Hereditary Paraganglioma-Pheochromocytoma Syndrome via the MAX Gene

Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndrome is a familial cancer syndrome which 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; Kirmani and Young 2012). 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). Sympathetic paragangliomas hypersecrete catecholamines, whereas parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the head and neck and most often are nonsecretory. The sympathetic extra-adrenal paragangliomas are generally located in the thorax, abdomen, and pelvis and are usually secretory. Pheochromocytomas typically hypersecrete catecholamines (Kirmani and Young 2012). 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) and for the hereditary PGL/PCC syndrome has been estimated at 1:25,000 to 1:50,000 (Welander et al. 2011).

Hereditary paraganglioma-pheochromocytoma syndrome is an autosomal dominant disorder and is mainly caused by variants in three genes (SDHD, SDHC, and SDHB), which are known by their syndromic names PGL1, PGL3, and PGL4. Hereditary PGL/PCC syndrome presents variable expressivity and age-related penetrance. SDHA, SDHB, SDHC, and SDHD are nuclear genes that 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. 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). Variants in MAX demonstrate parent-of-origin effects and generally cause disease only when the variant is inherited from the father. A proband with a hereditary PGL/PCC syndrome may have inherited the variant from a parent or have a de novo variant. An individual who maternally inherits a MAX variant has a low risk of developing disease; each of the individual's offspring is at a 50% risk of inheriting the disease-causing allele. An individual who paternally inherits an MAX variant is at high risk of manifesting pheochromocytomas and less commonly paragangliomas (Kirmani and Young 2012; Welander et al. 2011).

Approximately 13% of PGL/PCC tumors result from hereditary PGL/PCC syndrome (Welander et al. 2011). Germline variants in MAX have been estimated to be responsible for PCC/PGL in 1% of patients (Burnichon et al. 2012). 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). The majority of PGL/PCC tumors are sporadic (non-familial), but up to 45% of PGL/PCC tumors may have germline variants in a variety of genes (Opocher and Schiavi 2010).

The clinical sensitivity of deletion and duplications of the MAX gene in hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes is currently unknown; however a large deletion has been reported (Burnichon et al. 2012).

This test provides full coverage of all coding exons of the MAX gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.