Trazer a Bioquímica Envolvida na Osteocondromatose Múltipla Hereditária

BioMed Central Page 1 of 7 page number not for citation purposes Orphanet Journal of Rare Diseases Open Access Review Multiple osteochondromas Judith VMG Bovée Address Department of Pathology Leiden University Medical Center Leiden The Netherlands Email Judith VMG Bovée jvmgboveelumcnl Abstract Multiple osteochondromas MO is characterised by development of two or more cartilage capped bony outgrowths osteochondromas of the long bones The prevalence is estimated at 150000 and it seems to be higher in males maletofemale ratio 151 Osteochondromas develop and increase in size in the first decade of life ceasing to grow when the growth plates close at puberty They are pedunculated or sessile broad base and can vary widely in size The number of osteochondromas may vary significantly within and between families the mean number of locations is 1518 The majority are asymptomatic and located in bones that develop from cartilage especially the long bones of the extremities predominantly around the knee The facial bones are not affected Osteochondromas may cause pain functional problems and deformities especially of the forearm that may be reason for surgical removal The most important complication is malignant transformation of osteochondroma towards secondary peripheral chondrosarcoma which is estimated to occur in 055 MO is an autosomal dominant disorder and is genetically heterogeneous In almost 90 of MO patients germline mutations in the tumour suppressor genes EXT1 or EXT2 are found The EXT genes encode glycosyltransferases catalyzing heparan sulphate polymerization The diagnosis is based on radiological and clinical documentation supplemented with if available histological evaluation of osteochondromas If the exact mutation is known antenatal diagnosis is technically possible MO should be distinguished from metachondromatosis dysplasia epiphysealis hemimelica and Ollier disease Osteochondromas are benign lesions and do not affect life expectancy Management includes removal of osteochondromas when they give complaints Removed osteochondromas should be examined for malignant transformation towards secondary peripheral chondrosarcoma Patients should be well instructed and regular followup for early detection of malignancy seems justified For secondary peripheral chondrosarcoma enbloc resection of the lesion and its pseudocapsule with tumourfree margins preferably in a bone tumour referral centre should be performed Disease name and synonyms Multiple Osteochondromas MO MIM 133700 Hereditary Multiple Exostoses HME Multiple Heredi tary Exostoses MHE EXT diaphyseal aclasis multiple hereditary osteochondromatosis multiple cartilaginous exostoses Definition and diagnostic criteria Osteochondroma osteocartilaginous exostosis is a carti lage capped bony projection arising on the external sur face of bone containing a marrow cavity that is continuous with that of the underlying bone 1 A diag nosis of MO can be made when radiologically at least two osteochondromas of the juxtaepiphyseal region of long Published 13 February 2008 Orphanet Journal of Rare Diseases 2008 33 doi1011861750117233 Received 13 November 2007 Accepted 13 February 2008 This article is available from httpwwwojrdcomcontent313 2008 Bovée licensee BioMed Central Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License httpcreativecommonsorglicensesby20 which permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited Orphanet Journal of Rare Diseases 2008 33 httpwwwojrdcomcontent313 Page 2 of 7 page number not for citation purposes bones are observed In the majority of patients a positive family history andor mutation in one of the EXT genes can be detected 23 Epidemiology The prevalence of MO is estimated at 150000 persons within the general population 4 and seems to be higher in males maletofemale ratio 151 25 This is proba bly due to the fact that females tend to have a milder phe notype and are therefore more easily overlooked 2 The solitary sporadic form of osteochondroma is approxi mately six times more common than the occurrence within the context of MO Approximately 62 of the patients with multiple osteochondromas have a positive family history 2 Clinical description Osteochondromas develop and increase in size in the first decade of life ceasing to grow when the growth plates close at puberty They are pedunculated or sessile broad base and can vary widely in size The majority are asymp tomatic and located in bones that develop from cartilage especially the long bones of the extremities predomi nantly around the knee Figures 1 and 2A The facial bones are not affected The number of osteochondromas may vary significantly within and between families the mean number of locations is 1518 6 In addition in MO patients a variety of orthopaedic deformities can be found like deformities of the forearm shortening of the ulna with secondary bowing of radius 3960 467 Figure 2C inequality in limb length 1050 47 varus or valgus angulation of the knee 833 47 deformity of the ankle 254 47 and disproportion ate short stature 3744 256 Other complications of the osteochondromas include osseous and cosmetic deformities bursa formation arthritis 14 5 and impingement on adjacent ten dons nerves 226 5 vessels 113 5 or spinal cord 06 58 MO patients may have abnormal scar formation 9 Osteochondromas bear the risk for fracture of the bony stalk during physical exercise This is esti mated to occur in approximately 5 of osteochondromas 10 and may be reason for surgical removal Examples of radiographs demonstrating multiple osteochondromas around the knee A and at the pelvis and proximal femur B while C demonstrates the deformity of the forearm shortening of the ulna with secondary bowing of radius that is found in 3960 of the patients Figure 2 Examples of radiographs demonstrating multiple osteochondromas around the knee A and at the pelvis and proximal femur B while C demonstrates the deformity of the forearm shortening of the ulna with secondary bowing of radius that is found in 3960 of the patients Photograph of the legs of a 26 year old male showing multi ple lumps leading to deformity