Constitutional Disorders Of Bone Research Articles

Skeletal Dysplasias: An Overview.

Constitutional disorders of bone, commonly termed skeletal dysplasias (SDs), are inherited disorders of cartilage and/or bone that affect their growth, morphometry and integrity. Associated skeletal abnormalities are usually but not invariably symmetrical. They may be classified as osteochondrodysplasias, which are conditions associated with abnormalities of the growth (dysplasias) or texture (osteodystrophy) of bone and/or cartilage, or dysostoses, which are conditions secondary to abnormal blastogenesis (occurring at or around the 6th week of in utero life). Skeletal involvement may also occur in other multisystem hereditary and acquired syndromes. The 2010 Nosology and Classification of Genetic Skeletal Disorders listed 456 conditions, of which approximately 50 are perinatally lethal, and 316 are associated with one or more of 226 genes. When an SD is suspected, a standard series of radiographs, collectively known as a skeletal survey, should be performed. The diagnosis of individual conditions is highly dependent on radiographic pattern recognition, which is achieved through a systematic review of the images and enhanced by discussion with colleagues and through the use of available tools, such as atlases and digital databases. This article summarises a systematic approach to the diagnosis of SDs, demonstrated using examples of some of the more common lethal and non-lethal conditions.

Spondyloenchondrodysplasia with spasticity, cerebral calcifications, and immune dysregulation: Clinical and radiographic delineation of a pleiotropic disorder

Enchondromas are a feature of several constitutional disorders of bone, and the classification of different nosologic entities is still provisional. Among these disorders, spondyloenchondrodysplasia (SPENCD), as outlined by Schorr et al. [1976], is defined by the presence of radiolucent spondylar and metaphyseal lesions that represent persistence of islands of chondroid tissue within bone. Careful review of radiographic findings is needed to distinguish SPENCD from the many other disorders combining enchondromas with spinal lesions. Even when strict criteria are applied, it appears that SPENCD is clinically heterogeneous, as some SPENCD patients are neurologically intact while others present with spasticity, mental retardation, and cerebral calcifications in different combinations, and it has been suggested that SPENCD should be divided in two types. We herein report ten individuals from six families with SPENCD and illustrate the radiographic changes. Seven individuals had CNS manifestations including spasticity, developmental delay, and late-onset cerebral calcifications. We also noted that six individuals had clinical manifestations of autoimmunity (auto-immune thrombocytopenic purpura, auto-immune hemolytic anemia, auto-immune thyroiditis, and SLE) and one had been diagnosed with immune deficiency. Neurological and autoimmune manifestations were seen in different combinations within one single family. These observations suggest that SPENCD may be a single entity defined by specific radiographic features, but with remarkably pleiotropic manifestations that include CNS disease (spasticity, mental retardation, and calcifications), as well as immune dysregulation ranging from autoimmunity to immunodeficiency. The notion of recessive inheritance hitherto assumed is challenged by the observation of two apparently dominant pedigrees.

Orthopedic aspects of skeletal dysplasia in children.

Significant advances in the management of skeletal dysplasia have occurred during the past year. A revision of the Paris classification of constitutional disorders of bone has been proposed. New mutations have been identified in several disorders that confirm genetic heterogeneity within similar phenotypes. New clinical data of growth, fracture rates, and incidence of major skeletal and extraskeletal changes as well as the natural history and treatment of spinal deformities in osteogenesis imperfecta have been reported. Pilot studies of short-term growth hormone therapy in patients with achondroplasia and hypochondroplasia and nasal-osteocalcin therapy in osteogenesis imperfecta patients has been described, but the long-term effectiveness of these treatments remains to be determined. Extensive limb lengthening continues to be an important part of the treatment of patients of short stature in Europe, but complication rates continue to be very high. Both the current and future roles for this type of therapy are highly controversial. The potential for enzyme replacement therapy and retrovirus-mediated gene transfer in a variety of mucopolysaccharidosis disorders has been given new meaning by studies with cultured fibroblasts, which suggest that active enzymes can enter into and be synthesized in abnormal cells resulting in normalization of substrate turnover.

Pathologic spectrum of lethal short-limbed dwarfism

Based principally on radiological features, an international nomenclature for constitutional disorders of bone has recently been adopted. Pathological studies on these conditions may provide a better understanding of pathogenetic mechanisms. Lethal forms of short-limbed dwarfism are a group of chondrodysplasias that form a heterogeneous group of disorders that have been largely defined by clinical, genetic and radiological criteria. This group includes a number of disorders that may be readily differentiated on the basis of chondro-osseous histology. The histopathological features of most of these disorders are sufficiently distinctive to provide additional diagnostic criteria and to contribute to the understanding and delineation of these disorders. Achondrogenesis is the severest form of the lethal chondrodysplasias; type 1 is characterized by severe disorganization of endo chondral ossification and the chondrocytes contain intracytoplasmic inclusions; in type 2 achondrogenesis, the cartilaginous matrix is deficient and the chondrocytes are large and ballooned. In thanatophoric dwarfism, there is severe disruption of endochondral ossification and when associated with cloverleaf skull, osteoblastic and osteoclastic activity in the metaphyses is prominent. Homozygous achondroplasia shows disorganized endochondral ossification and physeal chondrocytes contain abundant glycogen. In campomelic dysplasia, dense mineralization in the provisional zone of calcification and reduction of cartilaginous trabeculae in the metaphysis occurs; it may be associated with sex reversal. Two variants of asphyxiating thoracic dystrophy have been defined: type 1 shows irregularity of the physeal-metaphyseal junction with poorly mineralized cartilage; type 2 shows a lacelike network of advancing cartilage at the metaphysis. The rhizomelic form of chondrodysplasia punctata has a distinctive Swiss-cheese appearance of the epiphyseal cartilage. Kniest syndrome is characterized by severe cartilaginous changes with defective cartilaginous maturation producing soft crumbly cartilage. The short rib-polydactyly syndromes may be differentiated by a rather distinctive pattern of abnormal endochondral ossification. Immunodeficiency syndromes may be associated with short limb dwarfism and are characterized by disturbances in the physeal growth plate. The major pathological differences between these disorders suggest a distinct pathogenetic mechanism.