1. [CASE 1 -- QUESTION 1] The ophthalmologist must evaluate which of his medications may be contributing to his visual symptoms and the spirometric decline. Which of the following most accurately identifies the receptor mechanisms involved and explains the relevant drug-disease interactions?

• A) Timolol (non-selective beta-blocker) is contributing to both his pulmonary deterioration and his cardiac bradycardia -- systemic absorption via nasolacrimal drainage produces beta-2 blockade in the lungs (worsening COPD, contributing to the FEV1 decline) and additive beta-1 blockade in the heart on top of metoprolol (compounding his sinus bradycardia at 54 bpm, risking complete heart block in a patient with HFrEF on a beta-blocker); the lens opacification and myopic shift are from a different cause (likely steroid-induced from prior treatments) and timolol is not involved; latanoprost (prostaglandin FP receptor agonist) may cause conjunctival hyperemia and iris pigmentation changes but does not affect the lens or refraction; tamsulosin (alpha-1A selective blocker for BPH) causes intraoperative floppy iris syndrome (IFIS) if cataract surgery is planned -- the iris dilator smooth muscle becomes flaccid due to chronic alpha-1A blockade, causing the iris to prolapse and billow during phacoemulsification.
• B) Latanoprost (prostaglandin FP receptor agonist increasing uveoscleral outflow) causes the myopic shift and lens changes by altering the refractive index of the vitreous humor through prostaglandin E2 receptor cross-activation; timolol contributes to bradycardia through additive beta-1 blockade with metoprolol but does not affect pulmonary function because topically applied eye drops are too dilute for systemic absorption; tamsulosin has no interaction with any aspect of this patient's ophthalmological or pulmonary presentation.
• C) The patient has two pharmacologically distinct problems: (1) Timolol systemic absorption via nasolacrimal drainage produces: additive beta-1 blockade on the already-metoprolol-treated heart (contributing to bradycardia at 54 bpm -- potentially provoking heart block in HFrEF), AND beta-2 blockade in the lungs (contributing to the FEV1 decline in COPD); timolol should be replaced with a non-adrenergic IOP-lowering agent; (2) Tamsulosin (alpha-1A blocker) causes intraoperative floppy iris syndrome (IFIS) by chronically blocking alpha-1A receptors on iris dilator smooth muscle -- when stimulated by phenylephrine mydriatic drops during cataract surgery, the denervation-supersensitive but alpha-1A-blocked dilator fails to maintain dilation, and the iris billows, prolapses, and constricts intraoperatively; the surgeon must be informed before any cataract surgery is planned; the myopic shift and lens opacification are age-related nuclear cataracts unrelated to current medications (though prior corticosteroid use, if any, should be reviewed); the visual loss from cataract is the primary ophthalmological problem requiring surgical planning.
• D) All four of this patient's ophthalmic and systemic medications are contributing to his problems: timolol causes bradycardia and lung disease; latanoprost causes lens opacification through prostaglandin-mediated lens epithelial toxicity; tamsulosin causes the myopic shift by relaxing the ciliary muscle (which is rich in alpha-1A receptors) and changing the curvature of the crystalline lens; furosemide (systemic) causes lens dehydration producing a hyperopic shift that partially compensates the tamsulosin-induced myopia, producing the net myopic shift; the correct management is to stop all four agents simultaneously and reassess.

2. [CASE 1 -- QUESTION 2] After replacing timolol with brimonidine 0.15% twice daily, the patient notes improved pulmonary function (FEV1 recovers to 64%) and his heart rate increases to 62 bpm. However, after four weeks he returns reporting that the brimonidine seems to be losing effectiveness -- his IOP has risen from 16 mmHg to 23 mmHg bilaterally. The ophthalmologist suspects brimonidine tachyphylaxis. Which of the following most accurately explains the molecular mechanism of brimonidine tachyphylaxis?

