Ann Pediatr Endocrinol Metab.  2022 Sep;27(3):236-241. 10.6065/apem.2142044.022.

Low-dose mitotane-induced neurological and endocrinological complication in a 5-year-old girl with adrenocortical carcinoma

• Heo YJ
• Yoo JH
• Choe YS
• Park SH
• Lee SB
• Kim HA
• Choi JY
• Lee YA
• Lim BC
• Chueh HW

• KMID: 2533344
• DOI: http://doi.org/10.6065/apem.2142044.022

Abstract

Mitotane is an adrenolytic drug that exhibits therapeutic effects within a narrow target range (14–20 μg/dL). Various complications develop if the upper limit is exceeded. We present the case of a 5-year-old girl with breast development, acne, and pubic hair who was diagnosed with an adrenal mass that was subsequently excised. The pathological finding was adrenocortical carcinoma with a high risk of malignancy, and adjuvant therapy (combined mitotane and radiation therapy) was recommended. Mitotane was initiated at a low dose to allow monitoring of the therapeutic drug level, and high-dose hydrocortisone was also administered. However, the patient exhibited elevated adrenocorticotropic hormone levels and vague symptoms such as general weakness and difficulty concentrating. It was important to determine if these symptoms were signs of the neurological complications that develop when mitotane level is elevated. Encephalopathy progression and pubertal signs appeared 6 months after diagnosis, induced by high mitotane level. The mitotane decreased to subtherapeutic level several months after its discontinuation, at which time endocrinopathy (central hypothyroidism, hypercholesterolemia, and secondary central precocious puberty) developed. The case shows that low-dose mitotane can trigger neurological and endocrinological complications in a pediatric patient, indicating that the drug dose should be individualized with frequent monitoring of the therapeutic level.

Keyword

Adrenocortical carcinoma; Mitotane; Adverse effects; Pediatrics

Figure

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  Fig. 1. (A) Computed tomography revealed a large hypervascular mass (7.3 × 7.0 cm) in the left suprarenal area, consistent with adrenocortical carcinoma. (B) Histopathological analysis of the adrenalectomy specimen revealed high nuclear grade and mitotic figures (H&E, x400).

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  Fig. 2. Serum concentration of mitotane and the daily doses and complications over time. Neurological complications began to appear when the mitotane serum level exceeded the target. The drug level gradually increased despite reduction of the dose and required 5 months to fall to within the target range after discontinuation. The numbers in and the lengths of the grey rectangles represent the daily doses relative to the body surface area and the durations of such drug administrations, respectively. The contents of the white rectangle are the mitotane complications that occurred during that period. The contents of the pentagon are the complications that persisted. The black dots are the measured mitotane serum concentrations, while the black lines represent the target range (14–20 μg/dL). CPP, central precocious puberty.

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  Fig. 3. Treatment by time after diagnosis. Hydrocortisone, levothyroxine, and a gonadotropin (GnRH) agonist were used to treat adrenal insufficiency, hypothyroidism, and central precocious puberty, respectively (complications of mitotane use). Calcium carbonate and vitamin D were employed to treat hypocalcemia caused by vitamin D deficiency, hypophosphatemia, and elevated alkaline phosphatase (ALP) level. The numbers above the black arrow are the times (months) after diagnosis. The white rectangle contains the treatments used during that period. The contents of the pentagon are the maintained treatment strategies.

Reference

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