Endocrine Abstracts (2017) 50 P302 | DOI: 10.1530/endoabs.50.P302

Unaffected genetic testing in families at risk of phaeochromocytoma or paraganglioma

Louise Izatt1, Paul Carroll2, Barbara McGowan2, Jake Powrie2, Mufaddal Moonim3, Audrey Jacques4, Rupert Obholzer5, Benjamin Whitelaw6, Ajith Kumar7 & Scott Akker8


1Clinical Genetics, Guy’s and St.Thomas NHS Foundation Trust, London, UK; 2Clinical Endocrinology, Guy’s and St. Thomas NHS Foundation Trust, London, UK; 3Histopathology, Guy’s and St. Thomas NHS Foundation Trust, London, UK; 4Clinical Radiology, Guy’s and St. Thomas NHS Foundation Trust, London, UK; 5Skull Base Surgery, Guy’s and St. Thomas NHS Foundation Trust, London, UK; 6Clinical Endocrinology, King’s College NHS Foundation Trust, London, UK; 7Clinical Genetics, Great Ormond Street NHS Trust, London, UK; 8Consultant Physician and Endocrinologist, St Bartholomew’s Hospital, London, UK.


75% of patients presenting with a phaeochromocytoma (PCC) or paraganglioma (PGL) have no relevant family history, but a germline pathogenic variant is identified in 30–40%. In our genetic endocrine clinic, over 80% of patients with malignant PCC or PGL have SDHA/SDHB/SDHC/SDHD/MAX or FH pathogenic variants identified, confirming high heritability in severe disease.

We describe a series of seven patients from five families concerned about their risk of developing PCC or PGL, as a parent had died from PCC or PGL and no genetic testing had been performed. One patient had a familial pattern of disease. Four had symptoms indicative of possible catecholamine excess. None had features of neurofibromatosis type 1. Baseline biochemical and radiological screening was performed and no abnormalities were detected. Routinely, genetic testing would only be offered if a diagnosis of PCC or PGL had been confirmed.

We obtained PCC or PGL tumour blocks from four of the deceased. Tumour DNA was extracted and partial genetic testing of SDHB and SDHD was successful in one case, but the tumour material was exhausted and no pathogenic variant was found. In three other cases, SDHB immunostaining on tumour tissue showed absent staining, indicating a possible SDHx pathogenic variant, however somatic tumour testing failed.

After careful discussion, unaffected or indirect testing was offered to each family, adopted from our experience in the genetics clinic of unaffected BRCA gene testing.

Three pathogenic variants were identified (2 SDHB, 1 SDHC), confirming an inherited susceptibility to PGL/PCC in three families.

Conclusion: Unaffected genetic testing in carefully selected cases may confirm a diagnosis, enabling timely surveillance and intervention in those with proven inherited PCC or PGL susceptibility. To reduce the need for unaffected testing, we recommend all patients with malignant PCC or PGL are offered genetic testing, as archival somatic tissue testing may not be informative.