Hereditary Multiple Osteochondromas Research Articles

Is total-body MRI useful as a screening tool to rule out malignant progression in patients with multiple osteochondromas? Results in a single-center cohort of 319 adult patients.

To evaluate the results of total-body (TB) MRI used as a screening tool for assessment or exclusion of malignant transformation in patients with hereditary multiple osteochondromas (HMO). In a single-institute cohort of MO patients, 366 TB-MRI examinations, including T1-weighted and STIR images, were performed for screening and follow-up purposes to rule out the malignant transformation, and retrospectively analyzed. In each patient, the presence and location of osteochondromas in the axial and appendicular bones were recorded. Forty-seven patients underwent a second TB surveillance in this period. STIR sequences were used to identify sites of increased signal intensity that could represent suspicious thickened cartilage caps or indeterminate reactive changes related to osteochondromas. In 82% of patients, one or more OC locations were determined in one or more flat bones. In 366 exams, nine OC (2,5 %) with suspicious imaging features were identified. These proved to be peripheral chondrosarcomas after targeted MRI and resection were performed. All nine malignant lesions were in flat bones (pelvis 5, ribs 3, scapula 1). Three of these patients were 19 years of age. In 12 patients who had peripheral or intraosseous low-grade chondrosarcoma in their history, before their first TB-MRI, no new lesions were identified. Twenty-three additional TB-MRI exams, demonstrating focal high T2 signal intensity, also gave rise to performing additional targeted MRI. One OC of the distal femur was excised and appeared benign. No suspicious cartilage caps were depicted on the remaining 22 targeted MRI exams but instead increased T2 signal was clarified by reactive changes (frictional bursitis, soft tissue edema) in close relation with benign osteochondromas. No malignant lesions were found in 47 patients who had a second TB surveillance (mean interval between exams 3.2 years, range 2-5 years). TB-MRI can identify malignant transformation of osteochondromas in HMO patients. All peripheral chondrosarcomas occurred in flat bones (ribs, scapula, pelvis) in our study. TB-MRI might assist in triage between higher risk patients with a high burden of OC, including the location of OC in main flat bones vs lower risk patients without OC of the flat bones.

Phenotypic and Molecular Spectrum of a Turkish Cohort with Hereditary Multiple Osteochondromas.

Hereditary multiple osteochondromas is an autosomal dominant disorder caused by heterozygous pathogenic variants in EXT1 or EXT2. We aimed to evaluate the clinical and molecular findings of a Turkish cohort with hereditary multiple osteochondroma. Thirty-two patients aged 1.3-49.6 years from 22 families were enrolled. Genetic analyses were made by EXT1 and/or EXT2 sequencing and chromosomal microarray analyses. We found 17 intragenic pathogenic variants in EXT1 (13/17) and EXT2 (4/17), 12 of which are novel. Four probands had EXT1 deletions, including 2 patients with partial EXT1 microdeletions involving exons 2-11 and 5-11, and 2 patients with whole-gene deletions. In 21 variants, the frequency of truncating and missense variants was 76.1% and 23.8%, respectively. Two families had no detectable variants in EXT1 and EXT2. All patients had multiple osteochondromas at the long bones, mainly at the tibia, forearm, femur, and humerus. Bowing deformity of the forearms (9/32) and the lower extremities (2/32), and scoliosis (6/32) were observed. The clinical severity was not different between patients with EXT1 or EXT2 variants. One patient with an EXT2 variant and another with an EXT1 microdeletion had the most severe phenotype with class III disease. Four patients with no EXT1 or EXT2 variants had milder phenotypes. Intrafamilial variability in disease severity was not observed. We report a hereditary multiple osteochondroma cohort with clinical and molecular data including 12 novel intragenic variants in EXT1 or EXT2, and 4 microdeletions involving EXT1. Taken together, our data expand the existing knowledge of the phenotype-genotype spectrum in hereditary multiple osteochondroma.

Modified gradual ulnar lengthening for treatment of Masada type IIb forearm deformity in children with hereditary multiple osteochondromas.

