Pathologic spectrum of lethal short-limbed dwarfism

Abstract

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.