Figure 1 Photograph of the legs of a 26 year old male showing multiple lumps leading to deformity Orphanet Journal of Rare Diseases 2008 33 httpwwwojrdcomcontent313 Page 3 of 7 page number not for citation purposes The majority of MO patients experiences pain 1112 approximately half of which concerns generalised pain 11 Therefore the number of MO individuals having pain has been underestimated and pain seems a problem that must be addressed when caring for MO patients The occurrence of pain was associated with MO related com plications and surgery 11 The most important complication of MO is malignant transformation of an osteochondroma which is esti mated to occur in 055 of patients 2451314 Clin ical signs of malignant transformation include an increase in size and pain 6 Malignant transformation of osteo chondroma leads to a secondary peripheral chondrosar coma in 94 of the cases 15 The suspicion of secondary chondrosarcoma is indicated by growth of the tumour after puberty the presence of pain or a thickness over 1 cm of the cartilaginous cap in adults Aetiology Two genes EXT1 and EXT2 located respectively at 8q24 and 11p11p12 have been isolated to cause MO 1619 Additional linkage to chromosome 19p has been found suggesting the existence of an EXT3gene 20 However the gene has never been identified Moreover the increased sensitivity of mutation detection and the use of new techniques screening for larger deletions such as MLPA have dramatically decreased the proportion of MO patients without an EXT1 or EXT2 mutation to 15 21 23 These data question the existence of an EXT3gene at 19p The EXT1 gene is composed of 11 exons and has a coding region of 2238 bp 1724 The EXT2gene contains 16 exons 1819 and its cDNA defines a single open reading frame of 2154 bp EXT1 and EXT2 are highly similar espe cially in the carboxy terminal region 1819 The EXT1 gene was reported to show linkage in 4466 of the MO families 2526 whereas EXT2 would be involved in 27 26 Germline mutations of EXT1 and EXT2 in MO patients have been studied extensively in Caucasian as well as Asian populations 27 In EXT1 mutations are more or less randomly distributed over the first 6 exons while the last 5 exons containing the con served carboxyterminal region contain significantly less mutations 27 Similarly in EXT2 most mutations are found in the first eight exons No mutational hotspots are found Approximately 80 of the mutations are either nonsense frameshift or splicesite mutations leading to premature termination of EXT proteins 252832 The majority of missense mutations also lead to defective EXT protein function 33 Mutations in EXT1 seem associated with a more severe phenotype as compared to EXT2 34 37 It has long been thought that osteochondromas are the result of skeletal dysplasia It is now however generally accepted that osteochondromas are neoplastic since genetic changes are found in the cartilage cap 13842 The EXTgenes are tumour suppressor genes Loss of the remaining EXT1 wildtype allele has been demonstrated in the cartilage cap of osteochondromas from MO patients 39 However in a considerable proportion of MO patients loss of the remaining wildtype allele could not be detected so far 43 In seven out of eight solitary osteo chondromas homozygous deletions of EXT1 are found 38 further supporting the twohit model Moreover the deletions were confined to the cartilage cap Thus the car tilage cap is the clonal neoplastic element while the stalk is reactive 38 Both EXT1 and EXT2 mRNA is ubiquitously expressed 1719 A high level of expression of Ext1 and Ext2 mRNA has been found in developing limb buds of mouse embryos 4445 and expression was demonstrated to be confined to the proliferating and prehypertrophic chondrocytes of the growth plate 46 In osteochondro mas and peripheral chondrosarcomas the expression of EXT1 andor EXT2 is decreased corresponding to the mutation status 47 The gene products exostosin1 EXT1 and exostosin2 EXT2 are endoplasmic reticulum localized type II trans membrane glycoproteins which form a Golgilocalised heterooligomeric complex that catalyzes heparan sul phate HS polymerization 4851 Heparan sulphate proteoglycans HSPG are large macromolecules com posed of heparan sulphate glycosaminoglycan chains linked to a protein core Four important HSPG families are syndecan glypican perlecan and isoforms of CD44 bearing variable exon 3 CD44v3 In osteochondromas in which EXT expression is decreased due to mutation or deletion the heparan sulphate proteoglycans seem to accumulate in the cytoplasm of the cell instead of being transported to be expressed at the cell surface 47 EXT and HSPGs are required for highaffinity binding of fibroblast growth factor to its receptor and for the diffu sion of the morphogens Hedgehog Hh human homo logues Indian IHH and Sonic Hedgehog SHH 5254 decapentaplegic dpp human homologues TGFbeta and BMP and wingless wng human homologue Wnt 5556 These three pathways are important during devel opment and are specifically active in the growth plate dur ing endochondral bone formation During normal growth IHh and PTHLH are involved in a delicate para crine feedback loop regulating proliferation and differen tiation of the chondrocytes of the growth plate Figure 3 In osteochondroma IHH signalling is still active and is probably cell autonomous 5758 PTHLH signalling Orphanet Journal of Rare Diseases 2008 33 httpwwwojrdcomcontent313 Page 4 of 7 page number not for citation purposes which is downstream of IHH and is responsible for chondrocyte proliferation is absent in osteochondroma while being upregulated upon malignant transformation of osteochondroma 5960 Wnt signalling and TGFbeta signalling are also active in the majority of osteochondro mas 57 The exact role of EXT in orchestrating these pathways leading to osteochondroma formation in MO patients needs to be further elucidated Diagnostic methods When a patient is suspected to have MO the full radiolog ical documentation histology if available patient his tory and family history have to be carefully reviewed Given the specific radiological and histological expertise needed and the rarity of the disorder and of those in the differential diagnosis