Premature Epiphyseal Closure of the Lower Extremities Contributing to Short Stature after cis-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.

Figure 1

This graph shows the patient's time of diagnosis (Dx) and surgery (Sx), along with duration of radiation therapy (RT), chemotherapy (Chemo Tx), and growth hormone treatment (GH Tx). The patient's growth chart reveals height trajectory far below the 5^th percentile (mid-parental height of 65 inches) with limited height increase before the initiation of growth hormone (GH) at approximately age 7 years. Height velocity briefly increased with the initiation of GH therapy but faltered shortly afterwards, despite continued GH treatment, due to prematurely closed epiphyseal growth plates of the lower extremities.

Figure 2

(A) Radiographs of the knee and (B) ankles at age 8.4 years revealed metaphyseal widening with diffuse skeletal demineralization and poor visualization of the growth plates at left and right distal and proximal femurs and tibias, demonstrating premature closure of epiphyseal growth plates. In contrast to closed lower extremity growth plates, bone ages from (C) January 1, 2013 (chronological age 7 years) and (D) April 24, 2014 (chronological age 8.4 years) were normal and less than 2 standard deviations below chronological age with open growth plates.