Search

In this study, we present a specified hinge positioning method to achieve satisfying and steerable lengthening and angulation to correct forearm multiple hereditary exostoses (MHE) combined with severe radiocapitellar joint dislocation using Ilizarov ring fixators.Between January 2014 and December 2018, a total of 30 forearms of 23 patients (11 males, 12 females; mean age: 18.3±6.8 years; range, 8 to 35 years) who suffered from type IIa (n=2) or IIb (n=28) MHE with severe radiocapitellar joint luxation were retrospectively analyzed. All patients were treated with Ilizarov external fixators with our specified hinge positioning method. Range of motion of the elbow, forearm and wrist and Visual Analog Scale (VAS), as well as Disabilities of Arm, Shoulder, and Hand (DASH) score, and radiological parameters, including radial articular angle (RAA), ulnar variance (UV) and carpi slip (CS), were recorded preoperatively and at final follow-up and were compared.Clinical and radiological outcomes were evaluated. Range of motion of the elbow, forearm and wrist, VAS, DASH and radiological features, including RAA, CS, and UV were significantly improved, except for range of motion of the forearm supination. Temporary nail track infection was seen in two of the forearms and was controlled with oral antibiotics. None of the patients developed radial head dislocation again.Clinical and radiological outcomes of this novel hinge positioning method are satisfactory in treating MHE with severe radial head dislocation, and this method can be an alternative treatment for MHE by setting a milestone for accurate radiocapitellar joint reduction.

The burden of upper extremity (UE) osteochondromas on function and self-perception among pediatric patients is unclear. The purpose of our study was to study the impact of osteochondromas in comparison to population norms and to evaluate solitary versus multiple osteochondromas on subjective UE function as measured by patient rated outcomes.We utilized the CoULD (Congenital Upper Limb Differences) Registry to review all pediatric patients presenting with osteochondromas between January 2014 and February 2021. Demographic information was collected and patients were classified as having either single or multiple osteochondromas. Patient-Reported Outcome Measurement Information System (PROMIS) and Pediatric Outcomes Data Collection Instrument (PODCI) tools were utilized for assessment. Scores for PODCI subscales of UE function, Pain/comfort, and Happiness and PROMIS domains of UE Function, Pain, Depression, Anxiety, and Peer Relations were reviewed. Differences between groups were analyzed using the Student t test.Ninety-nine patients met inclusion criteria for the study with an average age of presentation of 9.3 years and 61 patients (62%) were male. Overall, patients demonstrated worse UE Function as well as greater Anxiety and Depression in comparison to the population normals on PROMIS assessment. Patients also demonstrated worse patient and parent reported PODCI UE, Sports and Physical Functioning, Pain/Comfort and Global Functioning scores compared with population norms but demonstrated better than average happiness scores. Patients with multiple osteochondromas demonstrated greater PROMIS pain interference and more disability in PODCI Sports and Physical Functioning, Pain/Comfort and Global Functioning compared with those with solitary osteochondromas.Patients with UE osteochondromas have worse overall function in comparison to population norms, exceeding established minimally clinically important difference values. In addition, patients with multiple osteochondromas reported more pain and poorer physical function than those with solitary osteochondromas. Physicians should be alert to the physical and psychosocial burden of this disease.Level II-prognostic.

Aims Chondrosarcoma is the second most common primary sarcoma of bone: conventional chondrosarcoma accounts for 85% of all cases. Conventional chondrosarcoma may be central or peripheral. Most studies group central and peripheral chondrosarcomas together, although there is growing evidence that their clinical behaviour and prognosis differ. The aims of this study were to analyze any differences in characteristics between central and peripheral chondrosarcomas and to investigate the incidence and role of different syndromes. Methods Data from two international tertiary referral sarcoma centres between January 1995 and December 2018 were retrospectively reviewed. The study population consisted of 714 patients with surgically treated conventional chondrosarcoma of the pelvis and limbs. Results In patients with Ollier’s disease and Mafucci’s syndrome, 12/20 (60%) and 2/5 (60%) of malignancies, respectively, were in the limbs, most frequently in the proximal humerus, proximal tibia, and in the hands and feet. In patients with hereditary multiple exostosis (HME), 20/29 (69.0%) of chondrosarcomas were in the pelvis and scapula, specifically in the ilium in 13/29 (44.8%) and the scapula in 3/29 (10.3%). In central chondrosarcoma, survival of patients with Ollier’s disease and non-syndromic patients was the same (p = 0.805). In peripheral chondrosarcoma, survival among HME patients was similar (p = 0.676) in patients with tumours of the pelvis and limbs. Conclusion Both central and peripheral chondrosarcoma have specific characteristics. HME is frequently seen in patients with a peripheral chondrosarcoma, in whom tumours are commonly located in the ilium and scapula. The incidence of Ollier’s disease is uncommon in patients with a central chondrosarcoma. Disease-specific survival is equal in different subtypes after adjustment for histological grade. The local recurrence-free survival is the same for different locations and subtypes after adjustment for surgical margin. Cite this article: Bone Joint J 2021;103-B(5):984–990.

Background Multiple hereditary exostoses (MHE) lead to the development of pedunculated or sessile osteocartilaginous lesions. Vertebral involvement occurs in MHE and encroaching intracanal exostoses can result in devastating consequences. Magnetic resonance imaging (MRI) of the entire spine has been used to screen for vertebral exostoses to detect high-risk patients. The primary purpose of this investigation is to determine the incidence of vertebral and encroaching intracanal exostoses in patients with MHE. A secondary purpose is to determine if pelvis and rib exostoses serve as "harbinger" lesions of vertebral involvement in MHE. Methods A retrospective chart review was performed on 39 patients (21 male and 18 female individuals) with MHE who underwent routine spinal screening with noncontrast entire spine MRI. The average age at screening was 12.3 years (range, 3 to 17 y). Screening was ordered consecutively on patients seen during the study period who were between ages 8 and 18 years or had complaints that could be related to encroaching intracanal exostoses. Results The incidence of vertebral exostoses in this cohort of 39 patients with MHE was 28% (11 total). An encroaching intracanal exostosis was seen in 3 patients (2 cervical, 1 thoracic). Nonencroaching vertebral exostoses were discovered in 8 patients. Sufficient pelvis and rib imaging to determine the presence of pelvis and rib exostoses was available in 8 of those with vertebral exostoses and 19 of those with no vertebral exostoses on screening MRI. In this cohort, the sensitivity and specificity of the presence of both pelvis and rib exostoses for determining the presence of spinal involvement in MHE are 88% and 5%, respectively. Conclusions Based on the results of this cohort, vertebral exostoses are common in MHE, and screening MRI of the entire spine can be used to determine which patients need close observation. If a more selective screening protocol is utilized, an entire spine MRI could be obtained for patients who desire increased physical activity levels or for patients with both pelvis and rib exostoses. At a minimum, treating physicians should monitor patients with MHE closely for neurological symptoms and have a low threshold to obtain advanced spinal imaging. Level of evidence Level III-diagnostic.

