Pheochromocytoma Syndromes, Hereditary Paraganglioma-Pheochromocytoma Syndromes, PGL/PCC, Synonyms: Familial Glomus Tumors, Familial Nonchromaffin Paragangliomas
Pheochromocytomas (PCC) and paragangliomas (PGL) are rare catecholamine-secreting tumors that arise from the chromaffin cells of the adrenal medulla and/or from extra-adrenal sympathetic and parasympathetic paraganglia1. Approximately 30% of all pheochromocytomas/paragangliomas (PGL/PCC) occur as a part of hereditary syndromes including von Hippel-Lindau (VHL) syndrome, multiple endocrine neoplasia type 2 (MEN 2), and neurofibromatosis type 1 (NF1) 2. The prevalence of pheochromocytoma/paraganglioma is not precisely determined, but incidence is approximately 1:300,000/year 1.
Pheochromocytoma is a tumor arising from adrenomedullary chromaffin cells that commonly produce one or more catecholamine neurotransmitters: adrenalin, noradrenaline, and dopamine 3. Secreting paraganglioma is a tumor derived from extra-adrenal chromaffin cells of the sympathetic paravertebral ganglia of thorax, abdomen, and pelvis. Paragangliomas that are not secreting arise from parasympathetic ganglia located along the vagal and glossopharyngeal nerves in the neck and at the base of the skull. About 80-85% of chromaffin-cell tumors are pheochromocytomas, whereas 15-20% are paragangliomas 4.
Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are clinically characterized by the following:
- Presence of multiple tumors, i.e. more than 1 paraganglioma or pheochromocytoma, including bilateral adrenal pheochromocytoma
- Presence of multifocal tumors with multiple synchronous or metachronous tumors
- Recurrent appearance of PGL/PCC
- Early onset of PGL/PCC presentation (age <45 years)
- Positive family history of PGL/PCC tumor.
Germline mutations in predisposition genes are identified in up to 30% of PGL/PCC 5. Germline mutations in the SDHx genes are the most common genetic cause of PGL/PCC, occurring in up to 25% cases 6. Furthermore, the most commonly associated genes with PGL/PCC are VHL (4–10%), RET (1–5%), and NF1 (1–5%) 1, 7 (Table 1).
The SDHx genes encode the subunits of the mitochondrial enzyme succinate dehydrogenase (SDH). SDH proteins are located on the inner mitochondrial membrane and function in the mitochondrial respiratory chain and the Krebs cycle. Tumors associated with SDH deficiency display notable upregulation of hypoxia-responsive genes and result in the development of PGL/PCC tumors.
PGL/PCC disorders are classified as types 1–5, depending on the location of the germline causing mutilation (see Table 1). The PGL subtype is characterized by the development of PGLs and/or PCs, together with a variable risk of developing of GIST tumors, renal cancers, or pituitary tumors. Clinical features of catecholamine excess in all PGL subtypes include hypertension, headache, sweating, palpitations, and high anxiety. These symptoms are paroxysmal and they can last for several minutes or longer, with variable intensity and frequency. Rarely, patients may present with catecholaminergic ‘crisis’ accompanied by acute cardiomyopathy and severe hypertension and sometimes even with multi-organ failure, such as lactic acidosis, encephalopathy, fever and hyperglycemia. In these cases, precipitating factors may be present including recent use of β-blockers, dopamine D2 agonists, corticosteroids or anesthesia.
