Leidy- Endo Genetics- Leah :) Flashcards Preview

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Flashcards in Leidy- Endo Genetics- Leah :) Deck (33):
1

#1 genetic cause for ambiguous genitalia?

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

2

Likely genetic cause of hypovolemia/ hypokalemia in a baby?

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

3

Genetic cause for teen with irregular periods + hirsutism

"non-classic" congenital adrenal hyperplasia

4

-#1 cause of congenital adrenal hyperplasia?
-Inheritance pattern?

-90% 21 hydroxylase def
-AR

5

-How is CAH classified?
-Which type is on the rise?

-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)

6

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

What are two additional risks associated with classic CAH?

-simple: large hyperplastic adrenals at birth + ambiguous genitalia

-salt wasting: simple + HYPOvolemia, HYPERkalemia

...also risk precocious puberty --> short stature

7

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

-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?

8

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

Cholesterol

9

Result of deficient 21 hydroxylase

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



10

Result of deficient 11 hydroxylase

-HTN due to excess aldo
-Excess androgens= ambiguous genitalia in females

11

Result of deficient 17 hydroxylase

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

12

What was the DIT rule of "1s" for CAH?

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)

13

-Which locus is involved in 21 hydroxylase def?
-What other genetic component plays a role?

-6p21.3
-HLA linkage

14

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

- 75% point mutations
- smaller percent due to gene deletions / large gene conversions

15

Compare the relative amount of active 21 hydroxylase in:
-classic salt wasting variant
-classic simple virilizing variant
-nonclassic

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

16

How is CAH screening done in the newborn nursery?

What treatments are available for CAH?

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

Treatment:
- Gluco/ mineralocorticoid replacement
- genital reconstruction

17

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

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

18

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

-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.

19

MEN 1:
3 tumors involved?
Inheritance pattern?

-3 P's:
-parathyroid
-pituitary
-pancreatic islet

-AD

20

MEN 2:
3 tumors + inheritance pattern

-TPP
-"thyrocalcitonin" = medullary carcinoma
-pheos
-parathyroid neoplasia

--AD

21

MEN 2A:

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

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

22

What two diseases may be assc with MEN 2A?

-cutaneous lichen amyloidosis
-hirschsprungs

23

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

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

24

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

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

25

Rate the aggressiveness of MTCs depending on their type.

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

26

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

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

27

Mutation assc with MEN syndromes?

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

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?

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

F*UCKING. USELESS.

29

Before RET gene screening, how was MEN screened for?

Annual:
-serum pentagastrin/ calcitonin and calcium
-urine metanephrines

30

How senstitive is RET gene analysis?

-excludes with 98% certainty

31

What is standard management for those WITH RET mutations?

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

-Continue Ca and catecholamine screens

-Screen family members

32

FAMILAIL medullary thyroid carcinoma screening?

-Annual calcitonin + neck US
-Genetic analysis (but not as sensitive as RET gene analysis for MEN syndromes)

33

Management of sporadic medullary thyroid carcinoma

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

SCREEN FOR RET IN ALL MTC CASES!!!!