Acromegaly and late-onset primary hyperparathyroidism in a female with a rare MEN1 gene variant of yet undetermined clinical significance (p.Val167Ala)

We report a case of a female, born in 1952, diagnosed with a rare Multiple Endocrine Neoplasia type 1 (MEN1) gene variant of uncertain clinical significance (p.Val167Ala) presenting with acromegaly, late-onset primary hyperparathyroidism (PHP) and bilateral adrenal tumors. The diagnosis of acromegaly due to pituitary macroadenoma was confirmed at the age of 45. After a non-radical transsphenoidal resection of the pituitary tumor, with histopathological confirmation of adenoma chromophobe, treatment with long-acting somatostatin analogue was introduced, resulting in successfully normalized both insulin-like growth factor and growth hormone values. Mild hypercalcemia was discovered for the first time during endocrinological follow-up at the age of 56, with elevated parathyroid hormone level and increased urine excretion of calcium. 99mTc-MIBI single-photon emission computed tomography/computed tomography showed no typical focal accumulation of the tracer, only an increased uptake in the topography of the upper right parathyroid. The radiological image of the hypothalamic-pituitary area remained stable since medical treatment implementation: pituitary magnetic resonance imaging showed the remnants of the pituitary gland, less than 1 mm in diameter, at the bottom of the sella turcica and two hypointense masses enhancing heterogeneously after contrast administration: 11x8x13 mm in the right lateral part of the turkish saddle and a similar 7x4x5 mm lesion on the left, in direct proximity to cavernous sinuses. Low density 25x16x21 mm tumor in the right adrenal gland and a similar 13 mm focal lesion in the left adrenal were confirmed in abdominal computed tomography. Endocrinological evaluation detected no abnormal hormonal function of the adrenal tumors. Sanger sequencing confirmed the MEN1 variant p.Val167Ala – a missense variant registered in NCBI dbSNP under the accession number rs748648909. In NCBI ClinVar, it was summarized to be of uncertain clinical significance (RCV000632131.2). So far, this variant has not been described in HGMD and UMD-MEN1 databases. Multiple neuroendocrine neoplasia type 1 is a rare genetic disorder with an autosomal dominant inheritance. 1336 MEN1 gene sequence abnormalities were described in only 10 years following the identification of the gene. The phenotype-genotype correlation among MEN1 patients in terms of tumor localization, age of onset and clinical aggressiveness has not been established yet. Further follow-up of the patient and cascade screening of her family members should be carried out to determine the clinical significance of the variant p.Val167Ala.