The Impact of Isolated Versus Multiple Osteochondromas: Analysis of the CoULD Registry.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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 OF EVIDENCE: Level II-prognostic.

Radial osteotomy for the correction of forearm deformities in hereditary multiple osteochondroma.

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.

Stüve-Wiedemann syndrome: recurrent neonatal infections caused by impairment of JAK/STAT 3 pathway.

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.

Novel exostosin-2 missense variants in a family with autosomal recessive exostosin-2-related syndrome: further evidences on the phenotype.

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.

SHP2 Regulates the Osteogenic Fate of Growth Plate Hypertrophic Chondrocytes.

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

Hereditary Multiple Exostoses: New Insights into Pathogenesis, Clinical Complications, and Potential Treatments.

PURPOSE OF REVIEW: Hereditary multiple exostoses (HME) is a complex musculoskeletal pediatric disorder characterized by osteochondromas that form next to the growth plates of many skeletal elements, including long bones, ribs, and vertebrae. Due to its intricacies and unresolved issues, HME continues to pose major challenges to both clinicians and biomedical researchers. The purpose of this review is to describe and analyze recent advances in this field and point to possible targets and strategies for future biologically based therapeutic intervention. RECENT FINDINGS: Most HME cases are linked to loss-of-function mutations in EXT1 or EXT2 that encode glycosyltransferases responsible for heparan sulfate (HS) synthesis, leading to HS deficiency. Recent genomic inquiries have extended those findings but have yet to provide a definitive genotype-phenotype correlation. Clinical studies emphasize that in addition to the well-known skeletal problems caused by osteochondromas, HME patients can experience, and suffer from, other symptoms and health complications such as chronic pain and nerve impingement. Laboratory work has produced novel insights into alterations in cellular and molecular mechanisms instigated by HS deficiency and subtending onset and growth of osteochondroma and how such changes could be targeted toward therapeutic ends. HME is a rare and orphan disease and, as such, is being studied only by a handful of clinical and basic investigators. Despite this limitation, significant advances have been made in the last few years, and the future bodes well for deciphering more thoroughly its pathogenesis and, in turn, identifying the most effective treatment for osteochondroma prevention.

Daughter and mother diagnosed with hereditary multiple exostoses: A case report and a review of the literature.

INTRODUCTION: Hereditary multiple exostoses (HME) or osteochondromatosis is a rare autosomal dominant disease characterized by multiple osteochondromas and skeletal deformities. PATIENT CONCERNS & DIAGNOSES: We present the case of a 5 years and 9 month-old patient who presented with inferior limb pain for approximately 6 months, associating also deformity of the right index finger for a month. Hand X-ray revealed a radiologic abnormality of the right radius, therefore the child was referred to our clinic for further investigations. The X-rays revealed multiple osteochondromas of the radius, metacarpal bones, hand phalangeal bones, femur, tibia, fibula, metatarsal bones, and foot phalangeal bones. We mention that the same radiological aspect was identified in the case of the patient's mother, undiagnosed until that moment. OUTCOMES: The particularity of this case consists in identification of a rare genetic pathology, HME in a 5-year-old patient, without any known familial history, after the occurrence of a nontraumatic joint dislocation of the right index finger. CONCLUSION: HME is a rare genetic condition, without a curative treatment, burdened by multiple complications, and whose diagnosis is usually established during childhood.

Distraction Osteogenesis of the Fibula to Correct Ankle Valgus in Multiple Hereditary Exostoses.

Gradual distal fibula lengthening (DFL), in conjunction with other procedures, was used to correct ankle valgus and short fibulae in three pediatric patients with multiple hereditary exostoses (MHE). The average amount of DFL was 15 mm with a mean follow-up of 2.9 years. Final radiographs showed that all three patients had a stable ankle mortise without evidence of talar tilt or widening. In conclusion, gradual DFL has the advantage of restoring anatomy in cases of ankle valgus due to short fibulae and MHE, and may be performed in conjunction with other procedures.

Surgical hip dislocation according to Ganz for excision of osteochondromas in patients with multiple hereditary exostoses.

