Skeletal dysplasias with increased bone density: Evolution of molecular pathogenesis in the last century Shagun Aggarwal ⁎ Department of Medical Genetics, Nizam's Institute of Medical Sciences and Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500082, India abstract article info Available online 5 May 2013 Keywords: Osteopetrosis Increased bone density Genetics History Skeletal dysplasias (SKD) with increased bone density form a discrete group of SKDs as per the Nosology and Classification of Genetic Skeletal Disorders, 2010 Revision. This group, with the prototype disorder being osteopetrosis, has evolved over the last century, with new entities being described & their molecular basis being increasingly elucidated. Osteopetrosis, which remained an enigma in the early part of its description, is now known to be genetically heterogenous. Other disorders in this group, which were initially described as variant forms of osteopetrosis, are now recognised to be distinct conditions. However, all these SKDs with increased bone density share their molecular pathogenesis as majority arise due to mutations in the genes governing osteoclast formation and function. © 2013 Elsevier B.V. All rights reserved. 1. Introduction Skeletal dysplasias with increased bone density comprise a group of 34 different conditions, characterised by excessive bone deposition of variable distribution and severity in the skeleton (Warman et al., 2011). The prototype of this group is osteopetrosis which was first described in 1904 by Albers Schonberg (Schonberg, 1904). This disor- der is characterised by a diffuse increase in bone mass and manifests clinically with varying degree of severity, ranging from a neonatal lethal form to an asymptomatic form presenting in adult life. In the early part of its description, it was considered to be a disease involv- ing the parathyroid gland with secondary bone involvement. How- ever, the molecular bases were found after 1980s onwards and it was realised that the clinical heterogeneity could be attributed to the under- lying molecular heterogeneity (Stark and Savarirayan, 2009). A large number of other disorders which were initially described as variant forms of ostepetrosis are increasingly realised as being clinically as well as genetically distinct (Horan and Beighton, 1978). The molecular pathogenesis of majority of conditions in this group is now known and is intricately linked to each other. Insight into the molecular path- ways offers opportunity for developing novel treatment strategies in the future. This group has indeed come a complete circle, starting as var- iants of osteopetrosis, segregation into distinct conditions and subse- quent recognition as functionally interconnected disorders. This article presents the evolution of this group from the recognition of osteopetrosis to the present day molecularly defined entities. 2. Osteopetrosis/Albers Schonberg disease/Marble bone disease 2.1. Early description and radiological features This disorder was first described in1904 by Albers Schonberg a German radiologist (Schonberg, 1904). He reported the characteristic radiographic findings of increased bone density in a 26 year old mer- chant with history of recurrent fractures. In a review in 1960 of 40 cases (Ellis, 1934), the radiographic findings of osteopetrosis were described as “Symmetrically arranged areas of greatly increased den- sity are seen involving both the membrane and cartilage bones; the base of the skull, the bodies of the vertebrae, and the long bones are generally most affected. The carpal bones often appear “ringed” with a dark shadow. The dense, compact bone encroaches on the medullary cavity, which may ultimately become almost entirely obliterated. The areas of sclerosis in some instances may be of uniform density through- out, or may show transverse lines of rarefaction. The contour of the bone in osteopetrosis is not altered by the sclerosis, although clubbing of the posterior clinoid process and of the ends of the long bones Gene 528 (2013) 41–45 Abbreviations: TCIRG1, T-cell, immune regulator 1, ATPase, H + transporting, lysosomal V0 subunit A3 [Homo sapiens]; SLC29A3, solute carrier family 29 (nucleoside transporters), member 3 [Homo sapiens]; SOST, sclerostin [Homo sapiens]; LRP5, low density lipoprotein receptor-related protein 5 [Homo sapiens]; RANKL, receptor activator of nuclear factor kappa B ligand [Homo Sapiens]; CA2, carbonic anhydrase II [Homo sapiens]; CLCN7, chloride channel, voltage-sensitive 7 [Homo sapiens]; OSTM1, osteopetrosis associated transmem- brane protein 1 [Homo sapiens]; PLEKHM1, pleckstrin homology domain containing, family M (with RUN domain) member 1 [Homo sapiens]; FERMT3, fermitin family member 3[Homo sapiens]; RANK, receptor activator of NF-KB [Homo Sapiens]; NEMO, NF-kappa-B essential modulator [Homo sapiens]; SNX10, sorting nexin 10 [Homo sapiens]; ANKH, anky- losis, progressive homolog (mouse) [Homo sapiens]; TGFB1, transforming growth factor, beta 1 [Homo sapiens]; WTX, Wilms tumor gene on the X chromosome protein [Homo sapiens]; LEMD3, LEM domain containing 3 [Homo sapiens]; AD, Autosomal dominant; AR, Autosomal recessive; SKD, Skeletal dysplasia. ⁎ Tel.: +91 7702700980. E-mail address: shagun.genetics@gmail.com. 0378-1119/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.gene.2013.04.069 Contents lists available at ScienceDirect Gene journal homepage: www.elsevier.com/locate/gene