BACKGROUND Osteochondromas occur most commonly in the distal femur, proximal tibia, and humerus. There are no large studies reviewing the outcome of treatment for patients with an osteochondroma involving the proximal fibula. The purpose of this study is to specifically understand the manifestations of a proximal fibular osteochondroma (PFO) on the preoperative peroneal nerve function, and how surgical management of the osteochondroma affects function immediately postoperatively and at long-term follow-up. METHODS This is an institutional review board-approved retrospective review of a consecutive series of patients with a PFO treated operatively at a single institution. The medical record was carefully reviewed to identify demographic data, clinical data especially the status of the peroneal function at various time points. RESULTS There were 25 patients with 31 affected extremities who underwent surgical excision of the PFO at an average age of 12.4 years (range, 3.0 to 17.9 y). There were 16 males and 9 females. The underlying diagnosis was isolated PFO in 2 (8%) patients and multiple hereditary exostosis in 23 (92%) patients. Preoperatively, 9 (29%) had a foot drop and 22 (71%) did not. Those with a preoperative foot drop underwent surgery at a younger age (9.1 vs. 13.8 y) (P

We analyzed osteoporosis in 20 HME patients. According to the T-score of BMD, 30% and 67.5% of the patients fell in the range of osteopenia in the lumbar spine and femoral neck. Our results indicate HME patients have low bone mass. They do not have abnormal bone metabolism. There are few reports of osteoporosis in hereditary multiple exostoses (HME) patients. Therefore, the purpose of this study was to analyze osteoporosis in HME patients. This retrospective cohort study included 20 patients diagnosed with HME. Patients underwent bone mineral density (BMD) measurement of the lumbar spine (n = 20) and femoral neck (n = 40). Bone metabolic parameters, including serum osteocalcin and urinary cross-linked N-telopeptide of type 1 collagen (NTx), were analyzed in all subjects. EXT1 and EXT2 genes were sequenced using genomic DNA. We also examined the correlation between genotype and BMD Z-score and T-score. The mean BMD values of the lumbar spine were 1.085 ± 0.116 g/cm2 (n = 11) in male and 1.108 ± 0.088 g/cm2 (n = 9) in female. The mean BMD values of the femoral neck area were 0.759 ± 0.125 g/cm2 (n = 22) in male and 0.749 ± 0.115 g/cm2 (n = 18) in female. Z-score of most HME patients show

Retrospective cohort study OBJECTIVES: To determine prevalence of hereditary multiple osteochondromas (HMO) and utility of MRI surveillance in a prospective Spine at Risk (SAR) program. Unidentified intraspinal exostoses in HMO can lead to neurologic injury in children during sedated procedures but no MRI guidelines exist. We sought to determine the prevalence and age of intraspinal exostoses from MRIs, and indications for MRI surveillance.Retrospective review was performed of pediatric HMO patients who underwent total spine MRIs at a single institution after a prospective SAR program was instituted. Charts were reviewed for MRI indication and findings, symptoms, surgery, and location of other exostoses. Fisher's exact test was used to compare categorical variables and T test to compare continuous variables. Predictive value of pelvic/rib exostoses was calculated for intraspinal lesions.Forty-three patients with HMO underwent total spine MRIs with average age of 11.5 years. Fifteen (35%) patients had exostoses on vertebral column, eight (19%) had intra-canal spinal exostoses. Higher prevalence of spine lesions occurred in symptomatic patients than asymptomatic (any spinal lesion: 73% prevalence in symptomatic vs 22% in asymptomatic, p 0.005; intra-canal spinal lesion: 46% vs 9%, p 0.05). Only two of the 11 'symptomatic presentations' could be attributable to intracanal spinal exostoses. Only one intra-canal exostosis found on asymptomatic surveillance was treated surgically. Presence of pelvic or rib exostoses were not strongly predictive of intra-canal lesions (23% PPV, 85% NPV, 63% sensitivity, 51% specificity).Even with the presence of intra-canal exostoses, true symptomatic lesions are rare. Rib and pelvic lesions were not predictive of intra-canal lesions in our population. We recommend obtaining MRIs at time of preoperative evaluation in asymptomatic children old enough to not need sedation, or in patients with true neurologic symptoms to prevent unnecessary sedation of younger children for surveillance MRI.III.

Objective To find novel potential gene mutations other than EXT1 and EXT2 mutations, to expand the mutational spectrum of EXT and to explore the correlation between clinical outcome and genotype in patients with hereditary multiple exostoses (HME). Methods The study recruited seven families diagnosed with multiple osteochondromas (MO). Family histories and clinical information were collected in detail through comprehensive physical and image examination. Patients with deformities and functional limitations were classified as "severe" and the remaining without functional limitations were classified as "mild," in accordance with previous study. Whole-exome sequencing (WES) was performed on a total of 13 affected individuals, 1 available unaffected relative, and 10 healthy unrelated individuals. Sanger sequencing was used to validate the screened mutations. Finally, the structural change in protein caused by pathogenic mutations was analyzed using information from the relevant database online and we attempted to correlate clinical phenotype with genotype in patients with HME. Results Other than EXT1 and EXT2, no novel potential gene mutations were found through WES. We identified nine heterozygous mutations in EXT1 or EXT2. Of these mutations, four have not been reported previously. These are c.996delT in exon 2 of EXT1 (family 1), c.544C > T in exon 3 of EXT2 (family 2), c.1171C > T in exon 7 of EXT2 (family 5), and c.823- 824delAA in exon 5 of EXT1 (family 7). The other five mutations have already been reported in previous works. It was surprising that we found two mutation sites, in exon 2 and exon 5, respectively, of EXT1 in 1 patient diagnosed with MO, when his father had two mutation sites, in exon 6 and exon 5, respectively, of EXT1 and EXT2 (family 4). In addition, 1 patient showed degeneration, while his father only exhibited slight symptoms (family 7). In our study, among 51 affected patients in seven families, the sex ratio (male vs female) was 58.9% (n = 30) vs 41.2% (n = 21). Male patients seemed to show more severe symptoms compared to females, but because the sample was small, we did not obtain statistically significance results. Conclusion Whole-exome sequencing to screen pathogenic gene mutations was applied successfully. Although no third-gene mutation associated with HME was found, a total of nine mutations across EXT1 and EXT2 were identified, four of which are novel. Our results expand the mutational spectrum of EXT and can be used in genetic counseling and prenatal diagnosis for patients with MO.

Background Multiple hereditary exostosis is a benign condition that can lead to significant forearm deformity secondary to physeal disturbances. As the child grows, the deformity can worsen as relative shortening of the ulna causes tethering, which may lead to increased radial articular angle, carpal slippage, and radial bowing, over time this tethering can also result in radial head subluxation or frank dislocation. Worsening of forearm deformities often require corrective reconstructive osteotomies to improve anatomic alignment and function. The purpose of this study is to evaluate the effectiveness of osteochondroma excision and distal ulnar tether release on clinical function, radiographic anatomic forearm alignment, and need for future corrective osteotomies. Methods The authors reviewed a retrospective cohort of preadolescent patients who underwent distal ulna osteochondroma resection and ulnar tethering release (triangular fibrocartilage complex). Patients were invited back and prospectively evaluated for postoperative range of motion, pain scores, self-reported and parent-reported Disabilities of the Arm, Shoulder, and Hand (DASH) and Pediatric Outcomes Data Collection Instrument (PODCI) scores. In addition, preoperative and final postsurgical follow-up forearm x-rays were reviewed. Results A total of 6 patients and 7 forearms were included in our study with an average age of 7.9 years at time of surgery. The average final follow-up was 7.4 years. With respect to range of motion, only passive radial deviation demonstrated improvement -20 to 14 degrees (P=0.01). Although there was not statistically significant change in radial articular angle, this study did find an improvement in carpal slip 75.7% to 53.8% (P=0.03). At final follow-up DASH score was 5.71 (σ=5.35), PODCI Global Function score was 95.2 (σ=5.81), and PODCI-Happiness score 98 (σ=2.74). Visual analogue scale appearance and visual analogue scale pain assessment were 1.67 (σ=1.21) and 1.00 (σ=1.26), respectively, at final follow-up. No patient in the cohort developed a radial head dislocation. Only one of 7 forearms required a corrective osteotomy within the study's follow-up time period. Conclusions Surgical excision of forearm osteochondromas with ulnar tether release in the preadolescent patients improves carpal slip, may help to prevent subsequent surgical reconstruction and provides satisfactory clinical results at an average 7-year follow-up. Level of evidence Level III-therapeutic study.

