Succinate dehydrogenase mutations

SDHB mutation carriers may develop benign or malignant phaeochromocytomas and paragangliomas, renal, gastrointestinal stromal and possibly thyroid tumours. SDHD is associated with phaeochromocytomas and paragangliomas. SDHC carriers often present with a single benign tumour only. The diagnosis requires genetic testing in all cases.

Urine metanephrine strongly positive or plasma metanephrine positive

Ensure full investigation has been performed at baseline

This should include the following in all patients with a phaeochromocytoma: thorough family history and documented family tree; 1x plasma metanephrine; chest radiograph; CT adrenals; MIBG scan and baseline pituitary function. Further cross sectional imaging will depend on results of MIBG scan, and on which gene defect is present: SDHB, SDHC or SDHD mutations.

Explain results and treatment options

Patients need to understand their diagnosis and the importance of adhering to medical treatment.

This is particularly important because the medication may not be well tolerated, but non compliance can have fatal consequences.

Initiate medical treatment with alpha blockade

Usual treatment starts with phenoxybenzamine. This may be started at a low dose eg 10mg daily, and should be gradually uptitrated to a usual maximum of 40-60mg in divided doses daily. Close BP monitoring is required and patients must be advised to keep up a high fluid intake.

This may have unpleasant side effects, for example dizziness, malaise and swollen ankles.

Doxazosin, usually in a sustained release preparation, may be used if phenoxybenzamine is unavailable or not tolerated. Dose should be titrated to the maximum tolerated.

Once a date is set for surgery, the dose of phenoxybenzamine should be uptitrated further until the patient develops significant hypotension and nasal congestion. This may require hospital admission, intravenous fluids or even blood transfusion for haemodilution and postural hypotension.

Add beta blockade for symptomatic tachycardia

Once a patient is fully alpha blocked, typically after about several weeks in an out patient setting, initiate beta blockade, for example with propranolol if they develop significant and symptomatic tachycardia.

This is not always necessary and must only be given after the patient is fully alpha blocked. Close BP monitoring is again required and the dose should be increased to the maximum tolerated or 240mg in divided doses.

Arrange surgery

Ideally patients will have been fully alpha and beta blocked over a period of at least six weeks prior to surgery.

Peri-operative management

Ideally, patients should be admitted preoperatively for intravenous alpha blockade prior to surgery.

If the patient is already on full oral treatment, administer intravenous phenoxybenzamine over three days prior to surgery.

Monitor postural blood pressure and haemoglobin over successive days.

Patients frequently require intravenous fluid support for dramatic falls in blood pressure. Full blood count should be checked daily, as a dramatic fall in haemoglobin may occur, which should be treated with pre operative blood transfusions if necessary. This occurs due to haemodilution as the vascular bed dilates and the intravascular volume expands. This preparation should prevent dramatic changes in blood pressure peri operatively, although an anaesthetist experienced in this procedure is essential.

If iv phenoxybenzamine is unavailable, the patient will require uptitration of their oral phenoxybenzamine in the week prior to surgery. This may also require admission and the dose should be increased by 10mg every 24hours until significant hypotension and nasal stuffiness occur. Patients may require intravenous fluid support as above, and ALL patients should start on iv fluids overnight before planned surgery to minimise the chance of significant perioperative hypotension.

Emergency management

In the acutely unwell patient, or one presenting with a crisis, the first priority should be fluid resuscitation. This should prevent a catastrophic fall in blood pressure occurring when alpha blockade is initiated.

Beta blockade is added only after the patient appears to be fully alpha blocked, which may take several days.

Post operative management

All medication may be stopped routinely. Blood pressure should be closely monitored. Arrange for urinary metanephrines to be repeated at six to 12 weeks.

Post operative follow up

Reasssess symptoms, blood pressure and metanephrines approximately three months post operatively.

Review and discuss the histological findings, malignant or benign, and arrange oncology multidisciplinary review for future management. Further screening and follow up depends on the genetic diagnosis.

Genetic counselling and further screening

Counselling and screening of both patients and their family members must be discussed.

No agreed international guidelines have been agreed for the follow up of SDH mutation carriers. However, phaeochromocytoma and extra-adrenal paragangliomas have been reported in SDHB, SDHC and SDHD carriers. Thyroid tumours have also been reported in SDHB and SDHD mutation carriers. Renal and gastrointestinal stromal tumours have also been described with SDHB, and there is a much higher association with malignant disease with SDHB. 

The frequency of clinical, biochemical and imaging follow ups suggested below is from the author's clinical experience only, and may well change with further research.

Family members

All family members should be screened and followed up in the same way as patients until proved to be non carriers of the mutation.

Baseline imaging at diagnosis of SDHB mutation

At diagnosis or gene confirmation, imaging of the abdomen, neck and thorax should be arranged.

MRI scanning is usually preferred to CT in patients requiring multiple surveillance images, since this does not expose the patient to ionising radiation.

Ultrasound may be preferred for initial imaging of the neck.

Annual follow up of SDHB

Annual follow up must include a review of symptoms, blood pressure and family history.

Annual follow up should also include: full blood count, urea and electrolytes, liver function test, 2x24hr urine metanephrines and urine microscopy. Imaging of the entire abdomen should be performed using CT or MRI every year.

Imaging of the neck and thorax should be considered every three years.

Baseline imaging at diagnosis of SDHD mutation

Carotid ultrasound scanning should be performed at baseline as well as imaging the adrenals and abdomen using CT or MRI in all gene carriers as well as confirmed patients.

Annual follow up of SDHD

Annual follow up must include a review of symptoms, blood pressure and family history.

Annual follow up should also include full blood count, urea and electrolytes, liver function test, and 2x24hr urine metanephrines. 

Consider repeat imaging of the adrenals, abdomen and neck every three to five years.

Genetic counselling and screening for SDHC mutation

Genetic counselling and screening of family members must also be discussed, although carriers of mutations in this gene tend to present with a solitary tumour.

Baseline imaging of SDHC

Carotid ultrasound scanning should be performed at baseline as well as imaging the adrenals and abdomen using CT or MRI in all gene carriers as well as confirmed patients.

Annual follow up of SDHC

Annual follow up must include a review of symptoms, blood pressure and family history.

Annual follow up should also include full blood count, urea and electrolytes, liver function test and 2x24hr urine metanephrines.  

Consider repeat imaging only if clinically indicated as this syndrome is not well characterised and tends to present with a single mass only.