An international consensus statement on the surveillance of asymptomatic SDH-X pathogenic variant carriers was published in 2021.r
Offer of recruitment into research is recommended.
Comments regarding the use of biochemical surveillance
There is evidence to support the routine use of catecholamine screening in patients at high risk of paraganglioma and phaeochromocytoma (PGL/PC).r
- Plasma free plasma metanephrines or urinary fractionated metanephrines have diagnostic sensitivities greater than 97% with better specificity (85–100%) than total metanephrines or catecholamines.r Free plasma metanephrines are preferred to urine.
- Measurement of parent catecholamines (noradrenaline, adrenaline and dopamine) has low diagnostic sensitivity (less than 85%) and is not recommended.
- Measurement of 3-methoxytyramine has higher sensitivity for dopamine secreting tumours and for head and neck tumours compared to measurement of metanephrines.
With SDHD pathogenic variants it is uncommon for tumours to develop under the age of 10 years and almost all are non-secreting, so measurement of metanephrines is not useful for SDHD pathogenic variant carriers in this age group.
See measurement of biogenic amines for instructions on ideal blood collection conditions.
Comments regarding the use of imaging
- Imaging modalities can detect biochemically “silent” PGL/PC that are missed by biochemical screening, but detected tumours may not need intervention, in particular non-secreting head and neck PGL.r
- Overall, the sensitivity of MRI/CT for screening of SDH-X carriers is 90–95% for head and neck PGL and 100% for PC but performs less well for thoracic and abdominal/pelvic PGL (sensitivity 45–54% at local centre, 76–83% in central centre). Specificity is 92–99%, 95% and 98–100% for head and neck PGL, PC, and thoracic/abdominal/pelvic PGL respectively.r
- MRI is the modality of choice for screening for head and neck PGL.
- Both MRI and CT scan have high sensitivity and specificity for PC.
- There is evidence to support a combination of anatomical and functional imaging (PET-CT/MRI) in the initial assessment of individuals with pathogenic variants in one of the SDH genes. The 2021 international consensus statement did not reach consensus regarding optimal PET radiopharmaceuticals due to variability in availability and cost.r However, joint guidelines published in 2019 recommended the use of 68Ga-DOTA-SSAs PET as the preferred option when available.r
- MRI-PET is preferable to CT-PET when available.
- Only imaging modalities without associated radiation exposure should be used for the surveillance of asymptomatic children.
- While not routinely recommended, ultrasound can be considered as an alternative for children who are unable to tolerate MRI.r
- A combination of anatomical and functional imaging can be considered in pathogenic variant carriers with abnormal biochemical screens or suspicious clinical symptoms/signs.
- There is international consensus not to modify screening intervals based on the presence or absence of metastatic disease in relatives.r
- The SDHD pathogenic variant c.242C>T p.Pro81Leu has been reported to be almost exclusively associated with HNPGL and a modified surveillance regimen has been proposed on this basis.r However, the recent consensus paper did not make any recommendations to modify surveillance based on variant type.r
There is evidence that living at high altitude increases the risk of developing head and neck paraganglioma compared with living at lower altitude but there is a lack of data to support increased penetrance for SDH-X pathogenic variant carriers.r
MRI screening for renal cell carcinoma should be done to coincide with PGL/PC surveillance.
SDH-X pathogenic variants are associated with a poorly defined but increased risk of gastric gastrointestinal stromal tumours (gastric GIST) which are not associated with somatic KIT or PDGFRA pathogenic variants. GIST should be searched for on surveillance imaging for PGL/PC. Additional screening for gastric GIST is not recommended, but pathogenic variant carriers who experience unexplained gastrointestinal symptoms (e.g. gastroesophageal reflux, vomiting, abdominal fullness, or abdominal pain), unexplained anaemia, gastrointestinal bleeding or an abdominal mass should be investigated with the possibility of gastric GIST in mind.
Maternally inherited pathogenic variants in SDHD and SDHAF2
There have been a small number of case reports of maternally inherited SDHD and SDHAF2 pathogenic variants causing disease. International consensus regarding the role of surveillance for maternally inherited SDHD and SDHAF2 pathogenic variants has not been reached.r All carriers should be counselled about the 50% risk of transmitting the pathogenic variant to their offspring.