The aim of the present study was to report a clinical survey of hereditary multiple exostoses (HME) in a large Chinese pedigree, and the identification of a novel deletion mutation of exostosin glycosyltransferase 2 (

Genu valgus is one of the most common limb deformities in hereditary multiple exostoses (HME). However, it is easily concealed and may account for subsequent osteoarthritis of the knee. The knees of 56 patients (33 men and 23 women) with HME were investigated bilaterally. Knee valgus was described by the mechanical axis deviation (MAD), mechanical lateral distal femoral angle (LDFA), and medial proximal tibial angle (MPTA). We investigated sex, age, BMI, total number of palpable osteochondromas, number of radiographic osteochondromas around the knee, forearm deformities, morphology and distribution of lesions, and correlations between these factors and genu valgus. The measurement of LDFA and MPTA was performed to identify the sources of genu valgus deformity. Based on the measurement of the mechanical axis, limbs were classified as genu valgus (n = 22) or normal mechanical axis groups (n = 90). The different severities of the genu valgus patients were classified by MAD. By bivariate logistic regression, genu valgus was significantly associated with more sessile and flared metaphyseal lesions. However, only the number of flared metaphyseal lesions had a significant influence on the severity of genu valgus. By analyzing the LDFA and MPTA, it was found that abnormalities of both proximal tibia and distal femur play important roles in genu valgus. Early detection of sessile and flared metaphyseal knee lesions in patients with HME can contribute to early intervention of genu valgus. Level of relevance: Level 2.

Background Stuve-Wiedemann syndrome (SWS) is a rare and severe genetic disease characterized by skeletal anomalies and dysautonomic disturbances requiring appropriate care. Peer support is mandatory to fill the lack of clinical recommendations in such rare diseases. We report a new case and provide the first systematic review of all previous published cases. Objective To better describe the timeline of SWS and to improve paediatric management. Data sources SWS English publications available on Pubmed until 31/03/2021. Study selection Case description combining typical osteo-articular and dysautonomic involvement (with 2 items by categories required for children 2 years). Data extraction Demographic, clinical, genetics and outcome data. Results In our cohort of 69 patients, the median age at report was 32 months. Only 46% presented antenatal signs. Mortality rate is higher during the first 2 years (42% 2 years) mainly due to respiratory failure, pulmonary arterial hypertension appearing to be a poor prognosis factor (mortality rate 63%). After 2 years, orthopaedic symptoms significantly increase including joint mobility restriction (81%), spinal deformations (77%) and fractures (61%). Conclusions Natural history of SWS is marked by a high mortality rate before 2 years due to dysautonomic disturbances. A specialized multidisciplinary approach is needed to address these early mortality risks and then adapt to the specific, mainly orthopaedic, needs of patients after 2 years of age. Further research is required to provide clinical guidelines and improve pre-natal counselling.

Genetic mosaicism caused by postzygotic mutations is of a great interest due to its role in human disease. Monozygotic twins arising from a single zygote are considered as genetically identical, and any differences likely to be caused by postzygotic events. Thus, phenotypically discordant monozygotic twins offer a unique opportunity to study genotype-phenotype correlation. Here, we present a three-generation family starting from a pair of monozygotic twins discordant for metachondromatosis due to postzygotic p.(Gln175His) variant in the PTPN11 gene. Both phenotypically discordant monozygotic twins harbor p.(Gln175His), however significant differences in mosaic ratio is observed not only between twins, but also within different tissue types within one individual. Phenotypic manifestation of p.(Gln175His) in examined family clearly depends on allele variant fraction (VAF). Individuals harboring constitutional mutation (VAF 50%) present typical metachondromatosis. Milder phenotype is observed in twin harboring high-level mosaicism in the tissue of ectodermal origin (VAF 45%), but not in a blood (VAF 5%). Finally, her twin sister harboring low-level mosaicism in blood (VAF 2%) and nonblood (VAF 12%) tissues is phenotypically normal. Our results provide insights into biological role of mosaicism in disease and further support the usefulness of nonblood tissues as an optimal source of DNA for the identification of postzygotic mutations in phenotypically discordant monozygotic twins.

Background: Multiple hereditary exostoses (MHE) also known as Multiple Osteochondromas is a rare benign bone tumour disease, characterized by multiple osteocartilaginous masses. The knee is one of the most affected sites. Anterior cruciate ligament (ACL) surgery is the most common and generally most successful surgical knee procedure; however, the association between MHE and ACL reconstruction is very rare and may represent a challenging procedure because of the anatomical anomaly related to presence of multiple masses around the knee. Here, we present a case report of ACL reconstruction in a patient affected by multiple exostoses. Case report: The patient was a 30-year-old woman affected by MHE, with an ACL tear arising after knee trauma. As the patient complained of pain, swelling and the knee “giving way”, she successfully underwent arthroscopic-assisted ACL reconstruction using quadrupled hamstring tendon grafts, with femoral suspension and double tibial fixations. Conclusion: Symptomatic ACL tears in a patient affected by MHE should be considered for arthroscopic reconstruction, which requires that particular attention be paid to tendons harvesting, tunnel placement and the choice of graft fixation system, given the presence of multiple masses around the knee. (www.actabiomedica.it)

Stüve-Wiedemann syndrome (SWS) is a rare genetic disorder characterized by skeletal dysplasia and severe dysautonomia, evidencing a difficult airway approach and likely increased malignant hyperthermia susceptibility. Developmental dysmorphism classically worsens with age, therefore translating in a poor prognosis. In this article, we describe a case of a 27-year-old woman diagnosed with SWS proposed for abscess drainage under dissociative anesthesia. This patient has outlived the life expectancy described for SWS, acknowledging the importance of reporting this rare adult clinical case in what SWS anesthetic management is concerned.

Backgrounds Though malalignment of lower legs is a common pathologic phenomenon in multiple hereditary exostoses (MHE), relationship between locations of exostoses and malalignment of lower legs remains unclear. This study examined radiographs of MHE patients in an attempt to evaluate the tendency of coronal malalignment of lower legs with different location of exostoses on lower legs consisting of two parallel long bones. Methods Between 2000 and 2017, we retrospectively reviewed the anteroposterior films of the teleo-roentgenographics of 63 patients with MHE. The patients were classified into four different groups depending on the locations of the exostosis, which occurred on both proximal and distal tibiofibular joints (A), proximal tibiofibular joint (B), distal tibiofibular joint (C), and not for the tibiofibular joint area (D). To evaluate the influence of the location of exostoses on coronal malalignment of lower legs, medial proximal tibia angle (MPTA), lateral distal tibia angle (LDTA), and fibular shortening were analyzed for each group. Results Significant difference was observed in multiple comparative analyses for each of the four groups. On MPTA radiologic analysis, group A showed greatest value with significant difference compared with groups C and D (vs. (B): p = 0.215; vs. distal joints (C): p = 0.004; vs. (D): p = 0.001). Group B showed significant difference only with group D (vs. distal joints (C): p = 0.388; vs. (D): p = 0.002), but for group C and D showed no significant difference. For LDTA, only group A showed significant difference compared to other groups (p p = 0.004; vs. (C): p = 0.655; vs. (D): p p = 0.002). Conclusions For evaluation of the coronal malalignment of lower legs in MHE patients, not only ankle around the distal tibiofibular joint but also proximal tibiofibular joint should be examined, in that, lower limb deformity occurred by two parallel long bone which has self-contained joint. Level of evidence Level III, retrospective comparative study.

