To the editor—In response to the May issue article by Parman et al. proposing oxidative damage as a mechanism of thalidomide teratogenicity1: It seems that few, if any, of the proposed mechanisms of thalidomide embryopathy take into account the fact that thalidomide's effects on the skeleton are restricted to enchondral bone formation (that is, bones that are formed through a cartilage intermediate.)

Most of the structural elements of the skull (including the teeth) are spared in thalidomide embryopathy, since they are not generated through enchondral intermediates. The os petrosum, on the other hand, is, and malformations of the os petrosum are common in thalidomide victims, resulting in damage to the inner ear and deafness. It is difficult to explain these profound differences in terms of general mechanism such as oxidative DNA damage.

Further progress in this field may result from the recent identification of the molecular defect responsible for Holt-Oram syndrome. The malformations associated with this syndrome closely resemble those caused by thalidomide with respect to upper limb and cardiac development. Holt-Oram syndrome is caused by mutations in TBX5, a member of the brachyury gene family2,3, and it is possible that interference with the normal expression or function of TBX gene products may be involved in thalidomide embryopathy. TBX5 is expressed around the time that developing embryo is most sensitive to thalidomide2.

Thalidomide victims still deserve our public and scientific attention. As they grow older, their medical problems increase. And there are many new cases related to the use of thalidomide to treat erythema nodosum leprosum (recently approved by the US Food and Drug Administration) and similar conditions.