Premature Epiphyseal Closure of the Lower Extremities Contributing to Short Stature after <b><i>cis</i></b>-Retinoic Acid Therapy in Medulloblastoma: A Case Report

Abstract

Background: Prolonged cis-retinoic acid (RA) exposure contributes to premature epiphyseal closure. cis-RA is administered in various treatment regimens for pediatric cancers, thus increasing the risk for bone deformities and compromised growth. Results: We present a case of premature epiphyseal closure in a 9-year-old female with a history of medulloblastoma and treatment with a multimodal regimen including cis-RA. She was subsequently diagnosed with radiation-induced endocrine late effects including hypothyroidism and growth hormone deficiency (GHD). Seven months after initiation of GH therapy, an increased prominence of the wrists and knees combined with a deceleration in growth velocity prompted further evaluation; radiographs revealed bilateral premature closure of the distal femur and proximal tibia growth plates despite normal left wrist bone age. Conclusion: High doses of vitamin A and its analogs are linked to premature closure of the lower-extremity growth plates in animals and children. Pediatric brain tumor patients are at increased risk of growth failure due to concurrent radiation-induced GHD, damage to the spinal bones, and cis-RA-associated premature closure of the lower-extremity growth plates, with significant reduction in adult stature. A better appreciation of the detrimental effect of cis-RA on the growing skeleton is needed to monitor at-risk patients and to provide timely interventions.

Palovarotene reduces heterotopic ossification in juvenile FOP mice but exhibits pronounced skeletal toxicity

“…Whether palovarotene-induced articular cartilage overgrowth is related to the pro-proliferative effects of retinoids on chondrocytes in other experimental settings ( Enomoto et al, 1990 ; Kwon et al, 2011 ) requires further investigation. Regardless of mechanism, these data indicate that palovarotene exhibits skeletal toxicity that is consistent with known effects of chronic retinoid treatment on synovial joint tissue in animal models ( Gartner et al, 1970 ; Clark and Seawright, 1968 ; Kubo et al, 2002 ) and in humans ( Noyes et al, 2016 ; Vahlquist, 1992 ).…”

MANAGEMENT OF ENDOCRINE DISEASE: Diagnostic and therapeutic approach of tall stature

“…In another example, retinoids are commonly used to treat cancer and skin problems, such as acne and hyperkeratotic disorders. Several reports in children exposed to retinoids have shown premature epiphyseal closure, mainly in lower limbs, with consequent development of short stature, usually around 4-5 years after a highdose treatment (105,106,107). Those findings were supported by animal models of hypervitaminosis A in rats and of use of retinoids in guinea pigs, showing a direct effect in epiphyseal plate (108).…”

Accelerated Skeletal Maturation in Disorders of Retinoic Acid Metabolism: A Case Report and Focused Review of the Literature

“…In addition, clinical observations of patients treated with RA derivatives also supports the hypothesis that RA accelerates bone maturation and thus promotes early growth cessation and adult short stature. This effect is likely dose-dependent and may thus not be as pronounced in acne patients treated with isotretinoin [42] as in oncology patients treated with high doses of RA [43,44]. …”