it is recommended that this review is performed by specialists in the field for instance through a national bone tumour registry consisting of cli nicians radiologists and pathologists If this review is indicative for MO the peripheral blood of the patient may be screened for germline mutations in EXT1 or EXT2 61 In case of a positive family history in which MO is clearly established in relatives the diagnosis of MO can be clini cally made and mutation analysis is not essential With the currently used methods it is possible to detect point mutations or gross deletions in almost 90 of MO patients 21236163 To evaluate possible malignant transformation in case of complaints or growth of the lesion after puberty the size of the cartilaginous cap can be well established with T2 weighted magnetic resonance MR imaging 64 A carti lage cap 15 cm should be regarded with caution The role of 18 Fluorodeoxyglucose positron emission tomog raphy 18FDG PET needs to be further established 65 Differential diagnosis Dysplasia Epiphysealis Hemimelica DEH Trevors dis ease tarsoepiphysial aclasis and metachondromatosis MC are considered in the differential diagnosis of soli tary and hereditary osteochondromas Despite their simi larities they were shown to be separate entities 66 and the EXT downstream pathway is not involved 67 DEH is a developmental disorder with cartilaginous over growth of a portion of one or more epiphyses 68 It pre dominantly affects the lower extremity on one side of the body It is usually restricted to either the medial most fre quent or lateral side of the limb hemimelic Similar to osteochondroma DEH is usually diagnosed prior to the age of 15 years more often in boys than in girls and growth of these lesions end at puberty as the growth plates close 6869 In contrast to MO malignant transforma tion has not been reported so far 68 and there does not appear to be any genetic transmission 6971 MC is a rare disorder exhibiting synchronous both mul tiple osteochondromas and enchondromas in children It has an autosomal dominant mode of inheritance 7274 but the disorder has not been mapped in the human genome so far MC related osteochondromas characteris tically occur in the hands and feet predominantly the dig its and toes and point toward the adjacent growth plate while in MO the osteochondromas are mainly located in the long or other tubular bones and point away from the epiphysis 72 Differentiation from MO is of great clinical significance because in patients with MC the lesions do not result in shortening or deformity of affected bones as in MO and may spontaneously decrease in size or resolve completely both clinically and radiologically 7274 Moreover MO should be distinguished from enchondro matosis Ollier disease and Maffucci syndrome in which multiple cartilage tumours are found in the medulla of bone with a predilection for the short tubular bones and a unilateral predominance 75 Growth plate signaling in the normal growth plate Figure 3 Growth plate signaling in the normal growth plate Indian Hedgehog protein IHh is expressed in the prehyper trophic cells and diffuses over a variable distance to its receptor Patched PTCH Subsequently increased secretion of ParaThyroid Hormone Like Hormone PTHLH is induced at the apical perichondrium via an incompletely understood mechanism PTHLH then diffuses to its receptor whose expression is restricted to the late proliferating chondro cytes inhibiting their further differentiation resulting in less IHh producing cells which closes the feedback loop Thus PTHLH regulates the pace of chondrocyte differentiation by delaying the progression of chondrocytes towards the hyper trophic zone allowing longitudinal bone growth Defective or absent EXT proteins leading to altered or absent HSPG expression at the cell surface may affect this negative feed back loop by disturbing the diffusion of IHh produced at the prehypertrophic chondrocytes towards its receptor Ptc Orphanet Journal of Rare Diseases 2008 33 httpwwwojrdcomcontent313 Page 5 of 7 page number not for citation purposes Upon histopathological examination of osteochondroma after surgical removal malignancy should be considered Malignant transformation in the cartilage cap of osteo chondroma leads to a secondary peripheral chondrosar coma Occasionally osteosarcomas and spindle cell sarcomas develop in the stalk of the osteochondroma 157680 Extremely rare is the occurrence of dedifferen tiated peripheral chondrosarcoma in which a lowgrade chondrosarcoma that developed within an osteochon droma dedifferentiates into a high grade sarcoma 8182 Genetic counselling MO is an autosomal dominant disorder Affected individ uals have 50 risk of transmitting the disorder to their offspring MO has nearly 100 penetrance If the exact mutation is known antenatal diagnosis is technically pos sible Management including treatment Osteochondromas are only removed when they cause pain when they give functional complaints for instance due to compression on nerves or vessels or for cosmetic reasons Surgical treatment of forearm deformities remains contro versial In a retrospective series 23 MO patients corrective osteotomy andor lengthening of forearm bones was not beneficial 83 Moreover one should consider the possi ble recurrence of ulnar shortening within 15 years when operating skeletally immature patients 8384 The most beneficial procedure was excision of the osteochondro mas The simple removal of an osteochondroma can improve forearm rotation and correct deformity 83 especially if there is an isolated tumour of the distal part of the ulna If the diagnosis of MO is established and all tumours are identified patients should be well instructed to seek ear lier medical attention if their condition changes for instance if there is pain or growth of a known lesion 61 It is important to realise that no new osteochondromas develop after puberty Moreover regular followup to dis cover potential malignant transformation at an early stage to enable adequate treatment should be considered The risk of malignant transformation of osteochondroma towards secondary peripheral chondrosarcoma is esti mated at 15 245131434 After skeletal