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Background Hereditary multiple exostoses (HME) is a rare skeletal disorder characterised by a widespread. distribution of osteochondromas originating from the metaphyses of long bones. Case presentation This case study examines a 55-year-old male cadaver bequeathed to the University of Liverpool who suffered from HME, thus providing an exceptionally rare opportunity to examine the anatomical changes associated with this condition. Conclusions Findings from imaging and dissection indicated that this was a severe case of HME in terms of the quantity and distribution of the osteochondromas and the number of synostoses present. In addition, the existence of enchondromas and the appearance of gaps within the trabeculae of affected bones make this a remarkable case. This study provides a comprehensive overview of the morbidity of the disease as well as adding to the growing evidence that diseases concerning benign cartilaginous tumours may be part of a spectrum rather than distinct entities.

Metachondromatosis is a rare disorder of autosomal inheritance with incomplete penetrance, which is characterized by formation of osteochondroma and enchondroma, caused by loss of function of the protein tyrosine phosphatase nonreceptor type 11 (PTPN11) gene. Diagnosis is made based on the distribution and orientation of lesions with history of regression of lesions with time and confirmed by genetic mutation of PTPN11 gene. We report a rare case of a 24-year-old male with Alport's syndrome with metachondromatosis due to missense variation in PTPN11 gene.

Ollier disease and Maffucci syndrome are the commonest enchondromatosis subtypes, arising from non-hereditary mutations in the IDH1 and IDH2 genes, presenting in childhood and being characterised by multiple enchondromas. Maffucci syndrome also includes multiple soft tissue haemangiomas. Aside from developing bony masses, osseous deformity and pathological fracture, ~ 40% of these patients develop secondary central chondrosarcoma, and there is increased risk of non-skeletal malignancies such as gliomas and mesenchymal ovarian tumours. In this review, we outline the molecular genetics, pathology and multimodality imaging features of solitary enchondroma, Ollier disease and Maffucci syndrome, along with their associated skeletal complications, in particular secondary chondrosarcoma. Given the lifelong risk of malignancy, imaging follow-up will also be explored. Metachondromatosis, a rare enchondromatosis subtype characterised by enchondromas and exostoses, will also be briefly outlined.

The maturation and function of osteoblasts (OBs) rely heavily on the reversible phosphorylation of signaling proteins. To date, most of the work in OBs has focused on phosphorylation by tyrosyl kinases, but little has been revealed about dephosphorylation by protein tyrosine phosphatases (PTPases). SHP2 (encoded by PTPN11) is a ubiquitously expressed PTPase. PTPN11 mutations are associated with both bone and cartilage manifestations in patients with Noonan syndrome (NS) and metachondromatosis (MC), although the underlying mechanisms remain elusive. Here, we report that SHP2 deletion in bone gamma-carboxyglutamate protein-expressing (Bglap+) bone cells leads to massive osteopenia in both trabecular and cortical bones due to the failure of bone cell maturation and enhanced osteoclast activity, and its deletion in Bglap+ chondrocytes results in the onset of enchondroma and osteochondroma in aged mice with increased tubular bone length. Mechanistically, SHP2 was found to be required for osteoblastic differentiation by promoting RUNX2/OSTERIX signaling and for the suppression of osteoclastogenesis by inhibiting STAT3-mediated RANKL production by osteoblasts and osteocytes. These findings are likely to explain the compromised skeletal system in NS and MC patients and to inform the development of novel therapeutics to combat skeletal disorders.

Rationale: Metachondromatosis (MC) is a very rare genetic disease, which is infrequently reported worldwide, which leads to osteochondroma and enchondromatosis. The disease has been shown to be associated with loss of function of the tumor suppressor gene “protein tyrosine phosphatase, non-receptor type 11” (PTPN11). Patient concerns: A 12-year-old female was admitted to the hospital with pain due to an enlarged mass in her left fifth finger. Diagnosis: Examination of the left hand by computed tomography (CT) revealed an expanding type of round and low-density lesion in the fifth proximal phalanx. The patient then underwent technetium-99m methylene diphosphonate single-photon emission CT/CT (99mTc-MDP SPECT/CT) to assess the nature of the lesion. The SPECT/CT image revealed dilated osteopathy and increased activity of the fifth proximal phalanx on the left hand. Unexpectedly, the examination of the right hand revealed slight expanded lesions and increased activities of the third metacarpal and proximal phalange, as well as the fourth proximal phalange and the middle phalanx. On the basis of the patient's symptoms and the results of the above-mentioned examinations, we diagnosed the patient as having MC in her hands. Intervention: Considering the pain of the fifth finger of the left hand, the patient underwent debridement of the fifth proximal phalanx of the left hand and internal fixation with bone graft taken from the body. Outcomes: The patient was discharged after a week of observation. One year later, she was admitted to the hospital again for removal of the bone healing internal fixation after osteoma surgery. Preoperative 99mTc-MDP SPECT/CT revealed that the left-handed lesions displayed postoperative changes, while the multiple lesions in the right hand increased in volume but remained unchanged in number. Lessons: This case revealed the CT and 99mTc-MDP SPECT/CT imaging features of MC. Specifically, SPECT/CT imaging contributed to the diagnosis of clinically asymptomatic bone lesions, and the 3D SPECT/CT fusion allowed a more comprehensive and intuitive view of the lesion by combining anatomy and function.

