Down's syndrome (DS), a human genetic abnormality usually caused by an extra chromosome 21, presents a wide range of major and minor anomalies, the most significant of which are mental retardation and congenital heart defects. The anomalous phenotype also includes short stature and neck, thin calvaria, and cartilage hypoplasia. The genesis of these skeletal features is unknown. Histopathologic sections of fetal cartilage from skull, vertebra, rib, and femur were studied in 16 fetuses with DS (17-22 wk old) and 13 control non-DS fetuses (19-22 wk old) with other pathologies not directly affecting skeletal growth. Rib growth cartilage morphology showed a previously unreported structural anomaly in DS, an increase in the hypertrophic portion with a concomitant decrease in proliferative and resting zones. The hypertrophic chondrocytic zone was markedly increased in DS compared with non-DS (149 +/- 68 microm versus 36 +/- 20 microm, and 26 +/- 12 versus 7 +/- 3 expressed in percent of the total length; p < 0.0001), whereas the proliferative zone (114 +/- 58 microm versus 165 +/- 43 microm, 20 +/- 10 versus 33 +/- 4 in percent of the total length; p < 0.001) and the resting zone (53 +/- 4 versus 59 +/- 6 in %, p < 0.009) were decreased. These features were not found in the femoral epiphyseal growth plate or in cartilage from vertebra and skull. Our results demonstrate an imbalance toward the hypertrophic phenotype. This abnormality, found in DS fetuses 17-22 wk old, may represent an early manifestation of an abnormal growth cartilage maturation pattern, which manifests postnatally in long bones, leading to diminished growth rates.