To investigate the effect of modified gradual ulnar lengthening in the treatment of Masada type IIb forearm deformity in children with hereditary multiple osteochondromas (HMO). From May 2015 to October 2020, 12 children with Masada type IIb forearm deformity caused by HMO underwent modified gradual ulnar lengthening in our hospital. Clinical and imaging data were retrospectively analyzed. Clinical evaluation included wrist flexion and extension, wrist ulnar and radial deviation, forearm pronation and supination, and elbow range of motion. The radiographic parameters measured included the radial articular angle, carpal slip, and relative ulnar shortening. The mean operative age of the 12 patients (9 male, 3 female) was 8.5 ± 2.7 years, the mean follow-up was 31.5 ± 5.7 months, and the mean ulnar lengthening was 43.3 ± 9.9 mm. There was no significant difference in the radial articular angle between the preoperative period and the last follow-up (from 36.5° ± 9.2° to 33.8° ± 5.1°, p > 0.05). However, significant changes were found in carpal slip (from 61.3% ± 18.8% to 33.8% ± 20.8%) and relative ulnar shortening (from 5.8 ± 3.5 mm to -0.9 ± 4.85 mm) (p < 0.05). The range of motion significantly improved after modified gradual ulnar lengthening, including wrist flexion (from 38.3° ± 6.2° to 55.8° ± 9.0°), wrist extension (from 45.0° ± 9.8° to 61.7° ± 8.1°), wrist ulnar deviation (from 41.3° ± 8.6° to 29.6° ± 7.8°), wrist radial deviation (from 18.3° ± 6.2° to 30.0° ± 5.6°), forearm pronation (from 44.6° ± 7.2° to 62.1° ± 8.6°), forearm supination (from 50.0° ± 7.1° to 52.9° ± 6.6°), and elbow range of motion (from 117.1° ± 10.1° to 127.9° ± 5.4°) (all p < 0.05). During follow-up, there was one case of needle tract infection and one case of bone nonunion. Modified gradual ulnar lengthening can effectively treat Masada type IIb forearm deformity caused by HMO and improve forearm function.

Chondrosarcoma in a Patient with Multiple Osteochondromatosis: A Case Report and Review of the Literature

Hereditary multiple osteochondromas (HMO) is an autosomal dominant disease diagnosed by the presence of two or more than two osteochondromas on radiographs. The majority of cases are asymptomatic. The presence of bony growth, pain, and compression of the surrounding structure are the usual presentations. Malignant transformation into chondrosarcoma is the most feared complication. A rapid increase in size, recurrence after the surgical excision, and infiltrating mass may suggest the conversion into chondrosarcoma. Radiological imaging helps in diagnosing malignant transformation. MRI is the investigation of choice to exclude cancer. We here by present a case of multiple osteochondromas with suspected malignant transformation due to rapidly increasing painful osseous swelling.

Radiographic evaluation of ulnar deformity in patients with hereditary multiple osteochondroma and its relationship with radial head dislocation

IntroductionIn patients who have hereditary multiple osteochondroma (HMO), progressive deformity of the forearm skeleton may lead to radial head dislocation. The latter is permanent, painful and causes weakness. HypothesisThere is a relationship between the amount of ulnar deformity and the presence of radial head dislocation in patients with HMO. Materials and methodsThis was a cross-sectional radiographic study comprising an analysis of anterior-posterior (AP) and lateral x-rays of 110 forearms in children having a mean age of 8 years and 4 months who were followed for HMO between 1961 and 2014. Four factors reflecting on the ulnar deformity in the coronal plane were investigated on the AP view and three factors in the sagittal plane were investigated on the lateral view to identify any relationship between ulnar deformity and radial head dislocation. The forearms were separated into two groups: with radial head dislocation (26 cases) and without radial head dislocation (84 cases). ResultsUlnar bowing, intramedullary angle of ulnar bowing, tangent ulnar angle and overall ulnar angle were significantly higher in the group of children who had a radial head dislocation (0.05 vs 0.03, p<.001; 161 vs 167, p<001; 156 vs 162, p<001; 50 vs 30, p<.001) in univariate and multivariate analyses. DiscussionUlnar deformity, evaluated using the method described here, is more often associated with radial head dislocation than other previously published radiological parameters. This provides new insight on this phenomenon and may help to determine which factors are associated with radial head dislocation and how to prevent it. ConclusionUlnar bowing in the context of HMO, especially when evaluated on AP radiographs, is significantly associated with radial head dislocation. Level of evidenceIII; case-control study.