Chondrocytes in the epiphyseal cartilage undergo terminal differentiation prior to their removal through apoptosis. To examine the role of ERK1 and ERK2 in chondrocyte terminal differentiation, we generated Osterix (Osx)-Cre; ERK1–/–; ERK2flox/flox mice (conditional knockout Osx [cKOosx]), in which ERK1 and ERK2 were deleted in hypertrophic chondrocytes. These cKOosx mice were grossly normal in size at birth, but by 3 weeks of age exhibited shorter long bones. Histological analysis in these mice revealed that the zone of hypertrophic chondrocytes in the growth plate was markedly expanded. In situ hybridization and quantitative real-time PCR analyses demonstrated that Matrix metalloproteinase-13 (Mmp13) and Osteopontin expression was significantly decreased, indicating impaired chondrocyte terminal differentiation. Moreover, Egr1 and Egr2, transcription factors whose expression is restricted to the last layers of hypertrophic chondrocytes in wild-type mice, were also strongly downregulated in these cKOosx mice. In transient transfection experiments in the RCS rat chondrosarcoma cell line, the expression of Egr1, Egr2, or a constitutively active mutant of MEK1 increased the activity of an Osteopontin promoter, whereas the MEK1-induced activation of the Osteopontin promoter was inhibited by the coexpression of Nab2, an Egr1 and Egr2 co-repressor. These results suggest that MEK1-ERK signaling activates the Osteopontin promoter in part through Egr1 and Egr2. Finally, our histological analysis of cKOosx mice demonstrated enchondroma-like lesions in the bone marrow that are reminiscent of human metachondromatosis, a skeletal disorder caused by mutations in PTPN11. Our observations suggest that the development of enchondromas in metachondromatosis may be caused by reduced extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK MAPK) signaling. © 2014 American Society for Bone and Mineral Research.

Transdifferentiation of hypertrophic chondrocytes into bone-forming osteoblasts has been reported, yet the underlying molecular mechanism remains incompletely understood. SHP2 is an ubiquitously expressed cytoplasmic protein tyrosine phosphatase. SHP2 loss-of-function mutations in chondroid cells are linked to metachondromatosis in humans and mice, suggesting a crucial role for SHP2 in the skeleton. However, the specific role of SHP2 in skeletal cells has not been elucidated. To approach this question, we ablated SHP2 in collagen 2α1(Col2α1)-Cre- and collagen 10α1(Col10α1)-Cre-expressing cells, predominantly proliferating and hypertrophic chondrocytes, using “Cre-loxP”-mediated gene excision. Mice lacking SHP2 in Col2α1-Cre-expressing cells die at mid-gestation. Postnatal SHP2 ablation in the same cell population caused dwarfism, chondrodysplasia and exostoses. In contrast, mice in which SHP2 was ablated in the Col10α1-Cre-expressing cells appeared normal but were osteopenic. Further mechanistic studies revealed that SHP2 exerted its influence partly by regulating the abundance of SOX9 in chondrocytes. Elevated and sustained SOX9 in SHP2-deficient hypertrophic chondrocytes impaired their differentiation to osteoblasts and impaired endochondral ossification. Our study uncovered an important role of SHP2 in bone development and cartilage homeostasis by influencing the osteogenic differentiation of hypertrophic chondrocytes and provided insight into the pathogenesis and potential treatment of skeletal diseases, such as osteopenia and osteoporosis.