• A) Brimonidine tachyphylaxis occurs because brimonidine is metabolized by the P450 enzyme CYP1A2 in the ciliary body epithelium -- repeated brimonidine instillation induces CYP1A2 in the ciliary body, accelerating brimonidine metabolism and reducing local drug concentration below the threshold needed for alpha-2 receptor activation; patients with high baseline CYP1A2 activity (rapid metabolizers) develop tachyphylaxis faster than slow metabolizers; this is purely pharmacokinetic tachyphylaxis with no receptor-level mechanism involved.
• B) Brimonidine is an alpha-2 adrenergic agonist that reduces IOP through two mechanisms: (1) reducing aqueous humor production by activating Gi-coupled alpha-2 receptors on ciliary body epithelium (reducing cAMP and aqueous secretion), and (2) increasing uveoscleral outflow via a mechanism that may involve prostaglandin-independent connective tissue remodeling in the uveoscleral pathway; tachyphylaxis results from Gi-coupled receptor desensitization through GRK-mediated phosphorylation of alpha-2 receptors on ciliary body cells and beta-arrestin recruitment, uncoupling the receptor from Gi and reducing cAMP suppression; concurrently, alpha-2 receptor downregulation (reduced receptor density from lysosomal degradation of internalized receptors) reduces the maximal IOP-lowering effect; this is pharmacodynamic tachyphylaxis analogous to beta-2 agonist tachyphylaxis in asthma; management: add a topical carbonic anhydrase inhibitor (dorzolamide) which lowers IOP by a non-adrenergic mechanism (CAI inhibition of ciliary body carbonic anhydrase) that is not subject to the same desensitization.
• C) Brimonidine tachyphylaxis is a purely pharmacokinetic phenomenon -- brimonidine induces the expression of the MDR1 (P-glycoprotein) efflux transporter in the corneal epithelium; repeated brimonidine exposure causes MDR1 upregulation, increasing drug efflux from the anterior chamber and reducing aqueous humor drug concentrations below therapeutic levels; the MDR1 induction is reversible within 4 weeks of drug discontinuation; patients on concurrent P-gp inhibitors (cyclosporine eye drops) do not develop brimonidine tachyphylaxis.
• D) Brimonidine activates alpha-2 adrenergic receptors on ciliary body epithelium through Gi coupling, reducing cAMP and aqueous humor production; sustained alpha-2 receptor activation triggers GRK2/3-mediated receptor phosphorylation and beta-arrestin recruitment, uncoupling the receptor from Gi (homologous desensitization, occurring within minutes to hours); with continued twice-daily dosing, internalized alpha-2 receptors are trafficked to lysosomes for degradation (downregulation, occurring over days to weeks), reducing total receptor density on ciliary body cells; the functional consequence is progressive loss of IOP-lowering efficacy (tachyphylaxis); this GRK-beta-arrestin mechanism is the same as beta-2 receptor tachyphylaxis in asthma from LABA use; adding dorzolamide (a CA-II and CA-XII inhibitor reducing aqueous secretion by a bicarbonate/proton pump mechanism independent of any adrenergic receptor) provides IOP lowering that is mechanistically orthogonal to the desensitized alpha-2 pathway.

3. [CASE 1 -- QUESTION 3] The patient is scheduled for bilateral cataract extraction. The surgeon asks about the risk of intraoperative floppy iris syndrome from tamsulosin and inquires whether stopping tamsulosin two weeks before surgery would eliminate the risk. Which of the following most accurately explains why short-term tamsulosin discontinuation does not reliably prevent IFIS?

