Two sibs, one girl and one boy, were observed in infancy with a severe lethal skeletal dysplasia syndrome that radiologically and histologically resembled Kniest dysplasia but clearly differed in clinical course and inheritance. Kniest dysplasia is a nonlethal syndrome, whereas both of these infants died in the neonatal period. Kniest dysplasia appears to be inherited as an autosomal dominant trait; the likely transmission in this family was autosomal recessive. Roentgenograms revealed dumbbell-shaped long bones superficially similar to Kniest dysplasia, but with markedly shortened diaphyses and metaphyseal irregularities. Chondro-osseous morphology demonstrated a superficially similar foamy "Swiss cheese" appearance to the cartilage matrix, as seen in Kniest dysplasia, but there were distinctly different changes in the growth plate and resting cartilage. Ultrastructurally, the chondrocytic endoplasmic reticulum was found to have an appearance different from that observed in either normal or Kniest cartilage. These cases likely represent a distinct chondrodysplasia.