Genetic Analysis of Pheochromocytoma and Paraganglioma Complicating Cyanotic Congenital Heart Disease.

CONTEXT: Pheochromocytoma and paraganglioma (PPGL) may appear as a complication of cyanotic congenital heart disease (CCHD-PPGL) with frequent EPAS1 mutations, suggesting a close link between EPAS1 mutations and tissue hypoxia in CCHD-PPGL pathogenesis. OBJECTIVE: Our aim is to further investigate the role of EPAS1 mutations in the hypoxia-driven mechanism of CCHD-PPGL pathogenesis, particularly focusing on metachronous and/or multifocal CCHD-PPGL tumors. METHODS: We performed whole-exome sequencing (WES) for somatic and germline mutations in 15 PPGL samples from 7 CCHD patients, including 3 patients with metachronous and/or multifocal tumors, together with an adrenal medullary hyperplasia (AMH) sample. RESULTS: We detected EPAS1 mutations in 15 out of 16 PPGL/AMH samples from 7 cases. Conspicuously, all EPAS1 mutations in each of 3 cases with multifocal or metachronous tumors were mutually independent and typical examples of parallel evolution, which is suggestive of strong positive selection of EPAS1-mutated clones. Compared to 165 The Cancer Genome Atlas non-CCHD-PPGL samples, CCHD-PPGL/AMH samples were enriched for 11p deletions (13/16) and 2p amplifications (4/16). Of particular note, the multiple metachronous PPGL tumors with additional copy number abnormalities developed 18 to 23 years after the resolution of hypoxemia, suggesting that CCHD-induced hypoxic environments are critical for positive selection of EPAS1 mutants in early life, but may no longer be required for development of PPGL in later life. CONCLUSION: Our results highlight a key role of activated hypoxia-inducible factor 2α due to mutated EPAS1 in positive selection under hypoxic environments, although hypoxemia itself may not necessarily be required for the EPAS1-mutated clones to progress to PPGL.

Congenital left ventricular aneurysm coexisting with left ventricular non-compaction in a newborn.

Described herein is the case of a rare combination of congenital left ventricular (LV) aneurysm and left ventricular non-compaction (LVNC) in a newborn. The patient developed refractory heart failure soon after birth and died at 5 months of age. The etiology of both congenital LV aneurysm and LVNC seems to be maldevelopment of the ventricular myocardium during early fetal life. Treatment should be individually tailored depending on clinical severity, and treatment options are limited. Given that this combination of congenital LV aneurysm and LVNC is significantly associated with poor prognosis, it appears that patients with congenital LV aneurysm and LVNC are candidates for early, aggressive intervention, including surgical aneurysmectomy and evaluation for transplantation. It is important to be aware of this combination of congenital LV aneurysm and LVNC, and to make earlier decisions on therapeutic strategy.