There is evidence to support the routine use of catecholamine screening in patients at high risk of paraganglioma and phaeochromocytoma.rr
- Urine and plasma free plasma metanephrines have diagnostic sensitivities greater than 97% with better specificity (85-100%) than total metanephrines or catecholamines.r
- Measurement of parent catecholamines (noradrenaline, adrenaline and dopamine) has low diagnostic sensitivity (<85%) and is not recommended.
- Some SDHD-related paraganglioma/phaeochromocytoma exclusively over produce dopamine, but not other catecholamines.r Consideration should be given to measuring plasma or urine 3-methoxytyramine.
Link to further information: Measurement of Biogenic Amines
There is prospective evidence to support a combination of anatomical and functional imaging in the initial assessment of SDH mutation carriers, and in mutation carriers with abnormal biochemical screens or suspicious clinical symptoms. However, evidence is lacking with regard to the best imaging surveillance for asymptomatic individuals, with normal biochemistry, who are at high risk of phaeochromocytoma/paraganglioma (see History icon for additional references).r
- Imaging by ultrasound, MRI and/or CT is able to detect biochemically “silent” and intermittently secreting phaeochromocytoma/paragangliomas that are missed by biochemical screening.rr
- MRI has 90-100% sensitivity and 50-97% specificity for adrenal phaeochromocytoma, and performs better than CT. But, extra-adrenal abdominal and thoracic tumours may be better detected by CT than by MRI, although the evidence is not clear.r
- MRI is the modality of choice for head and neck paraganglioma as they are usually non-functional and MRI performs better than CT.
- In individuals with abnormal biochemistry, functional imaging has clear utility for localising suspected functional tumours and ruling out metastatic disease, however its role in screening asymptomatic individuals, with normal biochemistry is not recommended because of the cumulative radiation dose.
- Because of the slow growing nature of the tumours MRI screening every 3 years is considered sufficient for individuals with SDHD and SDHAF2 mutations.
There is no accepted consensus on when to begin surveillance in SDH mutation carriers. The age to begin surveillance represents a balance between the burdens of biochemical testing and imaging (e.g. false positive result, radiation exposure, general anaesthesia in children) and the probability of detecting a tumour that needs intervention. Less than 4% of tumours are detected or symptomatic before 10 years of age, thus screening from 10 years would detect at least 96% of tumours. One group of authors suggest surveillance should begin at 10 years for SDHD. Another recommends radiological screening begin by age 14-16.
There is some evidence that altitude can modify the penetrance of SDHD, individuals living at lower altitudes demonstrating a less severe phenotype.
There are no consensus recommendations for renal screening in SDHD carriers. Ricketts et al suggest screening for Renal Cell carcinoma in SDHB mutation carriers via MRI to coincide with paraganglioma/phaeochromocytoma screening.r Some experts recommend managing the renal cancer risk in SDHD carriers as for SDHB.
Risk is low, so no evidence for specific thyroid screening.
SDH mutations are associated with a poorly defined risk of gastric gastrointestinal stromal tumours (gastric GIST) which are not associated with somatic KIT or PDGFRA mutations and are lacking SDHB on immunohistochemistry (i.e. paediatric type GIST). Although screening for gastric GIST is not recommended, mutation carriers who experience unexplained gastrointestinal symptoms such as abdominal pain, upper gastrointestinal bleeding, nausea, vomiting, difficulty swallowing, or who experience unexplained intestinal obstruction or anaemia should be investigated with the risk of gastric GIST in mind.
Parent of origin effect
Whilst children of SDHD mutation carriers are at 50% risk of carrying the mutation, only children of male carriers are at significant risk of developing SDHD-associated tumours. The mechanism of this parent of origin effect is unclear but it is not due to imprinting of the SDHD gene.
There are a small number of case reports describing SDHD-associated paraganglioma following maternal transmission of an SDHD mutation.
In contrast, the clinical details of more than 400 index cases with SDHD-associated tumours following paternal transmission of an SDHD mutation have been published. Where the extended family pedigrees have been published, there are no instances of SDHD-associated tumours following maternal transmission the SDHD mutation in any of these, thus maternal-disease transmission seems to be a rare event.