Ossification Of Interosseous Membrane Research Articles

Clinical, Radiographic, and Biomechanical Evaluation of the Upper Extremity in Patients with Osteogenesis Imperfecta.

Introduction: Osteogenesis imperfecta (OI) is a hereditary disorder primarily caused by mutations in type I collagen genes, resulting in bone fragility, deformities, and functional limitations. Studies on upper extremity deformities and associated functional impairments in OI are limited. This cross-sectional study aimed to evaluate upper extremity deformities and functional outcomes in OI. Methods: We included patients regardless of their OI subtypes with a minimum age of 7 years. Radiographic analysis of radial head dislocation, ossification of the interosseous membrane, and/or radioulnar synostosis of the forearm were performed, and deformity was categorized as mild, moderate, or severe. Clinical evaluation was performed using the Quick Disabilities of Arm, Shoulder, and Hand (qDASH) questionnaire and shoulder-elbow-wrist range of motion (ROM). Three-dimensional motion analysis of the upper limb was conducted using the Southampton Hand Assessment Procedure (SHAP). The SHAP quantifies execution time through the Linear Index of Function (LIF) and assesses the underlying joint kinematics using the Arm Profile Score (APS). Additionally, the maximum active Range of Motion (aRoM) was measured. Results: Fourteen patients aged 8 to 73 were included. Radiographic findings revealed diverse deformities, including radial head dislocation, interosseous membrane ossification, and radioulnar synostosis. Six patients had mild, six moderate, and two severe deformities of the upper extremity. Severe deformities and radial head dislocation correlated with compromised ROM and worse qDASH scores. The qDASH score ranged from 0 to 37.5 (mean 11.7). APS was increased, and LIF was reduced in OI-affected persons compared with non-affected peers. APS and LIF also varied depending on the severity of bony deformities. aRoM was remarkably reduced for pro-supination. Conclusion: Patients with OI showed variable functional impairment from almost none to severe during daily life activities, mainly depending on the magnitude of deformity in the upper extremity. Larger multicenter studies are needed to confirm the results of this heterogeneous cohort. Level of evidence: Retrospective clinical study; Level IV.

Generalized Arterial Calcification of Infancy (GACI): Optimizing Care with a Multidisciplinary Approach.

It is very unusual to see evidence of arterial calcification in infants and children, and when detected, genetic disorders of calcium metabolism should be suspected. Generalized arterial calcification of infancy (GACI) is a hereditary disease, which is characterized by severe arterial calcification of medium sized arteries, mostly involving the media with marked intimal proliferation and ectopic mineralization of the extravascular tissues. It is caused by inactivating variants in genes encoding either ENPP1, in a majority of cases (70–75%), or ABCC6, in a minority (9–10%). Despite similar histologic appearances between ENPP1 and ABCC6 deficiencies, including arterial calcification, organ calcification, and cardiovascular calcification, mortality is higher in subjects carrying the ENPP1 versus ABCC6 variants (40% vs 10%, respectively). Overall mortality in individuals with GACI is high (55%) before the age of 6 months, with 24.4% dying in utero or being stillborn. Rare cases show spontaneous regression with age, while others who survive into adulthood often manifest musculoskeletal complications (osteoarthritis and interosseous membrane ossification), enthesis mineralization, and cervical spine fusion. Despite recent advances in the understanding of the genetic mechanisms underlying this disease, there is still no ideal therapy for the resolution of vascular calcification in GACI. Although bisphosphonates with anti-calcification properties have been commonly used for the treatment of CAGI, their benefit is controversial, with favorable results reported at one year and questionable benefit with delayed initiation of treatment. Enzyme replacement therapy with administration of recombinant form of ENPP1 prevents calcification and mortality, improves hypertension and cardiac function, and prevents intimal proliferation and osteomalacia in mouse models of ENPP1 deficiency. Therefore, newer treatments targeting genes are on the horizon. In this article, we review up to date knowledge of the understanding of GACI, its clinical, pathologic, and etiologic understanding and treatment in support of more comprehensive care of GACI patients.