maturation a baseline bone scan is recommended 61 Furthermore baseline plain radiographs of areas that can not be manu ally examined like the chest pelvis and scapula can be performed 61 After the baseline documentation one should consider screening patients regularly for instance every year or every other year There are as yet no studies available that have proven efficacy of screening If lesions change over time further examination using magnetic resonance MR imaging including contrast enhanced MR sequences is indicated 61 In case of malignancy enbloc resection of the lesion and its pseudocapsule with tumourfree margins preferably in a bone tumour referral centre should be performed resulting in excellent long term clinical and local results The most common location is however the pelvis where the large cartilage cap can be difficult to excise In a series of 61 patients with grade I or II secondary peripheral chondrosarcoma of the pelvis published by Donati et al a 3 local recurrence rate was found after wide resection in contrast with 23 after inadequate excision 85 Prognosis Osteochondromas are benign lesions and do not affect life expectancy The risk of malignant transformation is 15 The prognosis for secondary peripheral chondrosa rcoma is depending on histological 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EXTrelated pathways are not involved in pathogene sisof Dysplasia Epiphysealis Hemimelica and Metachondro matosis J Pathol 2006 209411419 68 Murphey MD Choi JJ Kransdorf MJ Flemming DJ Gannon FH Imag ing of osteochondroma variants and complications with radiologicpathologic correlation RadioGraphics 2000 2014071434 69 Silverman FN Dysplasia epiphysealis hemimelica Semin Roent genol 1989 24246258 70 Ippolito E Tudisco C Dysplasia epiphysealis hemimelica Clin ical histological and histochemical features Ital J Orthop Trau matol 1983 9101107 71 Kuo RS Bellemore MC Monsell FP Frawley K Kozlowski K Dyspla sia epiphysealis hemimelica clinical features and manage ment J Pediatr Orthop 1998 18543548 72 Bassett GS Cowell HR Metachondromatosis Report of four cases J Bone Joint Surg Am 1985 67811814 73 Herman TE Chines A McAlister WH Gottesman GS Eddy MC Whyte MP Metachondromatosis report of a family with facial features mildly resembling trichorhinophalangeal syndrome Pediatr Radiol 1997 27436441 74 Kennedy LA Metachondromatosis Radiology 1983 148117118 75 Mertens F Unni KK Enchondromatosis Ollier disease and Maffucci syndrome In World Health Organization Classification of Tumours Pathology and genetics of tumours of soft tissue and bone Edited by Fletcher CDM Unni KK and Mertens F Lyon IARC Press 2002356357 76 van Lerberghe E Van Damme B van Holsbeeck M Burssens A Hoog martens M Case report 626 Osteosarcoma arising in a soli tary osteochondroma of the femur Skeletal Radiol 1990 19594597 77 Lamovec J Spiler M Jevtic V Osteosarcoma arising in a solitary osteochondroma of the fibula Arch Pathol Lab Med 1999 123832834 78 Matsuno T Ichioka Y Yagi T Ishii S Spindlecell sarcoma in patients who have osteochondromatosis A report of two cases J Bone Joint Surg Am 1988 70137141 79 Bovée JVMG Sakkers RJ Geirnaerdt MJ Taminiau AH Hogendoorn PCW Intermediate grade osteosarcoma and chondrosar coma arising in an osteochondroma A case report of a patient with hereditary multiple exostoses J Clin Pathol 2002 55226229 80 Tsuchiya H Morikawa S Tomita K Osteosarcoma arising from a multiple exostoses lesion case report Jpn J Clin Oncol 1990 20296298 81 Bertoni F Present D Bacchini P Picci P Pignatti G Gherlinzoni F Campanacci M Dedifferentiated peripheral chondrosarcomas a report of seven cases Cancer 1989 6320542059 82 Staals EL Bacchini P Mercuri M Bertoni F Dedifferentiated chon drosarcomas arising in preexisting osteochondromas J Bone Joint Surg Am 2007 89987993 83 Akita S Murase T Yonenobu K Shimada K Masada K Yoshikawa H Longterm results of surgery for forearm deformities in patients with multiple cartilaginous exostoses J Bone Joint Surg Am 2007 8919931999 84 Matsubara H Tsuchiya H Sakurakichi K Yamashiro T Watanabe K Tomita K Correction and lengthening for deformities of the forearm in multiple cartilaginous exostoses J Orthop Sci 2006 11459466 85 Donati D El Ghoneimy A Bertoni F Di Bella C Mercuri M Surgical treatment and outcome of conventional pelvic chondrosar coma Journal of Bone and Joint SurgeryBritish Volume 2005 871115271530 86 Evans HL Ayala AG Romsdahl MM Prognostic factors in chond rosarcoma of bone A clinicopathologic analysis with empha sis on histologic grading Cancer 1977 40818831 Home Rare Diseases Hereditary Multiple Osteochondromas Hereditary Multiple Osteochondromas Last updated September 19 2012 Years published 1993 2000 2008 2012 Acknowledgment NORD gratefully acknowledges Wim Wuyts PhD Department of Medical Genetics University and University Hospital of Antwerp Belgium for assistance in the preparation of this report DISEASE OVERVIEW Summary Hereditary multiple osteochondromas HMO is a rare genetic disorder characterized by multiple benign noncancerous bone tumors that are covered by cartilage osteochondromas often on the growing end metaphysis of the long bones of the legs arms and digits These osteochondromas usually continue to grow until shortly after puberty and may lead to bone deformities skeletal abnormalities short stature nerve compression and reduced range of motion Hereditary multiple osteochondromas is inherited as an autosomal dominant genetic condition and is associated with abnormalities mutations in the EXT1or EXT2 gene Introduction Hereditary multiple osteochondromas was formerly called hereditary multiple exostoses SYNONYMS httpsrarediseasesorgrarediseaseshereditarymultipleosteochondromas 27062024 1239 Página 1 de 10 diaphyseal aclasis EXT external chondromatosis syndrome hereditary multiple exostoses multiple cartilaginous exostoses multiple exostoses multiple exostoses syndrome multiple osteochondromas multiple osteochondromatosis SIGNS SYMPTOMS Hereditary multiple osteochondromas is a rare disorder that affects bone growth Bony tumors exostoses or osteochondromas covered with cartilage typically appear in the growth zones metaphyses of the long bones adjacent