• A) Tamsulosin has an extremely long elimination half-life (greater than 30 days) due to extensive tissue binding in the iris dilator muscle -- two weeks of discontinuation is insufficient to clear the drug from iris tissue, and tamsulosin molecules remaining at alpha-1A receptors continue blocking dilator function during surgery; at least 90 days of discontinuation is required for full tamsulosin clearance from iris tissue before safe cataract surgery.
• B) The iris dilator smooth muscle alpha-1A adrenergic receptors undergo structural and functional remodeling during prolonged tamsulosin exposure that cannot be reversed by short-term drug discontinuation -- chronic alpha-1A blockade in the iris dilator produces: (1) receptor upregulation (increased alpha-1A receptor density), which paradoxically does not restore dilator function because the upregulated receptors may be coupled differently after long-term antagonist exposure; (2) reduced smooth muscle contractile protein expression (atrophy of dilator smooth muscle from disuse) -- the iris dilator becomes physically unable to generate adequate tension to maintain dilation during surgery regardless of alpha-1A receptor availability; (3) altered mechanical properties of the iris stroma -- the floppy, billowing quality of the iris in IFIS reflects structural changes in the iris architecture that persist after drug discontinuation; two weeks of tamsulosin discontinuation restores systemic alpha-1A receptor function (urinary symptoms return) but does not reverse the iris-specific anatomical and receptor changes; the surgical team must plan for IFIS (iris hooks, Malyugin ring, intracameral phenylephrine) regardless of whether tamsulosin is stopped preoperatively.
• C) Stopping tamsulosin preoperatively is actually contraindicated because it causes rebound alpha-1A upregulation in the iris dilator -- the sudden restoration of endogenous NE signaling at upregulated alpha-1A receptors produces paradoxical iris hypercontraction and pupillary miosis that is worse than the IFIS seen during tamsulosin treatment; patients should remain on tamsulosin until surgery and the surgeon should simply use higher doses of intracameral phenylephrine to overcome the alpha-1A blockade.
• D) Short-term tamsulosin discontinuation does not prevent IFIS because IFIS is not caused by alpha-1A blockade at the time of surgery -- it is caused by permanent serotonergic damage to the iris dilator smooth muscle neurons from tamsulosin's off-target 5-HT2A receptor antagonism (a property shared by all alpha-1A selective agents); serotonergic denervation of the iris dilator is irreversible regardless of tamsulosin discontinuation duration; the surgical implications are permanent once IFIS-prone iris anatomy is established.

4. [CASE 1 -- QUESTION 4] One year after successful bilateral cataract surgery (performed with appropriate IFIS precautions), the patient develops new-onset atrial fibrillation. His cardiologist considers adding digoxin to his regimen for rate control. The pharmacology consultant must advise on the interaction between digoxin and his existing autonomic pharmacological milieu. Which of the following most accurately predicts the key interactions?

• A) Digoxin lowers ventricular rate in atrial fibrillation by two mechanisms: (1) direct inhibition of Na+/K+-ATPase in AV nodal cells, increasing intracellular sodium, triggering sodium-calcium exchange, raising intracellular calcium, and producing calcium overload-mediated AV nodal depression; and (2) indirect vagotonic effect via the CNS (sensitization of aortic baroreceptors, and enhancement of vagal efferent tone to the AV node via nucleus ambiguus) -- these two mechanisms act synergistically; in this patient, the vagotonic effect of digoxin is additive with the vagotonic effect of metoprolol (which reduces sympathetic tone at the AV node); caution: the combination of digoxin plus metoprolol plus timolol (now replaced with brimonidine) previously produced marked bradycardia and could have caused AV block; with timolol gone, digoxin-metoprolol combination provides rate control; brimonidine's central alpha-2 effects produce sedation and mild cardiovascular depression but do not significantly potentiate AV nodal blockade at therapeutic doses; tamsulosin has no cardiac interaction with digoxin; latanoprost has no systemic cardiovascular effects.
• B) Digoxin is contraindicated in this patient because his furosemide causes hypokalemia, which dramatically increases digoxin toxicity -- hypokalemia increases digoxin binding to Na+/K+-ATPase (competing potassium is reduced) and increases automaticity in ventricular myocytes, producing life-threatening ventricular arrhythmias; the combination of digoxin plus furosemide without potassium monitoring is uniformly fatal and should never be prescribed.
• C) Digoxin reduces ventricular rate in AF through enhanced vagal tone at the AV node (sensitizing baroreceptor afferents and increasing vagal efferent output) rather than through direct AV nodal cell effects -- the vagotonic mechanism means digoxin is effective at rest but loses rate control efficacy during exercise or stress (when sympathetic tone overwhelms vagal AV nodal suppression); in this patient with HFrEF already on metoprolol, adding digoxin provides additional resting rate control through a different (vagotonic vs. sympatholytic) mechanism; the critical interaction is furosemide-induced hypokalemia increasing digoxin toxicity by reducing competition at the Na+/K+-ATPase binding site -- potassium should be maintained above 4.0 mEq/L and digoxin levels monitored; tamsulosin, brimonidine, and latanoprost have no clinically significant interactions with digoxin.
• D) Digoxin interacts with brimonidine through shared alpha-2 receptor activity -- digoxin sensitizes myocardial alpha-2 receptors, and brimonidine's alpha-2 agonism at these sensitized receptors produces additive negative chronotropic effects at the SA and AV nodes; this alpha-2 synergy is the primary drug interaction concern; the interaction with furosemide-induced hypokalemia is of secondary importance compared to the digoxin-brimonidine alpha-2 sensitization.

