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

Abstract

Mitotane is an adrenolytic drug that exhibits a therapeutic effect 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; she was diagnosed with an adrenal mass that was then excised. The Pathological result was adrenocortical carcinoma with a high risk of malignancy, and adjuvant therapy (combined mitotane and radiation therapy) was commenced. Mitotane was initiated at a low dose to allow monitoring of the therapeutic drug level, and high-dose hydrocortisone was also commenced. However, the patient showed elevated adrenocorticotropic hormone levels and vague symptoms such as general weakness and difficulty in concentration. It was important to determine if these symptoms were signs of the neurological complications that develop when mitotane levels are elevated.Encephalopathy progression and pubertal signs appeared 6 months after diagnosis, induced by elevated mitotane levels. The mitotane levels decreased to sub-therapeutic levels several months after discontinuation of mitotane, at which time endocrinopathy (central hypothyroidism, hypercholesterolemia, and secondary central precocious puberty) also developed. The case shows that low-dose mitotane can trigger neurological and endocrinological complications in a pediatric patient; the drug dose should be individualized with frequent monitoring of the therapeutic level.

Neurological adverse events of mitotane in adrenocortical carcinoma: results of a pilot study

“…At mitotane discontinuation, neurological symptoms disappeared completely 6 months later. A case of neurological toxicity, characterized by attention-deficit hyperactivity disorder, has been reported also in a 5-year-old girl at a low dose of mitotane (1.25 g/m 2 /day) and with drug plasma concentration below the therapeutic range ( 41 ). At a mitotanemia increase (24 mg/L), the neurological symptoms worsened, and the patient developed daytime sleepiness, memory disturbances, slurred and repetitive speech, ataxia, and tremors.…”

Precocious puberty and other endocrine disorders during mitotane treatment for paediatric adrenocortical carcinoma – case series and literature review

“…Mitotane also has oestrogenic action, possibly impacting bone age advancement [ 30 ]. In the literature, there are only a few case reports of children in whom mitotane therapy recognized peripheral precocious puberty [ 28 , 30 ]. To our knowledge, our report of 4 patients with PP during the mitotane treatment is the largest study.…”

“…A 5-year-old girl described by You Joung Heo developed cognitive and concentration disturbances with behavior regression 2 months after the start of mitotane treatment; at the last follow-up (at the age of 6.6 years), she exhibited only mild sleep and memory disturbances [ 28 ]. Based on the analysed literature, neurological symptoms usually, but not always, occurred in children with mitotane levels above the therapeutic level.…”

Overview of endocrine tumor syndromes manifesting as adrenal tumors

“…Most adrenocortical tumors in adults are discovered incidentally, without excess adrenal hormone production, although 15% are functioning tumors [2]. In contrast, in the pediatric population, adrenal hormone excess is observed in about 80% to 90% of patients, with two age peaks: the first 5 years of life and adolescence [4,5]. In pediatric cases, androgen excess is the commonly observed presentation, followed by Cushing syndrome or a combination of both [4].…”