Metachondromatosis is a benign bone disease predominantly observed in the hands and feet of children or young adults demonstrating two different manifestations: a cartilage-capped bony outgrowth on the surface of the bone called exostosis and ectopic cartilaginous nodules inside the bone called enchondroma. Recently, it has been reported that loss-of-function mutations of the SHP2 gene, which encodes the SHP2 protein tyrosine phosphatase, are associated with metachondromatosis. The purpose of this study was to investigate the role of SHP2 in postnatal cartilage development, which is largely unknown. We disrupted Shp2 during the postnatal stage of mouse development in a chondrocyte-specific manner using a tamoxifen-inducible system. We found tumor-like nodules on the hands and feet within a month after the initial induction. The SHP2-deficient mice demonstrated an exostosis-like and enchondroma-like phenotype in multiple bones of the hands, feet, and ribs as assessed by X-ray and micro-computed tomography (CT). Histological assessment revealed the disorganization of the growth plate cartilage, a cartilaginous protrusion from the epiphyseal bone, and ectopic cartilage nodules within the bones, which is consistent with the pathological features of metachondromatosis in humans (ie, both exostosis and enchondroma). At molecular levels, we observed an abundant expression of Indian hedgehog protein (IHH) and fibroblast growth factor 2 (FGF2) and impaired expression of mitogen-activated protein kinases (MAPK) in the affected cartilage nodules in the SHP2-deficient mice. In summary, we have generated a mouse model of metachondromatosis that includes manifestations of exostosis and enchondroma. This study provides a novel model for the investigation of the pathophysiology of the disease and advances the understanding of metachondromatosis. This model will be useful to identify molecular mechanisms for the disease cause and progression as well as to develop new therapeutic strategies in the future.

The tyrosine phosphatase SHP2, encoded by PTPN11, is required for the survival, proliferation and differentiation of various cell types. Germline activating mutations in PTPN11 cause Noonan syndrome, whereas somatic PTPN11 mutations cause childhood myeloproliferative disease and contribute to some solid tumours. Recently, heterozygous inactivating mutations in PTPN11 were found in metachondromatosis, a rare inherited disorder featuring multiple exostoses, enchondromas, joint destruction and bony deformities. The detailed pathogenesis of this disorder has remained unclear. Here we use a conditional knockout (floxed) Ptpn11 allele (Ptpn11(fl)) and Cre recombinase transgenic mice to delete Ptpn11 specifically in monocytes, macrophages and osteoclasts (lysozyme M-Cre; LysMCre) or in cathepsin K (Ctsk)-expressing cells, previously thought to be osteoclasts. LysMCre;Ptpn11(fl/fl) mice had mild osteopetrosis. Notably, however, CtskCre;Ptpn11(fl/fl) mice developed features very similar to metachondromatosis. Lineage tracing revealed a novel population of CtskCre-expressing cells in the perichondrial groove of Ranvier that display markers and functional properties consistent with mesenchymal progenitors. Chondroid neoplasms arise from these cells and show decreased extracellular signal-regulated kinase (ERK) pathway activation, increased Indian hedgehog (Ihh) and parathyroid hormone-related protein (Pthrp, also known as Pthlh) expression and excessive proliferation. Shp2-deficient chondroprogenitors had decreased fibroblast growth factor-evoked ERK activation and enhanced Ihh and Pthrp expression, whereas fibroblast growth factor receptor (FGFR) or mitogen-activated protein kinase kinase (MEK) inhibitor treatment of chondroid cells increased Ihh and Pthrp expression. Importantly, smoothened inhibitor treatment ameliorated metachondromatosis features in CtskCre;Ptpn11(fl/fl) mice. Thus, in contrast to its pro-oncogenic role in haematopoietic and epithelial cells, Ptpn11 is a tumour suppressor in cartilage, acting through a FGFR/MEK/ERK-dependent pathway in a novel progenitor cell population to prevent excessive Ihh production.

Otofaciocervical syndrome (OFCS) is a rare disorder characterized by facial, ear, branchial, and musculoskeletal anomalies, along with hearing loss and mild intellectual disability. Clinically, its distinction from branchiootorenal syndrome can be difficult. To date, the coexistence of OFCS and metachondromatosis has not been reported. Here, we describe a sporadic patient with both OFCS and metachondromatosis. This novel association prompts us to do some remarks on the clinical variability of branchial-arch disorders; in fact, our observations are consistent with the highly variable expressivity of OFCS and illustrate the need of a more accurate characterization of these branchial-arch disorders. In the meantime, involvement of clavicles, scapulae and shoulders remains a distinctive feature of OFCS.