5. [CASE 2 -- QUESTION 1] The endocrinologist explains that the elevated normetanephrine (predominantly) with lesser metanephrine elevation reflects the biochemical phenotype of the tumor. Which of the following most accurately maps the patient's episodic symptoms to specific adrenergic receptor activations and explains why normetanephrine predominance predicts the symptom pattern?

• A) Normetanephrine is the COMT metabolite of norepinephrine -- predominant normetanephrine elevation indicates the tumor primarily secretes norepinephrine rather than epinephrine; norepinephrine activates alpha-1 receptors (producing vasoconstriction and hypertension) and beta-1 receptors (producing increased cardiac contractility and mild chronotropy), but has minimal beta-2 activity at physiological concentrations; the episodic hypertension, headache, and diaphoresis reflect massive NE-mediated alpha-1 vasoconstriction; the palpitations reflect both beta-1-mediated tachycardia and the baroreceptor reflex-mediated tachycardia in response to the severe hypertension; the inter-episodic hypertension (152/96 mmHg at baseline) reflects persistent low-level NE secretion maintaining elevated alpha-1 vascular tone; tumors secreting predominantly NE (normetanephrine-predominant biochemical phenotype) tend to produce sustained hypertension with episodic surges, in contrast to epinephrine-secreting tumors which more often produce episodic hypotension and tachycardia from beta-2 predominance.
• B) Normetanephrine is the MAO metabolite of norepinephrine produced inside the tumor cell cytoplasm -- high normetanephrine indicates the tumor has high intracellular MAO activity and is degrading most of its NE before secretion; the intact NE that escapes MAO degradation and is secreted produces the episodic hypertensive symptoms; tumors with high normetanephrine are paradoxically less dangerous than those with low normetanephrine because most of the catecholamine is pre-degraded intracellularly.
• C) The predominant normetanephrine elevation (NE secretion) versus lesser metanephrine (epinephrine secretion) reflects: NE activates alpha-1 (intense vasoconstriction -> severe hypertension, headache from cerebrovascular pressure surge, diaphoresis from massive sympathetic sudomotor activation), beta-1 (tachycardia and increased contractility -> palpitations), but has minimal beta-2 activity; the predominance of alpha-1 effects over beta-2 effects in this tumor's NE-dominant secretion pattern explains why her palpitations are less prominent than her hypertension -- NE-predominant pheo produces primarily hypertensive crises while epinephrine-predominant pheo (metanephrine-dominant) produces more pronounced tachycardia, anxiety, tremor, and sometimes paradoxical hypotension (from beta-2 vasodilation overwhelming alpha-1 vasoconstriction); the 5.8 cm adrenal mass producing predominantly NE is characteristic of a sporadic pheochromocytoma -- extra-adrenal paragangliomas also produce predominantly NE (lacking PNMT which is required to convert NE to epinephrine and is induced by local cortisol in the adrenal medulla).
• D) The elevated normetanephrine indicates adrenal cortical rather than medullary origin of the mass -- normetanephrine is the primary COMT metabolite of cortisol precursors in the zona fasciculata; the zone of the adrenal cortex responsible for cortisol production also produces normetanephrine as a byproduct; this biochemical pattern points to an adrenocortical carcinoma rather than pheochromocytoma; CT-guided biopsy is required to confirm the diagnosis before initiating alpha-blockade.