A Unique Case of Hereditary Multiple Osteochondromas in the Feet

This report describes the differential diagnosis of osseous growths in the first metatarsals of an adult male previously unreported in the literature. Examination of the remains via macroscopic analysis and conventional radiography identified unusual bilateral growths arising from the lateral aspects of the first metatarsals with growth directed towards the tarsometatarsal joint. Two exostoses in the ribs were also observed. Using the available evidence, hereditary multiple osteochondromas (HMO) was determined the likely causative disorder for the pedal growths based on the presence of cartilage caps on the ends of the growths, a lack of articular morphology, and the presence of a rib exostosis consistent with HMO. The potential bilateral expression of HMO in the first metatarsals in this case challenges the dominating diagnostic criteria that HMO growths are directed away from the growth plate and only occur in the metaphysis, expanding the spectrum of HMO’s manifestation in the human skeleton. Medical records for the decedent provided no indication of a disorder associated with the development of osteochondromas, nor any indication that medical treatment was undertaken to manage the growths.

NCMP-15. A CASE OF SYSTEMIC METASTATIC DIFFUSE LEPTOMENINGEAL GLIONEURAL TUMOR

Abstract INTRODUCTION Diffuse leptomeningeal glioneural tumor (DLGT) is a very rare central nervous tumor that has no standard of care for its treatment. This report illustrates a case of DLGT with a unique presentation and a first description of multiple systemic metastasis. Case: 19 year-old male with personal history of hereditary multiple osteochondromas and recent covid-19 infection who on investigation of headaches, progressive cranio-neuropathies, and right-sided weakness was found to have vasospasms resulting in acute infarcts in multiple vascular areas, and diffuse leptomeningeal enhancement in the thoracic spine and cauda equina. Patient underwent meningeal biopsy, after 2 months of first symptoms, which revealed DLGT per two different neuro-oncology centers. Course of disease was complicated with hydrocephalus needing shunt placement soon after diagnosis. Craniospinal radiation concurrent with temozolomide was started one month from diagnosis. Patient developed pancytopenia and chemotherapy was stop in the first weeks during radiation therapy. Metastatic disease to bone marrow was diagnosed in the second adjuvant temozolomide cycle through biopsy. One week after, on investigation of pleural effusion, lung metastasis were discovered on pleural cytology and thoracic computer tomography. Liquid biopsy showed non-actionable mutations on PIK3CA, BRAF and KRAS. Chemotherapy with carboplatin and vincristine was started with markedly improvement of pancytopenia and pleural effusions leading to cessation of frequent transfusions and auxiliary oxygen. Vincristine dose was decreased due to painful neuropathy and tinnitus. At the end of endovenous chemotherapy, worsening of disease was found with metastasis to muscles of the face and brain parenchyma. Patient was then enrolled in hospice, dying weeks after. CONCLUSION DLGT should be considered in the differential diagnosis of vasospasm. DLGT is a primary central nervous system that can metastasize to other organs. Although no standard of care is yet identified, chemotherapy with vincristine and carboplatin can be offered to systemic metastatic disease.

Reliability of the Masada Classification for Forearm Involvement in Patients With Hereditary Multiple Osteochondromas (HMO).

