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We report the clinical outcomes of eleven patients with succinate dehydrogenase subunit A (SDHA) germline mutations from three UK tertiary referral centres to highlight a more diverse and expanding clinical spectrum of associated phenotypes. We suggest that SDHA paraganglioma-related disease is not a low-risk condition as first described. Of our six index cases, two developed metastatic disease and a further one had local vascular invasion. One patient developed multiple metachronous disease. Therefore, we believe these patients, like those with SDHB and SDHD mutations, should be part of a surveillance programme. Paraganglioma (PGL)-associated mutations in SDHA have only been reported in a small number of patients worldwide. There is controversy over the necessity for surveillance screening in these patients, compared to SDHB and SDHD, as penetrance is thought to be lower (Benn et al. 2015) and variants exist with uncertain pathogenicity. Initial reports associated SDHA with autosomal recessive causes of juvenile encephalopathy (Leigh syndrome) (Bourgeron et al. 1995) and homozygous mutations in SDHA cause severe neurological dysfunction and cardiomyopathy (Renkema et al. 2015). SDHA mutations have now been associated with phaeochromocytoma and paraganglioma (PPGL) formation in an autosomal dominant manner. SDHA mutations account for only 3% of cases of familial PGL cases, with presumed low penetrance (Korpershoek et al. 2011) and therefore very little data on clinical features of SDHA-related PPGL exist. Six index cases were originally diagnosed between 1973 and 2011 and had histologically proven PPGL, who subsequently underwent genetic testing during the course of their follow-up and were confirmed to have an underlying SDHA germline mutation. We performed a retrospective analysis of their notes and describe their clinical outcomes. From these six index cases, cascade genetic testing occurred and identified five further asymptomatic carriers of SDHA mutations. All patients are now being followed up in specialised endocrine clinics and are undergoing annual screening, including annual clinical and biochemical assessment and cross-sectional imaging, although the frequency and modality of imaging differs between centres. To predict the pathogenicity of the DNA variants, the missense variants were investigated in silico using PloyPhen2 and SIFT. Table 1 provides a detailed summary of the patients described. The six index patients originally presented were aged 18, 34, 36, 46, 47 and 68 years. Five patients presented with a single lesion at diagnosis: intrathyroidal PGL, mediastinal PGL, phaeochromocytoma and two extraadrenal PGLs. One patient (patient 3) presented with two synchronous lesions: she had a 3-methoxytyramine (3MT)-secreting carotid body tumour and a noradrenalinesecreting thoracic PGL. All patients underwent surgical resection of the primary tumours. Two patients developed recurrence in the surgical bed and both patients went on to develop metastatic disease 16 and 37 years later (patients 8 and 9). One of these two patients (patient 8) also developed an additional five metachronous lesions 7–10 years after original diagnosis. These two cases are described in more detail. Patient 8 presented aged 46 years with headaches and malignant hypertension (210/130 mmHg). Urinary noradrenaline was very raised (Table 1) and imaging confirmed a 5 cm para-adrenal PGL, which was subsequently resected. He developed a symptomatic recurrence one year later, which was surgically resected. Eight years after his original diagnosis, he presented with symptoms of catecholamine excess and four new lesions were identified and resected. On surveillance imaging three years later, a new non-secretory lesion was identified. Surgical resection was undertaken one year subsequently due to increasing PGL size and plasma catecholamine levels. He remained well with no evidence of further disease on imaging until five years later when rising noradrenaline levels were noted and uptake in the left adrenal bed and in the vertebral body of L4 was

SDHA mutated paragangliomas may be at high risk of metastasis