Hereditary Paragangliomas-Pheochromocytoma Syndrome (Paragangliomas I)

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 03/10/2015
• Curation Status: Retracted (2.0.0)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
No assertions found.

Actionability Assertion Rationale

• This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Paraganglioma development / Surveillance	2	3C	2C	3	10CC

Severity of Outcome

Prevalence of the Genetic Condition

Paragangliomas 1 (PGL1) is one of several disorders that make up the hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndrome. Hereditary PGL/PCC represents 30% of all PGL/PCC, for which prevalence is approximately 1:500,000 for PCC and 1:1,000,000 for PGL. Approximately 30% of hereditary PGL/PCC is attributed to mutations in SDHD.

Clinical Features (Signs / symptoms)

Hereditary PGL/PCCs are rare neuroendocrine tumors represented by paragangliomas (occurring in any paraganglia from the skull base to the pelvic floor) and pheochromocytomas (adrenal medullary paragangliomas). Hereditary PGL/PCC syndromes may be associated with gastrointestinal stromal tumors. Symptoms of PGL/PCC result either from mass effects or catecholamine hypersecretion (e.g., sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, forceful palpitations, pallor, and apprehension or anxiety). Mutations in SDHD are more frequently associated with parasympathetic skull base and neck paragangliomas than other tumor types, with 50% presenting as multiple tumors.

Natural History (Important subgroups & survival / recovery)

PGL/PCCs may be fatal, but with staged tumor targeted treatment modalities some affected individuals have lived with their disease for 20 years or more. For PGL/PCCs that have not metastasized, operative treatment can be curative; however, once metastases have occurred the disease is uniformly fatal, with only 50% of affected individuals surviving beyond 5 years. No reliable pathology studies are available to distinguish a primary benign from a primary malignant PGL/PCC (malignancy rate ~15%). Compared to persons with sporadic tumors, individuals with germline mutations tend to present at younger ages and be more likely to have multifocal, bilateral, and recurrent diseases, or to have multiple synchronous neoplasms.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

Unknown

No information on the prevalence of SDHD mutations was available.

Penetrance (Includes any high-risk racial or ethnic subgroups)

Unknown

Penetrance of genetically determined PGLs/PCCs depends on the gene, age and tumor sites.

Tier 4

>= 40 %

An individual who inherits a SDHD mutation from his/her mother is at low but not negligible risk of developing diseases. An individual who inherits an SDHD mutation from his/her father is at high risk of manifesting PGL and, to a less extent, PCC.

Tier 4

>= 40 %

SDHD mutations appear to have a high but age-related penetrance; penetrance is 48% by age 30 and 86% by age 50. The penetrance of skull base/neck paragangliomas and extra-adrenal abdominal/thoracic tumors for SDHD mutations is 68% and 35%, respectively by age 40.

Tier 3

1-4 %

The prevalence of malignant paraganglioma in SDHD-mutation carriers is estimated to be 4% (95% CI: 2-7%).

Tier 1

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

No information on the relative risk related to SDHD mutations was available.

Expressivity

Variation in the prevalence, penetrance, and phenotypic expression of gene mutations may be population specific.

Tier 3

Intervention Effectiveness

Patient Management

At diagnosis, the following are recommended to establish the extent of disease: imaging studies using MRI/CT, 1231-MIBG, and possibly PET; a medical genetics consultation.

Tier 4

In young adults who have unexplained gastrointestinal symptoms (e.g., abdominal pain, upper gastrointestinal bleeding, nausea, vomiting, difficulty swallowing) or who experience unexplained intestinal obstruction or anemia, consideration of evaluation for gastrointestinal stromal tumors (GISTs) is recommended.

Tier 4

Surveillance

Regular clinical monitoring by a physician or medical team with expertise in treatment of hereditary PGL/PCC syndromes.

Tier 4

In persons with SDHD mutations, periodic (e.g., every 2 years) MRI or CT of the skull base and neck to detect paragangliomas and periodic (e.g., every 4 years) body MRI or CT and 123I-MIBG scintigraphy to detect paragangliomas or metastatic disease that may occur beyond the neck and skull base are recommended. Early detection of tumors can facilitate surgical removal, decrease related morbidity, and potentially result in removal prior to malignant transformation or metastasis. Screening should begin at age ten years or at least ten years before the earliest age at diagnosis in the family. Penetrance data suggest that if lifelong screening were to begin at age ten years, disease would be detected in all persons with SDHD mutations.

Tier 3

It is reasonable to consider lifelong annual biochemical and clinical surveillance. The findings of these evaluations should guide imaging studies.

Tier 3

Circumstances to Avoid

SDHD mutations may impair oxygen sensing; therefore, penetrance of hereditary PGL/PCC syndromes may be increased in those who live in high altitudes or are chronically exposed to hypoxic conditions. In one study, HPPS1 subjects diagnosed with single tumors at their first clinical evaluation lived at lower average altitudes and were exposed to lower altitude-years than those with multiple tumors ( P<0.012). Avoidance of habitation at high altitudes and activities that promote long-term exposure to hypoxia should be considered.

Tier 3

Activities such as cigarette smoking that predispose to chronic lung disease should be discouraged in persons who have a mutation in SDHD.

Tier 4

Nature of Intervention

Nature of Intervention

Regular screening is a low risk, moderately intensive intervention.

Context: Adult

Chance to Escape Clinical Detection

Pheochromocytomas and extra-adrenal sympathetic paragangliomas in PGL/PCC syndromes present in a manner similar to those in persons with sporadic (i.e., not inherited) tumors, most often coming to medical attention due to the signs and symptoms associated with catecholamine hypersecretion, or signs and symptoms related to mass effects from the neoplasm.Regular screening is recommended beginning at diagnosis, or earlier for family members. These screenings are above and beyond general population recommendations.

Context: Adult

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers

References List

Hereditary Paraganglioma-Pheochromocytoma Syndromes.. Gene Reviews (2012) URL: http://www.ncbi.nlm.nih.gov/books/NBK1548/

Hereditary pheochromocytoma-paraganglioma.. Orphanet (2010) URL: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=29072

PARAGANGLIOMAS 1; PGL1. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 168000, (2016) World Wide Web URL: http://omim.org/

van Hulsteijn LT, Dekkers OM, Hes FJ, Smit JW, Corssmit EP. (2012) Risk of malignant paraganglioma in SDHB-mutation and SDHD-mutation carriers: a systematic review and meta-analysis. Journal of medical genetics. 49(12):768-76.