(CSEMP038) CHEK2 VARIANT WITH THYROID CANCER AND AUTOIMMUNE ADRENALITIS

Abstract:

Introduction: Checkpoint kinase 2 (CHK2; CHEK2 gene) is a protein kinase involved in the DNA-damage-signaling pathway and is an upstream regulator of various DNA-damage-activated protein kinases. Various malignancies have been previously associated with CHEK2 gene mutations including thyroid, breast, colorectal, renal, adrenocortical and prostate cancers. CHK2 has not been previously associated with autoimmune etiologies.

Case Presentation: A 27-year-old woman presented with a new lump in her neck. Pathology confirmed a 1.5 cm differentiated papillary/follicular thyroid cancer stage T1BN0 after a right thyroidectomy. She underwent completion thyroidectomy and remained stable on TSH suppression with levothyroxine. Six years later, she presented with nausea, vomiting, platypnea and hypotension. Broad work-up was undertaken which included adrenal evaluation. This showed an AM cortisol of < 14 nmol/L and an ACTH 366 pmol/L. CT adrenals showed bilateral small adrenal glands. Her presentation was consistent with primary adrenal insufficiency and she was treated with IV hydrocortisone until transitioning to PO hydrocortisone and fludrocortisone. Subsequent testing returned positive for anti-adrenal antibodies. Genetic testing was undertaken which revealed a likely pathogenic EX2_3dup CHEK2 gene variant.

Discussion: CHEK2 is classically associated with malignancies, including rare reports of multiple endocrine gland tumours, pancreatic neuroendocrine tumours, and pituitary adenomas (e.g. Cushing’s disease and acromegaly). While CHEK2 has not been previously associated with autoimmune adrenalitis, some models have described the potential link between defective DNA repair mechanisms and autoantibody production in other autoimmune diseases. For example, in SLE, lower DNA repair capacity is thought to result in cellular apoptosis and autoantibody production.