AIMS: We report a prospective cohort study of the midterm results of surgical dislocation of the hip (according to Ganz) to perform resection of osteochondromas involving the femoral neck in patients with multiple hereditary exostoses (MHE). METHODS: Hip range of movement (ROM) was assessed pre- and post-operatively. Patients' judgment of post-operative reduction of pain, symptoms, the Rand 36-item Health Survey (RAND-36) and complications were analysed. RESULTS: Symptomatic osteochondromas of the femoral neck were removed in 20 hips (17 patients) between 2007 and 2012. There were nine men and eight women with a mean age at the time of surgery of 29 years (11 to 47). Mean follow-up was 46 months (26 to 73). At latest follow-up, mean ROM was significantly increased in all directions. Post-operatively the pain associated with the lesion was either significantly decreased or non-existent. There was a significant improvement in seven RAND-36 sub-domains. Encountered complications in four patients were pseudoarthrosis of the trochanteric osteotomy, traumatic separation of the trochanteric osteotomy, a pertrochanteric femoral fracture and avasvular necrosis. Histological analysis revealed osteochondromas in all hips. DISCUSSION: This study confirms the Ganz trochanteric flip osteotomy provided a reliable approach to osteochondromas of the femoral neck that are otherwise difficult to access for surgical resection. The procedure offered significant improvement in the quality of life, although one should be aware of the serious complications can arise despite the relatively safe procedure. TAKE HOME MESSAGE: When daily function and activities are affected, resection of osteochondromas of the proximal femur according to Ganz is indicated to significantly improve quality of life.

Beam Projection Effect in the Radiographic Evaluation of Ankle Valgus Deformity Associated With Fibular Shortening.

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.

Developmental pattern of the hip in patients with hereditary multiple exostoses.

BACKGROUND: Coxa valga is a common clinical feature of hereditary multiple exostoses (HME). The current study aimed to determine the unique developmental pattern of the hip in patients with HME and evaluate the factors that influence its progression. METHODS: Thirty patients (57 hips) with HME were divided into two groups according to the Hilgenreiner epiphyseal angle (HEA). Twenty-two patients (44 hips) including 13 men and 9 women were assigned to group 1 (HEA <25°), and 8 patients (13 hips) including 3 men and 5 women were assigned to group 2 (HEA ≥25°). The mean age at the initial presentation was 6.0 (4-12) years with 6.8 (4-11) years of follow-up in group 1, and 10.4 (8-13) years with 5.4 (2-9) years of follow-up in group 2. We measured the HEA, neck-shaft angle (NSA), acetabular index (AI), center-edge angle (CEA), and migration percentage (MP) for radiographic evaluation. RESULTS: Among the hips, 50 (87.7%) hips had coxa valga and 27 (47.4%) hips had abnormal MP (42.1% were borderline and 5.3% were subluxated). There was a significant difference in the HEA and NSA between the groups (p < 0.001 and p < 0.05, respectively). The HEA significantly correlated with the development of the NSA and no correlation was found between the HEA and AI, CEA, and MP. CONCLUSIONS: There was a significant relationship between the HEA at the initial presentation and the NSA at skeletal maturity. We should consider guided growth for patients with lower HEA to prevent significant coxa valga deformity with close follow-up.

Loss of function in heparan sulfate elongation genes EXT1 and EXT 2 results in improved nitric oxide bioavailability and endothelial function.

BACKGROUND: Heparanase is the major enzyme involved in degradation of endothelial heparan sulfates, which is associated with impaired endothelial nitric oxide synthesis. However, the effect of heparan sulfate chain length in relation to endothelial function and nitric oxide availability has never been investigated. We studied the effect of heterozygous mutations in heparan sulfate elongation genes EXT1 and EXT2 on endothelial function in vitro as well as in vivo. METHODS AND RESULT: Flow-mediated dilation, a marker of nitric oxide bioavailability, was studied in Ext1(+/-) and Ext2(+/-) mice versus controls (n=7 per group), as well as in human subjects with heterozygous loss of function mutations in EXT1 and EXT2 (n=13 hereditary multiple exostoses and n=13 controls). Endothelial function was measured in microvascular endothelial cells under laminar flow with or without siRNA targeting EXT1 or EXT2. Endothelial glycocalyx and maximal arteriolar dilatation were significantly altered in Ext1(+/-) and Ext2(+/-) mice compared to wild-type littermates (glycocalyx: wild-type 0.67±0.1 µm, Ext1(+/-) 0.28±0.1 µm and Ext2(+/-) 0.25±0.1 µm, P<0.01, maximal arteriolar dilation during reperfusion: wild-type 11.3±1.0%), Ext1(+/-) 15.2±1.4% and Ext2(+/-) 13.8±1.6% P<0.05). In humans, brachial artery flow-mediated dilation was significantly increased in hereditary multiple exostoses patients (hereditary multiple exostoses 8.1±0.8% versus control 5.6±0.7%, P<0.05). In line, silencing of microvascular endothelial cell EXT1 and EXT2 under flow led to significant upregulation of endothelial nitric oxide synthesis and phospho-endothelial nitric oxide synthesis protein expression. CONCLUSIONS: Our data implicate that heparan sulfate elongation genes EXT1 and EXT2 are involved in maintaining endothelial homeostasis, presumably via increased nitric oxide bioavailability.

