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Ollier Disease: Pathogenesis, Diagnosis, and Management See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/278787870 Ollier Disease: Pathogenesis, Diagnosis, and Management Article in Orthopedics · June 2015 DOI: 10.3928/01477447-20150603-58 · Source: PubMed CITATIONS READS 11 115 4 authors, including: Vijay K Jain Minakshi Bhardwaj Postgraduate Institute of Medical Education and Research PGIMER ,Dr. Ram Manohar Lohia Hospital,New Delhi,India 24 PUBLICATIONS 161 CITATIONS 122 PUBLICATIONS 301 CITATIONS SEE PROFILE SEE PROFILE Some of the authors of this publication are also working on these related projects: Rare tumour of salivary gland View project PUBLICATION View project All content following this page was uploaded by Minakshi Bhardwaj on 02 February 2016. The user has requested enhancement of the downloaded file. n Feature Article Ollier Disease: Pathogenesis, Diagnosis, and Management AVINASH KUMAR, MS; VIJAY KUMAR JAIN, MS; MINAKSHI BHARADWAJ, MD; RAJENDRA KUMAR ARYA, MS abstract Ollier disease (Spranger type I) is a rare bone disease that is characterized by mul- tiple enchondromatosis with a typical asymmetrical distribution and confined to the appendicular skeleton. The pathogenesis of enchondromatosis is not clearly understood. Recently, heterozygous mutations of PTHR1, IDH1 (most common), and/or IDH2 genes have been suggested by various authors as genetic aberrations. Genomic copy number alterations and mutations controlling many vital pathways are responsible for the pathogenesis of Ollier disease. A comprehensive description of all genetic events in Ollier disease is presented in this article. Clinically, Ollier disease has a wide variety of presentations. This article describes the plethora of clinical features, both common and rare, associated with Ollier disease. Multiple en- chondromas are most commonly seen in phalanges and metacarpals. Radiologically, Ollier disease presents with asymmetrical osteolytic lesions with well-defined, scle- rotic margins. In this article, various radiological features of Ollier disease, including radiographs, computed tomography, and magnetic resonance imaging, are also dis- cussed. Gross pathology, cytological, and histological features of both Ollier disease and its malignant transformation are outlined. Although treatment is conservative in most cases, different possible treatment options for difficult cases are discussed. In the literature, there is a paucity of data about the disease, including diagnosis, man- agement, prognostication, and rehabilitation, necessitating a comprehensive review to further define all of the possible domains related to this disease. Orthopedics.[ 2015; 38(6):e497-e506.] The authors are from the Department of Orthopedics (AK, VKJ, RKA) and the Department of Pathol- ogy (MB), PGIMER, Ram Manohar Lohia Hospital, New Delhi, India. The authors have no relevant financial relationships to disclose. Correspondence should be addressed to: Vijay Kumar Jain, MS, Department of Orthopedics, PGIMER, Ram Manohar Lohia Hospital, New Delhi, India 110001 ([email protected]). Received: January 12, 2014; Accepted: August 4, 2014. doi: 10.3928/01477447-20150603-58 JUNE 2015 | Volume 38 • Number 6 e497 n Feature Article hondromas are benign, generally asymptomatic tumors of hyaline Table 1 cartilage that are most commonly C Historical Contributions to the Evolution of Ollier Disease located in the phalanges of the hand. They are called enchondromas when they arise Year Author(s) Contribution 8,9 from the medullary canal. Rarely, they 1898 Ollier Coined dyschondroplasie (described as a unilateral lesion) arise on the surface of the bone and are 1923 Bentzon10 Interpreted as a typical reaction of the bones to an active hyperemia of the bone tissues, resulting from the anoma- referred to as periosteal chondromas or lies of the sympathetic nervous system juxtacortical chondromas. 1935 Hunter and Wiles11 First to identify the key distinguishing features such as a Enchondromas are the second most lack of heredity, childhood onset, and unilateral involve- common benign cartilaginous tumor af- ment in Ollier disease ter osteochondromas.1 Enchondromato- 1958 Jaffe12 Defined as the presence of either circumscribed foci or sis,2 or Ollier disease, is defined by the large masses of cartilage in the interior of bones presence of multiple enchondromas (3 or 1978 Spranger et al5 Classified and termed Ollier disease as multiple enchon- dromatosis more) and characterized by an asymmetric distribution of cartilaginous lesions that can be extremely variable in terms of their size, number, location, evolution, age of Table 2 onset and diagnosis, and requirement for Classification of Multiple Enchondromatosis surgery. The association of lymphangio- a mas with Ollier