Flashcards in Leidy- Endo Genetics- Leah :) Deck (33):
#1 genetic cause for ambiguous genitalia?
-classic congenital adrenal hyperplasia-- simple variant (i.e. no salt wasting)
Likely genetic cause of hypovolemia/ hypokalemia in a baby?
-classic congenital adrenal hyperplasia-- salt wasting variant (i.e. NOT simple)
Genetic cause for teen with irregular periods + hirsutism
"non-classic" congenital adrenal hyperplasia
-#1 cause of congenital adrenal hyperplasia?
-90% 21 hydroxylase def
-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)
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
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?
First molecule needed to start all steroid synthesis in the adrenals?
Result of deficient 21 hydroxylase
21: excess androgens due to blocked aldo + cortisol = ambiguous genitalia in females +/- SALT WASTING
Result of deficient 11 hydroxylase
-HTN due to excess aldo
-Excess androgens= ambiguous genitalia in females
Result of deficient 17 hydroxylase
HTN (excess aldo, LOW testosterone = ambiguous genitalia in MEN)
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)
-Which locus is involved in 21 hydroxylase def?
-What other genetic component plays a role?
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
Compare the relative amount of active 21 hydroxylase in:
-classic salt wasting variant
-classic simple virilizing variant
-salt wasting: ZERO enzyme activity
How is CAH screening done in the newborn nursery?
What treatments are available for CAH?
- Check levels of 17-OH progesterone (all states)
- Gluco/ mineralocorticoid replacement
- genital reconstruction
How is CAH screened for in pregnancy if patient is at risk?
-8-10 wk chorionic villus sampling --> karyotype/ DNA analysis
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.
3 tumors involved?
3 tumors + inheritance pattern
-"thyrocalcitonin" = medullary carcinoma
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%
What two diseases may be assc with MEN 2A?
-cutaneous lichen amyloidosis
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
What cells are neoplastic in medullary thyroid carcinoma?
What do they secrete?
How often are they related to MEN syndromes?
-calcitonin + CEA
-~30% are familial/ MEN related; 70% sporadic
Rate the aggressiveness of MTCs depending on their type.
-MOST = MEN 2B
-THEN sporadic = MEN 2A
How commonly are MTCs aggressive and to where do they met?
-20% very aggressive --> met to liver, lung, bone
Mutation assc with MEN syndromes?
-chromosome 10q point mutation --> RET proto-oncogene (a tyrosine kinase) activation
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)
Before RET gene screening, how was MEN screened for?
-serum pentagastrin/ calcitonin and calcium
How senstitive is RET gene analysis?
-excludes with 98% certainty
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
FAMILAIL medullary thyroid carcinoma screening?
-Annual calcitonin + neck US
-Genetic analysis (but not as sensitive as RET gene analysis for MEN syndromes)