A Case of Carney Triad Complicated by Renal Cell Carcinoma and a Germline SDHA Pathogenic Variant

Abstract Background: Carney triad is a rare multiple-neoplasia syndrome presenting as an association of paragangliomas (PGL), gastrointestinal stromal tumors (GIST), and pulmonary chondromas (CHO). Succinate dehydrogenase deficiency has been associated with several neoplasias, including Carney triad, renal cell carcinoma (RCC) and those associated with hereditary PGL/ pheochromocytoma (PHEO) syndromes. Clinical Case: A 57-year-old male diagnosed with hypertension at age 49, presented with a gradual increase in blood pressure over a period of 12 months. For seven years following his diagnosis of hypertension, the patient experienced episodic increases in blood pressure, to a systolic pressure greater than 180 mmHg associated with a tight band sensation around his forehead lasting half a day. Abdominal computed tomography (CT) revealed a left adrenal adenoma, a 5.1 cm para-aortic mass, and a right renal superior pole lesion measuring 2.5 cm, which was suspicious for a carcinoma. 123I-metaiodobenzylguanidine (123I-MIBG) and 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) scans were performed, which suggested the para-aortic mass to be consistent with a PGL. Additionally, 18F-FDG uptake was noted in the gastroesophageal region and was suspicious for a GIST. The left adrenal mass was not associated with 123I-MIBG or 18F-FDG activity. Chest CT demonstrated a right middle lobe lung lesion suggestive of a CHO, although no biopsy was performed. A diagnosis of Carney triad was made. The patient underwent surgical resection of the PGL and GIST, as well as a partial right nephrectomy. The PGL and GIST were positive for SDHA and negative for SDHB by immunohistochemical (IHC) staining. Pathology from the renal lesion was consistent with a 2.3 cm conventional clear cell renal carcinoma, with positive staining for SDHA and SDHB by IHC. The patient was found to harbor a germline heterozygous pathogenic variant (c.91 C>T, p.R31X) in SDHA which has been previously reported and results in loss of function of SDHA. SHDC hypermethylation was not detected in the PGL, GIST, or RCC. Additionally, DNA sequencing of the RCC did not indicate loss of heterozygosity at the variant region of interest. Although the SDHA disease-causing variant is responsible for the patients Carney triad phenotype, it is unclear if this variant is causative of the RCC. Conclusion: This is a novel presentation of a germline inactivating SDHA pathogenic variant in a patient with Carney triad complicated by RCC. However, an SDHA disease-causing variant was previously reported in a patient with comorbid GIST and RCC. This case provides further support to the increasing evidence that SDHx pathogenic variants may predispose patients to develop renal neoplasms.

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A case of Carney triad complicated by renal cell carcinoma and a germline SDHA pathogenic variant

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-20-0170 ◽

2021 ◽

Vol 2021 ◽

Author(s):

Rachel Wurth ◽

Abhishek Jha ◽

Crystal Kamilaris ◽

Anthony J Gill ◽

Nicola Poplawski ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Succinate Dehydrogenase ◽

Renal Cell ◽

Pathogenic Variant ◽

List Type ◽

Carney Triad ◽

Pathogenic Variants ◽

Cell Renal Carcinoma ◽

Tumor Level

Summary Succinate dehydrogenase deficiency has been associated with several neoplasias, including renal cell carcinoma (RCC) and those associated with hereditary paraganglioma (PGL)/ pheochromocytoma (PHEO) syndromes, Carney dyad, and Carney triad. Carney triad is a rare multitumoral syndrome characterized by co-existing PGL, gastrointestinal stromal tumor (GIST), and pulmonary chondroma (CHO). We report a case of a 57-year-old male who presented with para-aortic and gastroesophogeal masses, and a right renal superior pole lesion, which were classified as multiple PGLs, a GIST, and a clear cell renal carcinoma, respectively, on pathology following surgical resection. Additionally, a CHO was diagnosed radiologically, although no biopsy was performed. A diagnosis of Carney triad was made. SDHB immunohistochemical staining was negative for the PGL and the GIST, indicating SDH-deficiency. Interestingly, the renal cell carcinoma (RCC) stained positive for both SDHB and SDHA. Subsequent genetic screening of SDH subunit genes revealed a germline inactivating heterozygous SDHA pathogenic variant (c.91 C>T, p.R31X). Loss of heterozygosity was not detected at the tumor level for the RCC, which likely indicated the SDHA variant would not be causative of the RCC, but could still predispose to the development of neoplasias. To the knowledge of the authors this is the first reported case of an SDHA pathogenic variant in a patient with Carney triad complicated by RCC. Learning points The succinate dehydrogenase enzyme is encoded by four subunit genes (SDHA, SDHB, SDHC, and SDHD; collectively referred to as SDHx), which have been implicated in several neoplasias and are classified as tumor suppressor genes. Carney triad is a rare multiple-neoplasia syndrome presenting as an association of PGLs, GISTs, and CHOs. Carney triad is most commonly associated with hypermethylation of SDHC as demonstrated in tumor tissue, but approximately 10% of cases are due to pathogenic SDHx variants. Although SDHB pathogenic variants are most commonly reported in SDH-deficient renal cell carcinoma, SDHA disease-causing variants have been reported in rare cases.

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