A Rare Case of Hereditary Multiple Exostoses in a Woman.

Hereditary multiple exostosis (HME) is a rare genetic disorder characterized by multiple bony spurs or lumps, commonly affecting the long bones. This case report exposes the clinical presentation, diagnosis, and management of HME in a 28-year-old female nurse, who initially presented with persistent bilateral knee pain. After extensive evaluation involving orthopaedic and oncology specialists, the diagnosis of HME was made. Despite the discovery of multiple exostoses, the patient reported improvement following a tailored physiotherapy regimen. This case study underscores the complexity and broad spectrum of symptoms associated with HME. It emphasizes the importance of a multidisciplinary approach in diagnosing and managing such conditions, which can lead to better patient outcomes and an improved quality of life. By shedding light on the role of physiotherapy in managing rare genetic disorders such as HME, this case report contributes to the growing body of literature exploring noninvasive treatment options for these diseases.

Imaging of solitary and multiple osteochondromas: From head to toe - A review.

Osteochondromas account for 20%-50% of all benign bone lesions. These tumors may present as solitary non-hereditary lesions, which are the most common presentation, or as multiple tumors associated with hereditary conditions. Plain radiography is the imaging method of choice and demonstrates the typical cortical and medullary continuity of the tumor with the underlying bone. Magnetic resonance imaging is often performed to evaluate cartilage cap thickness, which correlates with malignant transformation. Other local complications include compression of adjacent neurovascular bundles, muscles, and tendons, bursitis, tendon tears, stalk fracture, and angular or rotational long bone deformities. Although the imaging features of osteochondromas are largely known, only a few papers in the literature have focused on their main complications and image-based follow-up. This paper aimed to illustrate the main complications of osteochondromas, suggest an image-based algorithm for management and follow-up and discuss differential diagnosis.

Venous malformation may be a feature of EXT1-related hereditary multiple exostoses: A report of two unrelated probands.

Hereditary multiple exostoses (HME), also known as hereditary multiple osteochondroma (HMO), is an autosomal dominant disorder caused by pathogenic variants in exostosin-1 or -2 (EXT1 or EXT2). It is characterized by the formation of multiple benign growing osteochondromas (exostoses) that most commonly affect the long bones; however, it may also occur throughout the body. Although many of these lesions are clinically asymptomatic, some can lead to chronic pain and skeletal deformities and interfere with adjacent neurovascular structures. Here, we report two unrelated probands that presented with a clinical and molecular diagnosis of HME with venous malformation, a clinical feature not previously reported in individuals with HME.

Clinical and Genetic Analysis of Multiple Osteochondromas in A Cohort of Argentine Patients.

Multiple Osteochondromatosis (MO, MIM 133700 & 133701), an autosomal dominant O-glycosylation disorder (EXT1/EXT2-CDG), can be associated with a reduction in skeletal growth, bony deformity, restricted joint motion, shortened stature and pathogenic variants in two tumor suppressor genes, EXT1 and EXT2. In this work, we report a cross-sectional study including 35 index patients and 20 affected family members. Clinical phenotyping of all 55 affected cases was obtained, but genetic studies were performed only in 35 indexes. Of these, a total of 40% (n = 14) had a family history of MO. Clinical severity scores were class I in 34% (n:18), class II in 24.5% (n:13) and class III in 41.5% (n:22). Pathogenic variants were identified in 83% (29/35) probands. We detected 18 (62%) in EXT1 and 11 (38%) in EXT2. Patients with EXT1 variants showed a height z-score of 1.03 SD lower than those with EXT2 variants and greater clinical severity (II-III vs. I). Interestingly, three patients showed intellectual impairment, two patients showed a dual diagnosis, one Turner Syndrome and one hypochondroplasia. This study improves knowledge of MO, reporting new pathogenic variants and forwarding the worldwide collaboration necessary to promote the inclusion of patients into future biologically based therapeutics.

Clinical survey of a pedigree with hereditary multiple exostoses and identification of EXT­2 gene deletion mutation.

