MK, 32yo F, presented with primary hyperparathyroidism (PHPT) age 26. Imaging revealed three enlarged parathyroid glands, and she underwent bilateral neck exploration and subtotal parathyroidectomy. There was no family history of endocrinopathy.
Genetic testing was negative for MEN1 gene mutations, but a CDKNB1 unclassified gene variant was noted (CDKN1Bc.482c>G p.SER161Cys). Genetic testing revealed her father had the same CDKNB1 variant, but with no known disease. Given her clinical syndrome, she was commenced on a screening protocol for MEN1.
Pituitary MRI demonstrated a 15x13x12mm left pituitary macroadenoma. Serial MRI abdomen and gastrointestinal hormone testing are normal. Serum calcium has remained between 2.55-2.65mmol/L, with an elevated PTH.
This case demonstrates a patient with clinical evidence of a MEN1 syndrome, manifesting with a pituitary adenoma and parathyroid hyperplasia, with no MEN1 gene mutation, but a mutation in CDKNB1 of uncertain significance.
Discussion
5-25% of patients with clinical MEN1 lack typical MEN1 gene mutations, and are labelled “phenocopies”1. Initially described in mouse models, mutations in the cyclin dependent kinase (CDK) inhibitor 1b gene (CDKN1B) have been identified in patients with multiple endocrine neoplasias, and these patients have been reclassified as MEN42.
Identifying pathogenicity of a genetic mutation is challenging. In our patient, the gnomAD database was reviewed and found that 48 healthy patients were heterozygotes for the same mutation as our patient without known manifestations of MEN. The CDKN1B gene is known to tolerate mutational burden without impaired gene function. Additionally, our patient’s mutation has not been reported in the literature, and has thus been labelled ‘unclassified’. Nevertheless, MK has a clinical diagnosis of MEN1.
PHPT in MEN1 requires subtotal or total parathyroidectomy. Recurrent/persistent PHPT occurs in 30-66% of patients after 8 years follow up3. Ectopic parathyroid glands may be present in thymic tissue, therefore prophylactic thymectomy should be considered with initial surgery4.