CHEK2 Germline Gene Variant in a Patient with a Somatotrophinoma and Primary Hyperparathyroidism – A Novel MEN1-like Syndrome?

Context Somatotrophinomas can occasionally occur in familial settings, and may be associated with known germline mutations such as MEN1, AIP, CDKN1B, PRKAR1A, SDHx, and MAX. Recently, the CHEK2 gene has emerged as a potential pituitary tumour predisposition gene. Objective A rare case of a patient with a pituitary somatotrophinoma and primary hyperparathyroidism (PHPT) associated with a likely pathogenic CHEK2 germline mutation, suggesting a novel MEN1-like phenotype. Methods We conducted a detailed clinical, biochemical, radiological and genetic evaluation of a 38-year-old woman presenting with features of acromegaly and PHPT. Genetic testing for known MEN1 syndrome-associated genes and broader pituitary tumour predisposition genes was performed. Results The patient presented with features of acromegay of 3 years duration, a collagenoma, Laboratory evaluation revealed an elevated IGF-1. Biochemical and imaging studies also revealed PTH-dependent hypercalcaemia and bilateral inferior parathyroid adenomas. Genetic testing for a panel of genes causing hypercalcemia—including MEN1 and CDKN1B—was negative; however, a pathogenic nonsense variant in CHEK2 [c.232C>T; p.(Gln78Ter); gnomAD frequency 0.0006%] was detected with exome sequencing. The patient underwent transsphenoidal resection of the pituitary tumour followed by gamma-knife radiosurgery, and is currently on long-acting octreotide 4-weekly. Parathyroidectomy was performed 1.5 years later. Conclusions This is first reported case of a CHEK2 germline mutation associated with somatotrophinoma, PHPT and collagenoma, mimicking the clinical MEN1 syndrome. These findings expand the spectrum of possible CHEK2 associated neoplasia, and highlight the need to consider CHEK2 testing as a possible candidate gene in patients with MEN1-like syndromes when common mutations have been excluded.