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 (EXT­2) gene. A patient with multiple exostoses with huge cartilage­capped tumors in scapula, knees and ankles received surgery in Department of Orthopedics (Shanghai Changhai Hospital). A total of 20 family members were recruited to the study, with seven members (five male; two female) diagnosed as HME. The family members of the patients with HME were examined, clinical data and peripheral blood samples were collected, and their DNA was sequenced. The incidence of HME in this family pedigree was 35%. Exostoses were most frequently in the tibiae with occurrence in six patients, followed by ribs, femurs, radii, fibulae, scapulae and humeri. DNA sequencing of peripheral blood revealed a novel deletion mutation, c.824­826delGCA, in exon 5 of the EXT­2 gene, which was observed in all the patients with HME, but not in the healthy family members. Several characteristics of HME in the pedigree were observed, such as susceptibility of male gender, decreased average age of onset and height and increased severity of clinical symptoms with generations.

Multiple Osteochondromas Comorbid With Enlarged Parietal Foramina, Elongated Styloid Processes, and Tibiofibular Synostosis.

OBJECTIVES: This study investigates a unique case of multiple osteochondromas (MO) comorbid with enlarged parietal foramina and correlates the findings with the existing literature. The aim of this study is to provide a deeper understanding of anatomic variation for physicians. METHODS: A 66-year-old White male donor was examined during a routine cadaveric dissection performed by medical students in an anatomy laboratory. Detailed exploration of the skeleton and organs was performed, and photographs were taken. Tissue samples were obtained from multiple outgrowths, and histopathologic examination was done. RESULTS: Bilateral bony growths were noted rising from the long bones of the upper and lower extremities (femur, tibia, fibula, and radius). An accessory muscle was found to be associated with the left radial bony growth. Histopathologic examination was positive for osteochondroma. Inspection of the skull revealed enlarged parietal foramina. Other findings included tibiofibular synostosis, abnormally shaped vertebral bodies and ribs, and elongated styloid processes of the skull. CONCLUSIONS: In combination with the histopathologic examination, the case report and literature review elucidate a more precise clinical picture for those affected with MO or similar disorders. This report also emphasizes the necessity of further investigation of the pathogenesis of MO and Potocki-Shaffer syndrome.

Peroneal Nerve Function Before and Following Surgical Excision of a Proximal Fibular Osteochondroma.

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<0.004) and postoperatively 5 (55.5%) had complete resolution, 3 (33.3%) had improvement, and 1 (11.1%) persisted requiring an ankle foot orthosis. Of the 22 who were normal preoperatively, 5 (22.7%) developed an immediate postoperative foot drop, 3 (60%) completely resolved, 1 (20%) improved, and 1 (20%) persisted and was found to have a transected nerve at exploration. In total, 23 of the 25 (92%) patients who had a PFO excision, had a normal or near-normal peroneal nerve function including those who had poor function preoperatively. CONCLUSIONS: Patients with a PFO have a preoperative peroneal nerve dysfunction 30% of the time and 23% of those who were normal preoperatively have postoperative dysfunction. Fortunately, nearly all patients have a complete recovery following excision of the osteochondroma. LEVEL OF EVIDENCE: Level IV.

Exostosis múltiple hereditaria presentación de caso / Multiple hereditary exostosis. Case report

RESUMEN La exostosis hereditaria múltiple es un trastorno autosómico dominante que se suele presentar en las dos primeras décadas de la vida. Caracterizada por el remodelado metafisaria alterado y crecimiento óseo asimétrico con acortamiento secundario de los huesos de las extremidades. Estas exostosis óseas rodeadas de cartílagos se hacen prominentes a las partes blandas, se diferencia de la enfermedad de Ollier en que esta última no es hereditaria. Se presentó el caso de una mujer de 36 años, que presentaba acortamiento de los miembros especialmente, cubito y radio, metacarpianos y metatarsianos. Su hijo de 18 años afectado también de dicha enfermedad presentaba una deformidad de Madelung asociada (acortamiento de cubito y radio con arqueamiento del radio) (AU).

ABSTRACT Multiple hereditary exostosis is an autosomal dominant disorder, usually found in the first two decades of life. It is characterized by the altered metaphyseal remodeling and asymmetric bone growth with a secondary shortening of extremities bones. These bone exostoses surrounded by cartilages become prominent to the soft parts, and are different from the Ollier disease because this last one is not hereditary. The authors present the case of a woman, aged 36 years, presenting a shortening of the members, especially ulna and radius, metacarpus and metatarsus. Her 18-years-old son was also affected by this disease, having an associated Madelug deformity (shortening of ulna and radius, and radius bowing) (AU).

