Endocrine Abstracts

JOINT1828

Introduction: Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant disorder caused by germline mutations of the tumor suppressor MEN1 gene. The most common manifestations include: primary hyperparathyroidism (PHPT), pituitary adenomas (PA) and gastroenteropancreatic neuroendocrine tumors (GEP-NET). The classical Sanger monogenic sequencing of the MEN1 gene is the gold standard for the genetic diagnosis. In 10-30 % of MEN1 patients, no mutation is identified through this technique and those are defined as genotype-negative (GN)-MEN1. GN-MEN1 typically has a more favorable clinical course than the genotype-positive MEN1. We herein report two cases of genotype-negative MEN1.

Case Presentation: The first patient, a 60-years-old woman with no family history of MEN1, presented with classic features of MEN1: primary hyperparathyroidism caused by double parathyroid adenomas, for which she underwent surgical excision of the left parathyroid glands, a non-functional pituitary microadenoma and a well-differentiated NET of the ileum, with hepatic and lymph node metastases, for which she was admitted to surgery. She is currently undergoing treatment with lanreotide. She associates non-functional left adrenal hyperplasia and a history of papillary thyroid carcinoma for which she underwent total thyroidectomy and radioactive iodine therapy. The Sanger sequencing of the MEN1 gene revealed no pathogenic variant. The second patient is a 33-years-old woman with two manifestations suggestive for MEN1: double pituitary microadenomas with prolactin secretion and primary hyperparathyroidism with no ecographic localisation, for which she will undergo parathyroid scintigraphy. There is no family history of MEN1. She associates non-functional bilateral andrenal hyperplasia. No MEN1 gene mutations have been identified by the Sanger sequencing.

Conclusion: Sanger sequencing of the MEN1 gene is the gold standard method for accurate detection of single nucleotide variants and small deletions/insertions, but it cannot identify gross gene deletions/insertions. Multiple ligation-dependent probe amplification (MLPA), a multiplex PCR technique that is able to detect large MEN1 coding region deletions/duplications should be considered in MEN1 index cases with negative MEN1 sequencing test. In addition, germline mutations in other genes that may cause a MEN1-like disorder, such as the AIP gene and the cyclin-dependent kinase inhibitor genes CDKN1A, CDKN2C, CDKN2B and CDKN1B, should be considered for further investigations. In conclusion, all methods of genetic testing have their limits, but a high clinical suspicion should be reason enough for more thorough research.