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SDHA, SDHB or SDHC-related familial paraganglioma-phaeochromocytoma – risk management

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Pathogenic variants in the SDHA, SDHB and SDHC genes are inherited in an autosomal dominant pattern.

In contrast to SDHD and SDHAF2, the tumour risk associated with pathogenic variants in the SDHA, SDHB and SDHC genes does not depend on the gender of the parent from whom the pathogenic variant is inherited.

This risk management guideline has been developed for individuals who have NOT been diagnosed with a relevant cancer/tumour. The care of affected individuals should be individualised based on their clinical situation, and the monitoring they need as part of their treatment and post-­treatment follow up.

The risk management of an individual with a pathogenic variant in two or more genes that confer a predisposition to cancer should also be individualised.

For SDHA:

For SDHB or SDHC:

  • Individuals who are known or obligate pathogenic variant carriers.
  • Individuals at 50% risk of inheriting a pathogenic variant.

Exclusion criteria

  • Individuals at 50% risk of inheriting a pathogenic variant in SDHA (as penetrance is very low and screening onerous, surveillance should only be offered to known or obligate SDHA pathogenic variant carriers).
  • Individuals with biallelic pathogenic variants in SDHA or SDHB and clinical features of mitochondrial complex II deficiency, Leigh syndrome or dilated cardiomyopathy 1GG.
  • Individuals who have inherited a pathogenic variant in another paraganglioma-phaeochromocytoma predisposition gene. (SDHD or SDHAF2  - see SDHD or SDHAF2-related paraganglioma-phaeochromocytoma – risk management)
Cancer/tumour type Risk of cancer/tumour *
SDHAr SDHBrr SDHCrr General population risk to
age 80 years
Most common to least commonr HNP >> PPGL PPGL > HNP HNP >> PPGL –
Any PGL/PCr Less than 5% to age 80 years Up to 37% to age 80 years Up to 18% to age 80 years Rare

Any PGL in childhood - penetrance at age 5, 10, 16, 18 yearsr

  

0.2%, 1.7%, 7.6%, 10.2%

With probands excluded:
0%, 0.3%, 1.2%, 2.2%

   Rare
Malignant PGL/PCr Uncommon

12% of combined symptomatic and asymptomatic individuals

41% of symptomatic individuals

 Uncommon Rare
Renalr Increased but risk small (less than 2%) 3–5% to age 80 years Increased but risk small (less than 2%) 1.4%**
Gastric GISTr Increased; GIST risk higher than PGL/PC risk Up to 1% to age 80 years Increased but risk small Less than1%
Pituitary adenomar Increased but less than 1% Increased but less than 1% Increased but less than 1% Unable to obtain

Abbreviations: PC = adrenal phaeochromocytoma; PGL = paraganglioma; PPGL = non-head and neck PGL and PC; HNP = head and neck PGL; GIST = gastrointestinal stromal tumour; RC = renal cancer; > = more common than; >> = much more common than.
*Penetrance figures may be over-estimates because of biased ascertainment.
**Source: Source: Australian Institute of Health and Welfare (AIHW) 2021 Cancer Data in Australia; Canberra: AIHW. <https://www.aihw.gov.au/reports/cancer/cancer-data-in-australia/contents/cancer-risk-data-visualisation>. (2017 data)

The choice of risk management strategy should take into account current age, other health issues and residual cancer risk.

See Checklist of symptoms and signs to review during follow up consultations.

Cancer/tumour type Recommendations^
  SDHA^^ SDHB SDHC
PGL/PC Assessment of symptoms, clinical examination and measurement of blood pressure Starting age 18 years 5 years 10 years
Frequency Annual Annual Annual
Metanephrines^^^ Starting age 18 years 5 years 10 years
Frequency Annual Annual Annual
68Ga-Dotatate PET-CT/MRI# Starting age/frequency Once, with initial imaging (only if surveillance imaging commences at
18 years or older)		 Once, with initial imaging (only if surveillance imaging commences at
18 years or older)		 Once, with initial imaging (only if surveillance imaging commences at
18 years or older)
MRI base of skull to coccyx Starting age 18 years 10 years 18 years
Frequency Once every 5 years Once every 2 years Once every 4 years
Renal cancer +
gastric GIST		 MRI to coincide with PGL/PC screening Starting age 18 years 10 years 18 years
Frequency Once every 5 years Once every 2 years Once every 4 years
Pituitary adenoma No evidence of benefit for screening

