Concurrent intraosseous cartilaginous lesions in patients with multiple osteochondromas identified on total-body MR imaging.

PURPOSE: To assess the prevalence of intraosseous cartilaginous lesions in patients with multiple osteochondromas based on total-body (TB) MRI examinations, used for screening purposes. SUBJECTS AND METHODS: Between 2013 and 2020, TB-MRI examinations were performed in 366 patients with proven multiple osteochondromas syndrome, to rule out malignant progression. For this study, presence, or absence of intraosseous central or eccentrical chondroid lesions, defined as lobulated lesions with low signal intensity on T1-weighted images, replacing bone marrow and high signal intensity equal to fluid on T2-weighted images in the bone marrow of the meta-diaphysis of (one of) the long bones, were recorded in the long bones as part of a TB-MRI protocol. RESULTS: In 62 patients out of the 366 MO patients (17%), one or more intraosseous chondroid lesions (either enchondroma or atypical cartilaginous tumor) were detected. The age of the patients at time of diagnosis ranged from 17 to 61 years (mean, 36). Size of the lesions varied from 4 to 69 mm (mean, 16.3 mm). The most common location was the proximal femur (n = 29), followed by the distal femur and proximal humerus (n = 18 and n = 10, respectively). In nine of the patients with an intraosseous chondroid lesion, a second and/or third TB-MRI were available during the period of evaluation (mean interval, 2.7 years between the exams). In none of these patients increase of these intraosseous lesions was noticed. CONCLUSION: Intraosseous chondroid lesions (enchondroma and ACT) appear to occur more frequently in MO patients than in the general population. TB-MRI allows to detect these, besides the identification of OC with suspicious features.

Haploinsufficiency of EXT1 and Heparan Sulphate Deficiency Associated with Hereditary Multiple Exostoses in a Pakistani Family.

Background and Objectives: Hereditary multiple exostoses (HME) is a disease characterized by cartilage-capped bony protuberances at the site of growth plates of long bones. Functional mutations in the exostosin genes (EXT1 and EXT2) are reported to affect the hedgehog signalling pathways leading to multiple enchondromatosis. However, the exact role of each EXT protein in the regulation of heparan sulphate (HS) chain elongation is still an enigma. In this study, a Pakistani family with HME is investigated to find out the genetic basis of the disease. Materials and Methods: Genotyping of eight members of the family by amplifying microsatellite markers, tightly linked to the EXT1 and EXT2 genes. Results: The study revealed linkage of the HME family to the EXT1 locus 8q24.1. Sanger sequencing identified a heterozygous deletion (c.247Cdel) in exon 1 of EXT1, segregating with the disease phenotype in the family. In silico analysis predicted a shift in the frame causing an early stop codon (p.R83GfsX52). The predicted dwarf protein constituting 134 amino acids was functionally aberrant with a complete loss of the catalytic domain at the C-terminus. Interestingly, an alternative open reading frame 3 (ORF3) caused by the frame shift is predicted to encode a protein sequence, identical to the wild type and containing the catalytic domain, but lacking the first 100 amino acids of the wild-type EXT1 protein. Conclusion: Consequently, haploinsufficiency could be the cause of HME in the investigated family as the mutated copy of EXT1 is ineffective for EXT-1/2 complex formation. The predicted ORF3 protein could be of great significance in understanding several aspects of HME pathogenesis.

Delineation of the clinical and radiological features of Stuve-Wiedemann syndrome childhood survivors, four new cases and review of the literature.

Stuve-Wiedemann syndrome (SWS; MIM 601559) is a rare autosomal recessive disease caused by mutations in the leukemia inhibitor factor receptor gene (LIFR). Common clinical and radiological findings are often observed, and high neonatal mortality occurs due to respiratory distress and hyperthermic episodes. Despite initially considered as a lethal disorder during the newborn period, in recent years, several SWS childhood survivors have been reported. We report a detailed clinical and radiological characterization of four unrelated childhood SWS molecularly confirmed patients and review 22 previously reported childhood surviving cases. We contribute to the definition of the childhood survival phenotype of SWS, emphasizing the evolving phenotype, characterized by skeletal abnormalities with typical radiological findings, distinctive dysmorphic features, and dysautonomia. Based on the typical features and clinical course, early diagnosis is possible and crucial to plan appropriate management and prevent potential complications. Genetic confirmation is advisable in order to improve genetic counseling to the patients and their families.

