Genetics in thyroid disease

Question 1

Discuss the genetics of MEN syndromes

Answer 1

MEN = Multiple Endocrine Neoplasia All inherited in an autosomal dominant fashion MEN1 - Mutation of MEN1 tumour supressor gene - codes for Menin which suppresses transcription, loss of function, two hit hypothesis. AKA Wermer syndrome. Affects tumour growth factor bets signalling. MEN2 - mutation of RET proto-oncogene, codes for a receptor tyrosine kinase - gain of function MEN2a MEN2b FMTC

Question 2

Presentations in MEN1

Answer 2

AD, highly penetrant, variable expression 90% inherited, 10% sporadic 1/35,000 Triple Ps - parathyroid (90% have hyperparathyroidism, usually four gland hyperplasia (ie not single adenoma)) - pituitary (anterior) - commonly prolactinomas - pancreatic - 80% have multiple adenomas, islet cell hyperplasia, often gastrinomas (ZES) More rarely Triple C - carcinoids, cortical (adrenal), cutaneous lipoma 1/3 of patients with MEN1 will die early from an MEN1 related malignancy

Question 3

Surveillance in MEN1

Answer 3

Gene analysis offered Test all people with isolated gastrinomas (25% will have MEN1) Surveillance - - annual PTH and Ca - insulin, gastrin, glucose, VIP, pancreatic peptide, glucagon, somatostatin - annual prolactin and IGF1 - annual chromogrannin A - 3-5 yearly MRI of pancreas and chromogrannin

Question 4

Presentations in MEN2a

Answer 4

MEN2 - RET proto-oncogene, gain of function, codes for a tyrosine kinase receptor MPH tumours (2Ps, 1M) - Medullary thyroid cancer (>90%) - Phaeochromocytoma (50%) - Hyperparathroidism - Hirschprungs - Lichen planus amyloidosis

Question 5

Presentations in MEN2b

Answer 5

MEN2 - RET proto-oncogene, gain of function, codes for a tyrosine kinase receptor Half inherited in AD fashion, half are sporadic Rarest and most virulent Distinguished by devleopmental defects and absence of hyperparathyroidism, average age of Dx by age 10 MMH (1P, 2Ms) - Phaechromocytoma - Medullary thyroid cancer (most) - Marfanoid characteristics, mucosal neuroma (and cafe au lait spots) Prophylactic thyroidectomy in age <2 Risk stratificatoin into three levels based on position of mutation on RET gene 1 - MEN2B and some MEN2a - thyroidectomy at age 6 months 2 - thyroid out <5 years 3 - not needed before 10 yo Post-op surveillance with calcitonin

Question 6

Differential Diagnosis of thyroid nodule

Answer 6

Solitary or benign Benign or malignant Benign - - colloid nodule - thyroid cyst - thyroiditis - follicular adenoma - hurthle cell adenoma - toxic adenoma - plummer disease (toxic MNG) Malignant - PTC - FTC - Hurthle cell thyroid cancer - Medullary thyroid cancer - Anaplastic thyroid cancer - Thyroid lymphoma - Metastatic disease (renal, pulmonary, breast)