 323–329 | Cite as

Osteoporosis-pseudoglioma syndrome: clinical, genetic, and treatment-response study of 10 new cases in Greece

  • Iordanis Papadopoulos
  • Evangelia Bountouvi
  • Achilleas AttilakosEmail author
  • Evangelia Gole
  • Argirios Dinopoulos
  • Melpomeni Peppa
  • Polyxeni Nikolaidou
  • Anna Papadopoulou
Original Article


Osteoporosis-pseudoglioma syndrome (OPPG) is a rare autosomal-recessive disorder, characterized by severe osteoporosis and early-onset blindness. Loss of function mutations in the gene encoding low-density lipoprotein receptor-related protein 5 (LRP5) have been established as the genetic defect of the disease. We report the clinical and genetic evaluation of ten OPPG cases in eight related nuclear families and their close relatives. Bone mineral density (BMD) in OPPG patients was assessed by dual-energy X-ray absorptiometry (DXA). Genotyping of LRP5 gene and targeted detection of index mutation were performed by DNA direct sequencing. Four patients were introduced to bisphosphonates. Mutational screening of LRP5 gene revealed the c.2409_2503+79del deletion in homozygous state, expected to result in a truncated protein. Among 44 members of the pedigree, 10 (22%) were identified homozygous and 34 (59%) heterozygous for this mutation. All patients had congenital blindness and 7 of them had also impaired bone mineral density. Four of them received bisphosphonates and responded with decreased bone pain and improvement in BMD; however, 3 patients presented with one fracture during treatment.

Conclusion: The current study presents the molecular and clinical profiles of 10 new OPPG cases, being part of an extended pedigree. Patients who received bisphosphonate treatment responded well with increase in their BMD, though fractures occurred during therapy.

What is known:

OPPG syndrome is a rare genetic disorder characterized by congenital blindness and juvenile osteoporosis.

Loss of function mutations in the gene encoding low-density lipoprotein receptor-related protein 5 (LRP5) is the genetic defect of the disease.

What is new:

Genetic and clinical phenotype of 10 new OPPG patients.

The ten new OPPG patients presented with phenotypical variability in osseous manifestations.


Bisphosphonates Blindness LRP5 mutation OPPG Osteoporosis 



amino acids


bone mineral density


dual-energy X-ray absorptiometry


familial exudative vitreoretinopathy


low-density lipoprotein receptor-related protein 5


osteoporosis-pseudoglioma syndrome


Authors’ contributions

Iordanis Papadopoulos contributed to the acquisition of data and molecular analysis. Evangelia Bountouvi contributed to the analysis and interpretation of data and drafting of the manuscript. Dr. Anna Papadopoulou performed the molecular studies and contributed to the study design, interpretation of the results, and editing of the manuscript. Dr. Attilakos, Dr. Dinopoulos, and Dr. Nikolaidou contributed to the conception of the study and clinical evaluation of the patients and reviewed the manuscript. Dr. Gole contributed to the molecular analysis. Dr. Peppa performed the bone mineral density measurements.

Compliance with ethical standards

The protocol was approved by the Institutional Review Board of the University Hospital “Attikon.”

Financial disclosure

The authors have no financial relationships relevant to this article.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Written informed consent was obtained from the participants and the parents of the participating children.

Conflicts of interest

All the authors declare that they have no conflicts of interest.