Response of enthesopathy in ENPP1 deficiency to enzyme replacement therapy in murine models and enthesopathy comorbidities and quality of life in ENPP1‐deficient adults

Biallelic ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) deficiency leads to cardiovascular calcification in infancy, FGF23‐mediated hypophosphatemic rickets in childhood, and osteomalacia in adulthood. Excessive enthesis mineralization and cervical spine fusion have been previously reported in patients with biallelic ENPP1 deficiency, but their effect on quality of life is unknown. We describe additional musculoskeletal complications in patients with ENPP1 deficiency, namely osteoarthritis and interosseous membrane ossification, and for the first time evaluate health‐related quality of life (HRQoL) in patients with this disease, both subjectively via narrative report, and objectively via the Brief Pain Inventory – Short Form, and a Patient Reported Outcome Measurement Information System Physical Function (PROMIS PF) short form. Residual pain, similar in magnitude to that identified in adult patients with X‐linked hypophosphatemia, was experienced by the majority of patients despite use of analgesic medications. Impairment in physical function varied from mild to severe. To assess murine ENPP1 deficiency for the presence of enthesopathy, and for the potential response to enzyme replacement therapy, we maintained Enpp1asj/asj mice on regular chow for 23 weeks and treated cohorts with either vehicle or a long‐acting form of recombinant ENPP1. Enpp1asj/asj mice treated with vehicle exhibited robust calcification throughout their Achilles tendons, whereas two‐thirds of those treated with ENPP1 enzyme replacement exhibited complete or partial suppression of the Achilles tendon calcification. Our combined results document that musculoskeletal complications are a significant source of morbidity in homozygous ENPP1 Deficiency, a phenotype which is closely recapitulated in Enpp1asj/asjmice. Finally, we show that a long‐acting form of recombinant ENPP1 prevents the development of enthesis calcification at the relatively modest dose of 0.3 mg/kg per week, suggesting that suppression of enthesopathy may be attainable upon dose escalation.

Does the Skeletal Phenotype of Osteogenesis Imperfecta Differ for Patients With Non-COL1A1/2 Mutations? A Retrospective Study in 113 Patients.

Osteogenesis imperfecta (OI) is a heritable disease characterized by bone fragility and other extra skeletal manifestations. Most patients with OI have mutations in the COL1A1 or COL1A2 genes. However, a significant minority of patients with clinical OI have non-COL1A1/2 mutations, which have become easier to detect with the use of genetic panels. Traditional understanding of OI pathogenesis was expanded because of these new mutations, and their phenotypic-genotypic relationship is largely unknown. We hypothesized that patients with non-COL1A1/2 mutations have different skeletal clinical presentations from those with OI caused by COL1A1/2 mutations. Patients were categorized into 4 groups according to our modified functional classification, namely, quantitative COL1A1/2 haploinsufficiency (group 1), qualitative COL1A1/2 dominant negative mutations (group 2), mutations indirectly affecting type I collagen synthesis, processing and posttranslational modification (group 3) and mutations altering osteoblast differentiation and function (group 4). Both group 3 and 4 were classified as non-COL1A1/2 mutation group. Of 113 OI patients included, 51 had COL1A1/2 quantitative haploinsufficiency mutations (group 1), 39 had COL1A1/2 qualitative dominant negative mutations (group 2), and 23 patients had OI caused by mutations in 1 of 9 other noncollagen genes (groups 3/4). Patients with non-COL1A1/2 mutations (groups 3 and 4) have severe skeletal presentations. Specifically, OI patients with non-COL1A1/2 mutations experienced more perinatal fractures, vertebral compression fractures and had more long bone deformities. Although the occurrence of scoliosis was similar, the cobb angle was larger in the non-COL1A1/2 mutation group. Radial head dislocations, ossification of interosseous membrane, extraskeletal ossification, cervical kyphosis, and champagne glass deformity of the pelvis were more frequent in this group. The clinical phenotype of OI in patients with non-COL1A1/2 is severe and has unique features. This information is useful for clinical diagnosis and prognosis. Level III.

Musculoskeletal Comorbidities and Quality of Life in ENPP1-Deficient Adults and the Response of Enthesopathy to Enzyme Replacement Therapy in Murine Models.

