What screening is recommended for someone with a positive Succinate Dehydrogenase (SDH) mutation?

Screening Recommendations for Individuals with Positive SDH Mutations

Individuals with positive Succinate Dehydrogenase (SDH) mutations should undergo annual biochemical screening with plasma or urine methoxycatecholamines and rapid whole-body MRI every 2 years, with specific surveillance protocols determined by the exact SDH gene variant and family relationship to the index patient. 1

Surveillance Recommendations by SDH Gene Type

SDHD and SDHAF2 Mutations

• For first-degree relatives (FDR) and second-degree relatives (SDR) who inherited the variant from their father:

  • Annual biochemical screening of methoxycatecholamines 1
  • Rapid whole-body MRI (RWB-MRI) every other year 1
  • Clinical check-up every 2 years 1

• For FDR and SDR who inherited the variant from their mother:

  • One-time biochemical screening 1
  • One baseline RWB-MRI; if normal, no further surveillance needed 1
  • This reduced surveillance is due to maternal imprinting, which means disease only develops if the risk allele is inherited from a father 1

SDHB Mutations

• For first-degree relatives:
  • Annual biochemical screening 1
  • RWB-MRI every other year 1
  • Clinical check-up every 2 years 1
  • More intensive surveillance is recommended due to higher risk of metastatic disease 1

SDHA, SDHC, TMEM127, and MAX Mutations

• For first-degree relatives:

  • Annual biochemical screening 1
  • RWB-MRI every other year (interval can be increased to every third year if normal) 1
  • Clinical check-up every 2-3 years 1

• For second-degree relatives:

  • One-time biochemical screening 1
  • One baseline RWB-MRI; if normal, no further surveillance needed 1

Biochemical Screening Details

• Biochemical screening should include measurement of methoxycatecholamines (normetanephrine, metanephrine, and methoxytyramine) in plasma or urine 1
• Plasma sampling should be performed after 30 minutes of rest in the supine position 1
• 3-methoxytyramine should be sampled after an overnight fast 1
• Analysis should be performed using liquid chromatography with detection by mass spectrometry 1
• Elevated levels of methoxyadrenaline suggest pheochromocytoma, while isolated elevation of 3-methoxytyramine suggests paraganglioma 1

Imaging Recommendations

• Rapid whole-body MRI (RWB-MRI) from the base of the skull to the pelvis is the preferred imaging modality 1, 2
• No gadolinium contrast is needed for screening 1
• For children under 15 years, an individualized surveillance program should be designed with a pediatrician 1
• If lesions are detected, targeted ultrasound, CT, PET-CT, and/or targeted MRI may be needed for confirmation and characterization 1
• For SDHD mutation carriers specifically, whole-body MRI should be performed at least every 2-3 years 1

Timing of Surveillance

• Surveillance should start from 5 years before the youngest age of onset in the family 1
• For individuals 15 years or older, adult screening protocols can be used 1
• Surveillance should continue at least up to age 70-75 years, followed by individualized re-evaluation 1

Special Considerations

• If a carrier develops symptoms, relevant investigation is recommended regardless of scheduled surveillance 1
• For patients with SDHD mutations specifically, lifelong follow-up is recommended due to risk of recurrence, metastasis, or progression 1
• The sensitivity of whole-body MRI (87.5%) is higher than biochemical testing (37.5%) for detecting SDH-related tumors 2
• The best diagnostic performance is obtained by combining anatomical imaging tests with somatostatin receptor scintigraphy (sensitivity 91.7%) 3

Common Pitfalls and Caveats

• Biochemical testing may be normal in patients with SDH-related tumors (10% can be biochemically silent) 4
• Certain medications can affect methoxycatecholamine levels: tricyclic antidepressants and monoamine oxidase inhibitors increase levels of methoxyadrenaline and methoxynoradrenaline, while levodopa raises levels of 3-methoxytyramine 1
• Plasma sampling done in sitting position will yield 25% higher methoxycatecholamine results compared to supine reference values 1
• SDHB-related paragangliomas often present with symptoms related to tumor mass effect rather than catecholamine excess 4