Src homology-2 domain-containing phosphatase 2 (SHP2), encoded by the PTPN11 gene, is a highly conserved, non-transmembrane protein-tyrosine phosphatase (PTP), found in all metazoans. The molecular details of SHP2 regulation by phosphotyrosyl (pTyr) peptide ligand binding are well-understood, and knowledge of these details is critical to understanding SHP2 function in health and disease. Studies using mice with gain- or loss-of-function alleles of Ptpn11 have provided much detail about the physiological functions and signaling pathways regulated by SHP2 at the cellular and whole organism levels. Germline mutations in PTPN11 cause Noonan syndrome, Noonan syndrome with multiple lentigines (previously, LEOPARD syndrome), as well as the cartilage tumor syndrome, metachondromatosis. Somatic PTPN11 mutations occur in several types of hematologic malignancy, most notably juvenile myelomonocytic leukemia and, more rarely, in neuroblastoma and other solid tumors. PTPN11 is crucial for transformation initiated by mutant receptor-tyrosine kinases (RTKs) and is an important effector of H. pylori virulence. However, the direct target(s) of SHP2 responsible for its physiological and pathological effects remain controversial and their identification remains a major goal for the future research.

The so-called "enchondromatoses" are skeletal disorders defined by the presence of ectopic cartilaginous tissue within bone tissue. The clinical and radiographic features of the different enchondromatoses are distinct, and grouping them does not reflect a common pathogenesis but simply a similar radiographic appearance and thus the need for a differential diagnosis. Recent advances in the understanding of their molecular and cellular bases confirm the heterogeneous nature of the different enchondromatoses. Some, like Ollier disease, Maffucci disease, metaphyseal chondromatosis with hydroxyglutaric aciduria, and metachondromatosis are produced by a dysregulation of chondrocyte proliferation, while others (such as spondyloenchondrodysplasia or dysspondyloenchondromatosis) are caused by defects in structure or metabolism of cartilage or bone matrix. In other forms (e.g., the dominantly inherited genochondromatoses), the basic defect remains to be determined. The classification, proposed by Spranger and associates in 1978 and tentatively revised twice, was based on the radiographic appearance, the anatomic sites involved, and the mode of inheritance. The new classification proposed here integrates the molecular genetic advances and delineates phenotypic families based on the molecular defects. Reference radiographs are provided to help in the diagnosis of the well-defined forms. In spite of advances, many cases remain difficult to diagnose and classify, implying that more variants remain to be defined at both the clinical and molecular levels.

Rationale Metachondromatosis (MC) is a very rare genetic disease, which is infrequently reported worldwide, which leads to osteochondroma and enchondromatosis. The disease has been shown to be associated with loss of function of the tumor suppressor gene "protein tyrosine phosphatase, non-receptor type 11" (PTPN11). Patient concerns A 12-year-old female was admitted to the hospital with pain due to an enlarged mass in her left fifth finger. Diagnosis Examination of the left hand by computed tomography (CT) revealed an expanding type of round and low-density lesion in the fifth proximal phalanx. The patient then underwent technetium-99m methylene diphosphonate single-photon emission CT/CT (Tc-MDP SPECT/CT) to assess the nature of the lesion. The SPECT/CT image revealed dilated osteopathy and increased activity of the fifth proximal phalanx on the left hand. Unexpectedly, the examination of the right hand revealed slight expanded lesions and increased activities of the third metacarpal and proximal phalange, as well as the fourth proximal phalange and the middle phalanx. On the basis of the patient's symptoms and the results of the above-mentioned examinations, we diagnosed the patient as having MC in her hands. Intervention Considering the pain of the fifth finger of the left hand, the patient underwent debridement of the fifth proximal phalanx of the left hand and internal fixation with bone graft taken from the body. Outcomes The patient was discharged after a week of observation. One year later, she was admitted to the hospital again for removal of the bone healing internal fixation after osteoma surgery. Preoperative Tc-MDP SPECT/CT revealed that the left-handed lesions displayed postoperative changes, while the multiple lesions in the right hand increased in volume but remained unchanged in number. Lessons This case revealed the CT and Tc-MDP SPECT/CT imaging features of MC. Specifically, SPECT/CT imaging contributed to the diagnosis of clinically asymptomatic bone lesions, and the 3D SPECT/CT fusion allowed a more comprehensive and intuitive view of the lesion by combining anatomy and function.

