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Multiple Endocrine Neoplasia Type 2

Multiple Endocrine Neoplasia Type 2. Melissa Sloman Royal Devon and Exeter Foundation Trust. Multiple Endocrine Neoplasia type 2 (MEN2). Autosomal dominant Endocrine cancer syndrome 3 recognised clinical variants MEN2A MEN2B Familial medullary thyroid carcinoma (FMTC)

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Multiple Endocrine Neoplasia Type 2

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  1. Multiple Endocrine Neoplasia Type 2 Melissa Sloman Royal Devon and Exeter Foundation Trust

  2. Multiple Endocrine Neoplasia type 2 (MEN2) • Autosomal dominant • Endocrine cancer syndrome • 3 recognised clinical variants • MEN2A • MEN2B • Familial medullary thyroid carcinoma (FMTC) • All variants show high penetrance of medullary thyroid carcinoma (MTC) • 90% of MEN2 patients will eventually show evidence of MTC

  3. Healthy thyroid gland (dissected) Thyroid lobes showing MTC lesions Medullary thyroid carcinoma (MTC) • First neoplastic manifestation of MEN2 and significant cause of death • Rare tumour of the C cells of the thyroid gland • Multifocal C cell hyperplasia  MTC • Progression from C cell hyperplasia to carcinoma is variable • Metastasis is common • Secretory product of C cell hyperplasia/MTC is calcitonin • High levels of calcitonin are important as a tumour marker

  4. Adrenal gland with phaeochromo-cytoma Healthy Adrenal Glands Phaeochromocytoma • Tumour of Chromaffin cellsin the adrenal medulla (unilateral or bilateral) • Chromaffin cells produce catecholamines – adrenaline, noradrenaline • Ability to suddenly produce large amounts of catecholamines  rise in blood pressure • Patients present with headaches, sweating, tachycardia, palpitations, and in rare cases sudden death • Usually presents after MTC • Only present in MEN2A and 2B

  5. Hyperparathyroidism • Presence of tumours (adenomas) in the one or more parathyroid glands • Parathyroid glands regulate the metabolism of calcium via action of parathyroid hormone (PTH) •  Secretion of PTH leads to hypercalcaemia, loss of calcium from bone, hypercalciuria and renal calculi • Most cases have no symptoms • Feature of MEN2A only

  6. Additonal features of MEN2B • Marfanoid body features • Appear in 75% of cases • Patients are very tall and thin with deformities of the chest and spine • Joints and ligaments are weak • Face is elongated with prominent “blubbery” lips and a characteristic wide-eyed expression • Mucosal neuromas • Found particularly on distal part of the tongue • Tumours composed of fibrous tissue and are connected with a nerve  painful

  7. Subtypes of MEN2 Eng C et al: JAMA 276:1575-1579 (1996)

  8. RET proto-oncogene • 10q11.2 • 21 exons over 53kb of genomic DNA • Receptor tyrosine kinase (1114 amino acids; 124kDa) • Cell surface receptor involved in signal transduction • Crucial role in development

  9. RET mutations in MEN2 10 11 12 13 14 15 16 17 18 19 20 1 2 3 4 5 7 8 9 6 L603Q C609R C609G C609S C609Y C611R C611G C611F C611S C611W C611Y C618R C618S C618G C618F C618Y C620R C620W C620Y C620S C620G C620F 1597ins9 E768D V778I Q781R L790F Y791F A883F S891A S904C M918T S922Y 1906ins12 1912ins9 C630F C630S C630Y C634R C634G C634S C634W C634Y C634F A640G V648I V804M V804L Y806C I852M R884L In red are the mutations identified at the Exeter molecular genetics laboratory

  10. Syndrome Exon MEN2A 10 11 MEN2B 15 16 883 918 10 11 13 14 FMTC Genotype-Phenotype correlations in MEN2 5’ Codons 609,611,618,620 630,634 Exon 10 Exon 11 Cysteine Rich Domain Transmembrane Domain 609,611,618,620 630,634 768,790,791 804 Exon 13 Exon 14 Tyrosine Kinase 1 Tyrosine Kinase 2 Exon 15 Exon 16 Mulligan LM et al J intern Med 238:343-346 (1995) 3’

  11. Biochemical Diagnosis MTC • Plasma calcitonin concentration is measured before, 2, and 5 minutes after intravenous administration of calcium • Positive test = stimulated level is > 3 times the basal level (or > 300ng/L) Phaechromocytoma • elevated levels of catecholamines and catecholamine metabolites in 24hr urine collection Parathyroid adenoma • simultaneously elevated serum concentrations of calcium and parathyroid hormone (PTH)

  12. 10 11 12 13 14 15 16 17 18 19 20 1 2 3 4 5 7 8 9 6 Molecular Analysis • Screening of exons 10, 11, 13, 14, 15 and 16 in the RET gene by direct sequencing • If negative sequencing of remaining 14 exons To establish or confirm the diagnosis of MEN2 in symptomatic individuals Predictive testing of at risk family members

  13. Mutation detection rate www.projects.ex.ac.uk/diabetesgenes/geneticslab/index

  14. Case study – Family W (FMTC) MW ∆50yrs (1972) Died 08/1995 (DNA stored before her death) EG ∆35yrsrs Died 1994 age 42

  15. PATIENT C618S Heterozygous for C618S (c.1853G>C) mutation in exon 10 of RET Gene CONTROL Case study – Family W (FMTC) Sequencing analysis carried out on MW in July 1996 Predictive testing and appropriate counselling now offered to the rest of the family

  16. Case study – Family W (FMTC) MW ∆50yrs (1972) Died 08/1995 Tested 07/1996 AW EG FR VW CK JW Age 43rs Age 39rs ∆35yrsrs Age 34 Age 34 1997 1996 1996 1997 Died 1994 age 42 PG WG JaW EW OW Age 4rs Age 6rs Age 18rs Age 16rs Age 8rs 1999 1999 1999 = Not inherited mutation = Clinically Affected (deceased) = Inherited mutation undergone thyroidectomy = Clinically Affected

  17. Benefits of Genetic testing • MTC is treated by total thyroidectomy • Success depends on degree of malignant progression and should be performed before age of possible metatases • Treatment is often curative and prognosis is good if surgery removes thyroid before metastasis • Treatment for metastatic MTC is difficult and ineffective with standard chemotherapy, X-ray, thermal radiation • Genetic testing allows earlier identification of at risk individuals  prophylactic thyroidectomy • Those who test negative are reassured that they (and their offspring) are unlikely to develop MTC

  18. Benefits of Genetic testing (2) Historically calcitonin stimulation test used for diagnosis • False negative results have been reported • Test relies on development of MTC and associated elevated calcitonin levels • Results can be difficult to interpret in younger individuals • Repeat testing needed at regular intervals when negative • Test is physically unpleasant involving chest and abdominal pain, flushing, nausea, and vomiting  Recommended that thyroidectomy decisions are based on genetic test results

  19. Timing of surgery Timing of prophylactic thyroidectomy in MEN2 <5 years <1 year 5-10 years Eng C et al: JAMA 276:1575-1579 (1996)

  20. Summary • MEN2 is an autosomal dominant inherited endocrine cancer syndrome • 90% of MEN2 patients will eventually show evidence of Medullary Thyroid Carcinoma • Mutations in the RET proto-oncogene predispose to MEN2 • Genetic testing allows identification of at risk individuals • Prophylactic thyroidectomy is primary preventative measure for all subtypes of MEN2

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