Tracheomalacia in a neonate with Kniest dysplasia: Histopathologic and ultrastructural features

Kniest dysplasia is an autosomal-dominant chondrodysplastic condition chara cterized by disproportionate dwarfism, short trunk, small pelvis, kyphoscol iosis, short limbs, prominent joints, premature osteoarthritis, and craniof acial manifestations. The craniofacial abnormalities include tracheomalacia , midface hypoplasia, cleft palate, early onset myopia, retinal detachment, prominent eyes, and sensorineural hearing loss. Radiologic features includ e dumbbell-shaped femora, platyspondylia with anterior wedging of vertebral bodies, coronal clefts of thoracolumbar vertebral bodies, low broad ilia, and short tubular bones with broad metaphyses and deformed large epiphyses. This form of chondrodysplasia is associated with mutations in type II coll agen splicing sequences. Mutations have been identified in the COL2A1 (type II collagen) gene between exons 12 and 24. Type II collagen is the predomi nant structural protein in cartilage, and mutations in this collagen accoun t for the Kniest dysplasia phenotype. Histopathologic and ultrastructural f eatures of epiphyseal plate cartilage have been described, but tracheal car tilage in an affected neonate has not been examined. The authors report the histopathologic and ultrastructural findings of anterior tracheal cartilag e from a 35-day-old female with suspected chondrodysplasia who had tracheom alacia with airway obstruction. The tracheal cartilage was moderately cellu lar, but lacked cystic and myxoid changes in its matrix. The chondrocytes h ad abundant cytoplasmic PAS-positive inclusions. Some of these inclusions w ere diastase-resistant and were also highlighted on Alcian blue staining. U ltrastructural examination revealed chondrocytes with greatly dilated rough endoplasmic reticulum containing granular proteinaceous material. There we re also frequent aggregates of typical glycogen. The defect in the COL2A1 g ene is secondary to mutations, especially at splice junctions, and this mar kedly disrupts triple helix formation. The mutated type II procollagen resu lts in intracellular retention within the chondrocytes. as abundant granula r proteinaceous material within the dilated RER. A relationship is known to exist between the proportion of mutated to normal type II collagen in the matrix and the severity of the phenotype. with low levels of normal type II collagen, the phenotypic manifestations become more severe, such as in ach ondrogenesis type II. Both the quantity and quality of type II collagen mod ulates the phenotypic expression of type II collagenopathies.