Taxonomy of rare genetic metabolic bone disorders
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This article reports a taxonomic classification of rare skeletal diseases based on metabolic phenotypes. It was prepared by The Skeletal Rare Diseases Working Group of the International Osteoporosis Foundation (IOF) and includes 116 OMIM phenotypes with 86 affected genes.
Rare skeletal metabolic diseases comprise a group of diseases commonly associated with severe clinical consequences. In recent years, the description of the clinical phenotypes and radiographic features of several genetic bone disorders was paralleled by the discovery of key molecular pathways involved in the regulation of bone and mineral metabolism. Including this information in the description and classification of rare skeletal diseases may improve the recognition and management of affected patients.
IOF recognized this need and formed a Skeletal Rare Diseases Working Group (SRD-WG) of basic and clinical scientists who developed a taxonomy of rare skeletal diseases based on their metabolic pathogenesis.
This taxonomy of rare genetic metabolic bone disorders (RGMBDs) comprises 116 OMIM phenotypes, with 86 affected genes related to bone and mineral homeostasis. The diseases were divided into four major groups, namely, disorders due to altered osteoclast, osteoblast, or osteocyte activity; disorders due to altered bone matrix proteins; disorders due to altered bone microenvironmental regulators; and disorders due to deranged calciotropic hormonal activity.
This article provides the first comprehensive taxonomy of rare metabolic skeletal diseases based on deranged metabolic activity. This classification will help in the development of common and shared diagnostic and therapeutic pathways for these patients and also in the creation of international registries of rare skeletal diseases, the first step for the development of genetic tests based on next generation sequencing and for performing large intervention trials to assess efficacy of orphan drugs.
KeywordsBone metabolism Genetic bone diseases Metabolic bone diseases Rare bone diseases Taxonomy
This paper was supported by the IOF.
Conflicts of interest
- 1.(2013) Report on the state of the art of rare disease activities in Europe; European Union Committee of Expert on Rare Disease. Overview of rare disease activities in Europe. Part I; pp. 1–78 http://www.eucerd.eu/upload/file/Reports/2013ReportStateofArtRDActivities.pdf
- 3.Available from: National Organization for Rare Diseases (NORD) of the United States: www.rarediseases.org. Accessed Jan 2015
- 6.For a list of rare diseases and their prevalence, please consult the Orphanet Reports Series “Prevalence of rare diseases: bibliographic data”, Orphanet Report Series, Rare Diseases collection, Number 1: Listed in alphabetical order of diseases, http://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphabetical_list.pdf. Accessed Jan 2015
- 8.(2010) 5th European conference on rare diseases. European reference networks & centers of expertise for rare diseases, pp. 1–75Google Scholar
- 9.Available from: EUROPLAN website: www.europlanproject.eu. Accessed Jan 2015
- 10.Commission Regulation (EC) No 847/2000 of 27 April 2000; OJ L 103, 28.4.2000Google Scholar
- 11.Macarthur D (2011) Orphan drugs in Europe: pricing, reimbursement, funding & market access issues, Edition www.justpharmareports.com
- 12.Inventory of Community and Member States’ incentive measures to aid the research, marketing, development and availability of orphan medicinal products. Revision 2005, http://ec.europa.eu/health/files/orphanmp/doc/inventory_2006_08_en.pdf. Accessed Jan 2015
- 13.Available from: Orphabioetic foundation: www.orphanbiotec-foundation.com. Accessed Jan 2015
- 14.Commission Regulation (EC) No 847/2000 of 27 April 2000 laying down the provisions for implementation of the criteria for designation of a medicinal product as an orphan medicinal product and definitions of the concepts ‘similar medicinal product’ and ‘clinical superiority’. Off J Eur Commun 103/5-103/8Google Scholar
- 15.Available from: Orphanet Activity Report 2012, http://www.orpha.net/orphacom/cahiers/docs/GB/ActivityReport2012.pdf. Accessed Jan 2015
- 18.Roldán EJA (2013) Proceedings from the VIII International Conference on Rare Diseases and Orphan Drugs (ICORD), St Petersburg (Russia). Rare J 1(suppl 1):1–48Google Scholar
- 19.Mäkitie O (2011) Molecular defects causing skeletal dysplasias. Camacho-Hübner C, Nilsson O, SŠvendahl L (eds) Cartilage and bone development and its disorders. Endocr Dev. Basel, Karger, vol 21, pp 78–84Google Scholar
- 20.(1970) International nomenclature of constitutional diseases of bones. Ann Radiol (Paris) 13(7):455–464Google Scholar
- 21.(1971a) A nomenclature for constitutional (intrinsic) diseases of bones. J Pediatr 78(1):177–179Google Scholar