An unusual diagnosis for an usual test.

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.

Identification of a 6-month-old baby with a combination of WAGR and Potocki-Shaffer contiguous deletion syndromes by SNP array testing.

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.

Surgical Management of Thoracic Multiple Exostoses.

Hereditary multiple exostoses is a rare autosomal dominant condition resulting in the development of multiple osteochondromas. We present the case of a 25-year-old woman with hereditary multiple exostoses who was referred for thoracic surgery assessment due to severe right-sided chest pain. Computed tomographic scan allowed preoperative planning for resection of the lesion. Under general anesthesia, right video-assisted thoracoscopic surgery was performed through a cosmetic retromammary incision. Complete removal of the tumor resolved symptoms, and she was discharged 2 days later. We show that video-assisted thoracoscopic surgery with a cosmetically placed muscle-sparing incision allowed accurate resection with faster recovery.

A rare association of pathological variant of Alport's syndrome caused by hemizygous 5' splice mutation in intron 10 of COL4A5 gene with metachondromatosis due to heterozygous missense variation in protein tyrosine phosphatase nonreceptor type 11 gene.

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

Multiple cartilaginous exostoses in a Swiss Mountain dog causing thoracolumbar compressive myelopathy.

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.

Identification of pathogenic mutations in 6 Chinese families with multiple exostoses by whole-exome sequencing and multiplex ligation-dependent probe amplification: Case series.

RATIONALE: Hereditary multiple exostoses (HMEs) is an autosomal dominant skeletal disorder. PATIENT CONCERNS: Six probands of the 6 unrelated Han Chinese families were identified as having HME. These patients had exostoses at multiple sites and significantly affected joints malformation and movement. DIAGNOSES: Hereditary multiple exostoses. INTERVENTIONS: To detect the genetic mechanism of HME in 6 unrelated Chinese families, whole-exome sequencing (WES) and multiplex ligation-dependent probe amplification (MLPA) were used after genomic DNA was isolated from peripheral blood leucocytes. Point mutations identified by these methods were verified by Sanger sequencing after PCR amplification. OUTCOMES: Six mutations in the EXT1 and EXT2 genes were identified, including a heterozygous deletion mutation from exon 2 to exon 8 (Family 1), a c.448C>T, p.(Gln150X) heterozygous nonsense mutation (Family 4), a c.1057-2A>T heterozygous splicing substitution (Family 5), and a c.1468dupC, p.(Leu490fs519X) (Family 6) heterozygous duplication mutation in the EXT1 gene in addition to a heterozygous deletion mutation from exon 2 to exon 3 (Family 2) and a c.1197C>G, p.(Tyr399X) heterozygous nonsense mutation (Family 3) in the EXT2 gene. LESSONS: Overall, we identified 5 novel mutations and 1 recurrent mutation in the EXT1 and EXT2 genes in 6 Chinese families with HME. Our findings expand the mutational spectrum of the EXT1 and EXT2 genes and are useful for genetic counseling and prenatal diagnosis.

Identification of risk factors affecting bone formation in gradual ulnar lengthening in children with hereditary multiple exostoses: A retrospective study.

