Genetics and Endocrinology

Question 1

What is the mnemonic for the MEN syndromes and are they dominant or recessive?

Answer 1

MEN1 = 3 P's
MEN2A = 2 P's
MEN2B = 1 P

All MEN are dominant!

Question 2

What are multiple endocrine neoplasias?

Answer 2

Heritable syndromes causing aberrant growth of endocrine tissues, which may benign or malignant. The endocrine tissues may be functional or nonfunctional

Question 3

What gene is mutated in MEN1, and what condition dominates the clinical picture of the disease?

Answer 3

Caused by mutation in MEN1, a gene coding for menin, a tumor suppressor on chromosome 11

Clinical course is dominanted by hyperparathyroidism -> most people have elevated serum calcium levels by the fifth decade. Parathyroid adenomas and parathyroid hyperplasia are very common.

Question 4

What are the 3 P’s of MEN1?

Answer 4

Pituitary tumors
Pancreatic endocrine tumors
Parathyroid adenomas

Question 5

What Pituitary tumors are common of MEN1?

Answer 5

Usually prolactinoma, may also be growth hormone secreting (mammosomatotroph precursor)

Question 6

What tumor is most specifically associated with MEN1 and thus all patients who have it should be screened?

Answer 6

Zollinger-Ellison syndrome (gastrinoma).

-> Used to be the major cause of death in this disorder before PPIs

Question 7

What are four tests which you should run to screen the health of individuals with MEN1?

Answer 7

1. Serum Ca+2 / PTH - check for primary hyper PTH (most common association)
2. Serum Gastrin -> ZES
3. Serum Prolactin -> most common pituitary adenoma
4. Fasting insulin / glucose -> other pancreatic malignancies

Question 8

What other pancreatic tumors are associated with MEN1? Why might you want to run a CT scan in these patients?

Answer 8

Pancreas: ZES > insulinoma > VIPomas / Glucagonomas which are very rare

CT scan may be useful for checking for thymoma -> malignant thymic carcinoid is a common cause of mortality on top of pancreas

Question 9

What type of gene is dysfunctional in MEN2A/2B?

Answer 9

RET -> proto-oncogene, a receptor tyrosine kinase which can now be targeted by new hormonal therapy

Question 10

What are the 2 P’s of MEN2A? What tumor is most characteristic of the MEN2 syndrome as a whole?

Answer 10

Parathyroid hyperplasia (remember parathyroid problems are in 1 and 2A, makes sense via Venn diagraphm)
Pheochromocytoma (occurs in both)

Most characteristic of both MEN2A and MEN2B:
Medullary Thyroid Carcinoma

Question 11

What is the 1 P of MEN2B? What other neoplasias / symptoms associated with it?

Answer 11

Pheochromocytoma

Also, obviously: Medullary thyroid carcinoma

+

1. Marfanoid Habitus -> long slender body
2. Mucosal neuromas

Question 12

What disease dominates the clinical course of MEN2? How does the aggressiveness compare between genetic causes?

Answer 12

Medullary thyroid carcinoma

MEN2B worse than MEN2A

Question 13

What are the oral findings of MEN2B? Intestinal findings?

Answer 13

I just told you dumb, mucosal neuromas -> they’re little mouth nerve tumors.

May find intestinal ganglioneuromas as well

Question 14

What is the general thyroid management from MEN2?

Answer 14

Measure base calcitonin levels. Then, do prophylactic thyroidectomy, always. Do serial calcitonins to check for appearance of parafollicular cells.

Question 15

What occurs if you have a homozygous inactivating mutation of the CaSR? What should be done?

Answer 15

Severe neonatal hyperparathyroidism

• > no suppression of PTH release
• > requires urgent parathyroidectomy

Question 16

What are pseudohypoparathyroidism (PHP) type 1a and pseudo-PHP?

Answer 16

GNAS1 is gene encoding alpha subunit of Gs protein coupled to PTH receptor
1a - maternal transmission, results in renal + bone unresponsiveness to PTH, giving AHO phenotype. Includes resistant to other G-protein using hormones i.e. TSH, LH, FSH, GnRH

pseudo-PHP - paternal transmission -> AHO phenotype but not kidney unresponsiveness

Question 17

What are pseudohypoparathyroidism type 1b and type 1c?

Answer 17

1b - GNAS1, maternally transmitted again, but deficiency in the regulator of the GNAS1 rather than protein itself -> hypocalcemia (renal PTH resistance) but not AHO

1c - G protein does not couple correctly - similar phenotype to 1a

Question 18

What is PHP 2?

Answer 18

Mutations in cAMP protein kinase regulator

-> similar to 1b: renal resistance to PTH, but no AHO phenotype

Question 19

What are the common features of autoimmune polyglandular syndrome Type 1, clinically? Remember this is the AIRE gene problem,

Answer 19

1. Hypoparathyroidism -> autoimmune
2. Addison’s disease -> adrenal insufficiency
3. Chronic mucocutaneous candidiasis -> autoimmune disorder characterized by lack of appropriate T cell immunity

Question 20

Is APS-2 more or less common than APS-1 and what causes it?

Answer 20

More common than APS-1 -> polygenic dominant, affects many different glandular systems with autoimmune disease

Question 21

What are common conditions caused by APS-2?

Answer 21

1. Addison’s disease - 100% of people
2. Graves’ disease - 70%
3. Type 1 diabetes - 50%

Question 22

Give one X-linked autoimmune polyendocrinopathy and the major protein affected in the syndrome.

Answer 22

Immunedysregulation, Polyendocrinopathy, and Enteropathy (X-linked) = IPEX

Major protein affected: FoxP3 T-reg regulation is lost

Question 23

What is defective in Prader-Willi to cause obesity?

Answer 23

Increased ghrelin levels

Question 24

What is the problem in Bardet-Biedl syndrome?

Answer 24

Ciliary dysfunction -> one autosomal recessive cause of obesity

-> like prader willi, this is a form of monogenic diabetes

Question 25

What is Maturity-Onset Diabetes of the Young (MODY) generally? What is the pattern of inheritance? What is it also called?

Answer 25

Pattern of inheritance - autosomal dominant. These are like strange, inherited, non-insulin-DEPENDENT (but often requiring), early onset diabetes

Also called monogenic diabetes, diabetes which is not as complex as Type 1 or Type 2 inheritance.

Question 26

What are two broad causes for MODY / monogenic diabetes?

Answer 26

1. Increased insulin resistance
   - > can be problems with insulin signalling
2. Defective insulin secretion -> usually enzymatic

Question 27

What is one really common form of MODY and how is this the poster child for the condition?

Answer 27

Glucokinase defect -> increased plasma levels of glucose are necessary to elicit normal levels of insulin secretion

-> insulin levels will be relatively within normal range, but there is a mild, stable fasting hyperglycemia