Identification of a novel EXT2 frameshift mutation in a family with hereditary multiple exostoses by whole-exome sequencing.

BACKGROUND: Hereditary multiple exostoses (HME), also referred to as multiple osteochondromas, is an autosomal dominant skeletal disease characterized by the development of multiple overgrown benign bony tumors capped by cartilage and is associated with bone deformity, joint limitation, and short stature. Mutations in exostosin glycosyltransferase (EXT)1 and EXT2 genes, which are located on chromosomes 8q24.1 and 11p13, contribute to the pathogenesis of HME. METHODS: In the present study, a genetic analysis of a four-generation Chinese family with HME was conducted using whole-exome sequencing (WES), followed by validation using Sanger sequencing. RESULTS: A novel heterozygous frameshift mutation in exon 5 of EXT2 (c.944dupT, p.Leu316fs) was identified in all affected individuals but was not detected in any unaffected individuals. This mutation results in a frameshift that introduces a premature termination codon at position 318 (p.Leu316fs) with the ability to produce a truncated EXT2 protein that lacks the last 433 amino acids at its C-terminal to indicate a defective exostosin domain and the absence of the glycosyltransferase family 64 domain, or to lead to the degradation of mRNAs by nonsense-mediated mRNA decay, which is critical for the function of EXT2. CONCLUSION: Our results indicate that WES is effective in extending the EXT mutational spectra and is advantageous for genetic counseling and the subsequent prenatal diagnosis.

Stüve-Wiedemann syndrome with multiple eruptive vellus hair cysts and clefted tongue.

Stüve-Wiedemann syndrome is a rare autosomal recessive congenital primary skeletal dysplasia, characterized by small stature, bowed long bones, joint restrictions, hyperthermic episodes, dysautonomia, and respiratory and feeding difficulties, that usually leads to early mortality. Cutaneous manifestations have rarely been reported. We report the case of a girl with Stüve-Wiedemann syndrome presenting with progressive development of multiple eruptive vellus hair cysts.

Unsuspected osteochondroma-like outgrowths in the cranial base of Hereditary Multiple Exostoses patients and modeling and treatment with a BMP antagonist in mice.

Hereditary Multiple Exostoses (HME) is a rare pediatric disorder caused by loss-of-function mutations in the genes encoding the heparan sulfate (HS)-synthesizing enzymes EXT1 or EXT2. HME is characterized by formation of cartilaginous outgrowths-called osteochondromas- next to the growth plates of many axial and appendicular skeletal elements. Surprisingly, it is not known whether such tumors also form in endochondral elements of the craniofacial skeleton. Here, we carried out a retrospective analysis of cervical spine MRI and CT scans from 50 consecutive HME patients that included cranial skeletal images. Interestingly, nearly half of the patients displayed moderate defects or osteochondroma-like outgrowths in the cranial base and specifically in the clivus. In good correlation, osteochondromas developed in the cranial base of mutant Ext1f/f;Col2-CreER or Ext1f/f;Aggrecan-CreER mouse models of HME along the synchondrosis growth plates. Osteochondroma formation was preceded by phenotypic alteration of cells at the chondro-perichondrial boundary and was accompanied by ectopic expression of major cartilage matrix genes -collagen 2 and collagen X- within the growing ectopic masses. Because chondrogenesis requires bone morphogenetic protein (BMP) signaling, we asked whether osteochondroma formation could be blocked by a BMP signaling antagonist. Systemic administration with LDN-193189 effectively inhibited osteochondroma growth in conditional Ext1-mutant mice. In vitro studies with mouse embryo chondrogenic cells clarified the mechanisms of LDN-193189 action that turned out to include decreases in canonical BMP signaling pSMAD1/5/8 effectors but interestingly, concurrent increases in such anti-chondrogenic mechanisms as pERK1/2 and Chordin, Fgf9 and Fgf18 expression. Our study is the first to reveal that the cranial base can be affected in patients with HME and that osteochondroma formation is amenable to therapeutic drug intervention.