Background Multiple Osteochondromas (MO) is a rare skeletal disorder frequently needing orthopaedic surgery. High prevalence of pain has been reported, however fatigue has not previously been investigated. Purpose Our aims were to investigate prevalence of fatigue and pain in Norwegian children and adults with MO. Furthermore to compare prevalence of fatigue with reported prevalence in other groups and explore some factors that may contribute to fatigue in this population. Methods Questionnaire data was obtained from 11 children and 21 adults, approximately one third of the estimated MO population in Norway. Fatigue and pain was measured with validated instruments. Results Children with MO reported significantly higher fatigue than healthy children. Adults reported significantly higher fatigue than the general Norwegian population. Six of 11 children and 20 of 21 adults reported pain. Severe fatigue was more prevalent in persons with high age, high pain intensity and many pain locations; however none of these differences were significant. Conclusion High prevalence of fatigue was found in Norwegian children and adults with MO. Such findings have not been previously reported. Pain was prevalent in both children and adults. This implies that fatigue and pain warrant specific attention in clinical practice and further research regarding persons with MO.

Stüve-Wiedemann syndrome (OMIM #601559) is a rare, autosomal recessive disorder characterized by skeletal dysplasia, consecutive infections, feeding difficulties and autonomic dysregulation. We present an Afro-Caribbean family with two siblings diagnosed with Stüve-Wiedemann syndrome. The underlying loss-of-function mutation in the leukemia inhibitory factor receptor gene is thought to impair proper functioning of the JAK/STAT 3 pathway. As this affects normal functioning of T-helper cells, these patients are prone to infections with uncommon pathogens as illustrated by this case.

Hereditary multiple osteochondromas (HMO) is a rare autosomal dominant skeletal disorder, caused by heterozygous variants in either EXT1 or EXT2, which encode proteins involved in the biogenesis of heparan sulphate. Pathogenesis and genotype-phenotype correlations remain poorly understood. We studied 114 HMO families (158 affected individuals) with causative EXT1 or EXT2 variants identified by Sanger sequencing, or multiplex ligation-dependent probe amplification and qPCR. Eighty-seven disease-causative variants (55 novel and 32 known) were identified including frameshift (42%), nonsense (32%), missense (11%), splicing (10%) variants and genomic rearrangements (5%). Informative clinical features were available for 42 EXT1 and 27 EXT2 subjects. Osteochondromas were more frequent in EXT1 as compared to EXT2 patients. Anatomical distribution of lesions showed significant differences based on causative gene. Microscopy analysis for selected EXT1 and EXT2 variants verified that EXT1 and EXT2 mutants failed to co-localize each other and loss Golgi localization by surrounding the nucleus and/or assuming a diffuse intracellular distribution. In a cell viability study, cells expressing EXT1 and EXT2 mutants proliferated more slowly than cells expressing wild-type proteins. This confirms the physiological relevance of EXT1 and EXT2 Golgi co-localization and the key role of these proteins in the cell cycle. Taken together, our data expand genotype-phenotype correlations, offer further insights in the pathogenesis of HMO and open the path to future therapies.

Multiple osteochondromas (MOs) or hereditary multiple exostoses is a rare autosomal-dominant disease characterized by growths of MOs, which are benign cartilage-capped bone tumors that grow away from the growth plates. Almost 90% of MOs have a molecular explanation and 10% are unexplained. MOs are genetically heterogeneous with two causal genes on 8q24.11 (EXT1) and 11p12 (EXT2), with a higher frequency in EXT1. MO is a very rare genetic disorder, and the genotype-phenotype of MO with EXT2 mutation has not been well investigated in Korea. We present the clinical radiographic and molecular analysis of a four-generation Korean family with 11 MO-affected members (seven males and four females). The affected members from the third generation available for molecular analysis and their detailed medical histories showed moderate-to-severe phenotypes (clinical classes II-III), including bony deformities and limb misalignment with pain requiring surgical correction. The x-rays showed MOs in multiple sites. A novel EXT2 frameshift mutation (c.590delC, p.P197Qfs*73) was revealed by targeted exome sequencing in the affected members of this family. In this article, we not only expand the phenotypic-genotypic spectrum of MOs but also highlight the phenotypic heterogeneity in a family with the same mutation. In addition, we compiled the mutation spectrum of EXT2 from a literature review and identified that exon 2 of EXT2 is a mutation hot spot. Early medical attention with diagnosis of MO through careful examination of the clinical manifestations and genetic analysis can provide the opportunity to establish coordinated multispecialty management of the patient.

Bony exostoses are benign osteocartilaginous growths that start close to growth plates. Approximately 30-60% of patients have forearm deformities. The commonly encountered forearm deformities in these patients are bowing of the radius, with or without ulnar drift of the carpus, radial head dislocation, shortening of the ulna, and radial head dislocation. The current study reported on the results of management of radial head dislocation for type IIb Masada and Oho classification of forearm deformities by Ilizarov ulnar lengthening and without tumor excision. A series of 12 patients with Masada type IIb deformity were treated by Ilizarov lengthening at AlHadra University Hospital, Alexandria, Egypt, during the period from January 2008 to June 2014. There were eight males and four females; the right forearm was affected in seven patients. The mean age of the patients was 8.7 years (range: 7.5-10 years). All cases showed ulnar shortening with distal ulnar exostosis and radial head dislocation (Masada type IIb). All patients were operated on under general anesthesia, with application of the Ilizarov frame to the forearm. The frame used was assembled of two complete rings; the proximal one was fixed to the proximal ulna and the distal ring was fixed to both radius and ulna. Ulnar osteotomy was performed between the two rings, followed by ulnar lengthening 10 days postoperatively to lengthen the ulna and pull down the radius. Over a follow-up period of 33.2 months (24-48 months), all patients showed spontaneous reduction of the radial head and correction of the forearm deformity. The range of motion improved: flexion increased from 117.5° (110-130°) to 145° (130-160°) and extension increased to 4.6° (0-10°), whereas it was 13.8° (10-20°) preoperatively and the supination increased from 46.3° (40-50°) preoperatively to 73.6° (65-80°) postoperatively. Pronation improved from a preoperative average of 37.9° (30-40°) to 70.8° (60-80°) at the end of follow-up. The average amount of ulnar length was 27.9 mm (25-35) and the duration of external fixation was 103.3 days on average, with a range of 90-130. Thus, the average external fixation index was 3.7 days/mm (range: 3.6-4.0). Gradual lengthening of the ulna and pulling down the radius with an Ilizarov frame is an excellent method for correction of forearm deformity in patients with multiple hereditary exostosis (Masada IIb). Early intervention is the key to achieving spontaneous reduction of the radial head in all patients without the need for corrective osteotomy or tumor excision. Level of evidence: level IV.

