Calcitonin-negative ‘MTC-like’ thyroid paraganglioma revealing an SDHD -related hereditary paraganglioma syndrome: functional confirmation of a non-canonical splice-site variant

Abstract Introduction Primary thyroid paraganglioma (TPGL) is a rare mimic of medullary thyroid carcinoma (MTC). We report an SDHD-related TPGL caused by a non-canonical splice-region variant. Case presentation A 36-year-old woman underwent thyroidectomy for a 20 mm EU-TIRADS 4 Bethesda III thyroid nodule with normal serum calcitonin. The initial assessment documented maternal papillary thyroid carcinoma but did not capture the paternal history of paraganglioma. Two histopathologic assessments favored an “MTC-like” lesion, prompting MTC-directed functional imaging. Review by a specialist endocrine pathologist demonstrated zellballen architecture, S100-positive sustentacular cells, and loss of SDHB staining, establishing the diagnosis of TPGL. A subsequently obtained three-generation history identified carotid body paragangliomas in her father and brother. Germline testing identified a heterozygous intronic SDHD variant, NM_003002.4:c.314+4A>G in all three affected relatives; peripheral blood RNA sequencing demonstrated activation of a cryptic donor site 4 bp downstream of exon 3, supporting a splice-disrupting effect. Conclusion A complete family history should be obtained early in the assessment of unusual thyroid tumours. Calcitonin-negative MTC-like lesions with discordant immunohistochemistry warrant specialist pathology review before an MTC-directed pathway is pursued.