ESA-SRB-AOTA 2019

Metastatic phaeochromocytoma, pituitary adenoma, pulmonary chondroscarcoma and lung adenocarcinoma in a patient with a novel MAX germline mutation. (#635)

Amanda Seabrook 1 2 3 , Catherine Luxford 1 , Judy Kirk 4 , Trish Dwight 1 3 , Roderick Clifton-Bligh 1 2 3
  1. Cancer Genetics, The Kolling Institute of Medical Research, Sydney, NSW, Australia
  2. Department of Endocrinology, Royal North Shore Hospital, Sydney, NSW, Australia
  3. The University of Sydney, Sydney, NSW, Australia
  4. Familial Cancer Service, Westmead Hospital, Sydney, NSW, Australia

Context: Phaeochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumours that arise from the chromaffin cells of the adrenal medulla or paravertebral autonomic ganglia. They are the most highly heritable cancer, with germline mutations having been identified in 14 driver mutations. Individuals harbouring one of these mutations are at risk of developing PPGL at a young age, with more aggressive features such as multifocal or metastatic disease1.

With the advent of whole exome sequencing, MAX (MYC-associated factor X) was the 10th germline driver mutation identified to cause hereditary PPGL. It is located on the long arm of chromosome 14 at position 23.3 (14q23.3). MAX is the most highly conserved dimerisation component of the MYC-MAX-MXD1 complex, which is involved in the regulation of cell proliferation, differentiation and apoptosis. These loss of function mutations are characterised by an autosomal dominant pattern of inheritance with a parent-of-origin effect2-3. There is mounting evidence MAX mutations have a role in pituitary tumorigenesis given the notable co-existence of pituitary adenoma in this cohort of individuals4. 

Case Description: We describe the case of 67 year-old female who underwent a bilateral adrenalectomy aged 21 for bilateral phaeochromocytoma. Recent functional imaging with 68Ga-DOTATATE demonstrated metastatic disease with intense uptake localised to an abdominal para-aortic lymph node and multiple lung lesions. Pertinent medical history includes a non-functioning pituitary adenoma and two additional lung pathologies; adenocarcinoma (FDG-avid) and pulmonary chondrosarcoma.  Next generation sequencing identified a novel MAX pathogenic variant (class IV, written c.22G>T). It was not found in population or variant databases. Analysis via in silico tools predicted a truncated protein product due to a premature translational stop signal at codon 8.

  1. King K. Pacek K. Familial Pheochromocytomas and Paragangliomas. Mol Cell Endocrinol. Mol Cell Endocrinol. 2014 Apr 5; 386(0): 92–100.
  2. Comino-Méndez I, Gracia-Aznárez FJ, Cascón A et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet. 2011 Jun 19;43(7):663-7. doi: 10.1038/ng.861.
  3. Burnichon N, Cascón A, Eisenhofer G, Gimenez-Roqueplo AP, Robledo M. MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma. Clin Cancer Res. 2012 May 15;18(10):2828-37. doi: 10.1158/1078-0432.CCR-12-0160. Epub 2012 Mar 27.
  4. O'Toole SM, Dénes J, Robledo M, Stratakis CA, Korbonits M. 15 YEARS OF PARAGANGLIOMA: The association of pituitary adenomas and phaeochromocytomas or paragangliomas. Endocr Relat Cancer. 2015 Aug;22(4):T105-22. doi: 10.1530/ERC-15-0241. Epub 2015 Jun 25.