to the areas where tendon and muscles attach to the bone These growths vary in size and number among affected individuals even within the same family Some individuals will present with a few large lumps while others will show several small growths The median age of diagnosis is three years and almost all affected individuals are diagnosed by 12 years of age In many cases no treatment is required If the exostoses are small they may have little or no effect on the patient However in more severe cases the growths may cause deformities of the forearm knees ankles spine andor pelvis They may impose upon nerves tendons andor blood vessels and interfere with movement or circulation causing substantial pain as a result of pinched nerves or compressed tendons Bones that develop exostoses most often are the upper arm humerus forearm knee and shoulder blades scapulae Bowing of the forearm and ankle are the problems that most often require surgical correction httpsrarediseasesorgrarediseaseshereditarymultipleosteochondromas 27062024 1239 Página 2 de 10 Approximately 40 percent of affected individuals have mild short stature as a result of shortened andor bowed legs If the vertebrae are affected spinal cord compression may result causing numbness and or paralysis Urinary obstruction has been observed due to exostoses of the pelvic area The bony growths that characterize this disorder continue to grow until shortly after puberty at which time normally new growth no longer develops The risk for development of malignant cancerous tumors mostly chondrosarcomas is approximately 1 to 5 CAUSES Hereditary multiple osteochondromas is inherited as an autosomal dominant genetic condition Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease The abnormal gene can be inherited from either parent or can be the result of a new mutation in the affected individual Approximately 10 of cases of HMO are thought to be the result of new mutations At present two genes EXT1 and EXT2 are known to show mutations in HMO patients and it is thought that these genes function as tumor suppressors For some affected individuals no mutation in either gene is detected In almost all these cases the mutation negative patients do not have a familial history for exostoses Most likely they have an EXT1 or EXT2 mutation in only part of their body cells and the mutation is absent or undetectable in blood cells which are usually used for DNA analysis Data indicates that individuals with EXT1 mutations may have more severe effects than those with EXT2 mutations The risk of passing the abnormal gene from affected parent to offspring is 50 for each pregnancy The risk is the same for males and females AFFECTED POPULATIONS The prevalence of HMO has been estimated to be about 1 of 50000 live births A high prevalence of this disorder has been reported in some isolated communities Hereditary multiple osteochondromas is a disorder that affects males and females in equal numbers but in general males tend to be more severely affected DISORDERS WITH SIMILAR SYMPTOMS httpsrarediseasesorgrarediseaseshereditarymultipleosteochondromas 27062024 1239 Página 3 de 10 Symptoms of the following disorders can be similar to those of hereditary multiple exostoses Comparisons may be useful for a differential diagnosis Metachondromatosis is a very rare autosomal dominant genetic disorder characterized by both enchondromatosis and multiple exostoses Enchondromatosis is characterized by slow growing tumors of cartilage cells near the ends of the long bones The multiple exostoses associated with this condition occur mostly in the digits and do not lead to deformity of the long bones or joints This condition is caused by a mutation in the PTPN11 gene LangerGiedion syndrome also known as trichorhinophalangeal syndrome type II TRPS2 is an extremely rare inherited multisystem disorder TRPS2 is characterized by fine thin hair unusual facial features progressive growth retardation resulting in short stature dwarfism abnormally short fingers and toes brachydactyly cone shaped formation of the growing ends of certain bones epiphyseal coning andor development of multiple bony growths exostoses projecting outward from the surfaces of various bones of the body In addition affected individuals may exhibit unusually flexible hyperextensible joints diminished muscle tone hypotonia excess folds of skin redundant skin andor discolored elevated spots on the skin maculopapular nevi Affected individuals may also exhibit mild to severe mental retardation hearing loss sensorineural deafness andor delayed speech development The range and severity of symptoms varies greatly from case to case TRPS2 is due to the absence of genetic material chromosomal deletions on chromosome 8 The size of the deletion varies from case to case but includes the EXT1 gene For more information on this disorder choose trichorhinophalangeal syndrome type II as your search term in the Rare Disease Database 11p11 deletion syndrome is a condition caused by a deletion of adjacent genes on chromosome 11 contiguous gene syndrome including the EXT2 gene This condition is characterized by ossification defects of the skull multiple exostoses and sometimes craniofacial abnormalities and mental retardation STANDARD THERAPIES The diagnosis of HMO is based on clinical features Xray findings and family history Molecular genetic testing of the EXT1 and EXT2 genes is available to confirm the diagnosis httpsrarediseasesorgrarediseaseshereditarymultipleosteochondromas 27062024 1239 Página 4 de 10 Treatment Surgery may be required to relieve pain improve movement restore normal circulation or for cosmetic reasons Malignant degeneration of a tumor is treated surgically possibly in combination with chemotherapy and radiation therapy Most of the malignant degenerations to cancers are to cartilage tumors or chondrosarcomas which are slow growing and generally insensitive to chemotherapy Monitoring the size of affected bones by annual scans to screen for malignant degeneration is sometimes recommended Rapid growth and increased pain are signs of a possible malignant change Genetic counseling is recommended for affected individuals and their families