The forearm deformity classified by Masada is a characteristic trait of patients with hereditary multiple exostoses (HME). Ulnar gradual lengthening, which was considered to be a safe and reliable procedure, was popular in treating these difficult deformities, however, delayed consolidation of the callus is uncommon but not rare in literature review. The purpose of this study was to try to identify the risk factors influencing bone healing in gradual ulnar lengthening in HME.We retrospectively reviewed patients with HME-induced forearm deformity who underwent gradual ulnar lengthening at our hospital from 2010 to 2016. Patients' demographic data, forearm deformity of Masada type, surgical procedure, ulnar diameter of osteotomy site, and external fixator type were recorded. We also reviewed radiographical data included gained length, axis deviation, callus form. Clinical outcome was assessed by the bone healing index (HI). Multiple linear regression was used to analyze the relationships between diffident parameters and the HI, the level of significance was set P <.05.Thirty-three patients were included in this study. The mean follow-up period was 1.5 (range 0.5-8) years. Circular external fixators were used in 5 patients and monolateral external fixators were used in 28 patients. The mean achieved length was 4.24 cm. The mean HI was 50.3 (range 26.6-99.3) days/cm. In patient with monolateral external fixator, patient's age was positively correlated with the bone HI (P = .001), while diameter and body mass index (BMI) were negatively correlated with the HI (P = .040, .018, respectively). Patient's sex, removal of distal ulnar exostoses, lengthening percentage, and axis deviation were non-significant in the regression model.When using monolateral external fixator for ulnar lengthening, patient's age, diameter of osteotomy site, and BMI are the most important risk factors related to bone formation. Pediatric orthopedic surgeons should consider these variables in order to avoid delayed union.

Is Routine Spine MRI Necessary in Skeletally Immature Patients With MHE? Identifying Patients at Risk for Spinal Osteochondromas.

BACKGROUND: Multiple hereditary exostoses (MHE) is an autosomal dominant condition leading to development of osteochondromas throughout the body. Although long bones are most often affected, spine involvement may occur and usually requires advanced imaging for diagnosis. However, the high cost of detection, infrequent occurrence, and very low likelihood of spinal cord compression and neurological injury, create a management conundrum. The purpose of our investigation is to identify patients at greatest risk for spinal lesions and refine indications for advanced imaging. METHODS: All MHE patients in a 24-year period were retrospectively reviewed. Skeletally immature patients with advanced imaging of the spine were further evaluated. The demographic characteristics, family history, clinical presentation, past surgical history, tumor burden, and distribution of patients with spinal lesions were compared with those without. RESULTS: In total, 227 MHE patients were identified and 21 underwent advanced spinal imaging. Spinal lesions were found in 8 of the 21 screened patients (38.1%, 3.5% overall), of which 4 were intracanal and 1 was symptomatic (4.8%, 0.4% overall). Only the symptomatic patient underwent excision of the spinal lesion. Patients with spinal lesions had higher tumor burden than those without (median, 28.5 vs. 19 locations; P=0.010). There was a significant association with rib (P=0.018) and pelvic (P=0.007) lesions, which may serve as "harbinger" lesions. The presence of both a rib and a pelvic lesion used as a screening tool for spinal lesions produces a sensitivity of 100% and specificity of 69%. CONCLUSIONS: Symptomatic spinal involvement in children with MHE is rare and tends to occur in patients with higher tumor burden. We recommend limiting advanced spine imaging to children with neurological symptoms or with rib and pelvic "harbinger" lesions. Patients without these findings are unlikely to have spine involvement needing intervention. This approach offers an opportunity to avoid unnecessary testing and substantially reduce costs of diagnostic imaging. LEVEL OF EVIDENCE: Level III.

The role of EXT1 gene mutation and its high expression of calcitonin gene-related peptide in the development of multiple exostosis.

OBJECTIVE: Screening and identifying the gene mutation of EXT1, EXT2 and EXT3 associated with multiple exostosis (ME) and the expression in tumor tissues. METHODS: Nine patients with multiple exostosis were collected and genomic DNA was extracted. Polymerase chain reaction (PCR) amplification and direct sequencing techniques were used to screen all exons, 5' and 3' ends of the EXT1, EXT2 and EXT3 related causative genes. EXT1, EXT2 and EXT3 gene were screened and quantified by RNA-SEQ and RT-qPCR. The concentration of calcitonin gene-related peptide (CGRP) in peripheral blood of tumor patients and normal controls was detected by ELISA. RESULTS: Between the two patients with ME, the EXT1 gene was found in one patient to have c.79 T>A mutation, which caused the change of p.M27T, the non polar methionine was replaced by the high frequency mutation of polar threonine, and the rest of patients was found the splicing mutation c.1284 + 8 delAT of the heterozygosity of the EXT1 gene. The serum CGRP concentration of ME patients (623 + 49 pg/ml) was significantly higher than that of normal controls (196 + 68 pg/ml), and EXT1 mutation patients were also higher than non mutation patients.