Hereditary pheochromocytoma-paraganglioma syndrome

Hereditary pheochromocytoma-paraganglioma syndrome (PPGL syndrome)

Last update: September 2025

What is hereditary pheochromocytoma-paraganglioma syndrome?

Hereditary pheochromocytoma-paraganglioma syndrome (ORPHA:29072; OMIM 614165, 115310, 605373, 601650, 168000; MONDO:0017366) is a rare genetic condition that increases the risk for different tumours, including:

  • Pheochromocytoma and paraganglioma, which are rare neuroendocrine tumours (incidence <1:100.000 per year). These tumours originate from chromaffin cells of the adrenal medulla or in (para)sympathetic neural ganglia, along the paravertebral axis from skull base to the pelvis. Tumours that develop in the adrenal gland are called pheochromocytomas (or intra-adrenal paragangliomas), while those that evolve outside are named paragangliomas (or extra-adrenal paraganglioma). Both tumours may produce excessive amounts of hormones, called catecholamines, causing a variety of symptoms such as palpitations, headaches, excessive sweating and nausea. These symptoms might be the first manifestation of the tumours. There are rare parasympathetic head and neck paragangliomas, whose diagnosis is often related to mass effect. Pheochromocytomas and paragangliomas are typically diagnosed within the third to fifth decade and are most often benign. Individuals with PPGL syndrome tend to develop tumours at a younger age (i.e., <45 years of age, including childhood cases), and are more likely to develop multifocal, multiple and/or recurrent disease or malignant tumours.
  • Other tumours occurring more likely in persons with PPGL syndrome are gastrointestinal stromal tumours (GIST), pulmonary chondromas and clear cell renal cell carcinoma.

Paraganglioma and pheochromocytoma are rare tumours (estimated incidence approximately 0.6 in 100,000 individuals per year). A significant proportion of these tumours (approximately 30-40%) occurs as part of the hereditary pheochromocytoma-paraganglioma syndrome. Therefore, all patients with these tumours should be offered genetic panel testing of associated genes. Approximately 3% of all individuals with hereditary pheochromocytoma-paraganglioma syndrome develop a gastrointestinal stromal tumour (typically without KIT or PDGFRA driver mutations, but with SDH deficiency). While SDH-deficient tumour syndrome can be used as alternative terminology when SDH genes are affected, the use of Carney-Stratakis dyad/syndrome (ORPHA:97286, OMIM606864) is not recommended.

What causes hereditary pheochromocytoma-paraganglioma syndrome?

Hereditary pheochromocytoma-paraganglioma syndrome can be caused by pathogenic germline variants in one of multiple genes (such as SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127 and MAX) and identification of a disease-causing variant establishes the diagnosis. The SDHx genes are the most frequently involved genes, accounting for at least half of the cases with hereditary pheochromocytoma-paraganglioma syndrome. They encode individual subunits of the mitochondrial succinate dehydrogenase enzyme complex which is relevant for energy production in mitochondria. Among them, SDHB is the most frequently affected gene, and is also the one associated with the highest risk of malignant disease. The likelihood to develop tumours depends on the affected gene and highest for SDHB estimated approximately 22-58% till the age of 60 years. In rare instances an epigenetic silencing (SDHC promoter hypermethylation) of selected cells of the body (post zygotic mosaicism) is the cause of multiple associated tumours (Carney triad; ORPHA:139411, OMIM604287). SDHx genes are tumour suppressor genes and typically, both copies of the affected gene are inactivated in the tumours. Pheochromocytomas and paragangliomas may also occur in families with other genetic tumour risk syndromes, including Von Hippel-Lindau syndrome (VHL gene), Multiple Endocrine Neoplasia type 2 (RET gene), Neurofibromatosis type 1 (NF1 gene), and Hereditary Leiomyomatosis and Renal Cell Cancer (FH gene).

How is hereditary pheochromocytoma-paraganglioma syndrome inherited?