Classifications describing forearm lesions in patients with Hereditary Multiple Osteochondromatosis (HMO) have been used to recommend surgical intervention and stratify outcomes; however, there is no consensus on which classification offers greater reliability. The purpose of this study was to determine the reliability of the Masada classification and newer classifications among pediatric hand surgeons. One hundred one patients with HMO between June 2014 and October 2019 were enrolled in the Congenital Upper Limb Differences (CoULD) Registry. Of those, 67 patients with 101 forearms were included. Four pediatric hand surgeons from the CoULD study group undertook an online evaluation. Each rater classified radiographs according to the Masada classification. Six weeks later, raters were asked to reclassify images according to the Masada, Gottschalk, and Jo classifications. Rater agreement for these classifications was assessed by estimating Fleiss kappa along with a 95% CI. Interrater agreement for Masada classification after the first reading was poor (κ=0.35; 95% CI=0.30-0.41) across all raters. Interrater agreement across the 4 raters decreased for the Masada classification from the first to the second reading (κ=0.35 vs 0.21; P <0.001). Intrarater agreement for the Masada classification ranged from 0.32 to 0.63 from the first to the second study reading. Gottschalk and Jo classifications yielded significantly better interrater agreement compared with Masada (κ=0.43 vs 0.21; P <0.001). Unclassifiable cases were highest in the Masada classification (34% to 44%) and lower in the Jo (17%) and Gottschalk (14%) classifications. Despite wide use, the Masada classification was found to have low reliability when classifying forearm deformities in HMO. Gottschalk offered more options for location, yet lacked deformity description including radial head dislocation. Jo classification offered more locations than Masada and incorporated radial head dislocation in some patterns. Based on the shortcomings in all 3 classification systems, the development of a more inclusive and reliable classification is warranted. Level II; Diagnostic.

RF30 | PSAT134 Autosomal Dominant Hereditary Multiple Osteochondromas Misdiagnosed As Paget's Disease of Bone

Abstract Background Autosomal dominant hereditary multiple osteochondromas is a rare genetic disorder with variable clinical manifestations. We present the case of a patient misdiagnosed with Paget's disease of bone found to have hereditary multiple osteochondromas. Clinical Case We present a 55-year-old male with history of chronic back and hip pain who presented to endocrinology clinic for evaluation of Paget's disease of bone. He was diagnosed with Paget's disease at age 16 after a bike accident resulting in knee pain where a "knot" was removed from his knee. He reported multiple "knots" in bones throughout adulthood but never sought treatment. He had history of elevated alkaline phosphatase on prior chemistries. He developed debilitating back, hip, and thigh pain resulting in immobility and suffered vertebral osteomyelitis from MRSA requiring laminectomy at age 52. On physical exam, massive maxillary and mandibular tori were noted along with bilateral cataracts and decreased muscle strength in upper and lower extremities. He underwent evaluation by oral surgery for extensive tooth decay and was recommended for extraction of teeth #12, 14, 15, and 17 with restorative needs for teeth #2, 4, 5, 13, 28, 30, 32. Labs notable for serum calcium 10.1 (ref: 8.4-10.5 mg/dl), phosphorus 4.2 (ref: 2.3-4.7 mg/dl), magnesium 1.8 (ref: 1.6-2.6mg/dl), PTH 34 (ref: 16-77 pg/ml), 25-OH Vit D 28 (ref: 25-80 ng/ml), 1,25 dihydroxyvitamin D 45.9 (ref: 19.9-79.3pg/ml), alkaline phosphatase 199 (ref: 40-150 unit/L), bone-specific alkaline phosphatase 52.5 (ref: 6.5 - 20.1 mcg/L). 24-hr urine calcium 0.06 g/24hr (ref: 0.04-0.35) from an 850ml urine volume. Procollagen type 1 n-terminal propeptide 179 (ref 22-105 UG/L). Prior MRI right hip showed "abnormal appearance of pelvic bony ring and proximal femurs with heterogenous marrow signal and cortical thickening suspicious for Paget's disease", as well as a 1.2cm circumscribed cystic focus within proximal right femoral diaphysis. Prior bone scan demonstrated diffusely uptake in pelvis, uptake in proximal right femur, focally intense uptake in L5 vertebrae. Plain film imaging demonstrated severe diffuse degenerative changes in cervical, thoracic and lumbar vertebrae and sessile osteochondromas arising from both scapulae, mild thoracic levoscoliosis. Genetic testing demonstrated loss-of-function mutation in the EXT-1 gene, diagnostic of hereditary multiple osteochondromas. Currently, there are no FDA-approved treatments for osteochondromas though studies involving biologic therapy are ongoing. This patient was referred to orthopedic oncology and OMFS for dental extraction and decision for conservative treatment with observation. Conclusion This case demonstrates how the rare entity of hereditary multiple osteochondromas can have variable clinical presentations leading to its misdiagnosis and highlights the need for ongoing research into non-surgical treatment options. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Monday, June 13, 2022 12:36 p.m. - 12:41 p.m.

