We read with great interest the article by Suda et al (1). The authors reported a patient with a novel germline deletion in the fumarate hydratase (FH) gene (c.737delT, p.Phe225Leufs*31) who presented with a cardiac myxoma and an adrenocortical adenoma. Interestingly, in contrast to the cardiac myxoma, the adrenal lesion did not harbor loss of heterozygosity (LOH) for the FH locus, and the level of the FH protein was not altered. It is therefore difficult to evaluate the direct role of this FH variant on the development of the adrenocortical tumor, but we agree with the authors that FH defects may at least participate in adrenocortical tumorigenesis as a modifier tumor suppressor gene (TSG). We first showed that FH could function as a potential TSG in the adrenal cortex in a patient with hereditary leiomyomatosis and renal cell cancer (HLRCC), bilateral macronodular adrenocortical hyperplasia, and mild Cushing syndrome (2).
We now report that we have also recently identified 3 missense FH variants that are rarely found in the general population, p.Y270C (gnomAD, allele frequency = 0.0000318), p.H318R (gnomAD, allele frequency = 0.00000398) and p.V435M (gnomAD, allele frequency = 0.0000875) in the germline of 2 unrelated and 2 related patients with Cushing syndrome caused by bilateral hyperplasia or adenoma. Although the p.Y270C variant is predicted to be benign in silico, p.H318R and p.V435M are predicted to be potentially damaging. These variants have not been previously described in HLRCC patients but the amino acid 318 altered here is also mutated in HLRCC (p.H318L, p.H318Y) supporting its importance for the function of FH. This variant (p.H318R) was also identified in 2 related patients presenting with familial adenomatous polyposis (FAP) caused by a germline APC pathogenic variant and no LOH of the FH gene in adrenal tissue. As in the paper by Suda et al (1), the FH variants that we have identified may play the role of a modifier defective TSG. Accordingly, the patients harboring the p.Y270C and p.V435M that we found both have an extra-adrenal phenotype with a pituitary tumor and hyperprolactinemia; however, no additional genetic changes have been identified in these patients.
In conclusion, these data support the hypothesis that FH variants may increase the risk for formation of adrenocortical tumors, but only rarely, if ever, are causative for oncogenesis in the cortex, unlike their known effects in the medulla, where they cause pheochromocytomas (3).
Glossary
Abbreviations
- HLRCC
hereditary leiomyomatosis and renal cell cancer
- LOH
loss of heterozygosity
- TSG
tumor suppressor gene
Additional Information
Disclosure Summary: Stratakis C.A. holds patents on the PRKAR1A, PDE11A, and GPR101 genes and his laboratory is the recipient of past and ongoing research grant support from Pfizer Inc. The other authors have nothing to disclose.
References
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