Whole-body MRI in assessing malignant transformation in multiple hereditary exostoses and enchondromatosis: audit results and literature review.

OBJECTIVE: To analyze the results of annual screening using whole-body magnetic resonance imaging (WBMRI) in patients with multiple hereditary exostoses (MHE) and enchondromatosis (EC), and estimate the risk for transformation to chondrosarcoma (CS) in these disorders. MATERIALS AND METHODS: A total of 62 patients (57 with MHE and five with EC) screened during a mean follow-up period of 4.6 years (range, 1-10 years) using 253 WBMRIs (median four WBMRIs per patient, range, 1-10) were analyzed retrospectively. The time of WBMRIs was compared with dates for diagnosed CSs. A supplementary literature review was performed focusing on the risk of malignant transformation. RESULTS: Ten patients had CS before being enrolled in the screening program, nine with MHE and one with EC. Three asymptomatic CSs were detected by screening; one in a patient with EC and two in patients with MHE, one of whom had CS previously. During the screening period, there was no occurrence of CS not detected by WBMRI in the study group. Histopathologically, the CSs were predominantly grade 1 and were, except for in two patients, located at the truncus, proximal femur, and shoulder girdle. Based on the current material and literature review, the risk of CS seems to be in the range of 2-3.7% for MHE and up to 50% for EC patients. CONCLUSIONS: MRI may be used as a screening method detecting malignant transformation in MHE and EC patients, but the efficacy has to be confirmed in long-term follow-up studies including cost analysis.

Heparan sulfate antagonism alters bone morphogenetic protein signaling and receptor dynamics, suggesting a mechanism in hereditary multiple exostoses.

Hereditary multiple exostoses (HME) is a pediatric disorder caused by heparan sulfate (HS) deficiency and is characterized by growth plate-associated osteochondromas. Previously, we found that osteochondroma formation in mouse models is preceded by ectopic bone morphogenetic protein (BMP) signaling in the perichondrium, but the mechanistic relationships between BMP signaling and HS deficiency remain unclear. Therefore, we used an HS antagonist (surfen) to investigate the effects of this HS interference on BMP signaling, ligand availability, cell-surface BMP receptor (BMPR) dynamics, and BMPR interactions in Ad-293 and C3H/10T1/2 cells. As observed previously, the HS interference rapidly increased phosphorylated SMAD family member 1/5/8 levels. FACS analysis and immunoblots revealed that the cells possessed appreciable levels of endogenous cell-surface BMP2/4 that were unaffected by the HS antagonist, suggesting that BMP2/4 proteins remained surface-bound but became engaged in BMPR interactions and SMAD signaling. Indeed, surface mobility of SNAP-tagged BMPRII, measured by fluorescence recovery after photobleaching (FRAP), was modulated during the drug treatment. This suggested that the receptors had transitioned to lipid rafts acting as signaling centers, confirmed for BMPRII via ultracentrifugation to separate membrane subdomains. In situ proximity ligation assays disclosed that the HS interference rapidly stimulates BMPRI-BMPRII interactions, measured by oligonucleotide-driven amplification signals. Our in vitro studies reveal that cell-associated HS controls BMP ligand availability and BMPR dynamics, interactions, and signaling, and largely restrains these processes. We propose that HS deficiency in HME may lead to extensive local BMP signaling and altered BMPR dynamics, triggering excessive cellular responses and osteochondroma formation.

Ptpn11 deletion in a novel progenitor causes metachondromatosis by inducing hedgehog signalling.