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) deficiency leads to cardiovascular calcification in infancy, fibroblast growth factor 23 (FGF23)-mediated hypophosphatemic rickets in childhood, and osteomalacia in adulthood. Excessive enthesis mineralization and cervical spine fusion have been previously reported in patients with biallelic ENPP1 deficiency, but their effect on quality of life is unknown. We describe additional musculoskeletal complications in patients with ENPP1 deficiency, namely osteoarthritis and interosseous membrane ossification, and for the first time evaluate health-related quality of life (HRQoL) in patients with this disease, both subjectively via narrative report, and objectively via the Brief Pain Inventory-Short Form, and a Patient Reported Outcome Measurement Information System Physical Function (PROMIS PF) short form. Residual pain, similar in magnitude to that identified in adult patients with X-linked hypophosphatemia, was experienced by the majority of patients despite use of analgesic medications. Impairment in physical function varied from mild to severe. To assess murine ENPP1 deficiency for the presence of enthesopathy, and for the potential response to enzyme replacement therapy, we maintained Enpp1asj/asj mice on regular chow for 23 weeks and treated cohorts with either vehicle or a long-acting form of recombinant ENPP1. Enpp1asj/asj mice treated with vehicle exhibited robust calcification throughout their Achilles tendons, whereas two-thirds of those treated with ENPP1 enzyme replacement exhibited complete or partial suppression of the Achilles tendon calcification. Our combined results document that musculoskeletal complications are a significant source of morbidity in biallelic ENPP1 deficiency, a phenotype which is closely recapitulated in Enpp1asj/asj mice. Finally, we show that a long-acting form of recombinant ENPP1 prevents the development of enthesis calcification at the relatively modest dose of 0.3 mg/kg per week, suggesting that suppression of enthesopathy may be attainable upon dose escalation. © 2021 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Thoracic Ossification of Ligamentum Flavum Caused By Skeletal Fluorosis: Breaking the Etiopathological Barrier -Answer to the Crippling Disease of the Society

Background: Thoracic ossification of ligamentum flavum (OLF) caused by skeletal fluorosis is rare [1]. Only six patients had been reported in the English literature. This study is the second study to the best of our knowledge in literature. Aims and Objectives: To evaluate the causation of ossification of ligamentum flavum due to fluorosis in accordance with reports from the first clinical series of this disease. Exact etiopathogenesis of thoracic ossification of yellow ligament is not known and causation due to fluorosis is rare, so this study was hypothesized [2]. Materials and Methods: This is a prospective study of patients with thoracic OLF due to skeletal fluorosis who underwent surgical management at the NIMS hospital between 2017 and 2018. A total of 16 cases were enrolled, (56.25%), 9 males and 7 (43.75%) females, age ranging from 37 to 62 years (mean 50.5 years). Imaging showed OLF together with ossification of interosseous membranes, including interosseous membranes of the forearm (14/16 patients 87.5%).Urinalysis showed a markedly high urinary fluoride level in 15 of 16 patients (93.75%).Ossified ligamentum flavum sent for estimation of fluoride levels in 16 patients showed high fluoride level in the bone ash prepared from the oyl in 15 patients and other structures sent as control were ,spinous process ,interspinous ligaments didn’t show any fluoride deposition. Results: Out of 16 patient 15 patient had fluoride levels more than 6000mg/kg, 7 patient had values between 6,000 – 7,000 mg/kg, 5 patient had values between 7,500 – 9,000 mg/kg and 3 patients had values > 8400 mg/kg. Controls were sent as spinous processes had normal fluoride level between 500-1000 mg/kg and interspinous ligaments sent showed no fluoride levels. Out of 16 patients 9 patients had multiple level dorsal OYL both contiguous and non-contiguous, contiguous in 4 patients and non – contiguous in 5 patients.7 patients had single level dorsal OYL. Most common segment involved in OYL is T9 and D10 level in 14 patients. Sato classification 6 were Type A, 5 were Type B, 3 were Type C, 2 were Type D Conclusion: This is the largest series of ossification of dorsal yellow ligament due to fluorosis. And consideration of fluorosis as one of the important etiological cause for OYL to be kept in mind and all patients with OYL to be screened for Fluorosis and this would also help as a preventive measure for the people around the surroundings of the affected person and would help the society from a crippling disability.

