01-30 Unusual Case of HTN (Pheo)

Question 1

What are the s/sx of a pheo?

Answer 1

1. HTN (episodic or continuous)
2. “Spells” (tremor, sweating, palps, h/a)
3. Postural hypotension
4. possible signs of familial cause (e.g. signs of NF-1)

Question 2

What is the best lab eval for pheo?

Answer 2

plasma metanephrines is best; can also do:
—24hr urine catecholamines + metabolites
—serum catecholamines

Question 3

What are the four familial causes of pheo?

—What is their inheritance pattern?

Answer 3

1. NF-1
2. VHL
3. MEN-2a&2b
4. SDH Types B & D
   —All have autosomal dominant inheritance

Question 4

NF-1
—presenting signs
—% of cases w/ a pheo
—type of mutation

Answer 4

PRESENTS
—cutaneous neurofibromas
—café-au-lait spots
—Lisch nodules (pathognomonic for NF)
—pheo (rarely)

%
—only 1% of NF1 cases have a pheo

MUTATION
—inactivating mutation of tumor suppressor (NF1) gene

Question 5

VHL
—presenting signs
—% of cases w/ a pheo
—type of mutation

Answer 5

PRESENTS
—retinal angioma
—cerebellar hemangioblastoma
—renal cancer
—pheo

%
—15% of VHL cases have a pheo

MUTATION
—inactivating mutation of VHL → causes increase signalling of HIF-1 (hypoxia-inducible factor); similar end mechanism with succinate DH mutation

Question 6

MEN-2a
—presenting signs
—% of cases w/ a pheo
—type of mutation

Answer 6

PRESENTS
—medullary thyroid cancer (MTC)
—pheo
—hyperparathyroidism

%
—50% of MEN2a pts have pheo

MUTATION
—activating mutation of proto-oncogene (RET)
—RET is a neural growth factor receptor

Question 7

MEN-2b
—presenting signs
—% of cases w/ a pheo
—type of mutation

Answer 7

PRESENTS
—MTC
—Pheo
—ALSO: mucosal neuromas (tongue/lips, e.g.) (not seen in MEN-2a)

%
—50% of MEN2a pts have pheo

MUTATION
—activating mutation of proto-oncogene (RET)

Question 8

MEN-1

Answer 8

Note: does NOT cause pheo

PRESENTATION
—hyperparathyroidism (same as MEN2) 95%
—pancreatic neuroendocrine tumors 40-60%
    ^^make gastrin → LOTS of ulcers
—pit adenomas 30%

MUTATION
—inactivating mutation of tumor suppressor (MENIN)

Question 9

MTC

Answer 9

Medullary Thyroid Cancer
—near inevitability if you have MEN2
—parafollicular (C-cell) tumor that secretes calcitonin
—C-cell hyperplasia precedes
—verify with Ca++ surge stimulation test and measurement of [calcitonin] s/p
—prophylactic thyroidectomy for kids from these kindreds who test positive on genetic screening!
—poor prognosis if can’t be resected (thus prophylactic removal)
—though new RET-TK inhibitors show promise

Question 10

SDHB/SDHD

Answer 10

Succinate Dehydrogenase
—often extrarenal pheos (“gangliomas”)
—~20% get pheo
—inactivating of SDH in citric acid cycle leads to build up of succinate → nucleus → stabilizes HIF-1 (hypoxia inducible factor)

Question 11

Approach to treatment of pheo

Answer 11

—medically stabilize w/ α- and β-blockade 1st for several weeks
—phenoxybenzamine = non-comp α-blocker
—during surgery: tie off venous outflow first, be very careful not to leak contents of tumor!

Question 12

Vandetanib

Answer 12

new p.o. tx for MTC

—RET tyr kinase inhibitor

Question 13

Key points from this lecture

Answer 13

1. Importance of a family history
2. Mutations in four different genes can cause familial pheochromocytoma
3. Implications of genotyping a MEN2 kindred- -prophylactic thyroidectomy -negative genotype
4. Genotype-phenotype correlation in MEN2
5. Implications for medical therapy of RET-related cancers- targeted therapy

Question 14

What lab tests could you order form MEN-2a?

—Think first: What goes wrong?

Answer 14

MTC → excess calcitonin
—test w/ Ca++-pentagastrin stimulation test

Pheo → excess catecholamines
—24hr urine or plasma metanephrines

Hyperparathyroidism → excess PTH
—check serum Ca, PTH