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.

[Identification of pathogenic variations in two Chinese pedigrees affected with hereditary multiple exostosis].

OBJECTIVE: To identify pathogenic variations of EXT1 and EXT2 genes in two Chinese pedigrees affected with hereditary multiple exostosis (HME). METHODS: Genomic DNA was extracted from peripheral blood samples using a phenol-chloroform method. PCR and Sanger sequencing was conducted to amplify the exons and the flanking intronic regions of the EXT1 and EXT2 genes. RESULTS: DNA sequencing has revealed a heterozygous missense variation c.812A>G (p.Tyr271Cys) in the exon 1 of EXT1 in pedigree 1, and a heterozygous frameshift variation c.1431dup (p.Ser478Leufs*43) in the exon 6 of EXT1 in the proband from pedigree 2. Both variations have co-segregated with the disease phenotype, which was also consistent with previous report. CONCLUSION: Two heterozygous pathogenic variations underlying HME have been identified. The result has facilitated genetic counseling and prenatal diagnosis for the affected pedigrees.

Advances in the pathogenesis and possible treatments for multiple hereditary exostoses from the 2016 international MHE conference.

Multiple hereditary exostoses (MHE) is an autosomal dominant disorder that affects about 1 in 50,000 children worldwide. MHE, also known as hereditary multiple exostoses (HME) or multiple osteochondromas (MO), is characterized by cartilage-capped outgrowths called osteochondromas that develop adjacent to the growth plates of skeletal elements in young patients. These benign tumors can affect growth plate function, leading to skeletal growth retardation, or deformations, and can encroach on nerves, tendons, muscles, and other surrounding tissues and cause motion impairment, chronic pain, and early onset osteoarthritis. In about 2-5% of patients, the osteochondromas can become malignant and life threatening. Current treatments consist of surgical removal of the most symptomatic tumors and correction of the major skeletal defects, but physical difficulties and chronic pain usually continue and patients may undergo multiple surgeries throughout life. Thus, there is an urgent need to find new treatments to prevent or reverse osteochondroma formation. The 2016 International MHE Research Conference was convened to provide a forum for the presentation of the most up-to-date and advanced clinical and basic science data and insights in MHE and related fields; to stimulate the forging of new perspectives, collaborations, and venues of research; and to publicize key scientific findings within the biomedical research community and share insights and relevant information with MHE patients and their families. This report provides a description, review, and assessment of all the exciting and promising studies presented at the Conference and delineates a general roadmap for future MHE research targets and goals.

Heterotopic Ossification of the Xiphoid Process after Abdominal Surgery for Traumatic Hemoperitoneum.

Heterotopic ossification of the xiphoid process is extremely rare, with only three cases previously reported. However, the surgical pathology for postoperative elongation of the xiphoid process after abdominal surgery has not yet been reported. We report a case of the postoperative elongation of the xiphoid process, 8 years after abdominal surgery for traumatic hemoperitoneum in a 53-year-old man. The patient underwent surgical excision of the elongated mass of the xiphoid process. Histopathology revealed multiple exostoses. Heterotopic ossification can occur after surgical trauma to soft or bone tissue. Surgical excision with primary closure is the treatment of choice for symptomatic heterotopic ossification.

Magnetic Resonance Imaging in Symptomatic Children With Hereditary Multiple Exostoses of the Hip.