Background: The autosomal dominant condition multiple osteochondromas, formerly called multiple hereditary exostoses, is associated with a risk of malignant progression of osteochondroma into secondary peripheral chondrosarcoma. Most patients with multiple osteochondromas have exostosin-1 or exostosin-2 gene mutations. To our knowledge, it has not been previously reported that patients may also harbor intraosseous (central) chondroid neoplasms, enchondromas, or atypical chondroid tumors or central chondrosarcomas. The combination of osteochondroma and enchondromas also exists in patients with metachondromatosis, a disorder associated with a protein tyrosine phosphatase non-receptor type 11 gene mutation. This study aims to establish any correlation between multiple osteochondromas and intraosseous cartilaginous neoplasms. Methods: We retrospectively reviewed all histologically proven intraosseous atypical chondroid tumors or chondrosarcomas in our prospective nationwide Dutch tertiary referral multiple osteochondromas database. Demographic, clinical, radiographic, histological, and genetic data were recorded. The institutional medical ethics review board approved the study. Results: From 195 adult patients, seven (3.6%) were identified with intraosseous atypical chondroid tumor or chondrosarcoma World Health Organization grade 1 and had a mean age of forty-two years; five of these patients were male. In all cases, radiographic and genetic findings were consistent with multiple osteochondromas, not metachondromatosis; three patients had an exostosin-1 mutation, four patients had an exostosin-2 mutation, and no patients had a protein tyrosine phosphatase, non-receptor type 11 mutation. Six patients underwent successful operative treatment without complications or recurrences after a mean follow-up duration of forty-eight months (range, twelve to 144 months). One patient was scheduled for surgery after biopsy and histologic confirmation. Of the seven patients, five (71%) also developed a peripheral chondrosarcoma in a known osteochondroma during the study period. Conclusions: Apart from osteochondromas or peripheral chondrosarcomas, multiple osteochondromas are also associated with intraosseous chondroid neoplasms, potentially resulting in central chondrosarcoma. Therefore, intraosseous lesions should not automatically be regarded as innocuous in this patient population. Level of Evidence: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Activation of the signalling molecule SHP2 is implicated in driving several cancers. In a newly described class of bone-progenitor cells, however, it seems that the protein acts as a tumour suppressor. See Letter p.491 Inactivation of PTPN11, which encodes the phosphatase SHP2, is the cause of the inherited cartilage tumour disorder metachondromatosis. Using a mouse model, Wentian Yang and colleagues show that deletion of the Ptpn11 gene in osteoclasts leads to metachondromatosis that originates in a newly identified mesenchymal progenitor population in the perichondrial groove of Ranvier. Ptpn11 loss acts by activating hedgehog signalling, and metachondromatosis can be ameliorated in this model by hedgehog pathway inhibitors. Therefore in contrast to other tumour types where it promotes tumour formation, Ptpn11 suppresses tumorigenesis in cartilage tissue.

Background: Metachondromatosis is a condition that causes gross conical metaphyseal expansion (sometimes irregular), cortical thinning, exostoses. Metachondromatous lesions occur mainly in the extremities and are roughly symmetrical. The lesions can involve the bones of the hand and all long bones in the arms and legs. The distribution in this case additionally involved the acromion process and ischia. The bone changes, although dramatic, can be confused with other types of metaphyseal dysplasia such as Gaucher disease and multiple exostoses. Objective: This paper will review the literature with regard to Metachondromatosis, Gaucher disease and Osteochondromatosis due to their similarities. The case study serves as an example of these findings and documents a history of fractures secondary to the obvious bone changes. Discussion: Clinical manifestations of these conditions and how they may present to the manual therapist are discussed. With respect to Metachondromatosis, the manual therapist needs to be mindful of pathological fractures that can occur with little trauma. Manual therapists are cautioned against using long bones as levers for spinal manipulation in these patients.

Src homology-2 protein tyrosine phosphatase (SHP-2) that is encoded by the PTPN11 gene in humans is an intracellular signaling molecule that couples growth factor receptors to activation of the Ras small GTP-binding protein that regulates cell growth, proliferation and differentiation. Germline mutations of PTPN11 are causative of Noonan syndrome and LEOPARD syndrome in humans in which there are recognized skeletal abnormalities that include growth retardation, spinal curvature and chest malformations. In addition, combined somatic and germline PTPN11 mutations have been shown to be responsible for a rare benign bone cartilaginous tumor disease known as metachondromatosis. In parallel, gene targeting studies performed in mice have revealed an essential role for SHP-2 as a regulator of bone and skeletal development. In this review the significance of these findings in mice to the understanding of the pathogenesis of skeletal abnormalities in humans with SHP-2 mutations is discussed.

Four members of a family – three of whom have facial features mildly resembling those of the trichorhinophalangeal syndrome, type I, and all of whom manifested appendicular bony prominences similar to trichorhinophalangeal syndrome, type II – were found to have the radiographic findings of metachondromatosis. The radiographic manifestations and evolution of metachondromatosis are depicted in this report.