Stüve-Wiedemann syndrome: LIFR and associated cytokines in clinical course and etiology.

Stüve-Wiedemann syndrome (STWS; OMIM #610559) is a rare bent-bone dysplasia that includes radiologic bone anomalies, respiratory distress, feeding difficulties, and hyperthermic episodes. STWS usually results in infant mortality, yet some STWS patients survive into and, in some cases, beyond adolescence. STWS is caused by a mutation in the leukemia inhibitory factor receptor (LIFR) gene, which is inherited in an autosomally recessive pattern. Most LIFR mutations resulting in STWS are null mutations which cause instability of the mRNA and prevent the formation of LIFR, impairing the signaling pathway. LIFR signaling usually follows the JAK/STAT3 pathway, and is initiated by several interleukin-6-type cytokines. STWS is managed on a symptomatic basis since there is no treatment currently available.

Filamin-interacting proteins, Cfm1 and Cfm2, are essential for the formation of cartilaginous skeletal elements.

Mutations of Filamin genes, which encode actin-binding proteins, cause a wide range of congenital developmental malformations in humans, mainly skeletal abnormalities. However, the molecular mechanisms underlying Filamin functions in skeletal system formation remain elusive. In our screen to identify skeletal development molecules, we found that Cfm (Fam101) genes, Cfm1 (Fam101b) and Cfm2 (Fam101a), are predominantly co-expressed in developing cartilage and intervertebral discs (IVDs). To investigate the functional role of Cfm genes in skeletal development, we generated single knockout mice for Cfm1 and Cfm2, as well as Cfm1/Cfm2 double-knockout (Cfm DKO) mice, by targeted gene disruption. Mice with loss of a single Cfm gene displayed no overt phenotype, whereas Cfm DKO mice showed skeletal malformations including spinal curvatures, vertebral fusions and impairment of bone growth, showing that the phenotypes of Cfm DKO mice resemble those of Filamin B (Flnb)-deficient mice. The number of cartilaginous cells in IVDs is remarkably reduced, and chondrocytes are moderately reduced in Cfm DKO mice. We observed increased apoptosis and decreased proliferation in Cfm DKO cartilaginous cells. In addition to direct interaction between Cfm and Filamin proteins in developing chondrocytes, we showed that Cfm is required for the interaction between Flnb and Smad3, which was reported to regulate Runx2 expression. Furthermore, we found that Cfm DKO primary chondrocytes showed decreased cellular size and fewer actin bundles compared with those of wild-type chondrocytes. These results suggest that Cfms are essential partner molecules of Flnb in regulating differentiation and proliferation of chondryocytes and actin dynamics.

A mountain among molehills: removing an impinging large femoral neck osteochondroma in a man with hereditary multiple exostoses.

A 31-year-old man with a history of hereditary multiple exostoses (HME) presented with persistent right groin pain and reduced hip range of movement. Examination demonstrated a positive FADIR (flexion, adduction and internal rotation) test suggesting femoroacetabular impingement (FAI). Investigations showed multiple sessile osteochondromata of the right femur with a dominant anterolateral femoral neck osteochondroma causing flexion block. The patient underwent an uncomplicated proximal femoral exostectomy. Six-week postoperative pain, range of movement and daily activity had greatly improved. This case highlights that even in the setting of multiple osteochondromata, excellent impingement relief can be achieved following selective proximal femoral exostectomy.

Multiple hereditary exostoses (MHE): elucidating the pathogenesis of a rare skeletal disorder through interdisciplinary research.

