193b - Endocrine Genetic Syndromes

Question 1

Carney complex

• Mutation:
• Inheritance:
• Presentation:

Answer 1

• Mutation: PRKARI1 inactivation
• Inheritance: Autosomal dominant
• Presentation:
  
  • Adrenocortical tumors -> Cushing syndrome
  • Thyroid nodules
  • Pituitary adenoma
  • Gonadal tumors
  • Myxomas, cafe au lait spots, lentigines

Question 2

Li Fraumeni Syndrome

• Mutation:
• Inheritance:
• Common tumors (4):

Answer 2

• Mutation: p53 (tumor suppressor
• Inheritance: Audtosomal dominant
• Common tumors (4):
  
  • Sarcoma
  • Breast cancer (pre-menopausal)
  • Brain (glioma, medulloblastoma)
  • Adrenocortical

Question 3

Describe the penetrance and expressivity of neurofibromatosis-1

Answer 3

• Complete penetrance
  
  • Everyone with the mutation will have the phenotype
• Variable expressivity
  
  • Pts with the same genotype may have different clinical symptoms

Question 4

Which tumors are common in both MEN2A and MEN2B?

How are they differentiated?

Answer 4

Medullary thyroic carcinoma, pheochromocytoma

• MEN2A - parathyroid hyperplasia
• MEN2B - intestinal ganglioneuromatosis, may have similar appearance to Marfan syndrome

MEN2 = GOF mutation in the RET protooncogene

Question 5

What causes McCune-Albright Syndrome?

Describe the triad of typical findings

Answer 5

Post-zygotic activating mutation of the alpha-subunit of Gs

NOT hereditary - somatic mutation, mosaic distribution

• Fibrous dysplasia of the bone
• Cafe au lait spots
  
  • Not as well circumscribed, less likely to cross midline than NF-1
• Precocious puberty
  
  • Due to cortisol overproduction - gonadotropin independent

Question 6

What is the treatment for Klinefelter’s syndrome?

Answer 6

Testosterone therapy

Question 7

Which congenital adrenal hypoplasia is most common?

What will the following labs show? (general)

• Mineralcorticoids:
• Cortisol:
• Testosterone:

Answer 7

21-alpha-hydroxylase deficiency

• Mineralcorticoids: low
  
  • Hypotension, hyponatremia, dehydration, hyperkalemia
• Cortisol: low
  
  • Shock
• Testosterone: high
  
  • Ambigious genitalia in XX
  • Precocious puberty in XY

Presents at ~1 week

Question 8

What is the most common cause of male hypogonadism?

Answer 8

Klinefelter’s Syndrome

• 47 XXY, due to non-dysjunction of sex chromosomes
• May be mosaic

Question 9

What 3 tumors are most common in MEN-1?

Which tumor has the highest penetrance?

Answer 9

• Parathyroid - highest penetrance
• Pituitary adenoma
• Pancreatic/duodenal tumors
• MEN-1 = mutation in tumor suppressor Menin*
• Loss of heterozygosity (2nd hit) -> tumor*

Question 10

Autoimmune Polyglandular Sydromes

• Mutation:
• Inheritance:
• Presentation (general):

Answer 10

• Mutation: AIRE gene
• Inheritance: Autosomal recessive
• Presentation (general): Autoimmune endocrine problems
  
  • Adrenal insufficiency, hypoparathyroidism, thyorid, other

Question 11

Which T1DM responds to sulfonylureas?

Answer 11

MODY3

Question 12

Describe the inheritance of Von Hippel Lindau

Answer 12

Autosomal dominant mutation in VHL gene

VHL is a tumor suppressor - 2 hit hypothesis

Question 13

What is the difference between allelic heterogeneity and locus heterogeneity?

Answer 13

• Allelic
  
  • Multiple different mutations can occur in the same gene to cause a specific phenotype
  • => must sequence the whole gene to find the defect
• Locus
  
  • Mutations in different genes can cause a similar phenotype
  • => must sequence multiple genes to find the defect

Question 14

In which genetic syndrome are pheochoromocytomas least common?

1. NFM-1
2. Von Hippel Linday
3. MEN-1
4. MEN-2A
5. MEN-2B

Answer 14

c. MEN-1
* MEN 1 = pituitary, pancreatic, parathyroid*