Evolution of skeletal hyperostoses caused by 13-cis-retinoic acid therapy

Seven patients with disorders of keratinization (ichthyosis in six and Darier disease in one) were treated with 13-cis-retinoic acid and followed with annual skeletal surveys for 4-6 years. Six of the seven patients developed hyperostoses attributable to the retinoid therapy, manifested as multifocal entheseal calcifications or ossifications in both the axial and appendicular skeletons. In general, the earliest appearing hyperostoses became the largest with time, although in some instances, growth ceased at some foci and progressed at others. The severity of skeletal involvement was seemingly independent of dose, and may have been related to the patient's age at time of therapy. Involvement of the spine was earlier and more pronounced than the appendicular involvement, consisting of tiny hyperostoses arising from the corners of the vertebral bodies, primarily in the cervical and thoracic spine; these later matured into either discrete ossific spurs, or focal or flowing ossification of the anterior longitudinal ligament. The most prominent appendicular hyperostoses were at the tendinous or aponeurotic insertions on the calcaneus, were often unilateral or asymmetric when small, and became bilateral with time. Appendicular hyperostoses occurring at locations besides the calcanei were much smaller, often unilateral, and occurred later (generally between the third and fifth years of therapy). Our findings indicate that the earliest hyperostoses occurring in patients with 13-cis-retinoic acid occur in the spine and feet, and become the most prominent with time. Most appendicular hyperostoses occur later, are smaller, and frequently are asymmetric or unilateral.