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J Clin Endocrinol Metab. 2015 Apr;100(4):1325-34. doi: 10.1210/jc.2014-3863. Epub 2015 Jan 12.

Pheochromocytoma and paraganglioma in cyanotic congenital heart disease.

Author information

Department of Cardiology (A.R.O., L.E.M., M.J.L., M.N.S., F.W.), Boston Children's Hospital, Boston, Massachusetts 02115; Division of Cardiovascular Medicine, (A.R.O., M.J.L., M.N.S., F.W.), Division of Endocrinology (A.V.), Diabetes, and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts 02115; Department of Medicine (J.Gi., M.R.), Columbia University Medical Center, New York, New York 10027; Adult Congenital Heart Disease Program (M.G.), University Hospital Zurich, CH-8032 Zurich, Switzerland; Department of Medicine (J.A.,A.H.), Division of Cardiology, University of California, Los Angeles, Medical Center, Ahmanson/UCLA Adult Congenital Heart Disease Center, Los Angeles, California 90095; Department of Cardiology (Y.K., L.X.D.), The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104; Department of Medicine (Y.K., L.X.D.), Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 19104; Division of Cardiology (J.Gr.), St Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4; The Heart Center (A.N.Z.), Nationwide Children's Hospital, Columbus, Ohio 43205; Department of Internal Medicine (A.N.Z.), The Ohio State University Wexner Medical Center, Columbus, Ohio 43210; Department of Medicine (G.A., E.O.), University Health Network and University of Toronto, Toronto, Ontario, CanadaM5G2C4; Department of Pediatrics (M.E.), Medical College of Wisconsin, Milwaukee, Wisconsin 53226; Center for Adrenal Disorders (A.V.), Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Boston, Massachusetts 02115.



Aberrant cellular oxygen sensing is a leading theory for development of pheochromocytoma (PHEO) and paraganglioma (PGL).


The objective of the study was to test the hypothesis that chronic hypoxia in patients with cyanotic congenital heart disease (CCHD) increases the risk for PHEO-PGL.


We investigated the association between CCHD and PHEO-PGL with two complementary studies: study 1) an international consortium was established to identify congenital heart disease (CHD) patients with a PHEO-PGL diagnosis confirmed by pathology or biochemistry and imaging; study 2) the 2000-2009 Nationwide Inpatient Survey, a nationally representative discharge database, was used to determine population-based cross-sectional PHEO-PGL frequency in hospitalized CCHD patients compared with noncyanotic CHD and those without CHD using multivariable logistic regression adjusted for age, sex, and genetic PHEO-PGL syndromes.


In study 1, we identified 20 PHEO-PGL cases, of which 18 had CCHD. Most presented with cardiovascular or psychiatric symptoms. Median cyanosis duration for the CCHD PHEO-PGL cases was 20 years (range 1-57 y). Cases were young at diagnosis (median 31.5 y, range 15-57 y) and 7 of 18 had multiple tumors (two bilateral PHEO; six multifocal or recurrent PGL), whereas 11 had single tumors (seven PHEO; four PGL). PGLs were abdominal (13 of 17) or head/neck (4 of 17). Cases displayed a noradrenergic biochemical phenotype similar to reported hypoxia-related PHEO-PGL genetic syndromes but without clinical signs of such syndromes. In study 2, hospitalized CCHD patients had an increased likelihood of PHEO-PGL (adjusted odds ratio 6.0, 95% confidence interval 2.6-13.7, P < .0001) compared with those without CHD; patients with noncyanotic CHD had no increased risk (odds ratio 0.9, P = .48).


There is a strong link between CCHD and PHEO-PGL. Whether these rare diseases coassociate due to hypoxic stress, common genetic or developmental factors, or some combination requires further investigation.

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