A RARE CASE OF HEREDITARY MULTIPLE EXOSTOSES

Background: A rare genetic condition, hereditary multiple exostoses (HME), follows the autosomal dominant pattern of inheritance. It is evident by multiple bony elevations on the appendicular skeleton by the age of 2 years. Case Report: Here, we present the 42-years-old patient known case of CKD presenting with uncontrolled hypertension and breathlessness; however, incidentally, it was noted that there is bilateral swelling in the knee and further investigated for X-ray and blood parameters. On assessing the similar pattern in family members, it was noted such swelling over the shoulder in the daughter and swelling in the wrist joint in the younger brother. Conclusion: Hereditary multiple osteochondromas are a hereditary ailment that should be studied. Despite tremendous advances in recent years, the intricacy and unresolved difficulties associated with HME remain a challenge for academics and physicians.

A Case Report of Hereditary Multiple Exostoses

Hereditary multiple exostoses (HME), also known as hereditary multiple osteochondromas, is a rare autosomal dominant genetic disorder featuring multiple exostoses (osteochondromas) mostly diagnosed in childhood, they arise near the growth plates of bones such as ribs, pelvis, vertebrae and predominantly long bones. CT and MRI imaging are required to examine anatomically difficult regions such as the pelvis and thorax, and X-rays are additionally helpful in finding associated deformities. In this article and through a case report, we mainly outline the input of imaging in the diagnosis, prognosis and therapeutic management of such condition

Surgical outcomes of spinal osteochondroma in children: A multicentre observational study

BackgroundSpinal osteochondroma (or exostosis) is a rare benign tumour whose clinical manifestations are delayed due to their slow growth and location. Few studies have addressed the characteristics and the diagnostic and therapeutic peculiarities of spinal osteochondroma in children. The objective of this multicentre observational study was to assess the outcomes of a cohort of children after surgery for spinal osteochondroma. HypothesisSurgical excision of spinal osteochondroma in children is not followed by complications or recurrences. Material and MethodsWe included consecutive children who had surgery between 2010 and 2018 at any of eight participating centres to remove spinal osteochondromas. The cause, clinical manifestations, and location of the lesions were collected. The surgical outcomes were evaluated after at least 2 years’ follow-up. ResultsWe identified 22 patients who had surgery to remove 26 spinal osteochondromas at a mean age of 12.8±2.6 years. Among them, 7 had a solitary osteochondroma (SO group) and 15 had hereditary multiple osteochondromas (HMO group). At diagnosis, 72% of patients had clinical signs (spinal pain, n=4; one or more lumps, n=5; and neurological manifestations, n=3). In the HMO group, the diagnosis was made during routine MRI screening for tumours involving the spinal canal. Most osteochondromas involved the cervical spine (n=13), with no difference between the two groups (p=0.9). The lamina was the most common location but 54% of the tumours were growing within the canal (92% in the HMO group). After a mean follow-up of 5.2±4.4 years, no patients had experienced any recurrences or complications related to the disease or treatment. DiscussionSurgical excision of spinal osteochondromas in children is effective, with no medium-term recurrences. Our results also confirm the low peri-operative morbidity, even when the canal is involved, and the absence of any effect at last follow-up on spinal alignment. All patients with neurological manifestations at diagnosis made a full recovery. Level of evidenceIV, retrospective observational cohort study.

Proximal clavicular osteochondroma: A report of an unusual site

Osteochondromas are benign surface tumors that comprise a large sum of all bone tumors. They can present as solitary lesions or part of a collective such as in hereditary multiple osteochondromas (HMO). Generally, they are asymptomatic but can present in some cases with complications such as pain, Horner syndrome, plexopathy, tendinopathy, and even erosion into adjacent structures. We present one case of clavicular osteochondroma that presented in our clinic and was treated surgically and later confirmed using histopathology. The patient's health record was reviewed for the following: demographics, visits, imaging modalities, management, outcome, and histopathology. Our 14-year-old patient had X-rays and ultrasound studies done, revealing characteristics of osteochondroma of the clavicle. The size of the lesion and resulting cosmetic deformity warranted surgical intervention. Osteotomy was done and the specimen was sent to histopathology which confirmed the prior suspicion of osteochondroma. Osteochondromas are mostly benign and asymptomatic but can develop serious complications. Thus, early detection and diligent observation, especially in young patients, are essential to prevent degeneration or complications.