Background: Multiple osteochondromas (MO) are an autosomal-dominant disease characterized by the growth of multiple cartilage-capped prominences in the growth plate region of the metaphysis in long and flat bones. Materials and Methods: To detect genetic mutations related to MO, a three-generation Chinese family with MO was evaluated using whole exome sequencing for mutation screening. The candidate pathogenic mutation was validated by Sanger sequencing. Results: A novel frameshift (NM_000401.3:c.1321del:p.Leu441TrpfsTer28) in exon 8 of the exotosin 2 (EXT2) gene was identified in two affected individuals. Codons 441 and 468 in the EXT2 gene are highly conserved among vertebrates as demonstrated by multiple sequence alignment. The c.1321 del C resulted in an amino acid change at codon 441, which generated a premature stop codon at position 468, causing complete loss of the glycosyltransferase domain. Conclusions: A novel frameshift mutation c.1321delC detected in the EXT2 gene may help in prenatal genetic screening and early diagnosis of MO.

Background Potocki–Shaffer syndrome (PSS) is a rare contiguous gene deletion syndrome marked by haploinsufficiency of genes in chromosomal region 11p11.2p12. Approximately 50 cases of PSS have been reported; however, a syndrome with a PSS-like clinical phenotype caused by 11p11.12p12 duplication has not yet been reported. Methods 11p11.12p12 duplication syndrome was identified and evaluated using a multidisciplinary protocol. Diagnostic studies included intelligence testing, thorough physical examination, electroencephalography (EEG), magnetic resonance imaging (MRI) of the brain, ultrasonography, biochemical tests and karyotype analysis. Next-generation sequencing analysis clarified the location of the chromosomal variations, which was confirmed by chromosome microarray analysis (CMA). Whole-exome sequencing (WES) was performed to exclude single nucleotide variations (SNVs). A wider literature search was performed to evaluate the correlation between the genes contained in the chromosomal region and clinical phenotypes. Results The proband was a 36-year-old mother with intellectual disability (ID) and craniofacial anomalies (CFA). She and her older son, who had a similar clinical phenotype, both carried the same 11p11.12p12 duplication with a copy number increase of approximately 10.5 Mb (chr11:40231033_50762504, GRCh37/hg19) in chromosome bands 11p11.12p12. In addition, she gave birth to a child with a normal phenotype who did not carry the 11p11.12p12 duplication. By literature research and DECIPHER, we identified some shared and some distinct features between this duplication syndrome and PSS. One or more of ALX4, SLC35C1, PHF21A and MAPK8IP1 may be responsible for 11p11.12p12 duplication syndrome. Conclusions We present the first report of 11p11.12p12 duplication syndrome. It is an interesting case worth reporting. The identification of clinical phenotypes will facilitate genetic counselling. A molecular cytogenetic approach was helpful in identifying the genetic aetiology of the patients and potential candidate genes with triplosensitive effects involved in 11p11.12p12 duplication.

Objectives. To discuss the mutational features and their relationships with disease in a family with hereditary multiple osteochondroma (HMO) from Guangxi Province (GXBB-1 family), China. Methods. Genomic DNA and total mRNA were extracted from peripheral blood cells of GXBB-1 family members. Whole elements of the EXT1gene and its transcript, including exons, introns, exon-intron boundaries, and coding sequence (CDS) clones, were amplified and sequenced. Allele-specific PCR was used to confirm the position and type of mutation. Results. All patients from the GXBB-1 family harbored the cosegregating heterozygous c.1056+1G>A mutation located in EXT1at an exon-intron boundary. Another three single-nucleotide polymorphisms (SNPs) were also detected in the patients, including IVS2+1G>A in intron 2, c.1844 T>C [p.Pro (CCT) 614Pro (CCC)] in exon 3, and c.2534G>A [p.Glu (GAG) 844Glu (GAA)] in exon 9. The latter two SNPs were synonymous variations. Conclusions. The heterozygous c.1056+1G>A mutation cosegregated with the phenotype, indicating that it is a pathogenic mutation in the GXBB-1 family. This mutation is reported for the first time in Chinese HMO patients. IVS2+1G>A and c.2534G>A have no relationship with the occurrence of disease. However, c.1844 T>C and c.1056+1G>A are linked, and their interaction needs to be further studied. c.1844T>C is a new SNP that has not been reported internationally.

Background Gradual ulnar lengthening is the most commonly used procedure in the treatment of Masada type I/II deformity in patients with hereditary multiple osteochondromas. However, the treatment remains controversial for the recurrence of deformity in growing children. This study aims to evaluate the clinical and radiological outcomes of ulnar gradual lengthening in our clinic. Methods We retrospectively reviewed patients who underwent ulnar lengthening by distraction osteogenesis from June 2008 to October 2017. The carrying angle (CA) and range of motion (ROM) of the forearm and elbow were clinically assessed, and the radial articular angle (RAA) and ulnar shortening (US) were radiologically assessed before lengthening, 2 months after external frame removal, and at the last follow-up. Results The current study included 15 patients (17 forearms) with a mean age of 9.4 ± 2.3 years at the index surgery. The mean follow-up period was 4.2 ± 2.4 years. There were 9 patients (10 forearms) with Masada type I deformity and 6 patients (7 forearms) with Masada type IIb deformity. The mean amount of ulnar lengthening was 4.2 ± 1.2 cm. The mean RAA improved from 37 ± 8 to 30 ± 7° initially (p = 0.005) and relapsed to 34 ± 8° at the last follow-up (p = 0.255). There was a minimal deterioration of US yet significant improvement at the last follow-up compared to pre-op (p < 0.001). At the last follow-up, the mean forearm pronation and elbow flexion increased significantly (p < 0.001 and p = 0.013, respectively), and the mean carrying angle also improved significantly (p < 0.001). No patient with type IIb deformity achieved a concentric radial head reduction. Conclusions Gradual ulnar lengthening significantly reduces cosmetic deformity and improves function in patients with Masada type I/IIb deformity. Our results supported early ulnar lengthening for patients with a tendency of dislocation of the radial head.

Objectives Hereditary multiple exostosis (HME) often involves forearm deformities. The aim of this study was to present the clinical results of 37 children who underwent ulnar lengthening with two different types of unilateral external fixators and to investigate the risk factors of complications. Methods We evaluated 37 children with forearm deformities caused by HME treated in our hospital from January 2008 to July 2019. The surgical procedures included resection of exostosis, osteotomy of the ulna, and gradual lengthening of the ulna with a unilateral external fixator. According to the type of fixator they received, the children were divided into two groups: group A received monorail fixators and group B received multi-joint fixators. Radiographic and functional parameters were assessed. Complications were recorded. Results All patients were followed-up for an average of 4.6 years (3.0 to 6.5). In both group A and group B, the ulna shortening (US), radial articular angle (RAA), carpal slip (CS), elbow flexion, forearm pronation, supination, and Mayo Elbow Performance Score (MEPS) values improved significantly from preoperatively to postoperatively (p < 0.05). However, the ulnar deviation was observed in 4 cases in group B and no cases in group A. According to logistic regression, the difference was only related to age (p < 0.05) and the type of external fixator (p < 0.05). Conclusions Ulnar lengthening with unilateral external fixation is a safe and effective procedure for the treatment of HME. Regarding complications, deviation of the ulna axis was more likely to occur in older children with multi-joint external fixators.

