Monogenetic Non-Diabetic Endocrine Syndromes

Question 1

What are the three main tumour sites involved in MEN Type 1?

Answer 1

(1) Parathyroid glands
(2) Pancreas (gastroenteropancreatic tract)

(3) Anterior pituitary

Question 2

What is the inheritance pattern of MEN1?

Answer 2

Autosomal dominant

Question 3

Which gene is mutated in MEN1 and on what chromosome is it located?

Answer 3

MEN1 gene on chromosome 11q13

Question 4

What is the classic triad for MEN1?

Answer 4

“3 Ps” – Pituitary, Parathyroid, Pancreas

Question 5

What type of pancreatic tumour is commonly seen in MEN1?

Answer 5

Insulinoma

Question 6

What are the leading causes of death in MEN1 patients?

Answer 6

1. Malignant pancreatic neuroendocrine tumours
2. Thymic carcinoids

Question 7

When should genetic testing for MEN1 be considered?

Answer 7

(1) When the patient has ≥2 MEN1-associated tumours

(2) A family history of MEN1

(3) Suspicious clinical features

(4) or is a first-degree relative of someone with a known MEN1 mutation.

Question 8

By what age should asymptomatic individuals at risk be tested for MEN1?

Answer 8

By age 5

Question 9

What is the primary goal of MEN1 management?

Answer 9

To prevent early morbidity and mortality from MEN1-associated tumours while preserving quality of life

Question 10

What genetic mutation causes MEN Type 2?

Answer 10

RET proto-oncogene mutation on chromosome 10q

= autosomal dominant

Question 11

What are the two main subtypes of MEN Type 2?

Answer 11

MEN2A (Sipple syndrome) and MEN2B

Question 12

What is unique to MEN2A compared to MEN2B?

Answer 12

Parathyroid hyperplasia

Question 13

What tumours are common to both MEN2A and MEN2B?

Answer 13

Medullary thyroid cancer (MTC) and phaeochromocytoma

Question 14

What is unique to MEN2B compared to MEN2A?

Answer 14

(1) Mucosal neuromas

(2) Marfanoid habitus

(3) Medullated corneal fibres

(4) Intestinal autonomic ganglion dysfunction

Question 15

Which subtype of MEN2 is more common?

Answer 15

MEN2A

Question 16

What is the typical first manifestation of MEN2?

Answer 16

Medullary thyroid cancer (MTC)

Question 17

What are the symptoms of metastatic MTC?

Answer 17

Neck mass, diarrhoea, flushing, and ectopic ACTH (not common)

= Cushing’s syndrome

Question 18

How is MEN2-associated pheochromocytoma typically present?

Answer 18

1. Often bilateral
2. May occur in childhood
3. Diagnosed by elevated plasma or urinary metanephrines

Question 19

What is the management of pheochromocytoma in MEN2?

Answer 19

Surgical resection with pre-operative alpha blockade

Question 20

How common is primary hyperparathyroidism in MEN2?

Answer 20

Occurs in about 30% of patients, especially in MEN2A

Question 21

What is the significance of early RET mutation testing in MEN2?

Answer 21

Allows early detection and prophylactic treatment (eg, thyroidectomy)

= which can prevent morbidity and mortality from MTC

Question 22

What kind of RET mutations are seen in MEN2B?

Answer 22

Usually de novo activating point mutations in the catalytic domain of the RET enzyme

Question 22

Which gene is responsible for MEN type 2?

Answer 22

RET gene

Question 22

Which 4 abnormalities occur in MEN2B?

Answer 22

1. Medullary thyroid cancer
2. Mucosal neuromas
3. Marfanoid habitus
4. Phaeochromocytoma

Question 23

What is the gene responsible for MEN type 1?

Answer 23

MEN1 gene

Question 23

A 50-year-old woman is referred to the ENT surgeon to screen her for thyroid cancer. She is the sister of a patient recently diagnosed with medullary thyroid cancer. The family history is suggestive of familial medullary thyroid cancer as 2 other first-degree relatives are also affected. She is otherwise clinically well and looks normal An ultrasound suggests malignant features and a FNAC confirms the diagnosis The patient reports to the ENT Doctor that she has been experiencing sweats, flushing and palpitations recently. She is referred to the Endocrinologists for further investigation What test should be done next?

Answer 23

Plasma metanephrines Likely MEN2 The best test with the highest sensitivity for picking this up is a plasma metapnephrines test. Once the diagnosis is confirmed genetic testing for the RET proto-oncogene should also take place

Question 24

MEN-1 is associated with what?

Answer 24

1. parathyroid hyperplasias 2. adenomas 3. gastrinomas 4. insulinomas 5. prolactinomas

Question 25

A 26-year-old male with a history of medullary thyroid cancer in childhood presents to A&E with a one-month history of intermittent palpitations, sweating, nausea and flushing. He is otherwise fit and well and does not drink alcohol or take any recreational drugs. There is a strong family history of thyroid cancer On examination, he is flushed and his blood pressure is 190/95 mmHg. Bloods show a calcium level of 3.00 mmol/L What is the most likely underlying diagnosis?

Answer 25

Multiple Endocrine Neoplasia-2a (MEN2A)

Question 25

A 30-year-old male presents to A&E after his partner found him at home drowsy, confused and verbally aggressive. He has had two similar episodes in the last month after going to the gym. She reports he previously had surgery on a gland in his neck and takes cholecalciferol, calcium carbonate and cabergoline On arrival, his capillary blood sugar is 2.5mmol/L which improves with treatment. A C-peptide is sent, paired with a serum glucose of 2.0mmol/L, and the result is in the normal range. Other investigations are normal. What is the most likely diagnosis?

Answer 25

Multiple Endocrine Neoplasia type 1

Question 25

An 18-year-old male presents with a lump on his neck, which he notices while shaving On examination, it is noted that the patient is particularly tall and thin with arachnodactyly and a high-arched palate. He has mucosal neuromas on the lips, tongue, and eyelids. A 2cm thyroid nodule is palpable Which hormone is likely to be elevated in this case and why?

Answer 25

Calcitonin = This patient has clinical signs typical of type 2 multiple endocrine neoplasia (MEN2). MEN2 is caused by autosomal-dominant mutations that can be inherited or occur sporadically. Tumours typically arise from RET proto-oncogene mutations causing medullary thyroid cancer and/or phaeochromocytoma

Question 26

A 35-year-old man presented with a history of recurrent peptic ulcers and hypercalcaemia Genetic testing revealed a mutation in a tumour suppressor gene on chromosome 11 What is the most likely diagnosis?

Answer 26

Multiple Endocrine Neoplasia Type 1 (MEN 1)

Question 27

A 32-year-old woman is admitted with haematemesis. She has a one-year history of recurrent peptic ulceration which has been unresponsive to ranitidine and omeprazole. She also complains of a milky white discharge from her breasts, and excessive thirst and urination. Endoscopy reveals a 3cm, actively bleeding ulcer in the duodenum. Blood tests reveal hypercalcaemia. What is the most likely diagnosis?

Answer 27

MEN1