Penetrance

Age-related penetrance. Penetrance estimates vary . Penetrance was initially believed to be quite high, but larger studies with less bias from probands suggest a much lower penetrance. No reliable penetrance data are currently available for MAX, SDHAF2, or TMEM127 pathogenic variants. Table 3. Estimated Penetrance for SDHx Pathogenic Variants

Source: GeneReviews — "Hereditary Paraganglioma-Pheochromocytoma Syndromes"

Diagnostic Criteria

The Endocrine Society guidelines for pheochromocytoma and paraganglioma , American College of Medical Genetics guidelines for cancer predisposition , and North American Neuroendocrine Tumor Society guidelines for metastatic or unresectable pheochromocytoma and paraganglioma recommend that all individuals with paraganglioma or pheochromocytoma (PGL/PCC) be referred for molecular genetic testing to evaluate for a hereditary PGL/PCC syndrome.

Suggestive Findings

A hereditary PGL/PCC syndrome should be suspected in any individual with a paraganglioma or pheochromocytoma, particularly individuals with the following findings [, , , ]:

Source: GeneReviews — "Hereditary Paraganglioma-Pheochromocytoma Syndromes"

Differential Diagnosis

The differential diagnosis of hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes includes sporadic pheochromocytoma and sporadic paraganglioma or other syndromes that predispose to pheochromocytomas or paragangliomas. Sporadic pheochromocytoma. The incidence of all pheochromocytoma is ~0.6 in 100,000, and 75% are thought to be sporadic (not associated with hereditary predisposition). Sporadic paraganglioma. The incidence of sporadic paraganglioma is not known. It is believed to be less common than sporadic pheochromocytoma, but the association with hereditary predisposition is higher than for pheochromocytoma. Several genetic disorders associated with an increased risk of pheochromocytomas and/or paragangliomas have additional clinical features that are not seen in individuals with hereditary PGL/PCC syndromes. Table 5. Disorders to Consider in the Differential Diagnosis of Hereditary Paraganglioma-Pheochromocytoma Syndromes

Management Guidelines

Clinical practice guidelines for the management of individuals with hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes due to SDHx pathogenic variants have been published [, , , ].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a hereditary PGL/PCC syndrome, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 6.

Hereditary Paraganglioma-Pheochromocytoma Syndromes: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

General

| Refer to expert on hereditary PGL/PCC syndromes (e.g., endocrinologist, oncologist); the specialist w/expertise in PGL/PCC should then complete the evaluations in this table. | Referral to other subspecialists (e.g., ENT, cardiology, gastroenterology) as needed

In those w/symptoms or biochemical findings of PGL/PCC

| • Cross-sectional imaging (CT/MRI) is preferred method to define tumor extent.

• Functional studies, such as somatostatin receptor-based imaging (e.g., 68Ga- DOTATATE PET-CT) or less commonly other functional studies (e.g., FDG-PET) can aid in defining cross-sectional imaging findings as PGL/PCC or allow for defining therapeutic options for metastatic disease.

| CT or MRI may be preferable based on suspected tumor location:

• HNPGLs are often best characterized by MRI.

• Thoracic PGLs are best characterized by CT.

• Abdominal tumors by either MRI or CT

Source: GeneReviews — "Hereditary Paraganglioma-Pheochromocytoma Syndromes"

Surveillance Guidelines

Individuals known to have a hereditary PGL/PCC syndrome and relatives at risk based on family history who have not undergone DNA-based testing need regular clinical monitoring by a physician or medical team with expertise in treatment of hereditary PGL/PCC syndromes. Although no clear data regarding when to start, best method, and how frequent biochemical studies and imaging should be done in at-risk individuals exist, it is reasonable to consider surveillance for all at-risk individuals . Surveillance recommendations should take into account the associated gene and penetrance. Gene-specific recommendations from expert consensus groups have been published but are based on limited data .

Table 8.

Hereditary Paraganglioma-Pheochromocytoma Syndromes: Surveillance for Individuals at Risk and Affected Individuals

Gene | Evaluation | Frequency1

SDHA | Clinical assessment for manifestations of PGL/PCC GIST | Annually | Beginning at age 6-15 yrs2

Plasma-free fractionated metanephrines or 24-hour urine fractionated metanephrines (optional dopamine or 3-methoxytyramine) for secreting PGL/PCC | Every 2 yrs in childhood; then annually in adults

Whole-body MRI to assess for PGL, PCC, RCC, GIST | Every 2-3 yrs

EGD for those w/unexplained anemia GI symptoms | As needed

Note: Surveillance is not recommended in persons w/SDHA pathogenic variant no personal or family history of PGL/PCC or other SDHA-related tumors (i.e., incidental finding) due to low penetrance .

Source: GeneReviews — "Hereditary Paraganglioma-Pheochromocytoma Syndromes"