disease and Maffucci syn- Condition Clinical Features drome (another enchondromatosis) has Ollier disease (Spranger type I) Multiple enchondromas of tubular and flat bones, predominantly unilateral been described in the literature.3,4 Maffucci syndrome (Spranger type II) Same as Ollier disease, with hemangiomas EPIDEMIOLOGY AND CLASSIFICATION Metachondromatosis (Spranger type III) Multiple enchondromas and exostoses The estimated prevalence of Ollier dis- Spondyloenchondrodysplasia (Spranger Multiple enchondromas with severe platyspon- type IV) dyly ease is 1 in 100,000.5-7 The true incidence of Ollier disease may be higher because Enchondromatosis with irregular spinal Multiple enchondromas with dysplasia of ver- lesions (Spranger type V) tebral bodies mild phenotypes without skeletal defor- Cheirospondyloenchondromatosis (for- Multiple enchondromas, severe hand and foot mities are sometimes not detected. Few merly generalized enchondromatosis) involvement, mild platyspondyly, erosion of cases of familial occurrence have been (Spranger type VI) iliac crests reported (Table 1).13-15 Dysspondylochondromatosis Multiple appendicular enchondromas with Spranger et al5 created a comprehen- hemivertebrae, dwarfism, limb-length dis- crepancy sive classification of enchondromato- Genochondromatosis Medial clavicular enlargement, lucent lesions ses based on radiographic appearance, of long bones anatomic site, and mode of inheritance. aSpranger type IV and genochondromatosis do not involve the hands, whereas other types, They divided enchondromatosis into 6 especially types I, II, III, and VI, do involve the hands. subtypes: type I, Ollier disease; type II, Maffucci syndrome; type III, metachon- dromatosis; type IV, spondyloenchon- drodysplasia; type V, enchondromatosis with mucopolysacchariduria, and enchon- ease is basically an abnormality of devel- with irregular spinal lesions; and type VI, dromatosis with concave vertebral bod- opment of the limb bud, which, in post- cheirospondyloenchondromatosis. Most ies. The modified Spranger classification fetal life, causes the long bones to grow in subtypes are nonhereditary, whereas some system is widely used to address types of diameter but not in length. Table 3 sum- are autosomal dominant or recessive. Ha- enchondromatosis, and the common sub- marizes all the proposed theories regard- lal and Azouz16 later added 3 subtypes to types are listed in Table 2.17 ing the pathogenesis of Ollier disease. this classification system based on case In 1943, Jaffe and Lichtenstein18 pro- reports of enchondromatosis: generalized PATHOPHYSIOLOGY posed that enchondromatous lesions are enchondromatosis with irregular vertebral The pathogenesis of enchondromatosis actually the displaced cartilaginous rests lesions, generalized enchondromatosis is still not clearly understood. Ollier dis- of normal physeal cartilage cells. This e498 COPYRIGHT © SLACK INCORPORATED n Feature Article theory is still widely accepted regarding the genesis of enchondroma. There are Table 3 formations of intraosseous cartilaginous Proposed Theories for the Pathogenesis of Ollier Disease foci in enchondromas that might result Displaced remnants of normal physeal cartilage cells18 from the abnormalities in signaling path- Hamartomatous growth of cartilage cells19-21 ways controlling the proliferation and dif- Failure of endochondral ossification22 24 ferentiation of chondrocytes. Migration of dysplastic nidus from physeal proliferative zone to primary ossification Heterozygous mutations24,25 and mis- zone in metaphyses23 24 sense mutations in parathyroid-related Failure of terminal differentiation of growth plate chondrocytes24 peptide type 1 receptor (PTHR1) or dys- Heterozygous mutations of PTHR1 gene25 regulation in the Indian hedgehog sig- Heterozygous mutations of IDH1 and/or IDH2 gene26-28 naling pathway (eg, overexpression of Loss of chromosomes (Chr 6 and Chr 3), deletions, amplifications, gains, and other hedgehog transcriptional regulator GLI2 genomic copy number neutral structural changes of subtle genes29,30 or activation of a hedgehog-responsive Familial31 GLI2-luciferase in a PTHR1 mutant25) may cause development of enchondroma- tous lesions in patients with Ollier disease. Recently, heterozygous mutations in also been reported in early adolescence the isocitrate dehydrogenase (IDH) gene and adulthood.37,38 These lesions usually Table 4 have been related to Ollier disease, mainly appear and grow before puberty but soon IDH1 (98%) and IDH2 (2%).26-28 These remodel into normal bone.6,39 Whereas Clinical Presentations of mutations exhibited a phenomenon of enchondromas occur equally in both sex- Ollier Disease intraneoplastic mosaicism similar to that es, Ollier disease is seen twice as often in Multiple swellings
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