Hereditary pheochromocytoma-paraganglioma syndrome is inherited in an autosomal dominant manner, meaning that each child of an affected individual has a 50% chance to inherit the familial pathogenic variant. The chance not to inherit the variant is also 50%. All individuals of the pathogenic variant are at an increased risk of developing syndrome-associated tumours, although tumours do not develop in every person (“incomplete penetrance”). Depending on the country there might be options for prenatal testing and preimplantation genetic testing when disease causing variants were identified. Pathogenic variants in some genes (SDHD, SDHAF2 and possibly MAX) are associated with a parent-of-origin effect: the tumour risk is increased almost exclusively when the causative variant is inherited from the father. The Carney triad (epigenetic silencing of SDHC) is not expected to be inherited.

What are the surveillance options for hereditary pheochromocytoma-paraganglioma syndrome in the EU?

If a pathogenic variant in associated genes has been detected in an individual, close follow-up is recommended, and healthy relatives should be offered predictive testing.

Currently, different guidelines for initial screening after diagnosis, treatment and care of patients with hereditary paraganglioma-pheochromocytoma syndrome exist and there are specific recommendations dependent on the affected gene.

A lifelong regular screening is advised for individuals with hereditary pheochromocytoma-paraganglioma syndrome. This typically includes clinical examinations and questionnaires, biochemical examinations (metanephrines) and imaging techniques (including magnetic resonance tomography). The surveillance is typically started during childhood and the intervals differ for children (According to “International consensus statement on the diagnosis and management of phaeochromocytoma and paraganglioma in children and adolescents” by Ruth T. Casey et al., a guideline endorsed by ERN GENTURIS in August 2025) and adults. Surveillance should preferably be performed at specialised centres.

Future directions:

This paragraph discusses aspects of the disease for which there is currently limited evidence. These aspects can be the subject of studies and research but are not yet part of current clinical practice.

Several therapies are under investigation for metastatic disease. Targeted therapies (e.g. belzutifan, temozolomide, tyrosine kinase inhibitors) and clinical trials should be evaluated. Immunohistochemistry (typically against SDHB) and mass spectrometric-based measurements of metabolites can be useful to characterize variants of uncertain significance.

More information regarding hereditary pheochromocytoma-paraganglioma syndrome:

GeneReviews® - Hereditary Paraganglioma-Pheochromocytoma Syndromes
 Orphanet: Hereditary pheochromocytoma-paraganglioma
OMIM: pheochromocytoma/paraganglioma syndrome 1
OMIM: pheochromocytoma/paraganglioma syndrome 2
OMIM: pheochromocytoma/paraganglioma syndrome 3
OMIM: pheochromocytoma/paraganglioma syndrome 4
OMIM: pheochromocytoma/paraganglioma syndrome 5
ClinGen: hereditary pheochromocytoma-paraganglioma
Orphanet: Carney triad
OMIM: Carney triad
Orphanet: carney-stratakis syndrome (the use of Carney-Stratakis dyad/syndrome is not recommended, OMIM606864)
Endo-ERN (Genetic Endocrine Tumour Syndromes)

ERN GENTURIS documents

Clinical practice guidelines

ERN GENTURIS care pathway

ERN GENTURIS patient journey

ERN GENTURIS publications

Endorsed by ERN GENTURIS*

International consensus statement on the diagnosis and management of phaeochromocytoma and paraganglioma in children and adolescents

Currently unavailable

Currently unavailable

Thematic Group 4: Other rare – predominantly malignant – genturis

* ERN GENTURIS uses AGREE II as a tool for the endorsement of guidelines. The quality of the guideline is evaluated through assessing the rigor and transparency of the guideline development process. The content of the guideline is not evaluated, although selection of the guideline for endorsement includes expert opinion on the usefulness of the content of the guideline.

 

ERN GENTURIS education

ERN GENTURIS webinars

ERN GENTURIS webinars - Thematic group 4: Other rare genturis

Hereditary pheochromocytoma-paraganglioma syndrome

 

ERN GENTURIS healthcare providers

A list of healthcare providers with expertise in Thematic Group 4: Other rare - predominantly malignant - genturis can be found here.

 

Patient associations for hereditary cancer syndromes

A non-exhaustive list of patient associations for genetic tumour risk syndromes in EU member states can be found here.