Endocrine Abstracts

Background: Adamantinomatous craniopharyngiomas (ACPs) are rare, benign, epithelial tumours of the sellar-suprasellar region. Craniopharyngiomas cause considerable morbidity and mortality due to local invasion and treatment-related damage to surrounding structures, including the hypothalamus and pituitary gland, leading to hypopituitarism and diabetes insipidus (DI). Trametinib is a highly selective mitogen-activated protein kinase (MEK) inhibitor, which has been recently used in the management of treatment-resistant brain tumours, including suprasellar low-grade gliomas, papillary craniopharyngiomas and Langerhans cell histiocytosis, by inhibiting the oncogenic MEK/ERK pathway. Despite being thought to have less side effects, off-target toxicities of such molecular therapies such as hyponatraemia have been described.

Case report: An 11-year-old girl presented with multiple relapses of an ACP which was initially diagnosed at age 3-years. Due to multiple progressions, she underwent several decompressive surgeries, proton beam therapy and Ommaya reservoir insertion. She developed a left hemispheric stroke post-irradiation and a right hemispheric stroke following surgical resection. Panhypopituitarism and optic atrophy were already present at diagnosis, and she subsequently developed hypothalamic obesity and impaired glucose tolerance. She had multiple episodes of adrenal crises and her DI was difficult to manage, required gradual escalation in desmopressin doses up to 1.4 mg/day in 5 divided doses. Multiple solid and cystic progressions led to increasing lethargy, headaches and decreased quality of life, requiring cyst aspiration every 7-10 days, providing temporary but not sustained improvement. A trial of Trametinib was commenced given positive immunohistochemistry for phosphor-ERK. At commencement, she had a serum sodium of 132 mmol/l. After one week, she presented with abdominal pain, diarrhoea, drowsiness and collapse with hyponatraemia (120 mmol/l) whereby desmopressin was withheld. Her desmopressin was restarted gradually and she was stabilised on 150 micrograms/day (11% of her original dose) to maintain eunatraemia.

Conclusion: Hyponatraemia is a known side-effect of Trametinib, hypothesised to be due to insertion of aquaporins into the renal tubules, and increased renal free water reabsorption. As such, patients with known DI need close sodium monitoring and close review of desmopressin doses when starting Trametinib under the supervision of a paediatric endocrinologist.