MON-509 RET Mutations in the MEN1 Syndrome: Is It an Innocent Bystander?

Abstract

IntroductionMENIN and RET mutations in MEN1 families, are rare, and, when they co-exist either mutation may predominate the clinical picture.We report a family, with both mutations, and, suspect that the RET mutation may not be an innocent bystander.Clinical CasesGM (36M): 2009: Presented with skin lesions and a lactotroph adenoma causing chiasmal compression. Treatment: Hypophysectomy and Cabergoline. This resulted in restoration of sexual function and fertility.2013: Developed hyperparathyroidism [Calcium 10.6mg% (8.5-10.5); PTH 610pg/ml (10-65); MIBG Scan: parathyroid adenomas]. Treatment: Subtotal parathyroidectomy with allotransplant.2015: Developed Zollinger-Ellison Syndrome [multiple gastric ulcers; S Gastrin: 516pg/ml; (0-180)]. Treatment: Pantoprazole.MRI Abdomen: Calcific atrophic pancreas and bilateral non-functioning adrenal adenomas.HM (32M): 2008: Skin lesions and Lactotroph adenoma. Treatment with Cabergoline resulted in restoration of sexual function and a reduction in breast and tumour size.2013: Hyperparathyroidism [Calcium 10.9mg%; PTH: 166pg/ml; Calcium excretion: 1160mg/24hrs (100-250); BMD: Osteopenia. MIBG 123 Scan: Avid uptake in Right Inferior parathyroid gland]. He underwent a subtotal parathyroidectomy with allotransplant.2015: Recurrent Hyperparathyroidism (Calcium 10.7mg%; PTH: 116pg/ml; MIBG 123 scan: Hyperfunction of the transplanted gland). Stable on treatment with Cinacalcet.Their mother, AM (42F): 1980: Detected to have a lactotroph adenoma when investigated for primary infertility and galactorrhoea. She was treated with Bromocriptine and delivered the boys in 1980 and 1984 respectively. She had recurrent renal calculi and hydronephrosis (? hyperparathyroidism). She succumbed to renal failure following surgery for a benign pancreatic cystadenoma in 1990.DiscussionWhole exome sequencing of GM and HM showed pathogenic mutations of both, MENIN and RET gene. The precise mutation was a stop gain mutation at exon 3 MENIN.C511T:p.Q171X . They (GM/HM) also harboured a mutation in the RET gene at exon 14 c. G2492T: p.G831V; g. chr10. This may be the first family in which the rare combination of these two mutations has been reported.The genomics and the clinical presentation suggest that the MENIN mutation predominates in the family, but the presence of bilateral adrenal adenomas in GM are significant on account of RET mutation. The latter may be a harbinger of serious disease in the future. The situation is further compounded by the recurrence of hyperparathyroidism in the allograft of HM. This may be caused due to chance or an unknown genetic/ epigenetic phenomenon in the two MEN mutated genes and RNA sequencing of the tumour tissue may explain the genetic phenomenon. The latter two events suggest that the RET mutations in MEN1 may not be an innocent bystander.