Endocrine Abstracts

MEN4 is a rare disease characterized by the development of multiple endocrine tumors caused by mutations in the CDKN1b gene encoding the cyclin dependent kinase inhibitor P27^Kip1. Here we report two new cases and address the potential link of MEN4 with autoimmunity. The 1st patient, a 66-year old woman, presented at 35 years high prolactin levels without evidence of pituitary adenoma, treated medically. At 51 years, she was diagnosed with mild primary hyperparathyroidism associated to osteoporosis without any parathyroid lesion initially identified. Thirteen years later a retro-esophageal parathyroid adenoma was revealed and removed with normalization of blood calcium level. The patient also had breast cancer at 37, papillary ovarian serous cystadenoma at 50 and multifocal micropapillary thyroid carcinoma at 55 years. Heterozygous mutation of CDKN1b gene was found: c.281C>T, p.Pro941Leu in exon 1, not previously reported. Surprisingly the patient also had a remarkable history of autoimmune diseases, with myasthenia gravis at 12 justifying thymectomy for hyperplasia, Sjögren syndrome, type III cryoglobulinemia and asthma. Her father suffered from diabetes and Grave’s disease, her paternal grand-mother from thyroiditis and breast cancer. The 2nd patient, a 70-year old lady was fortuitously diagnosed with a 27×30 mm non-functioning pituitary adenoma at 66 years during a stroke work-up. The volume progression and campimetric involvement led to surgery. Primary hyperparathyroidism was simultaneously discovered, attributed to a unique parathyroid lesion, not removed because of the absence of any complication (Calcium levels ~2.6 mmol/l, PTH 118 ng/ml (N:15–68)). A mild autonomous cortisol secretion linked to a centimetric adrenal nodule was also confirmed. She also had a history of Crohn’s disease treated with azathioprine then steroids and autoimmune thyroiditis. The familial history was difficult to assess because of cognitive impairment. A new heterozygous mutation in exon 1 of CDKN1b gene (c.206C>T, p.Pro69Leu) was identified. These two cases with proved germinal CDKN1b mutations are consistent with literature regarding MEN4, namely MEN1-like phenotype with late occurrence mostly focused on pituitary and parathyroid tumors. Interestingly, both cases were associated with multiple autoimmune disorders, including systemic and organ-related diseases. A previous meta-analysis has shown that CDKN1B was potentially involved in the pathophysiology of systemic lupus erythematosus, with a role in the induction of T-cell tolerance and B-cell lymphopoiesis. Future research about this rare condition will have to investigate this potential association, which confirms the link between neoplasia and immunity.