PREVALENCE OF POTENTIAL MRI-BASED EXCLUSIONARY FINDINGS IN OSTEOARTHRITIS CLINICAL TRIALS: DATA FROM THE OSTEOARTHRITIS INITIATIVE (OAI)

PREVALENCE OF POTENTIAL MRI-BASED EXCLUSIONARY FINDINGS IN OSTEOARTHRITIS CLINICAL TRIALS: DATA FROM THE OSTEOARTHRITIS INITIATIVE (OAI)

Modified osteotomy for treatment of forearm deformities (Masada IIb) in hereditary multiple osteochondromas: a retrospective review

PurposeApproximately 30% of patients with hereditary multiple osteochondromas (HMO) have forearm deformity and dysfunction. The aim of this retrospective study was to review our experience with the surgical treatment of children with HMO and Masada IIb forearm deformities.MethodsData of eight children treated for HMO Masada IIb forearm deformity at our hospital between 2015 and 2019 were collected from the hospital records and retrospectively reviewed. All patients underwent ulnar lengthening by distraction osteogenesis using either the Orthofix or Ilizarov external fixator. Range of movements at the elbow and wrist joints, and forearm supination/pronation, before and after the operation were recorded. Radiographs were evaluated by the Fogel method, and wrist joint function by the Krimmer method.ResultsFollow-up radiographs showed significant improvement in relative ulnar shortening after treatment (pre-operative 9.23 ± 5.21 mm; post-operative 0.33 ± 4.13 mm). Changes in radial articular angle (pre-operative 33.55° ± 3.88° to 32.78° ± 6.57°) and carpal slip (pre-operative 45.00% ± 19.09%; post-operative 43.13% ± 16.68%) were not significant. Elbow flexion and extension, wrist flexion and extension, ulnar and radial deviation at wrist, and forearm rotation were significantly improved after surgery. Wrist function was graded as excellent in seven patients and as good in one patient. One patient treated with the Ilizarov external fixator had poor radial head reduction.ConclusionUlnar lengthening with distraction osteogenesis is an effective treatment for HMO Masada IIb deformities. The optimum site for ulnar osteotomy appears to be at the proximal one-third to one-fourth of the ulna.

Mutational Analysis of EXT1in a Chinese Family Affected by Hereditary Multiple Osteochondroma.

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.

Hereditary Multiple Osteochondroma with Incomplete Penetrance in a Lebanese Family: A Case Report

Background: Hereditary multiple osteochondroma (HMO) is a rare autosomal dominant disease with high penetrance reaching 95 to 100%. It manifests during childhood in most of the times. The spectrum of the disease is wide. It is classified into 2 types depending on the number of cases and the penetrance in the same generation. The most feared complication of this disease is the malignant transformation. Establishing a screening protocol requires the identification of the true prevalence and penetrance of the disease. Case Report: A 17-year-old girl presented with multiple painful lesions in the lower extremities. Physical examination of the patient and her siblings allowed the diagnosis of HMO with incomplete penetrance, and the construction of a pedigree of the family. Surgical treatment was sufficient to control the patient’s symptoms. Conclusion: Being the first case in Lebanon, this report adds more awareness about this rare disease. By increasing awareness, this report can have an impact on the transmission and the number of affected cases in the country. Furthermore, these data, when added to the available evidence worldwide, can be used in the determination of true penetrance of the disease, and the creation of accurate classification and screening protocol.

