Multiple endocrine neoplasia type 2
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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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Multiple endocrine neoplasia type 2

Multiple Endocrine Neoplasia Type 2

Melissa Sloman

Royal Devon and Exeter Foundation Trust


Multiple endocrine neoplasia type 2 men2

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


Medullary thyroid carcinoma mtc

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


Phaeochromocytoma

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


Hyperparathyroidism

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


Additonal features of men2b

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


Subtypes of men2

Subtypes of MEN2

Eng C et al: JAMA 276:1575-1579 (1996)


Ret proto oncogene

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


Multiple endocrine neoplasia type 2

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


Genotype phenotype correlations in men2

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’


Biochemical diagnosis

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)


Molecular analysis

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


Mutation detection rate

Mutation detection rate

www.projects.ex.ac.uk/diabetesgenes/geneticslab/index


Case study family w fmtc

Case study – Family W (FMTC)

MW

∆50yrs (1972)

Died 08/1995

(DNA stored before her death)

EG

∆35yrsrs

Died 1994

age 42


Case study family w fmtc1

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


Multiple endocrine neoplasia type 2

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


Benefits of genetic testing

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


Benefits of genetic testing 2

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


Timing of prophylactic thyroidectomy in men2

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)


Summary

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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