Mutation in the genes encoding subunits of the succinate dehydrogenase enzyme complex, SDHB, SDHC and SDHD are associated with an increased risk of developing adrenal or extra-adrenal phaeochromocytoma and cervical paraganglioma. However, the penetrance in large kindreds has seldom been reported and the optimal screening for asymptomatic carriers has not been determined.
The index case had a previous history of carotid body tumour and later died with metastatic phaeochromocytoma, genetic screening demonstrated a point mutation (268C>T) in exon 3 of the SDHB gene. At risk relatives were offered genetic counselling and mutation screening, and those harbouring the 268C>T mutation underwent comprehensive clinical evaluation, measurement of plasma and urinary catecholamines, plasma metanephrine and normetanephrine, and radiological evaluation with neck USS, CT or MRI of neck, thorax abdomen.
19 of 21 relatives identified within a three generation pedigree accepted genetic screening of whom 12/19 were positive for the mutation. Of these, three reported symptoms consistent with catecholamine excess, six were asymptomatic and three await evaluation. Within the symptomatic patients, one had two unexplained syncopal attacks, equivocal urinary catecholamines and normal imaging, remaining on surveillance. One patient (palpitations, elevated urinary noradrenaline) is awaiting resection of a mediastinal phaeochromocytoma. A third subject had mild elevated urinary noradrenaline, and an apparent adrenal nodule that proved to be normal on histology. In the remaining six (asymptomatic) subjects, all biochemical and radiological evaluation has been normal. Radionuclide imaging was performed where abnormalities were detected.
Conclusion: A low penetrance of symptomatic chromaffin tumour was identified in this family with an SDHB mutation. Until more is known about the natural history of the condition, the optimum screening method and interval will remain under debate. It is of note that all three of the patients with abnormal biochemistry in this family would have been identified on symptomatic enquiry.