Analysis of genetic variants in a pedigree affected with hereditary multiple osteochondroma

To explore the genetic basis for a pedigree affected with hereditary multiple osteochondroma (HMO). Peripheral blood samples were collected from the proband and members of his pedigree with informed consent. Following extraction of genomic DNA, all coding exons and flanking intronic sequences (-10 bp) of the EXT1 and EXT2 genes were subjected to targeted capture and next generation sequencing (NGS). Suspected variant was verified by Sanger sequencing. A heterozygous nonsense variant (c.1911C>A) was found in exon 10 of the EXT1 gene in the proband and his affected father but not in a healthy sister and normal controls. The variant was classified as a pathogenic based on the guidelines of the American College of Medical Genetics and Genomics (PVS1+PM2+PP1). Bioinformatic analysis predicted that the c.1911C>A variant may be disease-causing via nonsense-mediated mRNA decay and anomalous splicing. The c.1911C>A variant probably underlay the disease in this pedigree. Discovery of this variant enriched the variant spectrum of HMO.

Identification of Novel Mutations in the EXT1 and EXT2 Genes of Chinese Patients with Hereditary Multiple Osteochondromas

Aim: To detect mutations in the EXT1 and EXT2 genes in four Chinese families with hereditary multiple osteochondromas (HMO). HMO is an autosomal dominant disorder characterized by the overgrowth of multiple cartilage-capped bones in the metaphysis of long bones and flat bones. Methods: Polymerase chain reaction-based amplification followed by DNA sequencing of the complete coding sequences of EXT1 and EXT2 was performed for four Chinese families with HMO. Results: The mutant allele was found in six patients: three mutations were found in EXT1 and two in EXT2. A novel frameshift mutation, which generates a premature stop codon at codon 586 and causes partial loss of the glycosyltransferase domain, was detected in exon 9 of EXT1 (F579Yfs*8). We hypothesize that F579Yfs*8 is a pathogenic mutation. Two novel missense mutations (G339S and V545D) were found in EXT1. The variant c.1634T>A (V545D) is apparently benign. In addition we found a novel deletion mutation in EXT2, c.856_864 del TTCCTCCTG, which results in the deletion of 286Phe, 287Leu, and 288Leu, that is likely pathogenic. Finally, we identified a likely benign variant in exon 13 of EXT2. c.2035-41T>C (rs3740878). Conclusions: We found three novel, potentially pathogenic mutations in EXT1 and EXT2, including a novel frameshift mutation. More importantly, our study results have expanded the spectrum of EXT mutations conducive to the genetic diagnosis and counseling of patients with HMO.

Hereditary multiple osteochondromas in Jordanian patients: Mutational and immunohistochemical analysis of EXT1 and EXT2 genes.

The aim of the present study was to investigate the molecular characteristics of hereditary multiple osteochondromas (HMO) in a subset of Jordanian patients with a focus on the genetic variants of exostosin (EXT1)/(EXT2) and their protein expression. Patients with HMO and their family members were included. Recorded clinical characteristics included age, sex, tumors number and location, joint deformities and associated functional limitations. Mutational analysis of EXT1 and EXT2 exonic regions was performed. Immunohistochemical staining for EXT1 and EXT2 was performed manually using two different commercially available rabbit anti-human EXT1 and EXT2 antibodies. A total of 16 patients with HMO from nine unrelated families were included, with a mean age of 13.9 years. A total of 75% (12/16) of the patients were male and (69%) (11/16) had a mild disease (class I). EXT mutation analysis revealed only EXT1 gene mutations in 13 patients. Seven variants were detected, among which three were novel: c.1019G>A, p. (Arg340His), c.962+1G>A and c.1469del, p. (Leu490Argfs*9). Of the 16 patients, 3 did not harbor any mutations for either EXT1 or EXT2. Immunohistochemical examination revealed decreased expression of EXT1 protein in all patients with EXT1 mutation. Surprisingly, EXT2 protein was not detected in these patients, although none had EXT2 mutations. The majority of Jordanian patients with HMO, who may represent an ethnic group that is infrequently investigated, were males and had a mild clinical disease course; whereas most patients with EXT1 gene mutations were not necessarily associated with a severe clinical disease course. The role of EXT2 gene remains a subject of debate, since patients with EXT1 mutations alone did not express the non-mutated EXT2 gene.