In a post I wrote almost 8 years ago (“A non-genetic risk factor for pheo?” in February 2015), I described an article that suggests cyanotic congenital heart diseases may predispose people to develop pheo. Since then, a few seminal papers have provided insights into that phenomenon. In my own practice, I have taken care of several patients with cyanotic congenital heart disease who develop pheo at young ages.
In 2018, a paper showed for the first time that 4 out 5 patients
with pheo and cyanotic congenital heart disease had somatic mutations in the
gene EPAS1 (which encodes hypoxia-inducible factor 2-alpha) in their pheo
tumors. These mutations are not inherited but develop spontaneously. Similar
mutations are also responsible for the polycythemia-paraganglioma-somatostatinoma
syndrome (see post “The story of Para and Poly: Are they related?” in September
2012). The difference is that the EPAS1 mutations in the pheo of people with cyanotic
congenital heart disease appear to only happen in the cells that give rise to
pheo (paraganglia cells, including cells of the adrenal medulla). In this year
(2022), a larger study confirmed the findings. It is thus pretty clear that hypoxia
favors the proliferation of paraganglia cells that harbor EPAS1 mutations,
resulting in pheo formation.
In my experience, people with cyanotic congenital heart disease
often have frequent imaging evaluations so that a pheo or para can be easily seen
so long as the doctors have a high alertness about those tumors. It is not
unusual for a small tumor to be omitted first but re-discovered years later.
The typical locations and imaging features of the tumors make the diagnosis
quite straightforward. It is not easy, however, to determine if the tumors are
functional in that whether they secrete catecholamines, because people with cyanotic
congenital heart disease often have slightly high pheo marker levels in the
absence of such tumors. Timing of surgical removal of the tumors is also quite
complicated. A tumor with clear evidence of catecholamine secretion should be
removed as soon as possible.
Dr. Pheo
