Presentation: Patient with phaeochromocytoma or extra-adrenal paraganglioma

A 26-year-old man is referred for abdominal pain, episodic headaches and a recent diagnosis of hypertension. On examination, his seated blood pressure is 155/80mmHg but there are no other clinical or cutaneous features of note. Plasma metanephrine testing reveals significantly elevated normetadrenaline with normal metadrenaline. A CT scan identifies a hypervascular retroperitoneal mass consistent with an extra adrenal abdominal paraganglioma, and a hypervascular neck mass consistent with a synchronous carotid body paraganglioma.

Genomic testing is indicated in patients presenting with any of the following:

• phaeochromocytoma below the age of 60;
• bilateral phaeochromocytoma at any age;
• phaeochromocytoma above the age of 60 (these patients should have succinate dehydrogenase B (SDHB) immunohistochemistry performed by a dedicated pathology laboratory and, if SDHB staining is lost or equivocal, genomic testing should then be considered);
• phaeochromocytoma and renal cell cancer or gastrointestinal stromal tumour at any age;
• paraganglioma at any age;
• metastatic phaeochromocytoma or paraganglioma at any age; and
• phaeochromocytoma or paraganglioma at any age and one or more first-, second- or third-degree relative with PPGL, renal cell cancer or a gastrointestinal stromal tumour at any age.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria, which includes information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For those working within NHS Wales, please consult the All Wales Medical Genomics Service website for information on how to arrange testing.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• For patients who meet test directory eligibility criteria and do not have a personal or family history of a genetic variant in a phaeochromocytoma or paraganglioma (PPGL) predisposition gene, select the following.
  • R223 Inherited phaeochromocytoma and paraganglioma excluding NF1. This currently comprises the following genes: DLST1, FH, MAX, MDH2, MEN1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, SLC25A11, TMEM127 and VHL. It involves small gene panel sequencing.
  • If no pathogenic variant is identified by gene panel sequencing, multiplex ligation-dependent probe amplification (MLPA) analysis for exon-level deletions and/or duplications will be undertaken for SDHB, SDHC and SDHD genes.
• For patients presenting with PPGL where a genetic diagnosis in a PPGL predisposition gene has been established in another family member, single gene testing for that specific familial variant can be considered. For example, R240 Diagnostic testing for known mutation(s) could be selected if the pathogenic variant report about the close family member is available and testing was performed in an accredited laboratory.
• For patients presenting with PPGL with a strong family history of gastrointestinal stromal tumour (GIST), consider:
  • R363 Inherited predisposition to GIST (this involves small gene panel sequencing and MLPA or equivalent).
• For patients presenting with PPGL with a strong family history of renal cell carcinoma, consider:
  • R224 Inherited predisposition to renal cancer (this involves small gene panel sequencing and MLPA or equivalent).
• For patients presenting with PPGL who have clinical features of neurofibromatosis type 1 (NF1) or a family history of NF1, consider:
  • R222 Neurofibromatosis type 1 (this involves single gene testing of the NF1 gene).
• For patients with metastatic PPGL, somatic (tumour) sequencing can be considered after discussion with your local Genomic Laboratory Hub (GLH).
• None of the tests outlined above include whole genome sequencing, so you should use your local GLH test order and consent (record of discussion) forms.
• These tests are DNA based, and an EDTA sample (purple-topped tube) is required. The sample is best stored at four degrees Celsius until it can be posted to the genomic laboratory.
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• NHS England: National Genomic Test Directory

For patients

• Pheopara Alliance: What is paraganglioma?
• Phaeo Para Support UK
• Phaeo Para Support UK: Hereditary phaeochromocytoma and paraganglioma syndromes (PDF, 20 pages)