Endocrine Abstracts

JOINT3281

Multiple endocrine neoplasia type 4 (MEN4), caused by heterozygous inactivating mutations of the CDKN1B gene, is a rare hereditary syndrome presenting a combination of multiple endocrine tumors. It is characterized by a great overlap with MEN1 syndrome, having primary hyperparathyroidism (PHPT) the highest penetrance. Other tumors including renal, gonadal, adrenal, and thyroid tumors may be present. Here we describe six new MEN4 kindreds. The germline DNA of all the probands underwent next generation sequencing using a panel of PHPT-related genes. The proband of family 1 was a 55-yr woman with PHPT and bilateral adrenal lesions. An inferior left parathyroid adenoma was removed leading to the remission of PHPT after 21 months follow-up. The proband and her two siblings, both having mild elevated PTH levels and normocalcemia, carried a CDKN1B variant (c. 482C>G, p. Ser161Cys). The proband of family 2 was a 29-yr woman with PHPT and uterine myoma. An inferior left parathyroid adenoma was excised, resulting in the remission of PHPT after 43 months of follow-up. The proband and her mother affected by PHPT carried the CDKN1B variant c. 356T>C, p. Ile119Thr. The proband of family 3 was a 42-yr woman with PHPT, pancreatic neuroendocrine tumor (PNET) and single adrenal lesion. Inferior and superior right parathyroid adenomas were removed, leading to the remission of PHPT after 45 months of follow-up. The proband’s mother was also affected by PHPT and is under surveillance. Both carried the CDKN1B variant c. 358G>A, p. Gly120Arg. The proband of family 4 was a 60-yr woman with PHPT, a non-functioning PNET, uterine myoma, bilateral adrenal hyperplasia, and melanoma. An inferior right parathyroid adenoma was removed leading to the remission of PHPT after 9 months of follow-up. She carried the CDKN1B variant c. 230A>C, p. Gln77Pro. The proband’s sister, affected by PHPT, and the healthy nephew carried the same variant. The proband of family 5 was a 30-yr woman with PHPT. A superior left parathyroid adenoma was removed leading to the remission of PHPT after 66 months of follow-up. The proband and the healthy mother carried the CDKN1B variant c. 470C>T, pThr157Ile. The proband of family 6 was a 59-yr woman with recurrent PHPT due to right inferior, and left superior and inferior parathyroid adenoma. She carried the CDKN1B variant c. 274C>T, p. Pro92Ser. The CDKN1B variants segregate with the disease in all kindreds although they were classified as variants of unknown significance. Their functional consequences remain to be established.