Overview of the genes in CENTOGENE´s Pheochromocytoma panel
|Gene||OMIM||Chr. locus||Protein |
|Frequency of mutations||Associated and allelic disorders|
|MAX||154950||14q23.3||Myc-associated factor X; transcritption factor||1.12% 8||Pheochromocytoma, susceptibility to (171300)|
|PRKAR1A||188830||17q24.2||Protein kinase cAMP-dependant a1; cAMP signaling||60-70% for Carney complex 1 9||Carney complex, type 1 (160980); Acrodysostosis 1, with or without hormone resistance (101800); Myxoma, intracardiac (255960); Pigmented nodular adrenocortical disease, primary, 1 (610489); Adrenocortical tumor, somatic|
|SDHA||600857||5p15.33||Succinate dehydrogenase 1; Mitochondrial enzyme||0.6-3% 10||Paragangliomas 5 (614165); Leigh syndrome (256000); Mitochondrial respiratory chain complex II deficiency (252011); Cardiomyopathy, dilated, 1GG (613642)|
|SDHAF2||613019||11q12.2||Succinate dehydrogenase 5; Mitochondrial enzyme||Rare, 4 families only 11||Paragangliomas 2 (601650)|
|SDHB||185470||1p36.13||22%-38% 6,7 |
12%-20% of skull base and neck PGL 12
24%-44% of chest, abdomen, pelvic PGL/PCC 12
|Cardiomyopathy hypertrophic 12 |
Cardiomyopathy dilated 1M
|Paragangliomas 4 (115310); Pheochromocytoma (171300), Paraganglioma and gastric stromal sarcoma (606864); Gastrointestinal stromal tumor (606764); Cowden syndrome 2 (612359)|
|SDHC||602413||1q23.3||Succinate dehydrogenase 3; Mitochondrial enzyme||4-8% 12, 13 |
5/121 In European population 14
|Paragangliomas 3 (605373); Paraganglioma and gastric stromal sarcoma (606864); Gastrointestinal stromal tumor (606764)|
|SDHD||602690||11q23.1||Succinate dehydrogenase 4; Mitochondrial enzyme||~30% for PGL1 |
~40%-50% of skull base and neck PGL 12, 13
~15% of chest, abdomen, pelvic PGL/PCC 12
|Paragangliomas 1, with or without deafness (168000); Pheochromocytoma (171300); Paraganglioma and gastric stromal sarcoma (606864); Cowden syndrome 3 (615106); Carcinoid tumors, intestinal (114900); Mitochondrial complex II deficiency (252011); Merkel cell carcinoma, somatic|
|TMEM127||613403||2q11.2||Transmembrane protein 127; tumor suppressor||>1% 16||Pheochromocytoma, susceptibility to (171300)|
|VHL||608537||3p25.3||von Hippel-Lindau tumor suppressor||10-20% 100% for von Hippel-Lindau disease 17||Pheochromocytoma (171300); Renal cell carcinoma, somatic (144700); von Hippel-Lindau syndrome (193300); Erythrocytosis, familial, 2 (263400); Hemangioblastoma, cerebellar, somatic|
Treatment for secreting PGL/PCC tumors primarily involves blood pressure control with alpha-blockers followed by surgery by specialized teams. If the tumors have not metastasized surgical resection can be curative, and further follow-up is required due to the risk of malignancy recurrence. For patients with developed metastases, treatment options including chemotherapy and targeted radiotherapy should be proposed.
CENTOGENE offers the Pheochromocytoma panel (genes: MAX, PRKAR1A, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, VHL) including full gene sequencing and deletion/duplication analysis of selected genes (SDHA, VHL, SDHD, SDHAF2, MAX, SDHB, SDHC). In addition, tests for any of the genes in the Pheochromocytoma panel can also be ordered individually, for full gene sequencing and deletion/duplication analysis.
The differential diagnosis of Pheochromocytoma-related disorders – depending on the major symptoms in the initial case – includes the following diseases:
- Non-hereditary PCC/PGL
- Neurofibromatosis type 1
- von Hippel-Lindau syndrome
- Multiple endocrine neoplasia type 2
- Carney triad
- Carney-Stratakis syndrom.
CENTOGENE offers advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on the PCR-free Whole Genome Sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and provides sequencing of entire gene at a more uniform coverage.
To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for pheochromocytoma using NGS Panel Genomic targeted towards this specific phenotype:
Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Pheochromocytoma panel. Copy Number Variants analysis derived from NGS data is also included.
Step 2: If no mutation is identified after analysis of the Pheochromocytoma panel, based on the approval and consent, we further recommend to continue the bioinformatics analysis of the data obtained by whole genome sequencing to cover genes that are either implicated in an overlapping phenotype or could be involved in a similar pathway but not strongly clinically implicated based on the current information in literature.
The following patients should be tested using CENTOGENE´s Pheochromocytoma panel:
- Individuals with characteristic PGL/PCC clinical findings or persons with a positive family history of pheochromocytoma
- Individuals without a positive family history of PGL/PCC, but with the specific clinical findings
- Genetic testing (using CENTOGENE´s Pheochromocytoma panel) is useful to confirm the diagnosis and identify the disease causing mutation within a family, regardless of intensity of clinical features, in order to allow for carrier testing and prenatal diagnosis.
Sequencing, deletion/duplication of Pheochromocytoma panel and related genes should be performed in all individuals suspected of having PGL/PCC syndrome and suspected phenotypes. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.
Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of the PGL/PCC and related disorders, identify at-risk family members, and allow for appropriate referral for patient support and/or resources.
More information on CENTOGENE´s Pheochromocytoma panel can be found in our genetic test catalogue.