Recently, loss-of-function mutations in PTPN11 were linked to the cartilage tumor syndrome metachondromatosis (MC), a rare inherited disorder featuring osteochondromas, endochondromas and skeletal deformation. However, the underlying molecular and cellular mechanism for MC remained incompletely understood. By studying the role of the Src homology-2 domain-containing protein tyrosine phosphatase Shp2 (encoded by mouse Ptpn11) in cathepsin K-expressing cells, we identified a novel cell population in the perichondrial groove of Ranvier. In the absence of Shp2, these cells exhibit elevated Indian hedgehog (Ihh) signaling, proliferate excessively and cause ectopic cartilage formation and tumors. Our findings establish a critical role for a protein-tyrosine phosphatase (PTP) family member, in addition to the well-known roles of receptor tyrosine kinases (RTKs), in cartilage development and homeostasis. However, whether Shp2 deficiency in other epiphyseal chondroid cells and whether signaling pathways in addition to the IHH/Parathyroid Hormone-related Peptide (PTHrP) axis attribute to the formation of enchondromas and osteochondromas remains elusive. Understanding how chondrogenic events are regulated by SHP2 could aid in the development of novel therapeutic approaches to prevent and treat cartilage diseases, such as MC and osteoarthritis (OA).

The tyrosine phosphatase Shp2, encoded by PTPN11 in humans, is associated with various forms of blood cell cancer and syndromes associated with aberrant signaling through the Ras–mitogen-activated protein kinase (MAPK) pathway. Inactivating mutations in PTPN11 also cause metachondromatosis, a bone disorder associated with excess bone formation (see Zaidi and Mendez-Ferrer). To investigate the mechanism by which loss of Shp2 function leads to metachondromatosis, Yang et al . engineered mice with a selective knockout (KO) of Shp2 in different sets of bone-associated cells. The LysM-KO animals lacked Shp2 in monocytes, macrophages, and osteoclast precursor cells, whereas the Cstk-KO mice lacked Shp2 in mature osteoclasts. Although the LysM-KO mice developed mild age-related osteopetrosis (an increase in bone density), the Cstk-KO mice developed many of the skeletal abnormalities seen in patients with metachondromatosis, including benign cartilage tumors. Lineage-tracing studies revealed that the Cstk-Cre reporter was expressed in a subset of perichondrial cells in the groove of Ranvier, and analysis of knee joint sections from the Cstk-KO mice showed an expansion of cells in the groove of Ranvier. Using yellow fluorescent protein (YFP) to tag the Cstk-KO cells, the bone lesions and most of the chondroid tumor cells in the Cstk-KO mice were found to consist of YFP + chondroid cells at various developmental stages. Flow cytometry showed that within the YFP + cell population, there were increased numbers of cells with mesenchymal progenitor markers, and, when cultured in vitro, these cells were able to differentiate into multiple different types of cells. Thus, these appear to represent a previously uncharacterized chondroid progenitor stem cell. Transcript analysis from the tumors from the Cstk-KO mice indicated that messenger RNAs encoding Indian hedgehog (Ihh) and parathyroid hormone-related protein (Pthrp) were increased. Shp2 activity is necessary for fibroblast growth factor 18 (Fgf18) to activate the Ras-MAPK-ERK (extracellular signal–regulated kinase) pathway and inhibit Ihh expression, and ERK signaling was decreased in the Cstk-KO progenitor cells. Treatment of the Cstk-KO mice with an inhibitor of the Hedgehog pathway reduced the severity of the skeletal overgrowth and improved mobility. Thus, this study identified a cartilage stem cell population that in the absence of functional Shp2 can become a source of benign bone tumors. In addition, this study delineated a pathway through which loss of Shp2 triggered excessive proliferation of these stem cells and showed that targeting Ihh signaling was an effective strategy for ameliorating symptoms. W. Yang, J. Wang, D. C. Moore, H. Liang, M. Dooner, Q. Wi, R. Terek, Q. Chen, M. G. Ehrlich, P. J. Quesenberry, B. G. Neel, Ptpb11 deletion in a novel progenitor causes metachondromatosis by inducing hedgehog signalling. Nature 499 , 491–495 (2013). [PubMed] M. Zaidi, S. Mendez-Ferrer, Tumour stem cells in bone. Nature 499 , 414–416 (2013). [Online Journal]