To detect variants of EXT1 and EXT2 genes among five pedigrees affected with multiple osteochondromas and provide prenatal diagnosis for the families based on the results.The EXT1 and EXT2 genes of the probands were analyzed by targeted next generation sequencing (NGS). Suspected pathological variants were validated by Sanger sequencing in the probands, their family members and 200 unrelated healthy controls. Multiple ligation-dependent probe amplification (MLPA) was used to confirm the presence of gross deletions. Prenatal diagnosis was provided for 2 couples carrying pathogenic or likely pathogenic variants.Five variants were detected in the pedigrees, which included EXT1 exon 2-3 deletion, c.1468dupC (p.Leu490ProfsX31), c.2084delC (p.Pro695LeufsX11), and EXT2 c.187delT (p.Phe63SerfsX29) and c.1362TG (p.Tyr454X). Among these, EXT1 exon 2-3 deletion, c.2084delC (p.Pro695LeufsX11) and EXT2 c.187delT (p.Phe63SerfsX29) were unreported previously. The three novel variants were not found among unaffected members of the pedigree and the 200 healthy controls. Upon prenatal diagnosis, the two fetuses were found to carry the same variants of the the probands.Pathological variants of the EXT1 and EXT2 genes probably underlie the multiple osteochondromas among the 5 pedigrees. Prenatal diagnosis based on the results can effectively reduce the birth of further offspring affected with the disease.

Background Hereditary multiple osteochondromas (HMO) is a genetic condition characterized by the presence of multiple osteochondromas, usually at the lateral side of the most active growth plate of a long bone. These lesions may persist, be asymptomatic during childhood, and may increase in number and size until growth plates close. Therefore, diagnosis of HMO in children and young people can be challenging; while short stature can be more evident at the onset of puberty, asymptomatic ostheocondromas can progress into different degrees of orthopedic deformity. Moreover, multiple complications may arise due to the presence of osteochondromas, including tendon and compression muscle pain, neurovascular disorders, obstetric problems, scoliosis and malignant transformation into secondary peripheral chondrosarcoma in adulthood. Case presentation We report the case of a girl admitted to our Institute for growth delay. While laboratory tests, including growth hormone stimulation test, were normal, left hand X-ray revealed multiple osteochondromas, suggestive for HMO. The genetic test for EXT1 and EXT2 genes confirmed the radiological diagnosis, with a mutation inherited from the mother who displayed the same radiological abnormalities along with recurrent limb pain episodes. Conclusions HMO is a genetic condition whose diagnosis can be challenging, especially in females. Every pediatricians should consider a skeletal dysplasia in case of unexplained growth delay and a skeletal survey might be fundamental in reaching a diagnosis.

WAGR 11p13 deletion syndrome is associated with abnormalities including (W) ilms tumor, (A) niridia, (G) enitourinary abnormalities, and growth and mental (R) etardation (WAGR). Potocki–Schaffer syndrome is a contiguous gene syndrome associated with deletions in 11p11.2, principal features of which are multiple exostoses, parietal foramina development delay, mental retardation, and facial dysmorphism. In some cases, males may have enlarged anterior fontanels and genital abnormalities. Each of these syndromes is very rare. Here we report a patient with both WAGR and Potocki–Shaffer syndromes who presented with aniridia, nystagmus, macular dysplasia, enlarged anterior fontanel, mental retardation, ptosis, low-set ears, micrognathia, and atrial septal defect at 6 months old. SNP array revealed a large (26.25 Mb)deletion: arr[hg19]11p15.1p11.2(18742043–44991839)× 1. Genetic testing allowed for diagnosis of this patient at a very young age. In addition to the postnatal phenotype of the patient, we found one prenatal symptom of these syndromes is oligohydramnios, which when present might indicate advanced prenatal diagnosis. This made the possibility of prenatal diagnosis for these syndromes.

BACKGROUND Ulnar lengthening is a consensus treatment for hereditary multiple exostoses with radial head dislocation in pediatric patients; however, the optimal amount of ulnar lengthening remains unclear. It is necessary to look for a parameter to decide the amount of ulnar lengthening that will avoid recurrence and complications. The purpose of the present study was to confirm that proportional ulnar length (ulnar length/radial length) can be used as a scale for ulnar lengthening in pediatric patients. METHODS The normal lengths of the ulna and radius in the pediatric population were measured in different age groups. The proportional ulnar length was calculated as ulnar length/radial length in each group. Thirty forearms in 26 patients with radial head dislocation were treated with ulnar lengthening and deformity correction. The goal of ulnar lengthening was to recover the normal proportional ulnar length. The function of the forearm was evaluated at the time of the latest follow-up. The preoperative and postoperative values for radial bowing, radioarticular angle, ulnar variance, and carpal slip were also compared. RESULTS The value of proportional ulnar length in the normal population consistently averaged approximately 1.1. In all cases, proportional ulnar length recovered to the normal value of 1.1. Reduction of the dislocated radial head was achieved in 28 forearms (93%); in 16 of these forearms, good-quality reduction was achieved and no recurrence of radial head dislocation was observed during follow-up. The function of the forearm improved markedly (p < 0.001). Ulnar variance improved from 2.51 to -0.79 cm (p < 0.001). Radial deformities improved according to measurements of radial bowing and the radioarticular angle (p < 0.001). All parents were satisfied with the postoperative appearance and function of the forearm. CONCLUSIONS Proportional ulnar length could be used as a scale to decide the amount of ulnar lengthening for radial head dislocation in pediatric patients with hereditary multiple exostoses. Ulnar lengthening according to proportional ulnar length and deformity correction can prevent recurrence of ulnar variance and avoid impingement of the wrist. LEVEL OF EVIDENCE Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Forearm deformities are often observed in patients with hereditary multiple osteochondroma, resulting in functional disability and cosmetic impairment. The aim of this study was to assess clinical and radiological outcomes after corrective osteotomy of the radius (COR). We performed a retrospective analysis of clinical and radiologic data from patients with forearm deformities who underwent COR combined with osteochondroma resection between 1978 and 2015. Seventeen patients (17 forearms) were included. The mean (range) age at surgery was 11.8 years (3.2-14.4), and the mean interval between surgery and last follow-up was 8.2 years (2-34.2). Range of motion was moderately increased and postoperative radiological assessments found significant improvements in ulnar variance, radial articular angle, bowing of the radius, and carpal slip. At last follow-up, a loss of ulnar variance correction was noted in 11 cases (mean loss: 4mm). The mean score on the Quick Disabilities of the Arm, Shoulder and Hand self-administered questionnaire was 13.9. Our results show that a forearm deformity in a patient with hereditary multiple osteochondroma is an appropriate indication for COR combined with osteochondroma resection and should be performed at the end of growth. This simple, safe technique corrects bowing of the radius and radius-ulna length discrepancy and could limit the risk of radial head dislocation. LEVEL OF EVIDENCE: IV.

Although the main causative genes for hereditary multiple exostoses (HME) are exostosin (EXT)‑1 and EXT‑2, there are numerous patients with HME without EXT‑1 and EXT‑2 mutations. The present study aimed to identify novel candidate genes for the development of HME in patients without EXT‑1 and EXT‑2 mutations. Whole‑exome sequencing was performed in a Chinese family with HME and without EXT‑1 and EXT‑2 mutations, followed by a combined bioinformatics pipeline including annotation and filtering processes to identify candidate variants. Candidate variants were then validated using Sanger sequencing. A total of 1,830 original variants were revealed to be heterozygous mutations in three patients with HME which were not present in healthy controls. Two mutations [c.C1849T in solute carrier family 20 member 2 (SLC20A2) and c.G506A in leucine zipper and EF‑hand containing transmembrane protein 1 (LETM1)] were identified as possible causative variants for HME through a bioinformatics filtering procedure and harmful prediction. Sanger sequencing results confirmed these two mutations in all patients with HME. A mutation in SLC20A2 (c.C1849T) led to a change in an amino acid (p.R617C), which may be involved in the development of HME by inducing metabolic disorders of phosphate and abnormal proliferation and differentiation in chondrocytes. In conclusion, the present study revealed two mutations [SLC20A2 (c.C1849T) and LETM1 (c.G506A) in a Chinese family with HME. The mutation in SLC20A2 (c.C1849T)] was more likely to be involved in the development of HME.

