SAT-511 - Metastatic SDHA-Related Paraganglioma in A Young Adult with A C.771-1G >C Splice-Acceptor Variant

Background: SDHA-related paragangliomas (PGLs) have been historically considered low penetrance with limited metastatic risk. Emerging evidence suggests a more aggressive phenotype, with reports of delayed metastases occurring 16–37 years after diagnosis. Case series indicate that up to 5 of 32 SDHA-mutated PGLs develop metastases, supporting an intermediate-to-high risk profile. We present a case of metastatic SDHA-PGL (c.771-1G>C variant) at initial presentation.

Clinical

Case: A 34-year-old man with no history of hypertension, catecholamine-related symptoms, or known family history presented with left-sided neck pain and a progressively enlarging mass over one year. Initial MRI revealed a 3.9 × 3.6 × 4.5 cm left carotid space mass; surgical intervention was delayed by the patient. Plasma metanephrine and normetanephrine levels were within normal limits (41 pg/mL [ref < 57] and 97 pg/mL [ref < 148], respectively). Functional imaging demonstrated Stage IV disease with DOTATATE-avid cervical mass and metastatic involvement of the cervical, thoracic, and lumbar spine, iliac wing, and liver.
More than one year after presentation, the patient underwent uncomplicated resection of a 4 cm PGL. Pathology demonstrated loss of SDHB expression with retained fumarate hydratase, chromogranin and synaptophysin positivity, and S100-positive sustentacular cells. Seven lymph nodes were negative, with no lymphovascular or perineural invasion. No locoregional recurrence was identified at 3-month follow-up.
Given high-volume metastatic disease, oncology recommended treatment with 177Lu-DOTATATE (Lutathera) in combination with somatostatin analogues following multidisciplinary discussion. Treatment initiation has been deferred due to fertility preservation considerations.
Germline testing revealed a likely pathogenic SDHA splice-acceptor variant (c.771-1G>C), associated with autosomal dominant hereditary PGL-pheochromocytoma syndromes and overlapping mitochondrial complex II deficiency disorders. SDHA variants have also been linked to gastrointestinal stromal tumors, renal cell carcinoma, and pituitary adenomas.

Conclusion: SDHA-PGL should not be considered a low-risk entity. Literature demonstrates metastatic rates similar to SDHB in some cohorts, contradicting earlier assumptions of low risk. Even in the absence of catecholamine excess, SDHA-PGL warrant lifelong biochemical and imaging surveillance and genotype-informed counseling. SDHA-mutated tumors may grow slowly yet metastasize decades after initial resection, emphasizing the need for lifelong follow-up. MRI, low dose Chest CT, and DOTATATE PET are the preferred surveillance modalities. The presented c.771-1G>C variant expands the known pathogenic and clinical spectrum of SDHA PGLs. This specific genotype has very limited published characterization.

PMID: 39133175

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