Keck School of Medicine of USC, Los Angeles, California.
Children's Hospital Los Angeles, University of Southern California, Los Angeles, California.
Pediatr Blood Cancer. 2020 Aug;67(8):e28236. doi: 10.1002/pbc.28236. Epub 2020 May 9.
Vitamin A-derived retinoids have been reported to cause skeletal abnormalities ranging from hypercalcemia to premature epiphyseal closure. Isotretinoin is a retinoid used as standard therapy for high-risk neuroblastoma and has been reported to cause premature epiphyseal growth plate arrest.
We identified patients from the Children's Hospital Los Angeles (CHLA) database with high-risk neuroblastoma diagnosed from 1991 to 2018 who experienced premature epiphyseal growth plate arrest and compared their characteristics to other patients with high-risk neuroblastoma. We then performed a literature review of this complication. Data collection included diagnosis age of neuroblastoma, presentation age, agent of exposure, dose, exposure range, and skeletal deformity.
Among 216 patients, high-risk neuroblastoma was diagnosed before age of five years (n = 165), between ages of 5 and 10 years (n = 41), and after 10 years of age (n = 13). Three out of 216 patients developed premature epiphyseal growth arrest after isotretinoin exposure (overall incidence = 1.38%). The incidence of bony abnormalities was significantly higher in patients diagnosed in 5- to 10-year age group than in other two groups (P = 0.014). Literature review identified eight additional patients with neuroblastoma who presented with retinoid associated skeletal abnormalities. The median range of isotretinoin exposure for these 11 patients was between 6.5 and 7.625 years (range, 2-14) with no cases of isotretinoin therapy completion before age 5 years.
Bone toxicity associated with isotretinoin exposure is a concern. Growth plate arrest is a serious adverse effect that is attributable to isotretinoin therapy. Our findings suggest the prepubescent growth plate may be most at risk, and we recommend special attention to this population.
已报道视黄醇衍生的类维生素 A 会导致骨骼异常，从高钙血症到骨骺过早闭合。异维 A 酸是一种用于高危神经母细胞瘤标准治疗的类维生素 A，已被报道会导致骨骺生长板过早停止。
我们从洛杉矶儿童医院 (CHLA) 数据库中确定了 1991 年至 2018 年间被诊断患有高危神经母细胞瘤的患者，这些患者出现了骨骺生长板过早停止，并将他们的特征与其他高危神经母细胞瘤患者进行了比较。然后，我们对该并发症进行了文献综述。数据收集包括神经母细胞瘤的诊断年龄、发病年龄、暴露物、剂量、暴露范围和骨骼畸形。
在 216 名患者中，高危神经母细胞瘤在五岁以下诊断（n=165）、五岁至十岁（n=41）和十岁以后诊断（n=13）。在异维 A 酸暴露后，有 3 名患者出现骨骺生长过早停止（总发生率=1.38%）。在五岁至十岁年龄组诊断的患者中，骨骼畸形的发生率明显高于其他两组（P=0.014）。文献综述还发现了另外 8 名患有神经母细胞瘤并出现与类维生素 A 相关骨骼异常的患者。这 11 名患者的异维 A 酸暴露中位数范围为 6.5 至 7.625 年（范围为 2-14 年），没有在五岁之前完成异维 A 酸治疗的病例。
异维 A 酸暴露相关的骨毒性是一个值得关注的问题。生长板停止是一种严重的不良反应，归因于异维 A 酸治疗。我们的研究结果表明，青春期前的生长板可能风险最大，我们建议对此人群给予特别关注。
