Analysis of the effects of isotretinoin on the premature epiphyseal closure in pediatric populations: a literature review

Context Oral isotretinoin, a systemic retinoid and a vitamin A derivative, has been widely utilized to treat acne in both adult and pediatric populations. Additionally, systemic retinoids have also been utilized to treat neuroblastoma in pediatric patients. Common side effects associated with oral isotretinoin include dry eyes, dry mouth, elevated liver enzymes, depression, and arthralgia. Less common side effects of isotretinoin include hearing loss, pseudotumor cerebri, anaphylaxis, and skeletal abnormalities including growth arrest. The U.S. Food and Drug Administration (FDA) has received reports of premature epiphyseal closure in patients treated with isotretinoin retinoids, which are commonly prescribed by primary care providers as a treatment for acne. It is important to raise awareness of the potential side effects of isotretinoin to enable informed treatment decisions before beginning an isotretinoin regimen. Objectives This chapter aims to elucidate that isotretinoin, given at various doses and durations, has been associated with growth plate abnormalities, which can lead to premature epiphyseal closure. Methods Two databases were utilized for the literature review and were conducted at different time periods. Our literature review was conducted between December 2020 and June 2021, utilizing PubMed with the following search terms: “isotretinoin” and “isotretinoin and premature epiphyseal closure.” In April 2021, we searched the FDA’s “Drug Data and Adverse Event Report System” utilizing the terms “isotretinoin” and “epiphysis premature fusion.” We included in our query reports of patients worldwide under 18 years of age with premature epiphyseal closure or growth plate damage secondary to isotretinoin. Studies published in English between 1980 and 2020 were also included, as well as background sources relating to an isotretinoin profile with side effects and dosing. We narrowed our search to exclude patients with a history of growth plate disorders due to trauma, malignancy, or other pathological processes, as well as patients with growth arrest due to endocrine factors. Growth plate abnormalities associated with retinoid derivatives other than isotretinoin were also excluded. Results A total of 28 items were selected for our literature review including: one FDA drug label, one FDA website of adverse reactions, 19 supplemental articles, six case reports, and one case series of premature epiphyseal closure secondary to isotretinoin. The FDA received 41 reports worldwide of premature epiphyseal closure related to isotretinoin in patients under 18 years of age. Additionally, premature epiphyseal closure and growth plate abnormalities occurred in nine patients with various durations and doses of isotretinoin ranging from the lowest dose of 0.5 mg/kg/day for a few months to 3.5 mg/kg/day for years. Conclusions Isotretinoin-induced premature epiphyseal closure and growth plate deformities seem to be linked to higher doses of isotretinoin for the duration of months to years. There have been reported cases of premature epiphyseal closure in individuals receiving therapeutic doses of isotretinoin for acne treatment, which are much lower compared to the high doses utilized for neuroblastoma. Based on this study, isotretinoin appears to impact the growth plates of proximal tibia and distal femur. A cause-and-effect relationship between isotretinoin and premature epiphyseal closure cannot be concluded.

Genu varum deformity due to premature epiphyseal closure after treatment with isotretinoin for neuroblastoma: A case report

Isotretinoin, a vitamin A derivative, is known to induce premature epiphyseal closure. We report the case of a 9-year-old boy with neuroblastoma who demonstrated premature epiphyseal closure after 1 year of isotretinoin treatment (72.3 mg/m2/day). A bone bridge developed on the bilateral proximal tibial growth plate resulting in genu varum. We performed hemiepiphysiodesis on the bilateral proximal tibia in anticipation of the spontaneous resolution of the bone bridge. Genu varum on the left side was corrected with the resolution of bone bridge. For the remaining bone bridge on the right side, arthroscopy-assisted physeal bar resection was performed, and genu varum on the right lower extremity was also corrected. A regular review of the alignment of the upper and lower limbs is necessary to provide timely intervention in patients using isotretinoin, considering the possibility of premature epiphyseal closure.

Treatment of tumor-like lesions in the femoral neck using free nonvascularized fibular autografts in pediatric patients before epiphyseal closure

Objectives Surgical resection of benign bone tumors and tumor-like lesions at the femoral neck presents a difficult reconstructive challenge. However, the safety and efficacy of free nonvascularized fibular autografts (FNFAs) in the treatment of femoral neck tumor-like lesions before epiphyseal closure in young patients remain unknown. Methods Sixteen pediatric patients who had not yet undergone epiphyseal closure were treated with FNFAs after resection of tumor-like lesions in the femoral neck from August 2012 to September 2016. All patients underwent supplementary skeletal traction through the supracondylar femur for 4 to 6 weeks after resection. Demographic data were recorded and clinical and radiological outcomes were evaluated during the follow-up. Results All patients could walk with partial weight bearing 4 weeks postoperative, and full weight bearing was permitted after a mean of 8 weeks. Graft union was attained in all 16 patients at a mean of 2 months. The donor site of the fibular cortical strut showed good regeneration in all patients. The Harris hip score significantly improved from 65% to 95%. Conclusions Application of an FNFA is a feasible method in the treatment of tumor-like lesions in the femoral neck before epiphyseal closure in pediatric patients. Level of Evidence Level IV.

Epiphyseal Closure Time of Radius and Ulna Bones of the Proximal Section

Accurate determination of age is important in the legal process; when a person’s age is unknown or must be authenticated, a forensic age identification method must be applied. One of such methods is to assess the epiphyseal closure on the bone through radiological examination. The main problem associated with the use of this method is the relevance of the reference population provided because epiphyseal closure is influenced by genetics and nutrition. This method needs data to represent each population. Radiological examination of elbow bones of 30 male patients aged 11-30 years and 18 female patients aged 14-28 years in Dr. Soetomo Hospital, Surabaya from January to April 2016 was carried out to determine the time of epiphyseal closure of the radius and ulna distal section. This was cross-sectional descriptive study. In conclusion, epiphyseal closure of proximal radius and ulna is complete at age 16 in males and 14 in females.