Hereditary Paraganglioma-Pheochromocytoma (PGL/PCC) Syndrome Panel

Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndrome is a familial cancer syndrome that results in neuroendocrine tumors. The diagnosis of hereditary PGL/PCC syndrome is based on physical examination, family history, imaging studies, biochemical testing, and molecular genetic testing. 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, palpitations, pallor, and apprehension or anxiety; Else et al. 2018. PubMed ID: 20301715).

Paraganglia are a group of neuroendocrine cells that originate from the embryonic neural crest and can secrete catecholamines. In PGL/PCC syndrome, paraganglia arise in either the paravertebral axis (base of the skull to the pelvis) for paragangliomas or the adrenal medulla for pheochromocytomas (Welander et al. 2011. PubMed ID: 22041710).

Sympathetic paragangliomas hypersecrete catecholamines, whereas parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the head and neck. The sympathetic extra-adrenal paragangliomas are generally located in the thorax, abdomen, and pelvis and are usually secretory. Pheochromocytomas typically hypersecrete catecholamines (Else et al. 2018. PubMed ID: 20301715).

The prevalence of PGL/PCC tumors in the United States has been estimated to be between 1:2500 to 1:6000 (Chen et al. 2010. PubMed ID: 20664475) and for the hereditary PGL/PCC syndrome it has been estimated at 1:25,000 to 1:50,000 (Welander et al. 2011. PubMed ID: 22041710).

Hereditary paraganglioma-pheochromocytoma syndrome is an autosomal dominant disorder and is mainly caused by pathogenic variants in three genes, (SDHD, SDHC, and SDHB), which are also known by their syndromic names PGL1, PGL3, and PGL4. The next most commonly mutated gene is SDHA (PGL5), which encodes a catalytic subunit of succinate-ubiquinone oxidoreductase. Hereditary PGL/PCC syndrome presents variable expressivity and age-related penetrance. The nuclear genes SDHA, SDHB, SDHC, and SDHD encode the four subunits of the mitochondrial enzyme succinate dehydrogenase (SDH). Another gene, SDHAF2 (also known as SDH5) encodes a protein that appears to be required for flavination of the SDHA subunit. Pathogenic variants in the MAX gene, which encodes a transcription factor that regulates cell proliferation, differentiation, and apoptosis, can also predispose individuals to PGL and PCC (Comino-Méndez et al. 2011; Burnichon et al. 2012).

Pathogenic variants in MAX, SDHD, and SDHAF2 demonstrate parent-of-origin effects and generally cause disease only when inherited from the father. A proband with a hereditary PGL/PCC syndrome may have inherited it from a parent or have a de novo variant, although the latter’s frequency is not known. An individual who maternally inherits a MAX, SDHD, or SDHAF2 pathogenic variant has a low risk of developing disease; however, each of the individual's offspring is at a 50% risk of inheriting the disease-causing allele. An individual who paternally inherits an MAX, SDHD, or SDHAF2 pathogenic variant is at high risk of manifesting PGL/PCC. Germline predisposing pathogenic variants have also been found in the gene TMEM127, which is a negative regulator of mechanistic target of rapamycin (mTORC1) and has an important role in cellular proliferation and cell death (Else et al. 2018. PubMed ID: 20301715).

Other genes causative for hereditary paraganglioma-pheochromocytoma syndrome include FH, NF1, VHL, RET, MEN1, and DLST. NF1 encodes for the protein neurofibromin, which is a tumor suppressor that activates GTPase and controls cellular proliferation (Friedman. 2019. PubMed ID: 20301288). The VHL gene is also a tumor suppressor. Inactivation of both alleles at the cellular level leads to abnormal activation of genes involved in hypoxia (Maher et al. 2011. PubMed ID: 21386872). The RET proto-oncogene is one of many receptor tyrosine kinases, cell-surface molecules that transduce signals for cell growth and differentiation via RET autophosphorylation and intracellular signaling (Santoro et al. 2004. PubMed ID: 15331579). MEN1 is a tumor suppressor gene involved in many vital processes, including transcriptional regulation, DNA replication, and DNA repair (Larsson et al. 1988. PubMed ID: 2894610; Lemos and Thakker. 2008. PubMed ID: 17879353). The FH gene is a tumor suppressor encoding fumurate hydratase, which is involved in the conversion of fumarate to L-malate in the tricarboxylic acid (Krebs) cycle (Maher. 2011. PubMed ID: 21071978; Sudarshan et al. 2007. PubMed ID: 17287871). The DLST gene encodes a component of the multi-enzyme complex 2-oxoglutarate dehydrogenase that is involved in the tricarboxylic acid (Krebs) cycle (Remacha et al. 2019. PubMed ID: 30929736; Buffet et al. 2021. PubMed ID: 33180916). In vivo experimental studies suggest that loss of DLST catalytic activity leads to a high alpha-KG/fumarate ratio and accumulation of the oncometabolite 2-hydroxyglutaric acid (2HG; Remacha et al. 2019. PubMed ID: 30929736).

See individual gene test descriptions for additional information on molecular biology of gene products.

Although the majority of hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndrome tumors are sporadic (non-familial), approximately 13% of all PGL/PCC tumors are caused by germline pathogenic variants in known PGL/PCC syndrome genes (Welander et al. 2011. PubMed ID: 22041710). Clinical sensitivity is dependent on tumor location. For the SDHB gene, pathogenic variants are detectable in up to 44% of hereditary PGL/PCC cases; pathogenic variants in the SDHC gene are detectable in up to 8% of PGL/PCC hereditary cases; pathogenic variants in the SDHA gene are detectable in up to 3% of hereditary PGL/PCC cases; and pathogenic variants in the SDHD gene are detectable in up to 50% of hereditary PGL/PCC cases (Else et al. 2018. PubMed ID: 20301715). The clinical sensitivity for SDHAF2 and TMEM127 pathogenic variants is currently unknown. Germline pathogenic variants in the MAX gene have been estimated to be responsible for PCC/PGL in 1% of patients (Burnichon et al. 2012. PubMed ID: 22452945). In addition to the known PGL/PCC syndrome genes, germline pathogenic variants in a number of other genes may also predispose to PGL/PCC tumors (Opocher and Schiavi. 2010. PubMed ID: 21115163). PGL/PCC tumors can also be found in >10% of other familial syndromes such as multiple endocrine neoplasia type 2 (MEN2), von Hippel–Lindau disease (VHL), and neurofibromatosis type 1 (NF1); they are seen less often in Carney triad and Carney–Stratakis syndrome and rarely in multiple endocrine neoplasia type 1 (MEN1; Welander et al. 2011. PubMed ID: 22041710). The clinical sensitivity of DLST and FH pathogenic variants in predisposition to PGL/PCC is unknown, but pathogenic variants in both of these genes have been previously reported (Castro-Vega et al. 2014. PubMed ID: 24334767; Remacha et al. 2019. PubMed ID: 30929736; Buffet et al. 2021. PubMed ID: 33180916).

Hereditary paraganglioma-pheochromocytoma syndrome deletion and duplication frequencies for the majority of these genes are unknown; however, deletions have been reported in the SDHB gene in 12% of patients (Cascón et al. 2006. PubMed ID: 16258955) and have also been reported less frequently in the SDHC, SDHD, and MAX genes.