BACKGROUND: Magnetic resonance imaging (MRI) is useful in evaluating nontraumatic hip pain. It provides information about associated injuries like labral/chondral tears or ischiofemoral impingement (IFI). However, in hereditary multiple exostoses (HME) there has been no report about MRI findings in symptomatic children with hip involvement. METHODS: Records of children with HME and hip osteochondromas, who had hip MRI/magnetic resonance arthrography, were reviewed. The presence of chondral lesions and labral tears, as well the presence of IFI, was recorded. IFI was defined as edema or fatty replacement/atrophy in the quadratus femoris muscle or decrease of the space for this muscle between the ischium and the proximal femur. The measurements used to determine the space included the ischiofemoral space, the quadratus femoris space, and the minimum ischiofemoral space (MIFS). All measurements were performed on axial T1-weighted images. RESULTS: Ten children were included (4 males, 6 females). In 2 patients, MRI was unilateral, therefore a total of 18 hips were analyzed. The indication for MRI was hip pain. Mean age, when MRI was performed, was 11.7 years. Labral tears were found in 44% (8/18) and chondral lesions in 33% (6/18) of the hips. The mean ischiofemoral space was 17.2 mm (SD, 7.3), the mean quadratus femoris space was 14.9 mm (SD, 5.3), and the mean MIFS was of 12.8 mm (SD, 5.9). IFI was seen in 44% (8/18) of hips. Two patients had bilateral IFI. MIFS was <10 mm in all hips with IFI (8/8). Of these hips, 88% (7/8) had edema of the quadratus femoris muscle and 38% (3/8) had fatty replacement/atrophy in the muscle. Osteochondromas were seen in the lesser trochanter in all hips with IFI (8/8) and in the ischium in 50% of them (4/8). CONCLUSIONS: In symptomatic children with HME of the hip, MRI is helpful in detecting the source of pain. A high percentage of these children have IFI and intra-articular lesions. These findings can play an important role in the indication and planning of the surgical approach. LEVEL OF EVIDENCE: Level IV-diagnostic study.

A genotype-phenotype study of hereditary multiple exostoses in forty-six Chinese patients.

BACKGROUND: Hereditary multiple exostoses (HME) is a rare autosomal dominant skeletal disorder that can cause a variety of clinical manifestations. We aimed to evaluate the general clinical phenotypic severity of HME by using a scoring system and correlate the genotypes with different clinical phenotypes in Chinese patients. METHODS: Forty-six patients from different families were prospectively enrolled. The mutations were identified by direct sequencing of PCR-amplified genomic DNA or by multiplex ligation-dependent probe amplification (MLPA). Patients' demographic data, height, age of onset, number of anatomical sites, forearm deformity, and lower extremity alignment were analysed according to genotype and gender. A scoring system was used to assess the severity of the clinical phenotype. RESULTS: Thirty (60%) patients presented mutations in the EXT1 gene, and 16 (32%) presented mutations in the EXT2 gene. The mean age of onset was 2.96 years. The mean number of involved anatomic sites was 15.35. Male patients had more lesion sites than female patients (15.97 vs. 13.77, p = 0.046). The height evaluation illustrated that 67% of the patients (31 of 46) were below the 50th percentile, and the patients with EXT1 mutations were shorter than those with EXT2 mutations (p = 0.005). Forearm deformity showed a significant correlation with the number of involved anatomical sites (r = 0.382, p = 0.009). Moreover, a higher total score was found in patients with EXT1 mutations (p = 0.001). CONCLUSIONS: The clinical manifestations of 46 Chinese HME patients were similar to those in previous reports of Western populations. Patients with EXT1 mutations have a more severe clinical phenotype than patients with EXT2 mutations.

SHP2 regulates chondrocyte terminal differentiation, growth plate architecture and skeletal cell fates.

