Leidy- Endo Genetics- Leah :)

Question 1

1 genetic cause for ambiguous genitalia?

Answer 1

-classic congenital adrenal hyperplasia– simple variant (i.e. no salt wasting)

Question 2

Likely genetic cause of hypovolemia/ hypokalemia in a baby?

Answer 2

-classic congenital adrenal hyperplasia– salt wasting variant (i.e. NOT simple)

Question 3

Genetic cause for teen with irregular periods + hirsutism

Answer 3

“non-classic” congenital adrenal hyperplasia

Question 4

• # 1 cause of congenital adrenal hyperplasia?

- Inheritance pattern?

Answer 4

• 90% 21 hydroxylase def

- AR

Question 5

• How is CAH classified?

- Which type is on the rise?

Answer 5

• classic v nonclassic
• Note: classic type can also be divided based upon presentation – simple v salt wasting

-non-classic incidence is on the rise, esp in NYC (incidence about 1-2/100)

Question 6

Symptoms of classic CAH:
(simple vs salt wasting types)

What are two additional risks associated with classic CAH?

Answer 6

• simple: large hyperplastic adrenals at birth + ambiguous genitalia
• salt wasting: simple + HYPOvolemia, HYPERkalemia

…also risk precocious puberty –> short stature

Question 7

Describe the clinical presentation of patient with non-classic CAH:

Answer 7

-onset of excess androgens in adolescence
(hirsutism, oligomeorrhea, acne)
*no adrenal insufficiency or ambiguous gentialia

…androgen excess in young girls, How do we know this isnt PCOS?

Question 8

First molecule needed to start all steroid synthesis in the adrenals?

Answer 8

Cholesterol

Question 9

Result of deficient 21 hydroxylase

Answer 9

21: excess androgens due to blocked aldo + cortisol = ambiguous genitalia in females +/- SALT WASTING

Question 10

Result of deficient 11 hydroxylase

Answer 10

• HTN due to excess aldo

- Excess androgens= ambiguous genitalia in females

Question 11

Result of deficient 17 hydroxylase

Answer 11

HTN (excess aldo, LOW testosterone = ambiguous genitalia in MEN)

Question 12

What was the DIT rule of “1s” for CAH?

Answer 12

Per DIT: “1 in first position = HTN; 1 in second position = excess androgens and ambiguous genitalia in FEMALES

BUT THERE IS A CAVEAT: You must remember that the INVERSE of this statement is also true…..
(NO 1 in second position = LOW testosterone= MALE get ambiguous genitalia; NO 1 in FIRST position = salt wasting hypovolemia/ hypoTN)

Question 13

• Which locus is involved in 21 hydroxylase def?

- What other genetic component plays a role?

Answer 13

• 6p21.3

- HLA linkage

Question 14

What genetic mutations are involved in the salt wasting variant of CAH/ 21 hydroxylase def?

Answer 14

• 75% point mutations

- smaller percent due to gene deletions / large gene conversions

Question 15

Compare the relative amount of active 21 hydroxylase in:

• classic salt wasting variant
• classic simple virilizing variant
• nonclassic

Answer 15

• salt wasting: ZERO enzyme activity
• simple: ~1%
• non-classic: 20-50%

Question 16

How is CAH screening done in the newborn nursery?

What treatments are available for CAH?

Answer 16

• Check levels of 17-OH progesterone (all states)

Treatment:

• Gluco/ mineralocorticoid replacement
• genital reconstruction

Question 17

How is CAH screened for in pregnancy if patient is at risk?

Answer 17

-8-10 wk chorionic villus sampling –> karyotype/ DNA analysis

Question 18

How can a fetus be treated en utero if CAH is confirmed?

Answer 18

• Give steroid/ dexamethasone to shut off ACTH production = less excess androgens in fetus to cause genital ambiguity
• *This treatment is EXPERIMENTAL

…stop treatment after birth in boys or unaffected females.

Question 19

MEN 1:
3 tumors involved?
Inheritance pattern?

Answer 19

• 3 P’s:
• parathyroid
• pituitary
• pancreatic islet

-AD

Question 20

MEN 2:

3 tumors + inheritance pattern

Answer 20

• TPP
• “thyrocalcitonin” = medullary carcinoma
• pheos
• parathyroid neoplasia

–AD

Question 21

MEN 2A:

how common are each of the 3 men 2 tumors in this variant?

Answer 21

• 100% get medullary thyroid carcinoma
• 1/2 get pheo
• parathyroid only 10-20%

Question 22

What two diseases may be assc with MEN 2A?

Answer 22

• cutaneous lichen amyloidosis

- hirschsprungs

Question 23

How does MEN 2B vary from 2A/ the traditional “TPP” pattern for type 2 MEN? (4)

Answer 23

• no parathyroid tumors
• 100% medullary thyroid ca, 50% pheos
• 100% MARFANOID HABITUS
• 100% intestinal ganglioneuromatosis + mucosal neuromas

Question 24

What cells are neoplastic in medullary thyroid carcinoma?
What do they secrete?
How often are they related to MEN syndromes?

Answer 24

• parafollicular cells
• calcitonin + CEA
• ~30% are familial/ MEN related; 70% sporadic

Question 25

Rate the aggressiveness of MTCs depending on their type.

Answer 25

• MOST = MEN 2B
• THEN sporadic = MEN 2A
• LEAST: familial

Question 26

How commonly are MTCs aggressive and to where do they met?

Answer 26

-20% very aggressive –> met to liver, lung, bone

Question 27

Mutation assc with MEN syndromes?

Answer 27

-chromosome 10q point mutation –> RET proto-oncogene (a tyrosine kinase) activation

Question 28

What ligand complexes with RET to form complete receptor? 
Where EXACTLY (this is F*CKING USELESS)  is locus 10q for the RET proto-oncogene effected?

Answer 28

• Glial Cell Derived Neurotrophic Fator (GDNF)
• Cytosine rich domain (less severe)
• Tyrosine kinase domain (worse, seen in MEN 2B)

F*UCKING. USELESS.

Question 29

Before RET gene screening, how was MEN screened for?

Answer 29

Annual:

• serum pentagastrin/ calcitonin and calcium
• urine metanephrines

Question 30

How senstitive is RET gene analysis?

Answer 30

-excludes with 98% certainty

Question 31

What is standard management for those WITH RET mutations?

Answer 31

-Thyroidectomy at appropriate age (before 5)
OR … annual calcitonin + neck US then remove if cancer appears

• Continue Ca and catecholamine screens
• Screen family members

Question 32

FAMILAIL medullary thyroid carcinoma screening?

Answer 32

• Annual calcitonin + neck US

- Genetic analysis (but not as sensitive as RET gene analysis for MEN syndromes)

Question 33

Management of sporadic medullary thyroid carcinoma

Answer 33

-Screen for RET because there is 6% chance germline mutation exists even without family Hx

SCREEN FOR RET IN ALL MTC CASES!!!!