6. [CASE 2 -- QUESTION 2] The endocrinologist initiates phenoxybenzamine 10 mg twice daily. After ten days the patient calls reporting lightheadedness when standing up from sitting, nasal stuffiness, and a resting heart rate of 102 bpm. The endocrinologist considers these findings. Which of the following most accurately identifies whether these findings represent expected pharmacological effects, therapeutic inadequacy, or adverse drug reactions, and guides the next management step?

• A) The lightheadedness, nasal stuffiness, and tachycardia all represent adverse drug reactions requiring immediate phenoxybenzamine discontinuation -- phenoxybenzamine is an overly potent drug that is rarely needed in modern pheochromocytoma management; doxazosin (a competitive alpha-1 selective blocker) should be substituted because it produces the same preoperative alpha-blockade without causing the orthostatic hypotension, nasal congestion, or reflex tachycardia that are characteristic toxicities of phenoxybenzamine.
• B) All three findings are expected and desirable pharmacological effects confirming adequate alpha-blockade: orthostatic lightheadedness reflects successful alpha-1 vascular bed expansion (the chronically catecholamine-constricted peripheral vasculature is now dilated, and the still-volume-contracted patient is postural-hypotension-prone -- requires high-sodium diet and fluid loading); nasal stuffiness reflects alpha-1 blockade in nasal mucosal vasculature producing vasodilation and mucosal congestion (a useful clinical marker of peripheral alpha-1 blockade adequacy -- nasal congestion is one of the target signs of adequate preoperative alpha-blockade); tachycardia at 102 bpm reflects two simultaneous mechanisms: (1) baroreceptor reflex-driven sympathetic beta-1 activation in response to vasodilation-induced BP reduction, and (2) phenoxybenzamine's additional alpha-2 blocking effect disinhibiting presynaptic NE release, amplifying the NE surge at cardiac beta-1 receptors; the heart rate of 102 bpm signals that beta-blockade is now appropriate to add -- ONLY after confirming adequate alpha-blockade (BP targets met, nasal congestion present, mild orthostatic drop); propranolol or atenolol can now be initiated to control heart rate before surgery.
• C) The orthostatic hypotension and nasal stuffiness are expected effects of alpha-1 blockade confirming drug activity; however, the resting tachycardia of 102 bpm indicates the phenoxybenzamine dose is too high and is producing excessive vasodilation with reflex sympathetic overdrive -- the dose should be reduced by 50%; beta-blockade should NOT be added at any point during preoperative preparation because beta-blockade in a pheochromocytoma patient increases the risk of intraoperative hypertensive crisis by blocking the beta-2-mediated safety valve that limits NE-induced vasoconstriction during tumor manipulation.
• D) The lightheadedness indicates phenoxybenzamine is working (vascular bed expansion from alpha-1 blockade), and nasal congestion is a recognized adequacy marker; however, the tachycardia (HR 102 bpm) is concerning -- this is a surgeon who needs to operate and cannot tolerate tachycardia; beta-blockade (propranolol 20-40 mg twice daily) should be added immediately, before the alpha-blockade is fully established, to control the heart rate; in a physician patient with professional obligations, the standard alpha-first-then-beta sequence can be modified because the patient can self-monitor for symptoms of hypertensive crisis.

