Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

A new pheochromocytoma syndrome: extending the phenotype associated with MAX mutations (#47)

Gregory Hockings 1 2 , Aideen McInerney-Leo 3 , Nicholas Hockings 1 , Jason Hockings 1 , Jessica Harris 3 , Sofia Velosa 1 2 , Anthony Gill 4 , Rory Clifton-Bligh 4 , Emma Duncan 2 3 5
  1. Endocrinology Unit, Greenslopes Private Hospital, Brisbane, Qld , Australia
  2. School of Medicine, University of Queensland, Brisbane, Qld , Australia
  3. The Diamantina Institute, University of Queensland, Brisbane, Qld , Australia
  4. Royal North Shore Hospital, Sydney, NSW, Australia
  5. Department of Endocrinology, Royal Brisbane & Women's Hospital, Brisbane, Qld , Australia

Phaeochromocytomas (PCC) and paragangliomas (PGL) are neuroendocrine tumours derived from neural crest cells.  PCC/PGL are extremely heritable: 30-40% of cases have a germline mutation in one of 13+ genes. Several of these genes are associated with syndromes (e.g. multiple endocrine neoplasia type 2).

We recruited a three-generation kindred with multiple cases of PCC.  The father of the proband died suddenly.  Of his five children (all males), the proband and two others were affected.  One brother with metastatic PCC also has recurrent acromegaly 40 years after initial presentation, at which time acromegaly resolved following pituitary surgery performed shortly after adrenalectomies.  Two sons of the other brother had paravertebral ganglioneuroma and abdominal neuroblastoma respectively.  This brother showed brown fat uptake on MIBG.

Whole exome sequencing on DNA from peripheral blood monocytes from the proband identified a novel heterozygous mutation in MAX (MYC-associated factor X gene), segregating perfectly with disease in the family.  PCC immunohistochemistry demonstrated completely negative MAX1 staining, supporting its pathogenic role.  The other tumours showed: a) MAX1-negative staining in most neuroblastoma cells, supporting a pathogenic role of MAX; b) negative staining in ganglioneuroma ganglion cells but variable staining in Schwannian stromal cells.  The resected pituitary tissue was unavailable.

This is the 4th family world-wide with PCC from germline MAX mutations, and the first with other neural crest tumours.  MAX is a tumour suppressor gene affecting the MXD1 protein family which regulates cell proliferation and differentiation.  Consistent with previous reports, we observed paternal transmission; however, no affected woman has had children.  Whether acromegaly is from a pituitary lesion – and, if so, whether immunochemistry shows MAX1 deficiency – or GHRH co-secretion is currently unclear.  However, if the former is true, this family has a novel MEN syndrome.  Either way, this family extends the phenotype associated with germline MAX mutations.