- 22.(1971b) International nomenclature of constitutional bone diseases. Constitutional bone diseases without known pathogenesis. Arch Fr Pediatr 28(5):553–557Google Scholar
- 23.Nomenclature for constitutional (intrinsic) diseases of bones. (1971c) Pediatrics 47(2):431–344. Nomenclature for the constitutional (intrinsic) diseases of bone. Radiology. 1971d; 99(3):699–702Google Scholar
- 25.Warman ML, Cormier-Daire V, Hall C, Krakow D, Lachman R, LeMerrer M, Mortier G, Mundlos S, Nishimura G, Rimoin DL, Robertson S, Savarirayan R, Sillence D, Spranger J, Unger S, Zabe B, Superti-Furga A (2011) Nosology and classification of genetic skeletal disorders—2010 revision. Am J Med Genet A 155A(5):943–968CrossRefPubMedGoogle Scholar
- 27.Boyce BF, Zuscik MJ, Xing L (2013) Biology of bone and cartilage. In: Thakker RV, Whyte MP, Eisman JA, Igarashi T (eds) 1 edn. Genetics of bone biology and skeletal diseases. Ch. 1 pp. 3–24Google Scholar
- 30.Kumar R, Riggs R (1980) Pathologic bone physiology. In: Urist MR (ed) Fundamental and clinical bone physiology. Lippincott, Philadelphia, pp 394–406Google Scholar
- 35.Fleisch H (1980) Homeostasis of inorganic phosphate. In: Urist MR (ed) Fundamental and clinical bone physiology. Lippincott, Philadelphia, pp 268–282Google Scholar
- 36.Burtis WJ, Wu T, Bunch C, Wysolmerski JJ, Insogna KL, Weir EC, Broadus AE, Stewart AF (1987) Identification of a novel 17,000-dalton parathyroid hormone-like adenylate cyclase-stimulating protein from a tumor associated with humoral hypercalcemia of malignancy. J Biol Chem 262:7151–7156PubMedGoogle Scholar
- 38.Juppner H, Silve C (2013) Genetic disorders affecting PTH/PTHrP receptor function. In: Thakker RV, Whyte MP, Eisman JA, Igarashi T (eds) Genetics of bone biology and skeletal diseases. Ch. 28, pp. 441–457Google Scholar
- 47.Ross PF (2013) Osteoclast biology and bone resorption. In: Primer on the metabolic bone diseases and disorders of mineral metabolism. Official publication of the American Society for Bone and Mineral Research (ASBMR) 8 edn Ch. 3 pp.25–33Google Scholar
- 52.Frattini A, Orchard PJ, Sobacchi C, Giliani S, Abinun M, Mattsson JP, Keeling DJ, Andersson AK, Wallbrandt P, Zecca L, Notarangelo LD, Vezzoni P, Villa A (2000) Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nat Genet 25:343–346CrossRefPubMedGoogle Scholar
- 53.Karsdal MA, Henriksen K, Sørensen MG, Gram J, Schaller S, Dziegiel MH, Heegaard AM, Christophersen P, Martin TJ, Christiansen C, Bollerslev J (2005) Acidification of the osteoclastic resorption compartment provides insight into the coupling of bone formation to bone resorption. Am J Pathol 166:467–47PubMedCentralCrossRefPubMedGoogle Scholar
- 57.Jansen ID, Mardones P, Lecanda F, de Vries TJ, Recalde S, Hoeben KA, Schoenmaker T, Ravesloot JH, van Borren MM, van Eijden TM, Bronckers AL, Kellokumpu S, Medina JF, Everts V, Oude Elferink RP (2009) Ae2a, b-deficient mice exhibit osteopetrosis of long bones but not of calvaria. FASEB J 23:3470–3481CrossRefPubMedGoogle Scholar
- 58.Gowen M, Lazner F, Dodds R, Kapadia R, Field J, Tavaria M, Bertoncello I, Drake F, Zavarselk S, Tellis I, Hertzog P, Debouck C, Kola I (1999) Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization. J Bone Miner Res 14:1654–1663CrossRefPubMedGoogle Scholar
- 61.Bergmann P, Body JJ, Boonen S, Boutsen Y, Devogelaer JP, Goemaere S, Kaufman JM, Rozenberg S, Reginster JY (2009) Evidence-based guidelines for the use of biochemical markers of bone turnover in the selection and monitoring of bisphosphonate treatment in osteoporosis: a consensus document of the Belgian Bone Club. Int J Clin Pract 63:19–26PubMedCentralCrossRefPubMedGoogle Scholar
- 69.Bergmann P, Body JJ, Boonen S, Boutsen Y, Devogelaer JP, Goemaere S, Kaufman JM, Reginster JY, Gangji V, Members of Advisory Board on Bone Markers (2009) Evidence-based guidelines for the use of biochemical markers, bone turnover: biomarkers of bone turnover. Int J Clin Pract CME 63(1):19–26CrossRefGoogle Scholar
- 70.Keen RW (2013) Sclerosing and displastic bone diseases. In: Primer on the metabolic bone diseases and disorders of mineral metabolism. 8 edn, Wiley, Ames, section VIII, pp 767–842Google Scholar
- 80.Guo D et al (2006) Identification of proteins involved in cytoskeletal rearrangement, anti-hypoxia and membrane channels in osteocytes over osteoblasts. J Bone Miner Res 21:S168Google Scholar
- 82.Robey PG, Boskey AL. The composition of bone. In: Primer on the bone metabolic diseases and disorders of mineral metabolism. Seventh ed. Official publication of the American Society for Bone and Mineral Research Ch. 6 pp. 32–38Google Scholar
- 83.Rossert J, de Crombrugghe B (1996) Type I collagen: structure, synthesis, and regulation. In: JP Bilezikian, Raisz LC, Rodan Ga (eds) Principle of bone biology. 1st edn. Ch. 10 pp. 127–142Google Scholar
- 84.Lian JB, Stein GS (2006) The cells of bone. In: Seibel MJ, Robins S, Bilezikian JP (eds) Dynamics of bone and cartilage metabolism. Academic, San DiegoGoogle Scholar