^The impact of lifestyle on cancer risk should be discussed e.g. exercise regularly, maintain a healthy weight, have a healthy diet, limit alcohol intake, do not smoke and avoid excessive sun exposure.
^^SDHA pathogenic variants have low penetrance (less than 5%) and the benefits of screening are unclear.
^^^Annual fasting free plasma metanephrines or 24 hour urine fractionated metanephrines, and if available plasma or urine 3-methoxytyramine; measurement of 3-methoxytyramine has higher sensitivity for head and neck tumours.
# If the timing of the PET scan coincides with scheduled MRI base of skull to coccyx, limiting the MRI to regions in which the PET scan may miss small lesions can be considered. This decision should be made in consultation with the relevant imaging service/s.

Screening cessation

For individuals who reach age 70 years, and who have had prior screening with no SDH-related abnormalities detected, the screening frequency can be reduced to once every five years. Screening can be ceased at age 80 years, provided no SDH-related abnormalities have been detected. For individuals over 80 years of age who have had no prior surveillance, one-off surveillance imaging can be considered depending on patient preference, life expectancy and co-morbidities.

Additional information

SDHA pathogenic variants demonstrate low penetrance. Particular care should be taken in formulating follow-up plans for asymptomatic individuals with SDHA pathogenic variants to avoid over-surveillance.

Pregnancy

Due to the high risk of adverse outcomes from secretory paraganglioma during pregnancy for both mother and fetus, it is highly recommended that plasma metanephrines be measured when planning pregnancy.r

Surgery

Plasma metanephrines should be measured prior to planned surgery.

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.

Paraganglioma/phaeochromocytoma

Surveillance

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 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.

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. 
Additional comments

There is international consensus not to modify screening intervals based on the presence or absence of metastatic disease in relatives.r

Risk reduction

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

Renal cancer

MRI screening for renal cell carcinoma should be done to coincide with PGL/PC surveillance.

Gastric GIST

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. The gastric GIST risk is highest for SDHA pathogenic variant carriers.r 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.

First degree blood relatives (parents/brothers/sisters/children) are at up to 50% risk of having inherited the pathogenic variant. More distant relatives may also be at risk of inheriting the pathogenic variant. Genetic relatives should be referred to a clinical genetics service or familial cancer centre to discuss predictive genetic testing.

Informing family members about hereditary cancer

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Version 1

Date Summary of changes
22/02/2022

Prior to September 2021 cancer genetics reference committee meeting, consensus via poll to split ID 3558 SDH-related familial paraganglioma-phaeochromocytoma – risk management into two separate protocols:

  • ID 4062: SDHA, SDHB or SDHC-related familial paraganglioma-phaeochromocytoma – risk management
  • ID 4066: SDHD or SDHAF2-related familial paraganglioma-phaeochromocytoma – risk management

New protocols discussed at September 2021 RCM. Discussions continued via MS teams and email. ID 4062 approved for publication with the following changes made:

  • Summary: minor wording changes
  • Target group - Exclusion criteria: minor wording changes
  • Lifetime risk of cancer/tumour: 
    • SDHB column: data updated
    • General population risk : updated to AIHW 2017 data
  • Cancer/tumour risk management guidelines table:
    • PGL/PC
      • Row added to table: 'Assessment of symptoms, clinical examination and measurement of blood pressure'
      • Row added to table: '68Ga-Dotatate PET- CT/MRI'
      • MRI base of skull to coccyx - SHDC: frequency changed from '3-5 yearly' to 'Once every 4 years'
    • Renal cancer + gastric GIST
      • Now combined in same row (previously GIST said 'No evidence of benefit for screening'
      • MRI to coincide with PGL/PC screening - SDHC: frequency changed from '3-5 yearly' to 'Once every 4 years' 
    • Footnote added: 'If the timing of the PET scan coincides with scheduled MRI base of skull to coccyx, limiting the MRI to regions in which the PET scan may miss small lesions can be considered. This decision should be made in consultation with the relevant imaging service/s.'
    • Screening cessation: paragraph added
  • Management of associated health problems: section added
  • Evidence for risk management guidelines: section reviewed and updated

Published as V.1. Review in 2 years. Approved on 22/02/2022, published on 10/05/2022.

ID 4062 replaces existing protocol ID 3558 SDH-related familial paraganglioma-phaeochromocytoma – risk management. The history section of ID 3558 is documented here

The information contained in this document is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to care or treatment. Any clinician seeking to apply or consult this document is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/4062

10 Aug 2022