  1. 1.
    Ai M, Heeger S, Bartels CF, Schelling DK (2005) Clinical and molecular findings in osteoporosis-pseudoglioma syndrome. Am J Hum Genet 77:741–753CrossRefPubMedCentralGoogle Scholar
  2. 2.
    Arantes HP, Barros ER, Kunii I, Bilezikian JP, Lazaretti-Castro M (2011) Teriparatide increases bone mineral density in a man with osteoporosis pseudoglioma. J Bone Miner Res 26:2823–2826CrossRefGoogle Scholar
  3. 3.
    Barros ER, Dias da Silva MR, Kunii IS, Lazaretti-Castro M (2008) Three years follow-up of pamidronate therapy in two brothers with osteoporosis-pseudoglioma syndrome (OPPG) carrying an LRP5 mutation. J Pediatr Endocrinol Metab 21:811–818CrossRefGoogle Scholar
  4. 4.
    Bayram F, Tanriverdi F, Kurtoglu S et al (2006) 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 19:275–279CrossRefGoogle Scholar
  5. 5.
    Cheung WM, Jin LY, Smith DK et al (2006) A family with osteoporosis pseudoglioma syndrome due to compound heterozygosity of two novel mutations in the LRP5 gene. Bone 39:470–476CrossRefGoogle Scholar
  6. 6.
    Chung BD, Kayserili H, Ai M, Freudenberg J, Üzümcü A, Uyguner O, Bartels CF, Höning S, Ramirez A, Hanisch FG, Nürnberg G, Nürnberg P, Warman ML, Wollnik B, Kubisch C, Netzer C (2009) 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 30:641–648CrossRefGoogle Scholar
  7. 7.
    Cui Y, Niziolek PJ, MacDonald BT et al (2011) Lrp5 functions in bone to regulate bone mass. Nat Med 17:684–691CrossRefPubMedCentralGoogle Scholar
  8. 8.
    Ferrari SL, Deutsch S, Antonarakis SE (2005) Pathogenic mutations and polymorphisms in the lipoprotein receptor-related protein 5 reveal a new biological pathway for the control of bone mass. Curr Opin Lipidol 16:207–214CrossRefGoogle Scholar
  9. 9.
    Fretz JA, Zella LA, Kim S, Shevde NK, Pike JW (2007) 1,25-Dihydroxyvitamin D3 induces expression of the Wnt signaling co-regulator LRP5 via regulatory elements located significantly downstream of the gene's transcriptional start site. J Steroid Biochem Mol Biol 103:440–445CrossRefPubMedCentralGoogle Scholar
  10. 10.
    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 GCM, 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 (2001) LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107:513–523CrossRefGoogle Scholar
  11. 11.
    Hartikka H, Makitie O, Mannikko M et al (2005) Heterozygous mutations in the LDL receptor-related protein 5 (LRP5) gene are associated with primary osteoporosis in children. J Bone Miner Res 20:783–789CrossRefGoogle Scholar
  12. 12.
    Jacobsen CM (2017) Application of anti-sclerostin therapy in non-osteoporosis disease models. Bone 96:18–23CrossRefGoogle Scholar
  13. 13.
    Kato M, Patel MS, Levasseur R, Lobov I, Chang BHJ, Glass DA II, Hartmann C, Li L, Hwang TH, Brayton CF, Lang RA, Karsenty G, Chan L (2002) Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J Cell Biol 157:303–314CrossRefPubMedCentralGoogle Scholar
  14. 14.
    Koay MA, Brown MA (2005) Genetic disorders of the LRP5-Wnt signalling pathway affecting the skeleton. Trends Mol Med 11:129–137CrossRefGoogle Scholar
  15. 15.
    Laine CM, Chung BD, Susic M, Prescott T, Semler O, Fiskerstrand T, D'Eufemia P, Castori M, Pekkinen M, Sochett E, Cole WG, Netzer C, Mäkitie O (2011) Novel mutations affecting LRP5 splicing in patients with osteoporosis-pseudoglioma syndrome (OPPG). Eur J Hum Genet 19:875–881CrossRefPubMedCentralGoogle Scholar
  16. 16.