Loss of PTPN11/SHP2 in mice or in human metachondromatosis (MC) patients causes benign cartilage tumors on the bone surface (exostoses) and within bones (enchondromas). To elucidate the mechanisms underlying cartilage tumor formation, we investigated the role of SHP2 in the specification, maturation and organization of chondrocytes. Firstly, we studied chondrocyte maturation by performing RNA-seq on primary chondrocyte pellet cultures. We found that SHP2 depletion, or inhibition of the ERK1/2 pathway, delays the terminal differentiation of chondrocytes from the early-hypertrophic to the late-hypertrophic stage. Secondly, we studied chondrocyte maturation and organization in mice with a mosaic postnatal inactivation of Ptpn11 in chondrocytes. We found that the vertebral growth plates of these mice have expanded domains of early-hypertrophic chondrocytes that have not yet terminally differentiated, and their enchondroma-like lesions arise from chondrocytes displaced from the growth plate due to a disruption in the organization of maturation and ossification zones. Furthermore, we observed that lesions from human MC patients also display disorganized chondrocyte maturation zones. Next, we found that inactivation of Ptpn11 in Fsp1-Cre-expressing fibroblasts induces exostosis-like outgrowths, suggesting that loss of SHP2 in cells on the bone surface and at bone-ligament attachment sites induces ectopic chondrogenesis. Finally, we performed lineage tracing to show that exostoses and enchondromas in mice likely contain mixtures of wild-type and SHP2-deficient chondrocytes. Together, these data indicate that in patients with MC, who are heterozygous for inherited PTPN11 loss-of-function mutations, second-hit mutations in PTPN11 can induce enchondromas by disrupting the organization and delaying the terminal differentiation of growth plate chondrocytes, and can induce exostoses by causing ectopic chondrogenesis of cells on the bone surface. Furthermore, the data are consistent with paracrine signaling from SHP2-deficient cells causing SHP2-sufficient cells to be incorporated into the lesions.

Dermochondrocorneal dystrophy (Francois syndrome) in a Mexican patient and literature review.

Dermochondrocorneal Dystrophy (OMIM 221800) is a very rare disease first described by Francois in 1949. It is characterized by the appearance of skin nodules, osteochondral deformities, and corneal opacities during childhood. Only a few cases have been reported. There is uncertainty about the inheritance pattern and no gene or genes have been associated to this disease. We report a patient from Mexican mestizo origin with the classic manifestations of Dermochondrocorneal Dystrophy. We perform a multidisciplinary assessment in order to contribute to the knowledge of the clinical presentation of this uncommon condition. Among the few documented patients, this is the third patient of Mexican ancestry reported with this syndrome.

Interactions of signaling proteins, growth factors and other proteins with heparan sulfate: mechanisms and mysteries.

Heparan sulfate (HS) is a component of cell surface and matrix-associated proteoglycans (HSPGs) that, collectively, play crucial roles in many physiologic processes including cell differentiation, organ morphogenesis and cancer. A key function of HS is to bind and interact with signaling proteins, growth factors, plasma proteins, immune-modulators and other factors. In doing so, the HS chains and HSPGs are able to regulate protein distribution, bio-availability and action on target cells and can also serve as cell surface co-receptors, facilitating ligand-receptor interactions. These proteins contain an HS/heparin-binding domain (HBD) that mediates their association and contacts with HS. HBDs are highly diverse in sequence and predicted structure, contain clusters of basic amino acids (Lys and Arg) and possess an overall net positive charge, most often within a consensus Cardin-Weintraub (CW) motif. Interestingly, other domains and residues are now known to influence protein-HS interactions, as well as interactions with other glycosaminoglycans, such as chondroitin sulfate. In this review, we provide a description and analysis of HBDs in proteins including amphiregulin, fibroblast growth factor family members, heparanase, sclerostin and hedgehog protein family members. We discuss HBD structural and functional features and important roles carried out by other protein domains, and also provide novel conformational insights into the diversity of CW motifs present in Sonic, Indian and Desert hedgehogs. Finally, we review progress in understanding the pathogenesis of a rare pediatric skeletal disorder, Hereditary Multiple Exostoses (HME), characterized by HS deficiency and cartilage tumor formation. Advances in understanding protein-HS interactions will have broad implications for basic biology and translational medicine as well as for the development of HS-based therapeutics.

What is the Proportion of Patients With Multiple Hereditary Exostoses Who Undergo Malignant Degeneration?