Other treatment is symptomatic and supportive CLINICAL TRIALS AND STUDIES Information on current clinical trials is posted on the Internet at wwwclinicaltrialsgov All studies receiving US government funding and some supported by private industry are posted on this government web site For information about clinical trials being conducted at the National Institutes of Health NIH in Bethesda MD contact the NIH Patient Recruitment Office Tollfree 800 4111222 TTY 866 4111010 Email prplccnihgov For information about clinical trials sponsored by private sources contact wwwcenterwatchcom Contact for additional information about hereditary multiple osteochondromas Wim Wuyts PhD Department of Medical Genetics httpsrarediseasesorgrarediseaseshereditarymultipleosteochondromas 27062024 1239 Página 5 de 10 University and University Hospital of Antwerp Prins Boudewijnlaan 43 2650 Edegem Belgium Phone 3232759706 Fax 3232759723 REFERENCES JOURNAL ARTICLES Bowen ME Boyden ED Holm IA et al Lossoffunction mutations in PTPN11 cause metachondromatosis but not Ollier disease or Maffucci syndrome PLoS Genet 2011 74e1002050 Pedrini E Jennes I Tremosini M et al Genotypephenotype correlation study in 529 patients with multiple hereditary exostoses identification of protective and risk factors J Bone Joint Surg Am 201193242294302 Jones KB Piombo V Searby C et al A mouse model of osteochondromagenesis from clonal inactivation of Ext1 in chondrocytes Proc Natl Acad Sci U S A 2010107520542059 Jennes I Pedrini E Zuntini M et alMultiple osteochondromas mutation update and description of the multiple osteochondromas mutation database MOdb Hum Mutat 20093012162016277 Bovée JV Multiple osteochondromas Orphanet J Rare Dis 200833 Alvarez CM De Vera MA Heslip TR Casey B Evaluation of the anatomic burden of patients with hereditary multiple exostoses Clin Orthop Relat Res 20074627379 Jaeger M Westhoff B Portier S et al Clinical outcome and genotype in patients with hereditary multiple exostoses J Orthop Res 2007251215411551 httpsrarediseasesorgrarediseaseshereditarymultipleosteochondromas 27062024 1239 Página 6 de 10 Stieber JR Dormans JP Manifestations of hereditary multiple exostoses J Am Acad Orthop Surg 2005132110120 Porter DE Lonie L Fraser M et al Severity of disease risk of malignant change in hereditary multiple exostoses A genotypephenotype study J Bone Joint Surg Br 20048610411046 Ropero S Setien F Espada J et al Epigenetic loss of the familiar tumorsuppressor gene exostosin1 EXT1 disrupts heparan sulfate synthesis in cancer cells Hum Mol Gent 20041327532765 Noonan KJ Feinberg JR Levanda A et al Natural history of multiple hereditary osteochondromatosis of the lower extremity and ankle J Pediatr Orthop 200222 1204 Bernard MA Hall CE Hogue DA et al Diminished levels of the putative tumor suppressor proteins EXT1 and EXT2 in exostoses chondrocytes Cell Motil Cytoskeleton 200148149162 Francannet C CohenTanugi A Le Merrer M et al Genotypephenotype correlation in hereditary multiple exostoses J Med Genet 200138430434 Bernard MA Hogue DA Cole WG et al Cytoskeletal abnormalities in chondrocytes with EXT1 and EXT2 mutations J Bone Miner Res 200015442450 McCormick C Duncan G Goutsos KT et al The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate Proc Natl Acad Sci USA 200097668673 Wicklund Cl Pauli RM Johnson D et al Natural history study of hereditary multiple exostoses Am J Med Genet 1995554346 Schmale GA Conrad EU 3rd Raskind WH The natural history of hereditary multiple exostoses J Bone Joint Surg Am 199476986992 INTERNET Schmale GA Wuyts W Chansky HA Raskind WH Updated September 5 2008 Hereditary Multiple Osteochondromas In GeneReviews at GeneTests Medical Genetics Information Resource database online Copyright University of httpsrarediseasesorgrarediseaseshereditarymultipleosteochondromas 27062024 1239 Página 7 de 10 Washington Seattle 19972012 Available at httpswwwgenetestsorg Accessed September 19 2012 Online Mendelian Inheritance in Man OMIM The Johns Hopkins University Exostoses Multiple Type I Entry No 133700 Last Edited June 1 2011 Available at httpswwwncbinlmnihgovomim Accessed September 19 2012 Online Mendelian Inheritance in Man OMIM The Johns Hopkins University Exostoses Multiple Type II Entry No 133701 Last Edited December 8 2009 Available at httpswwwncbinlmnihgovomim Accessed September 19 2012 Programs Resources RARECARE ASSISTANCE PROGRAMS NORD strives to open new assistance programs as funding allows If we dont have a program for you now please continue to check back with us ADDITIONAL ASSISTANCE PROGRAMS httpsrarediseasesorgrarediseaseshereditarymultipleosteochondromas 27062024 1239 Página 8 de 10 MedicAlert Assistance Program NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations httpsrarediseasesorgpatientassistanceprogramsmedicalertassistance program Rare Disease Educational Support Program Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORDs mission httpsrarediseasesorgpatientassistanceprogramsrarediseaseeducational support Rare Caregiver Respite Program This firstofitskind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder httpsrarediseasesorgpatientassistanceprogramscaregiverrespite PATIENT ORGANIZATIONS MHE Research Foundation httpsrarediseasesorgorganizationsmheresearchfoundation NIHNational Institute of Arthritis and Musculoskeletal and Skin Diseases httpsrarediseasesorgorganizationsnihnationalinstituteofarthritisand musculoskeletalandskindiseases Phone 7185690479 Email sarahzieglermheresearchfoundationorg Fax 2017861758 Phone 3014954484 Email NIAMSinfomailnihgov Fax 3017186366 httpsrarediseasesorgrarediseaseshereditarymultipleosteochondromas 27062024 1239 Página 9 de 10 MHE Coalition httpsrarediseasesorgorganizationsmhecoalition MHE and Me A Support Group for Kids with Multiple Hereditary Exostoses httpsrarediseasesorgorganizationsmheandmeasupportgroupforkids withmultiplehereditaryexostoses Phone 4408428817 Email CheleZ1yahoocom Phone 8452586058 Email mheandmeyahoocom Fax 8452586058 Understanding Rare Disease Living with a Rare Disease Community Support Advancing Research Driving Policy Get Involved httpsrarediseasesorgrarediseaseshereditarymultipleosteochondromas 27062024 1239 