BACKGROUND Forearm deformity occurs in one third of patients with multiple hereditary exostoses (MHE). Conservative and surgical treatment are aimed at preventing radial head subluxation and/or dislocation. Dislocation has been associated with isolated distal ulnar lesions, radial bowing, and ulnar shortening. Risk factors for radial head subluxation have not been clearly elucidated. This study aimed to identify risk factors for all radial head instability in MHE, to optimize early detection and prevent frank dislocation. METHODS This multicenter retrospective case-control investigation included MHE patients with forearm lesions seen between 2000 and 2017 at 2 tertiary care children's hospitals. Demographic, clinical factors, radiographic measures, and surgical history were quantified. Comparisons were made between forearms that developed radial head instability versus those that remained stable and between those that progressed to radial head subluxation versus those that progressed to dislocation. RESULTS This study included 171 forearms in 113 patients with MHE, who presented at a mean age of 8.0 years with a median follow-up time of 6.0 years. Nine forearms progressed to radial head subluxation (mean age: 10.2 y), and 24 forearms had radial head dislocation (mean age: 9.9 y). Five subluxations and 3 dislocations occurred despite preventative surgery. Initial radial bowing (7.2% vs. 8.5%, P=0.04), ulnar variance (-5.8% vs. 11.0%, P

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.

Biallelic exostosin-2 (EXT2) pathogenic variants have been described as the cause of the Seizures-Scoliosis-Macrocephaly syndrome (OMIM 616682) characterized by intellectual disability, facial dysmorphisms and seizures. More recently, it has been proposed to rename this disorder with the acronym AREXT2 (autosomal recessive EXT2-related syndrome). Here, we report the third family affected by AREXT2 syndrome, harboring compound missense variants in EXT2, p.Asp227Asn, and p.Tyr608Cys. In addition, our patients developed multiple exostoses, which were not observed in the previously described families. AREXT2 syndrome can be considered as a multiorgan Congenital Disorder of Glycosylation caused by a significant, but non-lethal, decrease in EXT2 expression, thereby affecting the synthesis of the heparan sulfate proteoglycans, which is relevant in many physiological processes. Our finding expands the clinical and molecular spectrum of the AREXT2 syndrome and suggests a possible genotype/phenotype correlation in the development of the exostoses.

This study aimed to report the radiographic presentation of involved hips in children with hereditary multiple exostoses (HME). This included radiographic hip measurements, osteochondromas location, and relationship with hip subluxation.Anteroposterior pelvis radiographs of children with HME, seen between 2003 and 2014, were retrospectively reviewed. Only patients who were skeletally immature at the first visit were included. One radiograph per patient per year was reviewed. Radiographs were examined for the presence of osteochondromas and their locations. Different parameters were evaluated: femoral neck-shaft angle, Reimer migration percentage (MP), Sharp acetabular angle, Wiberg angle, femoral head-neck ratio (coronal plane), and Shenton line. All measured radiographs were divided into 3 age groups:≤8,8 and13, and ≥13 years. Differences of the measured parameters with age were evaluated. Children with hip subluxation were identified and any relationship with osteochondromas locations, as well as MP changes over time, was recorded. Radiographs of children with a minimum 2-year follow-up were identified and changes of their hip measurements and osteochondromas' presence over time were recorded.A total of 51 children (102 hips) with HME were identified. In most locations, there was an overall increase of the occurrence of osteochondromas in the older age groups. However, in the medial femoral neck, a significantly less numbers of osteochondromas were found after 13 years of age (P=0.018). There was a decrease in MP with age (P0.05). There was also an increase in Sharp and Wiberg angles in the older patients (P0.05). Hips with broken Shenton line decreased in number with age (P 0.028). Hip subluxation was encountered in 23 hips. No specific location of osteochondromas was found to have a relationship with subluxation. Thirty-six children had a minimum follow-up of 2 years (mean age at first visit 8.5 y and at last visit 13.1 y). In these children, an increased occurrence of lesions was found in medial femoral neck and ischium (P0.05) between the first and the last visit.In children with HME, radiographic evaluation of the hip is necessary based on the high percentage of hip involvement. When hip osteochondromas are found, radiographic surveillance is recommended to detect hip subluxation. Surgery may certainly be necessary for symptomatic osteochondromas. However, given the possibility of improvement in hip parameters with age, early surgical treatment to improve hip longevity does not seem to be warranted.Level IV-prognostic study.

Radial head dislocation in multiple osteochondroma leads to functional impairment and cosmetic problems, and surgical intervention has not been successful to date, with high rates of redislocation. Simple correction of the longitudinal axis and distraction oste8ogenesis of the ulna without corrective osteotomy of the radius were performed within 1 year of radial head dislocation. The mean age of the patients was 7.2 years and the postoperative follow-up duration was 63.6 months. In all cases, the dislocated radial head was repositioned without surgical invention involving the radius. All patients were pain free, with no impairment of daily activity, and all were satisfied with the cosmetic appearance, indicating successful medium-term postoperative outcomes for our surgical procedure.

Multiple hereditary exostoses (MHE) are a rare disorder characterized by the growth of bony protrusions. Elbow involvement is found in a considerable number of patients and varies from the presence of a simple osteochondroma to severe forearm deformities and radial head dislocation. Patients encounter a variety of symptoms, for example, pain, functional impairment, and cosmetic concerns. Several types of surgical procedures, therefore, can be offered, ranging from excision of symptomatic osteochondromas to challenging reconstructions. In this paper, we will discuss the essential basics of visualizing, planning, and treatment options of forearm deformities in MHE. In more detail, we will describe our current surgical technique as a salvage procedure for Masada type II forearm deformities in patients with MHE.

International audience; Acrodysostosis (MIM 101800) is a dominantly inherited condition associating (1) skeletal features (short stature, facial dysostosis, and brachydactyly with cone-shaped epiphyses), (2) resistance to hormones and (3) possible intellectual disability. Acroscyphodysplasia (MIM 250215) is characterized by growth retardation, brachydactyly, and knee epiphyses embedded in cup-shaped metaphyses. We and others have identified PDE4D or PRKAR1A variants in acrodysostosis; PDE4D variants have been reported in three cases of acroscyphodysplasia. Our study aimed at reviewing the clinical and molecular findings in a cohort of 27 acrodysostosis and 5 acroscyphodysplasia cases. Among the acrodysostosis cases, we identified 9 heterozygous de novo PRKAR1A variants and 11 heterozygous PDE4D variants. The 7 patients without variants presented with symptoms of acrodysostosis (brachydactyly and cone-shaped epiphyses), but none had the characteristic facial dysostosis. In the acroscyphodysplasia cases, we identified 2 PDE4D variants. For 2 of the 3 negative cases, medical records revealed early severe infection, which has been described in some reports of acroscyphodysplasia. Subdividing our series of acrodysostosis based on the disease-causing gene, we confirmed genotype-phenotype correlations. Hormone resistance was consistently observed in patients carrying PRKAR1A variants, whereas no hormone resistance was observed in 9 patients with PDE4D variants. All patients with PDE4D variants shared characteristic facial features (midface hypoplasia with nasal hypoplasia) and some degree of intellectual disability. Our findings of PDE4D variants in two cases of acroscyphodysplasia support that PDE4D may be responsible for this severe skeletal dysplasia. We eventually emphasize the importance of some specific assessments in the long-term follow up, including cardiovascular and thromboembolic risk factors.

