Pheochromocytoma Genetics
The correct answer is C: Up to 40% of pheochromocytomas are associated with germline mutations.
Genetic Burden of Pheochromocytoma
The traditional teaching that pheochromocytomas are "mostly sporadic" is outdated and clinically dangerous. Approximately 30-40% of all pheochromocytomas and paragangliomas (PPGLs) harbor germline mutations in susceptibility genes 1, 2, 3. This represents a substantially higher hereditary burden than the previously estimated 10-15% from older literature 4.
Key Evidence Supporting High Hereditary Frequency
Even in apparently sporadic cases (no family history, single tumor, older age at presentation), germline pathogenic variants occur in 5.6-14% of all PPGLs, including 4.5-11% of isolated pheochromocytomas 1.
When including all patients regardless of presentation, the frequency of germline mutations in RET, VHL, SDHB, and SDHD together approaches 30% in unselected series 1, 4.
Population-based and hospital-based series consistently demonstrate mutation rates of 20-30% when comprehensive genetic testing is performed 4.
Why Other Answers Are Incorrect
A. "Most are sporadic" - FALSE
This statement is misleading because while 60-70% lack identified germline mutations, 30-40% having hereditary causes is far too high to dismiss genetic testing 1, 2, 3. The clinical implication is that genetic evaluation should be standard, not exceptional.
B. "Genetic testing is unnecessary" - FALSE
Current guidelines from both the Endocrine Society and European Society of Endocrinology recommend that all patients with PPGL be considered for genetic testing 1. The American College of Medical Genetics specifically recommends genetic testing consideration for any individual with a personal history of or first-degree relative with paraganglioma or pheochromocytoma 1, 2, 5.
D. "Only bilateral tumors are genetic" - FALSE
While bilateral tumors increase the probability of finding germline mutations, unilateral, apparently sporadic tumors still harbor germline mutations in 5.6-14% of cases 1. Many hereditary syndromes present with unilateral disease initially 1.
E. "Genetic causes occur only in children" - FALSE
Hereditary pheochromocytomas occur across all age groups. For example, TMEM127 mutations have a median age of onset of 47 years (range 18-76 years) 1. While young age increases suspicion, adult presentation is common in hereditary cases 1.
Clinical Implications
Universal Genetic Testing Recommendation
All patients with pheochromocytoma should be offered genetic testing, regardless of age, family history, or tumor characteristics 1. The analysis should minimally cover RET, SDHB, SDHD, and VHL, with generous inclusion of NF1 and FH 1.
Critical Pitfalls to Avoid
Do not rely on family history alone: Maternal imprinting in SDHD and SDHAF2 means family history may appear negative if the mutation was inherited from the mother 2, 5.
Do not assume unilateral = sporadic: Even single, unilateral tumors have significant germline mutation rates 1.
Do not skip genetic testing in older patients: Reduced penetrance means many hereditary cases present later in life 1.
Prognostic Importance
Identifying germline mutations has critical implications for patient management and family screening. SDHB mutations carry the highest risk of malignancy (28.6% metastatic rate) and significantly affect survival 2, 5, 6, making genetic identification essential for appropriate surveillance and counseling.