Página 10 de 10 1 OSTEOCONDROMATOSE MÚLTIPLA HEREDITÁRIA 1 INTRODUÇÃO A osteocondromatose múltipla hereditária OMH também conhecida como exostose múltipla hereditária é uma desordem genética rara caracterizada pela formação de múltiplos tumores ósseos benignos denominados osteocondromas Estes tumores se originam principalmente nas metáfises dos ossos longos como os ossos dos braços e das pernas e são cobertos por uma camada de cartilagem A condição geralmente se manifesta na infância com os osteocondromas crescendo até a puberdade período em que o crescimento ósseo normalmente cessa OMH é transmitida de forma autossômica dominante significando que uma única cópia alterada do gene é suficiente para causar a doença Esta desordem está associada a mutações nos genes EXT1 e EXT2 que desempenham papéis cruciais na biossíntese de heparan sulfato uma macromolécula essencial para várias funções biológicas Este artigo tem como objetivo explorar detalhadamente as macromoléculas bioquímicas envolvidas na OMH os mecanismos que levam ao desenvolvimento da doença os aspectos clínicos da condição e as abordagens terapêuticas disponíveis incluindo o papel crucial dos profissionais de terapia ocupacional no manejo desta condição complexa e multifacetada 2 DESENVOLVIMENTO 21 Macromoléculas Bioquímicas Envolvidas Na osteocondromatose múltipla hereditária as principais macromoléculas bioquímicas envolvidas são as proteínas exostosina1 EXT1 e exostosina2 EXT2 Estas proteínas são glicoproteínas de membrana localizadas no retículo endoplasmático onde desempenham um papel fundamental na síntese do heparan sulfato HS As proteínas EXT1 e EXT2 formam um complexo heterooligomérico localizado no aparelho de Golgi que é responsável pela polimerização do heparan sulfato uma glicosaminoglicana essencial para várias funções biológicas O heparan sulfato é uma molécula complexa composta por cadeias de dissacarídeos que são 2 modificadas enzimaticamente por sulfatases produzindo uma grande diversidade de estruturas de heparan sulfato que desempenham papéis críticos na sinalização celular Esta molécula é crucial para a ligação de alta afinidade de fatores de crescimento de fibroblastos FGF aos seus receptores bem como para a difusão de morfógenos importantes como os membros da família Hedgehog Indian Hedgehog e Sonic Hedgehog e Wnt Estes morfógenos desempenham papéis essenciais na regulação do crescimento e diferenciação das células durante o desenvolvimento ósseo A falta ou defeito das proteínas EXT1 ou EXT2 devido a mutações nos genes correspondentes resulta em uma produção inadequada de heparan sulfato comprometendo a sinalização celular e levando ao desenvolvimento de osteocondromas Além disso as proteínas EXT1 e EXT2 são necessárias para a formação e manutenção da matriz extracelular que é crucial para a integridade estrutural e funcional dos tecidos A deficiência na produção de heparan sulfato também pode afetar a interação celular com a matriz extracelular resultando em defeitos no crescimento e diferenciação celular 22 Mecanismos que Levam à Doença Os mecanismos patológicos subjacentes à osteocondromatose múltipla hereditária envolvem mutações germinativas nos genes EXT1 ou EXT2 que são essenciais para a produção de heparan sulfato Essas mutações atuam de forma dominante negativa onde uma única cópia mutada do gene é suficiente para causar a doença As proteínas EXT1 e EXT2 funcionam como supressores de tumor e suas mutações resultam em uma síntese defeituosa de heparan sulfato Essa deficiência afeta a sinalização das vias de crescimento ósseo especificamente nas regiões metafisárias dos ossos longos onde ocorre o crescimento ósseo ativo durante a infância e adolescência A deficiência de heparan sulfato interfere na regulação do ciclo celular dos condrócitos levando à formação anormal de exostoses Estes osteocondromas são neoplasias benignas que surgem devido à proliferação descontrolada de condrócitos na placa de crescimento resultando em protuberâncias ósseas cobertas por cartilagem Além disso a perda da função dos genes EXT1 ou EXT2 pode levar à ativação anômala de outras vias de sinalização como as vias Hedgehog e Wnt que são críticas para o crescimento e diferenciação 3 dos condrócitos A falha na regulação adequada dessas vias pode resultar em uma proliferação celular descontrolada contribuindo ainda mais para a formação de osteocondromas A deficiência de heparan sulfato também pode afetar a interação celular com a matriz extracelular resultando em defeitos na adesão celular migração e organização tecidual A complexidade desses mecanismos patológicos destaca a necessidade de uma compreensão abrangente das vias moleculares e celulares envolvidas na OMH para o desenvolvimento de intervenções terapêuticas eficazes 24 Aspectos Clínicos Os aspectos clínicos da osteocondromatose múltipla hereditária são variados e podem afetar significativamente a qualidade de vida dos indivíduos afetados Os osteocondromas geralmente se desenvolvem na infância com a maioria dos casos sendo diagnosticados por volta dos três anos de idade e quase todos antes dos 12 anos Esses tumores continuam a crescer até a puberdade quando o crescimento ósseo normal cessa Os sintomas clínicos podem variar amplamente entre os pacientes mesmo dentro da mesma família Em muitos casos os osteocondromas são assintomáticos e podem passar despercebidos mas em outros casos podem causar dor significativa deformidades ósseas e problemas funcionais graves As áreas mais frequentemente afetadas incluem o úmero o antebraço o joelho e as escápulas Deformidades comuns incluem o encurvamento do antebraço e do tornozelo que muitas vezes requerem correção cirúrgica Aproximadamente 40 dos indivíduos afetados apresentam estatura baixa devido ao encurtamento eou curvatura das pernas Além disso a compressão da medula espinhal por osteocondromas na coluna vertebral pode resultar em sintomas neurológicos graves como dormência ou paralisia Outras complicações incluem a formação de bursite artrite e em cerca de 1 a 5 dos casos a transformação maligna dos osteocondromas em condrossarcomas A prevalência estimada da OMH é de aproximadamente 1 em 50000 nascimentos com maior severidade observada