Abstract An interdisciplinary and international group of clinicians and scientists gathered in Philadelphia, PA, to attend the fourth International Research Conference on Multiple Hereditary Exostoses (MHE), a rare and severe skeletal disorder. MHE is largely caused by autosomal dominant mutations in EXT1 or EXT2, genes encoding Golgi-associated glycosyltransferases responsible for heparan sulfate (HS) synthesis. HS chains are key constituents of cell surface- and extracellular matrix-associated proteoglycans, which are known regulators of skeletal development. MHE affected individuals are HS-deficient, can display skeletal growth retardation and deformities, and consistently develop benign, cartilage-capped bony outgrowths (termed exostoses or osteochondromas) near the growth plates of many skeletal elements. Nearly 2% of patients will have their exostoses progress to malignancy, becoming peripheral chondrosarcomas. Current treatments are limited to the surgical removal of symptomatic exostoses. No definitive treatments have been established to inhibit further formation and growth of exostoses, prevent transition to malignancy, or address other medical problems experienced by MHE patients, including chronic pain. Thus, the goals of the Conference were to assess our current understanding of MHE pathogenesis, identify key gaps in information, envision future therapeutic strategies and discuss ways to test and implement them. This report provides an assessment of the exciting and promising findings in MHE and related fields presented at the Conference and a discussion of the future MHE research directions. The Conference underlined the critical usefulness of gathering experts in several research fields to forge new alliances and identify cross-fertilization areas to benefit both basic and translational biomedical research on the skeleton.

Can deformity of the knee and longitudinal growth of the leg be predicted in patients with hereditary multiple exostoses? A cross-sectional study.

BACKGROUND: There is a high rate of knee deformity in patients with hereditary multiple exostoses (HME), and a quarter of patients have a limb length discrepancy. METHODS: A prospective database of 172 patients with HME was compiled. Patient demographics, knee deformity and range of movement, leg length and height, and number of exostoses around the knee were recorded. RESULTS: Nine out of 10 patients with HME were affected by exostoses around the knee, of which the distal femur was the most common site to be involved. Approximately 20% of patients had a valgus deformity and 16% had a fixed flexion deformity of the knee, with 25% having a diminished range of movement. Height was directly proportional to leg length and a quarter of patients were below the 10th centile for height. The presence of a distal femoral exostosis was an independent predictor of knee deformity (p=0.002), diminished range of movement (ROM) (p<0.001), and smaller stature (p<0.001) on multivariate analysis. In addition increasing age, prior surgery, genotype, and gender were also intendant predictors of ROM and height. CONCLUSION: Future studies analysing if surgical excision improves knee function and limits deformity would need to assess whether this is dependent upon anatomical site, as our results suggest that distal femoral exostoses may have the greatest affect upon these outcomes. LEVEL OF EVIDENCE: Level II.

Forearm deformity in patients with hereditary multiple exostoses: factors associated with range of motion and radial head dislocation.

BACKGROUND: There is a high rate of forearm deformity in patients with hereditary multiple exostoses, with many patients developing radial head dislocation associated with ulnar shortening. METHODS: One hundred and six patients with hereditary multiple exostoses who were fifteen years of age or older were identified with use of a previously compiled database. An independent observer measured flexion and extension of the elbow and wrist as well as supination and pronation of the forearm and recorded the number of exostoses affecting the forearm. Proportional ulnar length was calculated as a percentage of the measured height of the patient ([ulnar length/height] ×100). RESULTS: Exostoses were identified in 183 (86%) of the 212 forearms that were examined. The distal part of the radius was the most common site and was affected in 73% of the patients. One in seven patients had a dislocated radial head, which was associated with reduced proportional ulnar length (p < 0.001). Both radial head dislocation (p < 0.001) and proportional ulnar length (p < 0.001) were confirmed to be independent risk factors associated with forearm rotation on multivariate regression analysis. In conjunction with other risk factors, both of these factors could be used to predict forearm motion. In addition, a reduced proportional ulnar length was also an independent risk factor for radial head dislocation (p < 0.001). CONCLUSIONS: Proportional ulnar length could be used as a tool to identify patients who are at risk for diminished forearm motion and radial head dislocation during childhood. Surgical intervention could potentially be offered before deterioration in function and dislocation of the radial head occurs.