Germline fumarate hydratase mutations (FH) are a well-known cause of renal cell carcinoma and leiomyoma, but were only described in 2013 to also drive phaeochromocytoma/paraganglioma (PPGL) development. So far nine individuals with PPGLs due to familial FH mutations have been described. Here we add to the list by presenting the cases of two women with FH mutations previously not reported in PPGL.
Metabolic screening of Krebs cycle metabolites by LC-MS/MS identified two phaeochromocytomas with fumarate of 500 and 114 ng/mg tissue (median of 421 samples 1.87 ng/mg, 97.5 percentile 10.425 ng/mg, 2.5 percentile 0.085 ng/mg). Next generation panel sequencing, validated by Sanger sequencing, identified a novel disease-causing variant in the FH gene in Patient 1 (c.700A>G p.Thr234Ala) and a variant only reported in a paediatric case of FH deficiency in Patient 2 (c.T908C p.Leu303Ser). Both missense mutations are described as damaging with Polyphen-2 scores of 0.632 and 1.0, respectively. Loss-of-heterozygosity was confirmed in the tumour tissue.
Both patients presented with hypertension and symptoms of catecholamine excess, and after referral to the specialist centre (2006; 2011) right adrenal masses were detected. In both cases, biochemical workup showed urinary and/ or plasma increases confined to normetanephrine. Patient 2’s father suffered from renal cell carcinoma; whereas Patient 1’s family history presented with a thyroid tumour and melanoma. Until now there is no clear indication of metastatic disease, but follow-up is continuing.
Considering all FH-mutated PPGL cases to date, germline FH mutations appear to predominantly lead to adrenal phaeochromocytomas (9 of 11 cases) with a noradrenergic biochemical phenotype. As reported earlier, patients are at risk of multiple tumours, recurrence and metastatic disease emphasising the need for identification of these patients and regular follow-up.