em homens O diagnóstico da OMH é feito com base nas características clínicas histórico familiar e achados radiológicos e pode ser confirmado por testes genéticos para detectar mutações nos genes EXT1 e EXT2 4 25 Tratamento O tratamento da osteocondromatose múltipla hereditária é multifacetado e inclui tanto intervenções cirúrgicas quanto manejo clínico contínuo A remoção cirúrgica dos osteocondromas é indicada principalmente quando eles causam dor significativa comprometem a função ou resultam em deformidades que interferem na qualidade de vida do paciente A cirurgia também pode ser necessária para melhorar a circulação e aliviar a compressão de nervos ou tendões Além disso a vigilância regular é crucial para detectar precocemente qualquer transformação maligna dos osteocondromas que pode ocorrer em cerca de 1 a 5 dos casos Recomendase a realização de exames de imagem anuais para monitorar o crescimento dos osteocondromas e identificar sinais de degeneração maligna Aconselhamento genético é altamente recomendado para indivíduos afetados e suas famílias ajudandoos a compreender a natureza da doença o risco de transmissão para a prole e as opções de manejo disponíveis Os profissionais de terapia ocupacional desempenham um papel vital no manejo da OMH ajudando a manter a funcionalidade e a qualidade de vida dos pacientes Isso inclui fornecer educação sobre a doença recomendar adaptações no ambiente doméstico e escolar para facilitar as atividades diárias e desenvolver programas de exercícios para melhorar a mobilidade e a força muscular O suporte emocional e psicossocial também é essencial pois a OMH pode ter um impacto significativo na saúde mental e bemestar dos pacientes 3 CONCLUSÃO A osteocondromatose múltipla hereditária é uma condição genética complexa que requer uma abordagem multidisciplinar para seu manejo eficaz A compreensão detalhada das bases bioquímicas e genéticas da doença juntamente com os mecanismos patológicos que levam à formação dos osteocondromas é fundamental para o desenvolvimento de estratégias de tratamento eficazes Os aspectos clínicos da OMH são variados e podem afetar significativamente a qualidade de vida dos pacientes exigindo um manejo cuidadoso e contínuo O papel dos profissionais de 5 saúde especialmente dos terapeutas ocupacionais é crucial para fornecer um cuidado abrangente que aborda não apenas os aspectos físicos da doença mas também os impactos emocionais e sociais na vida dos pacientes A integração de estratégias de manejo clínico e suporte terapêutico pode ajudar a melhorar a funcionalidade aliviar os sintomas e proporcionar uma melhor qualidade de vida para aqueles afetados pela osteocondromatose múltipla hereditária 4 REFERÊNCIAS BOVÉE Judith VMG Multiple osteochondromas Orphanet Journal of Rare Diseases Leiden University Medical Center Leiden The Netherlands 2008 Disponível em httpwwwojrdcomcontent313 Acesso em 27 jun 2024 NATIONAL ORGANIZATION FOR RARE DISORDERS NORD Hereditary Multiple Osteochondromas Symptoms Causes Treatment Disponível em httpsrarediseasesorgrarediseaseshereditarymultipleosteochondromas Acesso em 27 jun 2024 Osteocondromatose Múltipla Hereditária Análise Bioquímica Mecanismos Aspectos Clínicos e Tratamento Nome do Apresentador Instituição Data Sumário 1 Introdução 2 Macromoléculas Bioquímicas Envolvidas 3 Mecanismos que Levam à Doença 4 Aspectos Clínicos 5 Tratamento 6 Papel do Terapeuta Ocupacional 7 Conclusão 8 Referências Introdução Definição de Osteocondromatose Múltipla Hereditária OMH Características principais Múltiplos osteocondromas Localização ossos longos Idade de início infância Herança autossômica dominante Genes envolvidos EXT1 e EXT2 Macromoléculas Bioquímicas Envolvidas Proteínas EXT1 e EXT2 Glicoproteínas de membrana Localização retículo endoplasmático Função síntese de heparan sulfato HS Complexo hetero oligomérico no aparelho de Golgi Heparan sulfato HS Composição cadeias de dissacarídeos Funções Ligação de fatores de crescimento FGF Difusão de morfógenos Hedgehog Wnt Deficiência de HS devido a mutações nos genes EXT1 e EXT2 Impacto na matriz extracelular e adesão celular Mecanismos que Levam à Doença Mutações germinativas nos genes EXT1 ou EXT2 Dominância negativa Função de EXT1 e EXT2 como supressores de tumor Síntese defeituosa de heparan sulfato Interferência na sinalização das vias de crescimento ósseo Proliferação descontrolada de condrócitos Formação de exostoses Ativação anômala de outras vias de sinalização Hedgehog Wnt Impacto na interação celular com a matriz extracelular Aspectos Clínicos Desenvolvimento dos osteocondromas na infância Diagnóstico 3 a 12 anos Variação dos sintomas entre pacientes Áreas mais afetadas úmero antebraço joelho escápulas Deformidades comuns Encurvamento do antebraço e tornozelo Estatura baixa 40 Compressão da medula espinhal Complicações Bursite artrite Transformação maligna em condrossarcomas 15 Diagnóstico Características clínicas Histórico familiar Testes genéticos Tratamento Intervenções cirúrgicas Remoção de osteocondromas Alívio de dor e compressão Importância do monitoramento regular Exames de imagem anuais Aconselhamento genético Compreensão da doença Risco de transmissão Opções de manejo Papel do Terapeuta Ocupacional Educação sobre a doença Prevenção de complicações Adaptações no ambiente Facilitação das atividades diárias Ajustes no ambiente doméstico e escolar Programas de exercícios Melhorar mobilidade Aumentar força muscular Suporte emocional e psicossocial Impacto na saúde mental e bemestar Conclusão Importância de uma abordagem multidisciplinar Necessidade de estratégias de manejo clínico e suporte terapêutico Impacto positivo na funcionalidade e qualidade de vida dos pacientes Referências BOVÉE Judith VMG Multiple osteochondromas Orphanet Journal of Rare Diseases Leiden University Medical Center Leiden The Netherlands 2008 Disponível em httpwwwojrdcomcontent313 Acesso em 27 jun 2024 NATIONAL ORGANIZATION FOR RARE DISORDERS NORD Hereditary Multiple Osteochondromas Symptoms Causes Treatment Disponível em httpsrarediseasesorgrarediseaseshereditary multipleosteochondromas Acesso em 27 jun 2024 Perguntas e Discussão Espaço para perguntas e discussão com a audiência