Adrenocortical Adenoma, Carcinoma and Pheochromocytoma in A Mother-Daughter Pair Due to A Pathogenic MSH6 Variant

Background:
Pathogenic MSH6 variants may cause Lynch syndrome, an autosomal dominant cancer predisposition syndrome driven by DNA mismatch repair mutations and most commonly associated with colorectal and endometrial malignancies. Although adrenal neoplasms have been described in association with MSH6 mutations, they remain exceedingly rare. This report represents the first case of a familial cluster involving a combination of adrenocortical adenoma, carcinoma and pheochromocytoma.

Case Presentation:
We report a unique mother–daughter pair found to share a pathogenic MSH6 variant (c.3840_3846delGGAGACT, p.E1281Lfs*44), identified following the diagnosis of adrenal tumors in both individuals. The mother had a remote history of a large, nonfunctional left adrenocortical carcinoma (ACC) measuring 13 × 9 cm, treated with open adrenalectomy and adjuvant radiotherapy. Thirteen years later, during an evaluation for gastroenteritis, an incidental growing right adrenal mass was identified. Hormonal evaluation was negative for cortisol, androgen, or mineralocorticoid excess. She subsequently underwent a right mini back scope adrenalectomy (MBSA) and pathology revealed a 3.2-cm nonfunctional oncocytic ACC with an intact capsule and R0 margins. Notably, immunohistochemistry (IHC) demonstrated retained MSH6 expression. The daughter presented with paroxysmal hypertension, headaches, and palpitations. Abdominal imaging revealed a left adrenal mass, and biochemical testing confirmed catecholamine excess with elevated plasma and urinary normetanephrines. She also underwent a partial left MBSA and pathology confirmed a 3.1-cm pheochromocytoma along with a synchronous 1-cm adrenocortical adenoma. Following these diagnoses, genetic evaluation identified the familial MSH6 mutation, with no clinical or biochemical evidence of other hereditary syndromes.

Conclusion:
This familial cluster demonstrates a broad spectrum of adrenal pathology including metachronous ACC, benign adenoma, and pheochromocytoma in the presence of a germline MSH6 variant. The presence of retained IHC expression despite a pathogenic frameshift mutation highlights the limitations of protein staining in specific MSH6 variants and underscores the necessity of genomic characterization. These findings suggest that the endocrine manifestations associated with mismatch repair deficiency may be broader than previously recognized. Recognition of adrenal tumors in this genetic context has critical implications for endocrine surveillance and suggests that adrenal pathology may represent an underrecognized manifestation of mismatch repair deficiency, highlighting the need for further molecular characterization of the link between MSH6 and adrenal tumorigenesis.

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