BACKGROUND: Multiple hereditary exostoses is an autosomal-dominant skeletal disorder that has a wide-ranging reported risk of malignant degeneration to chondrosarcoma. QUESTIONS/PURPOSES: The aims of our study were to use a large, web-based survey approach to characterize (1) the demographic distribution of patients with multiple hereditary exostoses, (2) the number of surgeries performed related to one's diagnosis of multiple hereditary exostoses, and (3) the proportion of survey respondents who described experiencing malignant degeneration in a large international, heterogeneous cohort of patients with multiple hereditary exostoses. METHODS: An anonymous web-based survey was distributed to several online support groups and social media networks designed to support and educate patients with multiple hereditary exostoses and their families. The survey collected demographic and epidemiologic data on 779 respondents. Data were recorded to assess respondents' disease burden and the rate of malignant degeneration. RESULTS: Females represented a slightly greater proportion of those with multiple hereditary exostoses who responded (56% female; 419 of 742 patients). Median age for all respondents was 28 years (range, < 1-85 years). Median age for males was 25 years (range, < 1-85 years), while median age for females was 29 years (range, < 1-82 years). The mean age at diagnosis of male and female respondents was in the mid-first decade (5.4 years ± 7.2 years). The mean number of surgeries a patient had undergone was 7.3 (± 7.1 surgeries). The proportion of respondents who experienced malignant transformation was 2.7% (21 of 757 respondents), at a mean age of 28.6 years (± 9.3 years). The most common sites of malignant change from benign exostoses included the pelvis (eight of 21 respondents) and scapula (four of 21 respondents). CONCLUSIONS: In the largest and most geographically diverse study of patients with multiple hereditary exostoses of which we are aware, we found the proportion of patients with multiple hereditary exostoses who have undergone malignant degeneration to be consistent with those reported in prior studies. Our study perhaps more accurately assessed the proportion of patients who undergo malignant transformation of multiple hereditary exostoses. As with prior studies on this topic, the proportion of malignant change may be expected to represent a high-end estimate as recruitment and selection bias likely predisposes for patients with more severe disease, whereas patients with lesser disease may be unaware of their diagnosis. In discussing the sequelae of multiple hereditary exostoses, clinicians perhaps might use this study to offer an unspecific statement of risk of malignant degeneration of multiple hereditary exostoses among the population at large. LEVEL OF EVIDENCE: Level IV, prognostic study.

Multiple Skeletal Deformities in a Middle-Aged Man.

A 54-year-old man was seen in our endocrinology clinic with evidence of a limited range of motion in his left foot. He had a history of diabetes mellitus type 2 and atrial fibrillation. His family history included evidence of skeletal deformities in some of his relatives. This could imply the potential existence of a hereditary condition. It is worth noting that spontaneous mutations have been reported in some cases. A pertinent physical examination revealed a surgical scar on the patient's left knee, a hallux valgus deformity on his left foot with compromised joint function, and painless bony prominences on that same foot. The skeletal survey findings were consistent with multiple hereditary exostoses. Multiple osteochondromatosis (MO) is a rare genetic disorder associated with serious complications that may significantly affect the health related quality of life of anyone having the disorder. To prevent further complications, these patients require long-term follow-up with regular clinical and radiological examinations.

[Osteochondroma in children and adolescents].

Osteochondroma is called a benign cartilage-forming tumor arising from an aberrant subperiosteal cartilage. Multiple osteochondromas syndrome (MOS) is an autosomal dominant disease, the basis for which is mutations in the EXT (EXT1 or EXT2) genes. Osteochondroma is one of the most common benign bone tumors. According to the WHO data, it is detectable in 35% of benign bone tumors and 8% of all surgically removed bone tumors. A total of 491 cases of bone tumors were analyzed in the children and adolescents diagnosed at the Department of Pathoanatomy, Russian Children's Clinical Hospital, Moscow, in 2009 to 2014. All the patients with osteochondroma were divided into 2 groups: 1) sporadic cases (n = 63) and 2) tumors included in MOS (n = 33). Both groups showed a preponderance of boys (39 boys and 24 girls in Group 1 and 21 boys and 12 girls in Group 2). Clinical, radiological, and morphological criteria for the diagnosis and differential diagnosis of osteochondromas in children and adolescents are given.