Phaeochromocytomas/paragangliomas (Pheo/PGL) are tumours of the neuroendocrine system. Roughly a third of these tumours are inherited, driven by genes such as VHL, EPAS-1, EGLN-1, SDH A, SDH B, SDH C, SDH D, SDH AF, RET, and a couple of others. Several of these genes, epitomised by Hypoxia Inducing Factor (HIF), are activated in response to hypoxia. HIF-beta is constitutive, while HIF-alpha is inducible. Several of the SDH genes are also "turned on" by hypoxia. When these genes are constitutively activated in the absence of hypoxia, say due to a mutation, they are said to mimic "pseudohypoxia".
In the 1960s, it became apparent that pheo/PGL was more common in subjects with chronic hypoxia, specifically in two subgroups- in subjects with congenital cyanotic heart disease (CCHD) and in subjects living at high altitudes. Subjects with CCHD in particular, have a much higher incidence of pheo/PGL than the general population. The incidence of pheo/PGL in subjects with non-cyanotic congenital heart disease such as VSD, PDA, ASD and bicuspid aortic valve is no different than the general population.
Similarly subjects living at high altitudes have a higher risk of paragangliomas.
In the latest issue of New England Journal of Medicine, Vaidya and colleagues found that activating somatic mutations in EPAS-1, which codes for HIF-2 alpha, were present in 4 out of 5 subjects with CCHD presenting with pheo/PGL. To put this in perspective, the incidence of EPAS-1 activating mutations in subjects with pheo/PGL who do not have CCHD is only 5-6%.
In developed countries, most subjects with CCHD would have had surgical corrections such as Fontan's procedure in childhood. While the duration of uncorrected CCHD correlates positively with the risk of pheo/PGL, corrective procedures do not ameliorate risk. These tumors can arise many decades later.
Most of these subjects have striking polycythaemia. The latter is of course seen in tumours other than pheo/PGL. For example germ line mutations in VHL lead to the Von Hippel Lindau syndrome, with a higher risk of haemangioblastomas and renal cancer. Somatic mutation in VHL leads to a higher risk of renal cell cancer, and can again be associated with polycythaemia.
It is tempting to hypothesise that the hypoxia inducible genes, when chronically activated by hypoxia itself, through the agency of EPAS-1, as in CCHD, or constitutively (and inappropriately) activated by germline and somatic mutations in genes such as VHL, lead to increased risk of tumours- pheo/PGL in the case of CCHD, pheo/PGL & renal cell cancer with germline VHL mutations, and renal cell cancer in somatic VHL mutations.
It is worth clarifying here that VHL is an inbuilt inhibitor of HIF-alpha. When VHL is mutated (with inactivation), HIF-alpha becomes disinhibited and is free to act as a growth promoting gene (new blood vessels, pheo/PGL, renal cell cancer).
There is no suggestion that acquired causes of hypoxia in adulthood such as heavy smoking or chronic lung disease lead to a higher risk of pheo/PGL. It appears that the drive from hypoxia must start very early in life, such as with CCHD, in order to lead to activating mutations such as in EPAS-1, that would in turn increase the risk of pheo/PGLs.
Since many of the symptoms of CCHD mimic pheo/PGL (tachycardia, palpitation, headache, fatigue), physicians dealing with such patients should have a high index of suspicion for pheo/PGL.
Interestingly the profile of secreted catecholamines in pheo/PGL arising in CCHD is very similar to those where pheo/PGLs arise as part of an inherited syndrome due to "pseudohypoxia" mimicking mutations (VHL, SDH-x). Such subjects have high levels of noradrenaline and normetanephrines and almost normal levels of adrenaline and metanephrines.
In the 1960s, it became apparent that pheo/PGL was more common in subjects with chronic hypoxia, specifically in two subgroups- in subjects with congenital cyanotic heart disease (CCHD) and in subjects living at high altitudes. Subjects with CCHD in particular, have a much higher incidence of pheo/PGL than the general population. The incidence of pheo/PGL in subjects with non-cyanotic congenital heart disease such as VSD, PDA, ASD and bicuspid aortic valve is no different than the general population.
Similarly subjects living at high altitudes have a higher risk of paragangliomas.
In the latest issue of New England Journal of Medicine, Vaidya and colleagues found that activating somatic mutations in EPAS-1, which codes for HIF-2 alpha, were present in 4 out of 5 subjects with CCHD presenting with pheo/PGL. To put this in perspective, the incidence of EPAS-1 activating mutations in subjects with pheo/PGL who do not have CCHD is only 5-6%.
In developed countries, most subjects with CCHD would have had surgical corrections such as Fontan's procedure in childhood. While the duration of uncorrected CCHD correlates positively with the risk of pheo/PGL, corrective procedures do not ameliorate risk. These tumors can arise many decades later.
Most of these subjects have striking polycythaemia. The latter is of course seen in tumours other than pheo/PGL. For example germ line mutations in VHL lead to the Von Hippel Lindau syndrome, with a higher risk of haemangioblastomas and renal cancer. Somatic mutation in VHL leads to a higher risk of renal cell cancer, and can again be associated with polycythaemia.
It is tempting to hypothesise that the hypoxia inducible genes, when chronically activated by hypoxia itself, through the agency of EPAS-1, as in CCHD, or constitutively (and inappropriately) activated by germline and somatic mutations in genes such as VHL, lead to increased risk of tumours- pheo/PGL in the case of CCHD, pheo/PGL & renal cell cancer with germline VHL mutations, and renal cell cancer in somatic VHL mutations.
It is worth clarifying here that VHL is an inbuilt inhibitor of HIF-alpha. When VHL is mutated (with inactivation), HIF-alpha becomes disinhibited and is free to act as a growth promoting gene (new blood vessels, pheo/PGL, renal cell cancer).
There is no suggestion that acquired causes of hypoxia in adulthood such as heavy smoking or chronic lung disease lead to a higher risk of pheo/PGL. It appears that the drive from hypoxia must start very early in life, such as with CCHD, in order to lead to activating mutations such as in EPAS-1, that would in turn increase the risk of pheo/PGLs.
Since many of the symptoms of CCHD mimic pheo/PGL (tachycardia, palpitation, headache, fatigue), physicians dealing with such patients should have a high index of suspicion for pheo/PGL.
Interestingly the profile of secreted catecholamines in pheo/PGL arising in CCHD is very similar to those where pheo/PGLs arise as part of an inherited syndrome due to "pseudohypoxia" mimicking mutations (VHL, SDH-x). Such subjects have high levels of noradrenaline and normetanephrines and almost normal levels of adrenaline and metanephrines.
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