7. [CASE 2 -- QUESTION 3] The patient undergoes successful laparoscopic right adrenalectomy. During tumor manipulation, her blood pressure spikes to 248/158 mmHg. The anesthesiologist administers IV phentolamine 5 mg followed by IV sodium nitroprusside infusion. The blood pressure is controlled at 145/88 mmHg. Ten minutes after the tumor is removed, her BP falls to 78/48 mmHg and heart rate is 118 bpm. Which of the following most accurately explains the mechanism of the post-tumor-removal hypotension and guides the correct management?

• A) The post-removal hypotension results from phentolamine and nitroprusside drug accumulation -- both agents have long half-lives (phentolamine 19 hours, nitroprusside 6 hours) and their effects persist for several hours after infusion is stopped; the hypotension reflects residual drug effect rather than loss of tumor-derived catecholamine support; treatment is to stop all antihypertensive infusions and wait for drug clearance; IV calcium gluconate can hasten phentolamine reversal by restoring vascular smooth muscle calcium availability.
• B) The hypotension and compensatory tachycardia after adrenalectomy result from the sudden cessation of massive catecholamine secretion from the tumor -- the peripheral vasculature is now fully dilated from phenoxybenzamine preoperative alpha-blockade and the residual IV phentolamine/nitroprusside, without the vasoconstrictive support of tumor-derived NE that had been maintaining vascular tone intraoperatively; simultaneously, the patient's vascular bed has been expanded by preoperative alpha-blockade without fully correcting the chronic volume deficit from years of catecholamine-induced venoconstriction; treatment: (1) stop all antihypertensive agents immediately; (2) aggressive IV fluid resuscitation (crystalloid boluses to restore intravascular volume); (3) if hypotension persists despite volume resuscitation, vasopressor support with norepinephrine -- NOT epinephrine (tumor cells may still be producing small amounts of catecholamine from any remaining chromaffin tissue); avoid vasopressin unless norepinephrine is insufficient; (4) monitor for rebound hypoglycemia (loss of tumor-derived catecholamine suppression of insulin secretion may cause insulin-mediated hypoglycemia in the postoperative period).
• C) Post-adrenalectomy hypotension is caused by acute adrenocortical insufficiency from surgical disruption of the right adrenal cortex -- removal of the adrenal gland eliminates cortisol production from the zona fasciculata, producing Addisonian crisis characterized by hypotension, tachycardia, and hyponatremia; treatment is IV hydrocortisone 100 mg immediately followed by continuous infusion; vasopressors should not be used because they mask the underlying cortisol deficiency without treating the cause.
• D) The post-removal hypotension results from sudden loss of tumor-derived catecholamine support for vascular tone, compounded by the residual alpha-blockade from phenoxybenzamine (whose irreversible binding cannot be pharmacologically reversed -- vascular alpha-1 receptors remain blocked until new receptor protein is synthesized over 24-48 hours) and the relative volume depletion despite preoperative fluid loading; the compensatory tachycardia reflects baroreceptor reflex activation and possibly relative hypovolemia; management: stop antihypertensive infusions immediately; aggressive IV crystalloid resuscitation (2-4 liters boluses guided by cardiac output monitoring); vasopressor support with norepinephrine if volume alone is insufficient; monitor blood glucose (rebound hypoglycemia risk from insulin release unmasked by catecholamine withdrawal); if the contralateral adrenal gland is normal, acute adrenocortical insufficiency is unlikely in this patient having unilateral adrenalectomy, but cortisol level should be checked if hemodynamics remain unstable.