Introduction Metachondromatosis is a rare genetic disease of osteochondroma and enchondroma formation, caused by loss of function of the PTPN11 gene. It is distinct from other similar conditions such as multiple osteochondromas and hereditary multiple exostoses by the distribution and orientation of lesions, and pattern of inheritance. Lesions typically occur in hands, feet, femora, tibiae and the pelvis. Lesions are typically reported to regress in adulthood. Methods We reviewed the current literature on metachondromatosis, and present four new cases in a family with metachondromatosis. Results Long-term follow up data reveal spontaneous regression of lesions by skeletal maturity. Complications may include nerve palsy due to the mass effect of lesions, avascular necrosis of the femoral head and angular deformity of long bones. Histopathological analysis has demonstrated that lesions in metachondromatosis are a mix of osteochondromas and enchondromas; however, one case of chondrosarcoma has been reported. Conclusion Lesions associated with metachondromatosis may cause a variety of complications due to mass effects; however, they are often asymptomatic, cause cosmetic concerns and, importantly, most regress spontaneously. Regular clinical review with selective imaging to monitor for such complications is appropriate, but uncomplicated lesions are unlikely to require surgical intervention.

The disorders discussed here reflect localized disturbances of the endochondral growth plate development or localized disturbances of bone maturation. In the first category are dysplasia epiphysealis hemimelica, hereditary multiple exostoses and its variant Langer–Giedion syndrome, and enchondromatosis and its variants Maffucci syndrome and metachondromatosis. They are due to asymmetrical, displaced, or aberrant growth of endochondral cartilage tissues that interferes with normal skeletal development, and which may occur as an isolated finding or in concert with other disease manifestations. Some conditions are inherited, but others occur sporadically. The second category comprises fibrous dysplasia of bone, which can be monostotic or polyostotic as an element of McCune–Albright syndrome, and cherubism. Fibrous dysplasia results from somatic activating mutations of GNAS1 , which produce McCune–Albright syndrome if they occur early in development or isolated bone lesions if they occur later. Cherubism, which is characterized by painless symmetrical swelling of the jaws during childhood, results from heterozygous mutations of the adapter protein SH3BP2.

The disorders discussed here reflect localized disturbances of the endochondral growth plate development or localized disturbances of bone maturation. In the first category are dysplasia epiphysealis hemimelica, hereditary multiple exostoses and its variant Langer–Giedion syndrome, and enchondromatosis and its variants Maffucci syndrome and metachondromatosis. They are due to asymmetrical, displaced, or aberrant growth of endochondral cartilage tissues that interferes with normal skeletal development and which may occur as an isolated finding or in concert with other disease manifestations. Some conditions are inherited, but others occur sporadically. The second category comprises fibrous dysplasia of bone, which can be monostotic or polyostotic as an element of McCune–Albright syndrome, and cherubism. Fibrous dysplasia results from somatic activating mutations of GNAS1, which produce McCune–Albright syndrome if they occur early in development or isolated bone lesions if they occur later. Cherubism, which is characterized by painless symmetrical swelling of the jaws during childhood, results from heterozygous mutations of the adaptor protein SH3BP2.

Case: A nine-year-old boy had multiple osteochondromas in the hands, feet, and tibiae, many of which pointed toward the adjacent joint. Although several were treated surgically, others resolved spontaneously. A heterozygous mutation in the PTPN11 gene was identified by genetic analysis of peripheral blood, so the patient was diagnosed with metachondromatosis despite the absence of enchondromatous lesions. Conclusion: To the best of our knowledge, this is the first reported case of a patient with metachondromatosis without any enchondromatous lesions.

Metachondromatosis (MC) and hereditary multiple osteochondromas (HMO) are thought to be distinct disorders, each with characteristic x-ray and clinical features. Radiographic differences are the current mainstay of differential diagnosis. Both disorders are autosomal dominant, but the majority of patients with HMO have mutations in EXT-1 or EXT 2 genes. The genetic defect in MC is unknown, although recent studies indicate a possible identifiable mutation. The cancer risk in HMO is thought to be greater than in MC, although the small number of cases make such conjecture imprecise. The purpose of this report is to review existing literature and examine whether radiographic findings in HMO and MC can be reliable as a stand-alone means of differential diagnosis. Three members of a multi-generational family with an autosomal dominant exostosis syndrome were studied by clinical examination and complete skeletal survey. The roentgenographic characteristics of all osteochondromas were analyzed. The father underwent gene sequencing for EXT-1 and EXT-2, which revealed a novel EXT-2 mutation. Typical radiographic and clinical findings of both HMO and MC were seen throughout the family as well as in individuals. These family study findings contradict many of the long-standing clinical and x-ray diagnostic criteria for differentiating MC from HMO. The phenotypic crossover between the two conditions in this family, and results of genetic analysis, suggest that in the absence of a definitive genetic diagnosis, radiographic and clinical diagnosis of past and future cases HMO and MC may not be as reliable as previously assumed.

Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to EXT1 and EXT2, the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in PTPN11 in 4 of the 11 families. Sanger sequence analysis of PTPN11 coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire PTPN11 gene identified an additional family with a 15 kb deletion spanning exon 7 of PTPN11. Microdissected MC lesions from two patients with PTPN11 mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced PTPN11 in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence PTPN11 mutations. We conclude that heterozygous loss-of-function mutations in PTPN11 are a frequent cause of MC, that lesions in patients with MC appear to arise following a “second hit,” that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing PTPN11 mutations, and that PTPN11 mutations are not a common cause of Ollier disease or Maffucci syndrome., Author Summary Children with cartilage tumor syndromes form multiple tumors of cartilage next to joints. These tumors can occur inside the bones, as with Ollier disease and Maffuci syndrome, or on the surface of bones, as in the Multiple Osteochondroma syndrome (MO). In a hybrid syndrome, called metachondromatosis (MC), patients develop tumors both on and within bones. Only the genes causing MO are known. Since MC is inherited, we studied genetic markers in an affected family and found a region of the genome, encompassing 100 genes, always passed on to affected members. Using a recently developed method, we captured and sequenced all 100 genes in multiple families and found mutations in one gene, PTPN11, in 11 of 17 families. Patients with MC have one mutant copy of PTPN11 from their affected parent and one normal copy from their unaffected parent in all cells. We found that the normal copy is additionally lost in cartilage cells that form tumors, giving rise to cells without PTPN11. Mutations in PTPN11 were not found in other cartilage tumor syndromes, including Ollier disease and Maffucci syndrome. We are currently working to understand how loss of PTPN11 in cartilage cells causes tumors to form.

Metachondromatosis is a rare, inherited disease that was described in 1971 by Maroteaux1. He chose the name metachondromatosis to emphasize the evolving or changing nature of the chondromatous lesions1-5. The complete form of the disease is characterized by multiple metaphyseal juxtaepiphyseal exostoses, metaphyseal enchondromas, periarticular calcifications, and frequent unilateral or bilateral Legg-Calve-Perthes-like changes in the femoral head, resembling osteonecrosis1-3,6-8. The metachondromatosis-associated exostoses are true osteochondromas with cartilaginous caps and characteristically point toward the adjacent joint, often involve the bones of the hands and feet, and do not produce shortening or growth disturbance of the affected bone8. The periarticular calcifications are due to peripheral enchondral ossification in epiphysis-based exophytic enchondromas. The enchondromatous lesions, unlike those of multiple enchondromatosis, most often affect the iliac crests and the metaphyses of certain long bones, showing similar radiographic irregularities. Metachondromatosis-associated enchondromas may appear as metaphyseal enchondromas6,9, have a periarticular flowery appearance3,6,9, or be similar to lesions seen in lytic metastatic disease3,8. The reported locations of these lesions include the iliac crest, proximal and distal end of the femur, proximal part of the fibula, distal end of the tibia, distal aspect of the radius, proximal part of the humerus, and hands and feet4,6,8,9. The disorder has not been mapped in the human genome. The mode of inheritance is autosomal dominant1-3,6,8. Clinical features of metachondromatosis include firm, nontender nodules adjacent to joints in the hands and feet, less frequently at the site of large joints, appearing during the first decade of life6. A common complication is nerve compression that …

We report the case histories, radiographic and computed tomographic studies, and histologic findings of two children with metachondromatosis who developed avascular necrosis (AVN) of the femoral ossific nucleus. The first was a 9-year-old boy with involvement of both femoral heads; the second was an 8-year-old girl with involvement of her right femoral head. The changes were associated with either exostoses or enchondromalike lesions of the femoral neck. Interference with the integrity of the lateral epiphyseal vessels by these lesions would explain the avascular changes that occurred. The findings in these cases and other reports associating AVN with skeletal dysplasia should encourage treating physicians to analyze carefully a sudden increase in hip pain or rapid radiographic development of femoral head collapse in a child with a skeletal dysplasia. Recognition of true AVN, in contrast to the gradual evolution of head shape change in typical skeletal dysplasia, may change treatment recommendations and prognosis.