Poster Presentation The Joint Annual Scientific Meetings of the Endocrine Society of Australia and the Society for Reproductive Biology 2017

Expanding the phenotype of the fumarate hydratase germline mutation familial cancer syndrome  (#255)

Veronica Boyle 1 , Kelly Sullivan 1 , Trish Dwight 2 , Diana (Dindy) Benn 2 , Anthony Gill 2 , Roderick Clifton-Bligh 2 , Michael Croxson 1
  1. Auckland District Health Board, AUCKLAND, New Zealand
  2. Kolling Institute of Medical Research, The University of Sydney, Sydney, New South Wales, Australia

Germline pathogenic variants in the Krebs cycle enzyme Fumarate hydratase (FH) have been associated with Hereditary Leiomyomatosis and Renal Cell Cancer syndrome (HLRCC) and pheochromocytoma. 

We describe a kindred in whom phaeochromocytoma (PC) and/or paraganglioma (PGL) was associated with a pathogenic variant c.1142C>T (p.Thr381Ile) mutation in exon 8 of FH. We also describe, for the first time, the association of FH with gastrointestinal stromal tumour (GIST) in one affected case.

The proband presented aged 31 years with hypertension and was found to have a phaeochromocytoma, which was resected. He had a non-secretory paraaortic paraganglioma aged 54 years. Other family members affected by PC/PGL include a niece and two cousins. The proband provided consent for genetic testing and his DNA was sequenced on a targeted amplicon panel, which discovered the heterozygous FH pathogenic variant. Immunohistochemistry of his paraganglioma confirmed FH deficiency. The variant has been identified in other family members.

The proband’s affected mother (aged 78 years) was recently treated for GIST, discovered during investigation of syncope and hypotension. CT abdomen showed a 7.7cm x 7.2cm x 7.1cm mass, appearing to arise from the left adrenal gland. On the basis of mildly raised plasma normetanephrine (1839 and 1338pmol/L, NR <900pmol/L), the mass was suspected to be a phaeochromocytoma and the patient was treated with phenoxybenzamine prior to surgery. It was apparent intraoperatively that the mass arose from the greater curvature of the stomach. A partial gastrectomy was performed and histology confirmed a GIST. Immunohistochemistry staining was CD117 (KIT), CD34 and DOG1 positive. FH staining showed a normal pattern with distribution within the cytoplasm.

To our knowledge this is the first report of a GIST in a person with an FH germline mutation. In this patient, it is uncertain whether the GIST was sporadic or represents a previously unrecognized FH phenotype.

  1. Tomlinson IP, Alam NA Rowan AJ et al for the Multiple Leiomyoma Consortium. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer Nature Genetics. 2002 Apr;30(4):406-10. Epub 2002 Feb 25
  2. 2. Clark GR1, Sciacovelli M, Gaude E, Walsh DM, Kirby G, Simpson MA, Trembath RC, Berg JN, Woodward ER, Kinning E, Morrison PJ, Frezza C, Maher ER. Germline FH mutations presenting with pheochromocytoma. J Clin Endocrinol Metab. 2014 Oct;99(10):E2046-50. doi: 10.1210/jc.2014-1659. Epub 2014 Jul 8