    Lara-Castillo N, Johnson ML (2015) LRP receptor family member associated bone disease. Rev Endocr Metab Disord 16:141–148CrossRefPubMedCentralGoogle Scholar
  17. 17.
    Levasseur R (2008) Treatment and management of osteoporosis-pseudoglioma syndrome. Expert Rev Endocrinol Metab 3:337–348CrossRefGoogle Scholar
  18. 18.
    Levasseur R, Lacombe D, de Vernejoul MC (2005) LRP5 mutations in osteoporosis-pseudoglioma syndrome and high-bone-mass disorders. Joint Bone Spine 72:207–214CrossRefGoogle Scholar
  19. 19.
    Mosekilde L, Torring O, Rejnmark L (2011) Emerging anabolic treatments in osteoporosis. Curr Drug Saf 2011(6):62–74CrossRefGoogle Scholar
  20. 20.
    Papadopoulou A, Gole E, Nicolaidou P (2013) Hereditary rickets. How genetic alterations explain the biochemical and clinical phenotypes. Endocr Metab Immune Disord Drug Targets 13:324–334CrossRefGoogle Scholar
  21. 21.
    Qin M, Hayashi H, Oshima K, Tahira T, Hayashi K, Kondo H (2005) Complexity of the genotype-phenotype correlation in familial exudative vitreoretinopathy with mutations in the LRP5 and/or FZD4 genes. Hum Mutat 26:104–112CrossRefGoogle Scholar
  22. 22.
    Saarinen A, Saukkonen T, Kivela T et al (2010) Low density lipoprotein receptor-related protein 5 (LRP5) mutations and osteoporosis, impaired glucose metabolism and hypercholesterolaemia. Clin Endocrinol 72:481–488CrossRefGoogle Scholar
  23. 23.
    Spiegelman VS, Slaga TJ, Pagano M, Minamoto T, Ronai Z, Fuchs SY (2000) Wnt/beta-catenin signaling induces the expression and activity of betaTrCP ubiquitin ligase receptor. Mol Cell 5:877–882CrossRefGoogle Scholar
  24. 24.
    Streeten EA, McBride D, Puffenberger E, Hoffman ME, Pollin TI, Donnelly P, Sack P, Morton H (2008) Osteoporosis-pseudoglioma syndrome: description of 9 new cases and beneficial response to bisphosphonates. Bone 43:584–590CrossRefPubMedCentralGoogle Scholar
  25. 25.
    Streeten EA, Ramirez S, Eliades M, Jaimungal S, Chandrasekaran S, Kathleen R, Holmes Morton D, Puffenberger EG, Herskovitz R, Leonard MB (2015) Fractures on bisphosphonates in osteoporosis pseudoglioma syndrome (OPPG): pQCT shows poor bone density and structure. Bone 77:17–23CrossRefPubMedCentralGoogle Scholar
  26. 26.
    Tuysuz B, Bursali A, Alp Z, Suyugul N, Laine CM, Makitie O (2012) Osteoporosis-pseudoglioma syndrome: three novel mutations in the LRP5 gene and response to bisphosphonate treatment. Horm Res Paediatr 77:115–120CrossRefGoogle Scholar
  27. 27.
    Xia CH, Liu H, Cheung D, Wang M, Cheng C, du X, Chang B, Beutler B, Gong X (2008) A model for familial exudative vitreoretinopathy caused by LPR5 mutations. Hum Mol Genet 17:1605–1612CrossRefPubMedCentralGoogle Scholar
  28. 28.
    Zacharin M, Cundy T (2000) Osteoporosis pseudoglioma syndrome: treatment of spinal osteoporosis with intravenous bisphosphonates. J Pediatr 137:410–415CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Iordanis Papadopoulos
    • 1
  • Evangelia Bountouvi
    • 1
  • Achilleas Attilakos
    • 1
    Email author
  • Evangelia Gole
    • 1
  • Argirios Dinopoulos
    • 1
  • Melpomeni Peppa
    • 2
  • Polyxeni Nikolaidou
    • 1
  • Anna Papadopoulou
    • 1
  1. 1.Third Department of Pediatrics, National and Kapodistrian University of Athens“Attikon” University General HospitalAthensGreece
  2. 2.Second Department of Internal Medicine, Research Institute and Diabetes Center, National and Kapodistrian University of Athens“Attikon” University General HospitalAthensGreece

Personalised recommendations