New Genes in Bone Development: What's New in Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a heritable bone dysplasia characterized by bone fragility and deformity and growth deficiency. Most cases of OI (classical types) have autosomal dominant inheritance and are caused by mutations in the type I collagen genes. During the past several years, a number of noncollagenous genes whose protein products interact with collagen have been identified as the cause(s) of rare forms of OI. This has led to a paradigm shift for OI as a collagen-related condition. The majority of the non-classical OI types have autosomal recessive inheritance and null mutations in their respective genes. The exception is a unique dominant defect in IFITM5, which encodes Bril and leads to hypertrophic callus and interosseous membrane ossification. Three recessive OI types arise from defects in any of the components of the collagen prolyl 3-hydroxylation complex (CRTAP, P3H1, CyPB), which modifies the collagen α1(I)Pro986 residue. Complex dysfunction leads to delayed folding of the procollagen triple helix and increased helical modification. Next, defects in collagen chaperones, HSP47 and FKBP65, lead to improper procollagen folding and deficient collagen cross-linking in matrix, respectively. A form of OI with a mineralization defect is caused by mutations in SERPINF1, whose protein product, PEDF, is a well-known antiangiogenesis factor. Defects in the C-propeptide cleavage enzyme, BMP1, also cause recessive OI. Additional genes, including SP7 and TMEM38B, have been implicated in recessive OI but are as yet unclassified. Elucidating the mechanistic pathways common to dominant and recessive OI may lead to novel therapeutic approaches to improve clinical manifestations.

Osteogenesis imperfecta type V

Osteogenesis imperfecta type V was first described in 2000. It is a distinct clinical entity with unique clinical, radiological, and histological features. Clinically, it is only moderately deforming. Patients have normal scleraand teeth. Radiological diagnostic criteria include a triad of calcification of the radioulnar interosseous membrane, presence of hypertrophic callus at fractures or post-operative sites, and radiodense metaphysealbandadjacenttogrowthplates(1). Histologically, it is distinguished by a mesh-like pattern of lamellation under polarized light microscopy for iliac bone samples. Ossification of the interosseous membrane of the forearm is a constant feature, although it may vary in its extent. The presence of ossification can severely limit movements of the forearm, and is associated with secondary dislocation of the radial head (1, 2). The frequency of radial head dislocation/subluxation is significantly higher in type V osteogenesis imperfecta (86%) than in the other types (0% to 29%) (3). The presence of interosseous membrane ossification in a pediatric patient, with or without radial head dislocation, should prompt radiologists to consider OI type Vas a diagnosis. The formationof hypertrophic callus, if present, isthe most conspicuous clinical symptom in OI type V (1). It is reported that while not all OI type V patients have hypertrophic callus formation, all patients with hypertrophic callus formation are OI type V in the proper clinical context (1, 4). Lesions form during the growth years at sites of rapid periosteal apposition. The long bones are most often affected, particularly in the lower extremities (4). Hypertrophic callus can be precipitated by fracture or surgery, or arise spontaneously. It can become very large or even mimic osteosarcoma (2, 5). In unclear cases, MRI and CT can be helpful in distinguishing hypertrophic callus from sarcoma (6, 7). Evolution of the lesions is variable, ranging from complete resolution to significant persisting morbidity.

Fluorose osseuse : à propos d’un cas

The authors report a case of skeletal fluorosis described in a 60 years old man living in south-west Tunisian. The main clinical sign is a severe functional legs disability. Radiographic examination has shown a diffused osteocondensation, with cervical spine degenerative discopathy, a pelvis bilateral osteoarthritis and an interosseous membrane ossification of forearms and legs. The skeletal fluorosis diagnosis has been confirmed by high serum and urinary fluoride levels.

Clinical and Radiological Manifestations of Osteogenesis Imperfecta Type V

We reviewed clinical manifestation of 12 patients from three Korean families. They showed mild to moderate bone fragility, and suggested an autosomal dominant inheritance pattern. Significant intrafamilial phenotype variability was obvious. Clinical, radiological, and histopathologic characteristics that distinguished this subtype from others include ossification of interosseous membrane of the forearm with radial head dislocation, hyperplastic callus formation, no evidence of type I collagenopathy and an abnormal histopathologic pattern. Severity of the interosseous membrane ossification was correlated with increasing age (p<0.01) and the radial head dislocation was thought to be a developmental problem rather than a congenital problem. Four children who had bisphosphonate treatment showed improved bone mineral density, radiological changes, and biochemical responses. Osteogenesis imperfecta type V was a distinctive subtype of osteogenesis imperfecta, which caused mild to moderate disability clinically.