8. [CASE 2 -- QUESTION 4] Six months post-adrenalectomy, the patient has recovered fully. BP is 124/78 mmHg on no medications and normetanephrine levels have normalized. She asks her endocrinologist what ongoing surveillance is required and whether she should be tested for hereditary pheochromocytoma syndromes. Which of the following most accurately identifies the genetic syndromes associated with pheochromocytoma, the specific receptor or signaling pathway mechanism underlying each, and the surveillance implications?

• A) Pheochromocytoma is almost always sporadic (greater than 95% of cases) with no hereditary contribution -- genetic testing is recommended only if the patient has a first-degree relative with pheochromocytoma or if the tumor is bilateral or multifocal; a unilateral 5.8 cm adrenal pheochromocytoma in a 44-year-old woman without family history requires no genetic evaluation; surveillance consists of annual plasma metanephrine measurement for 10 years; no surveillance is needed for the contralateral adrenal gland since sporadic pheochromocytoma virtually never recurs.
• B) Approximately 30-40% of all pheochromocytomas have a hereditary basis, even in apparently sporadic presentations without family history; the major genetic syndromes are: MEN2A/2B (RET proto-oncogene gain-of-function mutation activating RET receptor tyrosine kinase -- bilateral adrenal pheochromocytoma, medullary thyroid carcinoma, primary hyperparathyroidism in MEN2A; mucosal neuromas, marfanoid habitus in MEN2B); VHL syndrome (VHL tumor suppressor gene loss-of-function, activating HIF-1alpha-mediated transcription of VEGF and other growth factors -- pheochromocytoma plus hemangioblastomas, clear cell renal cell carcinoma, pancreatic cysts); NF1 (neurofibromin loss-of-function, activating RAS-MAPK signaling -- pheochromocytoma plus cafe-au-lait spots, neurofibromas, Lisch nodules); SDH subunit mutations (SDHB, SDHC, SDHD, SDHAF2 -- succinate dehydrogenase complex II subunit loss-of-function activating pseudohypoxia pathways via succinate accumulation and HIF-1alpha stabilization -- associated with extra-adrenal paragangliomas and malignant pheochromocytoma particularly SDHB); genetic testing should be offered to all patients with pheochromocytoma given the 30-40% hereditary rate, with multigene panel testing recommended; surveillance after successful resection includes annual plasma or urine metanephrines for life, given the 10-17% recurrence rate and the possibility of metachronous contralateral or extra-adrenal tumors.
• C) The three most common hereditary syndromes are MEN1 (MENIN tumor suppressor loss-of-function -- pituitary, parathyroid, and pancreatic tumors but NOT pheochromocytoma), Carney complex (PRKAR1A mutation -- cardiac myxomas, spotty skin pigmentation, and adrenocortical tumors but not pheochromocytoma), and Cowden syndrome (PTEN loss-of-function -- thyroid, breast, and endometrial tumors but not pheochromocytoma); pheochromocytoma is not associated with any hereditary tumor syndrome and genetic testing is therefore not indicated in pheochromocytoma patients.
• D) Hereditary pheochromocytoma occurs in approximately 30-40% of cases -- genetic testing should be offered to all patients; the major syndromes include MEN2 (RET kinase gain-of-function -- bilateral adrenal pheo, MTC, HPT), VHL (VHL loss-of-function -- HIF-pathway activation, pheo/paraganglioma plus RCC and hemangioblastomas), NF1 (neurofibromin/RAS-MAPK activation), and SDH mutations (SDHB being highest malignant risk, SDHD showing parent-of-origin imprinting with paternal transmission required for expression in most kindreds); surveillance for resected pheochromocytoma: annual biochemical testing (plasma/urine metanephrines) for at least 10 years, and lifelong if hereditary mutation identified; imaging surveillance guided by biochemical results or if hereditary syndrome identified; surveillance for contralateral adrenal, extra-adrenal sites, and distant metastases (particularly if SDHB mutation confirmed); the 5.8 cm size and the patient's age (44) both increase the prior probability of hereditary disease and strengthen the case for genetic evaluation.