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Review
. 2019 Sep 5;3(11):2135-2150.
doi: 10.1210/js.2019-00226. eCollection 2019 Nov 1.

Catecholamine-Secreting Tumors in Pediatric Patients With Cyanotic Congenital Heart Disease

Swashti Agarwal  1 , Ishita Jindal  1 , Andrea Balazs  1 , David Paul  1
Affiliations
Review

Catecholamine-Secreting Tumors in Pediatric Patients With Cyanotic Congenital Heart Disease

Swashti Agarwal et al. J Endocr Soc. .

Abstract

Catecholamine-secreting tumors are rare among the pediatric population but are increasingly being reported in children with sustained hypoxia secondary to cyanotic congenital heart disease (CCHD). With this review, we report the clinical characteristics of these tumors in children with CCHD. The articles included in the present review were identified using PubMed through February 2019. A manual search of the references retrieved from relevant articles was also performed. Pheochromocytomas and paragangliomas (PPGL) in children are commonly associated with high-risk germline or somatic mutations. There is evidently a higher risk of tumorigenesis in children with CCHD as compared with the general pediatric population, even in the absence of susceptible gene mutations. This is due to molecular mechanisms involving the aberrant activation of hypoxia-response elements, likely secondary to sustained hypoxemia, resulting in tumorigenesis. Due to overlapping symptoms with CCHD, the diagnosis of PPGL may be delayed or missed in these patients. We studied all previously reported PPGL cases in children with CCHD and reviewed phenotypic and biochemical features to assess for contributing factors in tumorigenesis. Larger studies are needed to help determine other potential predisposing factors and to establish screening guidelines in this high-risk population. A delay in diagnosis of the PPGL tumors can lead to exacerbation of cardiac failure, and therefore early diagnosis and intervention may provide better outcomes in these patients, necessitating the need for regular surveillance. We recommend routine biochemical screening in patients with sustained hypoxia secondary to CCHD.

Keywords: catecholamine secreting tumors; cyanotic congenital heart disease; hypoxia induced tumorigenesis; paraganglioma; pheochromocytoma.

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Figures

Figure 1.
Figure 1.
CT scan with contrast showed an enhancing mass arising from or in proximity to the left adrenal gland measuring 3.6 × 3.7 × 6.6 cm (arrows).
Figure 2.
Figure 2.
PET-CT imaging from the skull vertex to the base of feet the performed after the injection of 1.82 mCi of Ga-68-DOTA-TATE. Injection-to-scan interval: 1.5 h. Focal tracer uptake within the left upper quadrant mass possibly arising from the left adrenal gland (arrows).
Figure 3.
Figure 3.
Hypoxia-induced tumorigenesis. (A) Under normoxic conditions, HIFα is hydroxylated by PHDs at the two prolyl residues, bound to the E3 ubiquitin complex, and then degraded by proteosomes. It can also be hydroxylated at the asparagine residue by FIH-1, which prevents its interaction with CBP and p300 in the nucleus, ultimately inhibiting transcription. (B) PHDs and FIH-1 are oxygen-dependent enzymes and therefore are unable to hydroxylate HIFα under hypoxic conditions. This leads to decreased in degradation of HIFα and increased transcription of hypoxia related genes. CBP, cAMP-response element binding protein; Cul2, Cullin 2; E2, E2 ubiquitin-conjugating enzyme; FIH-1, factor inhibiting HIF-1; p300, histone acetyltransferase p300; PHD, prolyl hydroxylase domain protein; pVHL, von Hippel-Lindau protein; Rbx1, Ring box protein 1; SDH, succinate dehydrogenase; SSAT2, spermidine/spermine N1-acetyltransferase 2; UQ, ubiquitin.
Figure 4.
Figure 4.
Correlation of age at onset and SpO2. Box: deceased, diagnosed on autopsy (n = 2). Circle: presented with symptoms (n = 14). Excluded were three patients diagnosed incidentally on autopsy (reason for death unknown) and two patients with no reported SpO2.
Figure 5.
Figure 5.
Type of CCHD vs location of PPGL. AV, atrio-ventricular; HLH/SV, hypoplastic left heart; TA, tricuspid atresia; TGA, transposition of great vessels; TOF, Tetralogy of Fallot. *Complex CCHD (patients with more than one etiology for cyanosis).
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