The aim of this study is to evaluate the clinical, radiographic short-term results and complications after surgical hip dislocation in young patients (≤18 years). Clinical and radiographic outcomes were assessed in patients who underwent a surgical hip dislocation Ganz-type approach between 2008 and 2012. Diagnosis included Legg–Calve–Perthes disease, slipped capital femoral epiphysis, femoroacetabular impingement, osteonecrosis of the femoral head, multiple hereditary exostoses and pigmented villonodular synovitis. Clinical data, the modified Harris hip score, nonarthritic hip score, 12-item short form health survey, the Stulberg classification, morphometric indexes, signs of osteonecrosis and osteoarthrosis were used for the evaluation. After a mean 3 years follow-up (range 0.5–6 years), 53 hips (51 patients) were evaluated. The most common diagnoses were Legg–Calve–Perthes disease, slipped capital femoral epiphysis, femoroacetabular impingement and multiple hereditary exostoses. Mean age at surgery was 14 years (range 10–18 years). Through this approach femoral head-neck osteoplasty, Dunn-type osteotomy, labrum refixation, synovectomy, femoral head mosaicplasty open reduction and fixation for slipped capital femoral epiphysis were performed, finally in association with pelvic or intertrochanteric osteotomy. At follow-up, better outcome scores were obtained, progression of the osteonecrosis of the femoral head was observed in four cases and three further patients required the implant of a total hip prosthesis. After 3 years follow-up, results are comparable to previous studies and patients have a high rate of satisfaction, however the effectiveness of those procedures have to be proved on the long term. Results and complications seem to be related with preoperative lesion(s) and type of treatment. Level IV, retrospective study, case series.

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.

Multiple osteochondromas (MO) is an autosomal skeletal disease with an elusive molecular mechanism. To further elucidate the genetic mechanism of the disease a three-generation Chinese family with MO was observed and researched, and a novel frameshift mutation (c.335_336insA) in the exotosin 1 (EXT1) gene of one patient with MO was observed through exome sequencing. This was further validated by Sanger sequencing and comparison with 200 unrelated healthy controls. Immunohistochemistry and multiple sequence alignment were performed to determine the pathogenicity of the candidate mutation. Multiple sequence alignment suggested that codon 335 and 336 in the EXT1 gene were highly conserved regions in vertebrates. Immunohistochemistry revealed that EXT1 protein expression levels were decreased in a patient with MO and this mutation compared with a patient with MO who had no EXT1 mutation. Owing to the appearance of c.335_336insA in exon 1 of EXT1, a premature stop codon was introduced, resulting in truncated EXT1. As a result integrated and functional EXT1 was reduced. EXT1 is involved in the biosynthesis of heparan sulfate (HS), an essential molecule, and its dysfunction may lead to MO. The novel mutation of c.335_336insA in the EXT1 gene reported in the present study has enlarged the causal mutation spectrum of MO, and may assist genetic counseling and prenatal diagnosis of MO.

BACKGROUND Fibular shortening is one of the most common causes of ankle valgus deformity in children, and is frequently observed in patients with hereditary multiple exostoses (HME). It has been observed that the lateral distal tibial angle (LDTA) measured on the teleoradiograph differs from that on the ankle anteroposterior (AP) radiograph. The effect of the beam projection angle in the measurement of ankle valgus deformity associated with fibular shortening in HME patients was investigated. METHODS Fourteen ankles showing valgus deformity associated with fibular shortening from 14 HME patients comprised the short fibula group. Nineteen ankles with normal ankle alignment from 19 patients comprised the control group. The LDTA on the AP radiograph, teleoradiograph, and 3 coronal planes of 3-dimensional computed tomographic scans were measured and compared. RESULTS In the short fibula group, the LDTA measured on the ankle AP radiograph was significantly larger than that on the teleoradiograph (79.6±4.3 vs. 75.0±6.2 degrees, P=0.001), whereas there was no significant difference in the control group (P=0.36). In the short fibula group, the LDTAs measured on the 3 coronal planes of 3-dimensional computed tomography showed that the ankle valgus measurement significantly increased from anterior to posterior planes (P=0.001), whereas there was no significant difference in the control group (P=0.85). CONCLUSIONS Measurement of ankle valgus deformity depends on the direction of beam projection and ankle valgus deformity is more severe in the posterior coronal plane of the ankle joint. This discrepancy should be taken into consideration in the planning of ankle valgus deformity management. LEVEL OF EVIDENCE Level IV-diagnostic.

Background Multiple cartilaginous exostoses are a rare, benign, proliferative condition of cartilage and bone. They can be asymptomatic, or they may cause pain, lameness, paresis and even paralysis, depending on their location and size. In cases of spinal cord or nerve root compression, surgery is the treatment of choice. Therefore, an advanced imaging diagnostic work-up is indicated. Due to the unclear pathophysiology and progression of this condition, it is difficult to predict its prognosis. Case presentation A 9-month-old female Swiss Mountain dog was presented with a history of gait abnormalities, kyphosis and hypersensitivity consistent with a thoracolumbar myelopathy. Multiple calcified masses, most prominent at the Th7–Th9 level and the L2–L3 level, were observed. Magnetic resonance imaging of the thoracolumbar vertebral column revealed severe dorsal spinal cord compressions near the dorsal arch of the Th7–Th9 and L2–L3 vertebrae. Two of these masses were removed surgically. The successful removal of both masses was confirmed by postoperative computed tomography. The histopathological examination of the resected tissue revealed multiple cartilaginous exostoses. The first neurological and magnetic resonance follow up examination carried out 6 months postoperatively showed improvement of the clinical status. At that time, no mass regrowth was observed. The last follow up neurological examination carried out 15 months postoperatively showed gait improvement and resolution of pain. Conclusion This is the first case report of multiple cartilaginous exostoses with a complete pre- and postoperative evaluation and a 15 month follow-up.

To detect EXT1 and EXT2 gene mutations in two pedigrees affected with hereditary multiple exostosis (HME).The coding regions and exon/intron boundaries of the EXT1 and EXT2 genes were analyzed by targeted next-generation sequencing (NGS). Suspected mutations were confirmed by Sanger sequencing of the probands, their family members and 200 unrelated healthy controls. Gross deletion was confirmed by quantitative PCR (qPCR) analysis and multiple ligation-dependent probe amplification (MLPA) analysis.Two mutations were detected in the pedigrees, which included EXT2 gene c.337_338insG mutation in pedigree 1 and deletion of entire EXT1 in pedigree 2. Analysis of sequencing data revealed that a novel heterozygous mutation (c.337_338insG) in EXT2 gene in proband 1 and his father. The same mutation was not found among healthy family members and 200 unrelated healthy controls. As shown by NGS and MLPA analysis, proband 2 carried a heterozygous deletion of entire EXT1 gene. The same deletion was also found in her mother by qPCR.Mutations of the EXT1 and EXT2 genes probably underlie the HME in both pedigrees. NGS combined with Sanger sequencing, qPCR and MLPA is effective for attaining the diagnosis.