Pheochromocytomas and paragangliomas may be a rare symptom of HLRCC

HLRCC is a kidney cancer predisposition syndrome characterised by skin lesions, uterine fibroids and papillary renal cancers, and caused by heterozygous inactivating mutations in the FH gene. HLRCC is a very rare disease which affects roughly 300 families worldwide. As with all rare diseases, while proving association with common symptoms of HLRCC is straight forward, proving associations with rarer symptoms in an already small population is incredibly difficult due to scant information. Although not previously reported symptoms of HLRCC, a recent study by Castro-Vega et al. suggests that germline FH mutations are the underlying cause of 0.8% of pheochromocytomas and paragangliomas and therefore may also be a rare symptom of HLRCC.

Pheochromocytomas (PCC) and paragangliomas (PGL) are rare tumours of the neuroendocrine system. PCCs form in the adrenal gland just above the kidney, while PGLs can occur throughout the autonomic nervous system, particularly in the head, neck, and abdomen. While they are benign in the majority of cases, between 10-20% are malignant and more than a third of cases are familial (Gimenez-Roqueplo et al., 2012, Lloyd et al., 2004). There are 11 known PCC and PGL susceptibility genes, including the VHL gene (Fishbein and Natahnson, 2012). This is unsurprising as both PCC and PGL are known symptoms of the cancer susceptibility syndrome caused by mutations in VHL, Von Hippel-Lindau Syndrome.

In a previous study, whole exome sequencing identified that a germline FH missense mutation was the underlying cause of a PCC (Letouze et al., 2013). In order to determine if FH mutations are a common cause of PCC/PGLs, the authors sequenced the FH gene in a cohort of 598 PCC/PGL patients from France and Spain. They found a further four patients carried a pathogenic germline FH mutation – one splicing mutation and three novel missense mutations. Therefore germline FH mutations are a rare cause of PCC and PGLs.

Tumour samples from three patients were available, two of which showed loss of heterozygosity at the FH locus, and one of which had acquired a second hit mutation, indicating that loss of FH activity drove tumorigenesis in these cases. Of the five patients with an FH mutation, only one presented with a single benign tumour. The other four patients either had multifocal tumours, metastatic tumours, or both. As generally only 10-20% of PCC/PGLs are malignant, this suggests that FH mutations cause more aggressive disease.

FH catalyses the step in the Citric Acid Cycle that immediately follows that catalysed by Succinate dehydrogenase (SDH), and mutations in all four genes that make up SDH (SDHA, B, C and D) cause PCCs and PGLs. As well as a similar clinical phenotype – SDHB mutations in particular cause aggressive disease (Amar et al., 2007) – IHC testing on FH-null tumours showed the same molecular phenotype as SDHB-null tumours; low 5-hydroxymethylcytosine (5hmC) and high S-(2-succinyl) cysteine (2SC) staining. Therefore, FH and SDH mutations drive tumorigenesis through the same mechanism and cause clinically and molecularly similar tumours.

Of the five patients identified in this study, only one had any symptoms of HLRCC. Whether this is because the remaining four patients don’t have HLRCC, or because HLRCC was undiagnosed in these patients is unknown. It is possible that there is no overlap between the mutations that cause PCC/PGLs and the FH mutations that cause HLRCC, meaning that they are essentially two different diseases despite being caused by mutations in the same gene. However, two of the mutations identified in this study have been reported in seven cases of HLRCC and in one case of Fumarase deficiency, which is caused by biallelic mutations in FH. This suggests that there is at least partial overlap in the aetiology of these three diseases and it is therefore possible that PCCs and PGLs are a rare, hitherto unrecognised, symptom of HLRCC.


  • Amar L, Baudin E, Burnichon N, Peyrard S, Silvera S, Bertherat J, Bertagna X, Schlumberger M, Jeunemaitre X, Gimenez-Roqueplo AP, & Plouin PF (2007). Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. The Journal of clinical endocrinology and metabolism, 92 (10), 3822-8 PMID: 17652212
  • Castro-Vega LJ, Buffet A, De Cubas AA, Cascón A, Menara M, Khalifa E, Amar L, Azriel S, Bourdeau I, Chabre O, Currás-Freixes M, Franco-Vidal V, Guillaud-Bataille M, Simian C, Morin A, Letón R, Gómez-Graña A, Pollard PJ, Rustin P, Robledo M, Favier J, & Gimenez-Roqueplo AP (2014). Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Human molecular genetics PMID: 24334767
  • Fishbein L, & Nathanson KL (2012). Pheochromocytoma and paraganglioma: understanding the complexities of the genetic background. Cancer genetics, 205 (1-2), 1-11 PMID: 22429592
  • Gimenez-Roqueplo AP, Dahia PL, & Robledo M (2012). An update on the genetics of paraganglioma, pheochromocytoma, and associated hereditary syndromes. Hormone and metabolic research, 44 (5), 328-33 PMID: 22328163
  • Letouzé E, Martinelli C, Loriot C, Burnichon N, Abermil N, Ottolenghi C, Janin M, Menara M, Nguyen AT, Benit P, Buffet A, Marcaillou C, Bertherat J, Amar L, Rustin P, De Reyniès A, Gimenez-Roqueplo AP, & Favier J (2013). SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer cell, 23 (6), 739-52 PMID: 23707781
  • Lloyd R, Tischler A, Kimura N, McNicol A, & Young JW (2004). WHO Classification of Tumours, Volume 8 Pathology and Genetics of Tumours of Endocrine Organs. Third edition. ISBN13: 9789283224167 – the primary online resource for anyone interested in BHD Syndrome.

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