Pheo/APS/MEN

Question 1

Which HLA alleles are associated with risk of developing type 1 diabetes?

Answer 1

• HLA DR3,DQ2 and DR4,DQ8
• Present in 95% of those with DM1 and only 40% of general population
• DQ rather than DR genotype is more specific
• Specifically, lack of Aspartic acid at position 57 on DQ Beta chain allows autoantigen to fit better in the antigen-binding groove

Question 2

Which environmental factors are associated with the development of DM1?

Answer 2

• Infectious agents
  
  • Prenatal rubella infection (20%)- molecular mimicry increases risk of multiple autoimmune disorders
  • Coxsackievirus protein P2-C- amino acid similarity between this protein and GAD enzyme
• Diet (Controversial)
  
  • Prevention trials have all failed:
    
    • EDNIT (European Diabetes NIicotinamide Intervention Trial)
    • DPT1 and 2 (Diabetes prevention trials)
• Toxins ?

Question 3

What environmental factor is important in developing autoimmune thyroid disease?

Answer 3

• Iodine intake (dietary, or in drugs such as amiodarone or x-ray contrast media)
• HLA class is not strongly linked

Question 4

List 4 diabetes autoantibodies

Answer 4

• Anti-GAD65
• Anti-IA-2 (tyrosine phosphatase)
• Anti-insulin
• Anti-islet cell
• Anti ZnT8

Question 5

Addisons is associated with other endocrinopathies in ____ of cases

Answer 5

50%

Question 6

List 2 adrenal antibodies (ACA’s = adrenal cortex antibodies)

Answer 6

• Anti 21-hydroxylase
• Anti 17-alpha-hydroxylase
• Anti P450 scc (side chain cleavage)

Question 7

When is autoimmune hypophysitis most common?

Answer 7

In women (8:1 vs men), during the latter half of pregnancy and first 6 months postpartum

Question 8

List one parathyroid autantibody

Answer 8

Anti-CaSR

Question 9

Compare APS 1 vs 2

Answer 9

• APS1
  
  • Autosomal recessive, AIRE gene
  • F = M, onset in infancy
  • Endocrinopathy: Addisons, hypoparathyroidism, hypogonadism (less commonly DM1 and hypothyroidism)
  • Derm: chronic mucocutaneous candidiasis, alopecia, vitiligo
• APS2
  
  • Polygenic, some HLA association
  • F > M, onset age 20-40
  • Endocrinopathy: thyroid disease, DM1, Addisons (less commonly hypogonadism)
  • Derm: vitiligo

Question 10

What is the classic triad for APS1?

Answer 10

1. Chronic mucocutaneous candidiasis
2. Autoimmune hypoparathyroidism
3. Adrenal insufficiency

Question 11

How do you diagnose APS 2?

Answer 11

Clinically, with the presence of 2 of:

• Adrenal insufficiency
• Autoimmune thyroid disease
• Type 1 diabetes

Question 12

What is the classic triad seen in IPEX?

What is the gene?

Answer 12

• Watery diarrhea
• Eczematous dermatitis
• Endocrinopathy/Autoimmune disease (most commonly DM1- including neonatal, but may have thyroid disease, Coombs positive anemia, thrombocytopenia, neutropenia, tubular nephropathy)
• Gene: FOXP3, X-linked inheritance

Question 13

• Pheochromocytomas are located in the ______ and secrete ______.
• Paragangliomas are located in the _____ and secrete ______.

Answer 13

• Pheochromocytomas are located in the adrenal medulla and secrete epinephrine and norepinephrine.
• Paragangliomas are located in the paraganglia and secrete norepinephrine.

Question 14

Why does epinephrine deficiency co-exist in all causes of cortisol deficiency?

Answer 14

Cortisol is necessary to produce enzyme PNMT, which catalyzes the conversion of NE –> E

Question 15

List 2 mechanisms by which patients with DM1 develop autonomic neuropathy

Answer 15

1. Glucose neurotoxicity
2. Autoimmunity

Question 16

List 3 genetic conditions that predispose to pheochromocytoma/paraganglioma

Answer 16

1. VHL: Von Hippel Lindau type 2
2. SDHA/B/C/D: Succinate Dehydrogenase complex subunit A/B/C/D
3. RET: MEN2A and 2B
4. NF1: Neurofibromatosis
5. EGLN2 and 1: Prolyl Hydroxylase Domain 1 and 2

Question 17

List 3 surveillance measures for patients with VHL2

Answer 17

1. Regular BP monitoring
2. Age 10-15: yearly retinal exams and BP measurements, plasma free normetanephrines
3. Age >15: Twice yearly BP, plasma free normetanephrines
4. Every 2 years: MRI brain/spinal cord and MRI abdomen
5. If biochemical screening abnormal: MRI plus MIBG scan or 18F-FDA PET scan

Question 18

List 3 surveillance measures for patients with SDHB mutations

Answer 18

• Regular BP monitoring
• Twice yearly physical exam and BP monitoring, plasma free metanephrines and serum chromogranin A
• Yearly ultrasound of neck, abdomen, pelvis
• Every 3 years: MRI chest, abdomen, pelvis (PHEO, PGL and renal cell carcinoma)
• MRI head and neck (PGL)
  *

Question 19

List 3 surveillance measures for patients with RET mutations (MEN2)

Answer 19

• Twice yearly BP monitoring and physical exam, plasma free metabephrine, serum calcium/albumin and calcitonin
• Prophylactic thyroidectomy by age 5 years (MEN2A) and 6 months (for codon 918 mutations in MEN 2B)
• Yearly thyroid ultrasound
• Before surgery/pregnancy: screen for pheo with plasma free metanephrines

Question 20

List 3 surveillance measures for patients with NF1

Answer 20

• Twice yearly physical exam and BP, dermatologic exam for neurofibromas
• Yearly CBC with differential, plasma free metanephrines, eye exam with visual fields
• Before surgery/pregnancy: plasma free metanephrines

Question 21

What are the characteristics of MEN2A? MEN2B?

Answer 21

• MEN2A
  
  • Medullary thyroid carcinoma (remove by 5y)
  • Hyperparathyroidism
  • Pheochromocytoma
  • Also cutaneous lichen amyloidosis and Hirschsprung disease
• MEN2B (90% have methionine to threonine substitution on codon 918)
  
  • Aggressive medullary thyroid carcinoma
  • Mucosal neuromas
  • Pheochromocytomas
  • Adrenal medullary hyperplasia (remove by 6mos)
  • Marfanoid habitus, scoliosis/kyphosis, pectus excavatum, high arched feet, club foot

Question 22

What is more likely to metastasize, pheochromocytoma or paraganglioma?

Answer 22

Paraganglioma

Question 23

What is the clinical presentation of pheochromocytoma?

Answer 23

• Hypertension
• Headaches
• Diaphoresis
• Palpitations or tachycardia
• Anxiety
• Tremor
• Abdominal/chest pain
• Pallor
• Nausea/vomiting

Question 24

List 6 medications that may confound the results of plasma catecholamines or metanephrines

Answer 24

1. Acetaminophen
2. Amphetamines
3. Local anesthetics
4. Bronchodilators
5. Decongestants, ephedrine, epinephrine
6. Labetalol
7. Levodopa
8. Metoclopramide
9. MAOI’s
10. Nitroglycerin
11. Phenoxybenzamine
12. SSRI’s, TCA’s

Question 25

List 3 medical options for preoperative alpha blockade in patients with PHEO

Answer 25

* Phenoxybenzamine * Doxazocin * Calcium channel blockers (nicardipine)

Question 26

Why are beta blockers contraindicated in PHEO before adequate alpha blockade?

Answer 26

Can cause increased BP due to nonselective beta blockade. Unpredictable effects. May use once alpha blockade has been achieved

Question 27

What are the major characteristics of MEN1, MEN2A and MEN2B

Answer 27

* MEN1: parathyroid glands, endocrine pancrease and pituitary * MEN2A: medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism * MEN2B: medullary thyroid carcinoma, pheochromocytoma, NO hyperpara

Question 28

What types of enteropancreatic tumors are seen in MEN1?

Answer 28

* Gastrinoma * Insulinoma * Non-functioning and PPoma * Glugaconoma * VIPoma

Question 29

What types of pituitary adenomas are most common in MEN1?

Answer 29

* Prolactinoma (with or without GH) * GH secreting * Nonfunctional * ACTH secreting

Question 30

What does MEN1 code for? What is the inheritance of MEN1?

Answer 30

Menin, a tumor suppressor gene Autosomal dominant inheritance

Question 31

List 2 surgical approaches to treat parathyroid hyperplasia in MEN1

Answer 31

1. Resection of 3.5 glands (leaving half of a gland in an attempt to prevent hypoparathyroidism). Higher rate of recurrence. 2. Total parathyroidectomy with transplantation of most normal appearing tissue to the nondominant forearm. Higher rate of hypoparathyroidism.