A Clinical Roadmap to Investigate the Genetic Basis of Pediatric Pheochromocytoma: Which Genes Should Physicians Think About?

Table 1

Clinical features of PHEO-associated genes at a pediatric age.

Clinical features						Ancillary surveys
PHEO-associated genes	Youngest age at diagnosis (years)	Most common associated tumors and features	Frequency (%)
			Multifocal tumors	Bilateral PHEO	Metastatic PHEO	Biochemical phenotype	SDHA/B IHC
VHL	4	(i) CNS hemangiomas	4.6–5.6	19.0–39.0	4.3	NA	+ve/+ve
		(ii) Renal cysts
		(iii) RCC
		(iv) pNET
		(v) Pancreatic cysts
		(vi) Abdominal PGL
		(vi) Thoracic PGL
RET	8	(i) MEN2A (MTC, pHPT)	Rare	66.0–100.0	Rare	A	+ve/+ve
		(ii) MEN2B (MTC, marfanoid habitus, ganglioneuromatosis of the gut/oral mucosa)
NF1	7	(i) Café au lait spots	Rare	Rare	33.3–66.6	A	+ve/+ve
		(ii) Axillary/inguinal freckling
		(iii) Neurofibromas
		(iv) Lisch nodules of the iris
		(v) Typical osseous lesions
		(vi) Optic glioma
		(vii) Carcinomas (breast, lung, colorectal)
		(viii) Sarcomas, GIST
		(ix) Melanoma
SDHB	6	(i) Abdominal PGL	68.0	Rare	57.0	NA; D	+ve/−ve
		(ii) Thoracic PGL
		(iii) HN PGL
		(iv) RCC
		(v) GIST
		(vi) Pituitary adenoma
		(vii) Chondroma
SDHD	5	(i) HN PGL	66.9	6.9–12.5	Rare	NA; D	+ve/−ve
		(ii) Thoracic PGL
		(iii) RCC
		(iv) GIST
		(v) Pituitary adenoma
		(vi) Chondroma
SDHA	8	(i) HN PGL	9.0	4.0	11.0	NA; D	−ve/−ve
		(ii) Abdominal PGL
		(iii) GIST
		(iv) Pituitary adenomas
HIF2A	8	(i) Polycythemia since early childhood	66.6	Rare	Rare	NA	+ve/+ve
		(ii) Abdominal PGL
		(iii) Duodenal somatostatinomas
		(iv) Retinopathy
PHD1	14	(i) Polycythemia	100	ND	ND	NA	ND
		(ii) Abdominal/thoracic PGL
MAX	13	(i) Abdominal PGL	14.3	41.0	20.0	NA; NA, A	+ve/+ve
		(ii) Thoracic PGL
FH	6	(i) Abdominal PGL	42.8	0.0	28.6	NA	ND
		(ii) Thoracic PGL

−ve: negative; +ve: positive; CNS: central nervous system; GIST: gastrointestinal stromal tumor; HN: head and neck; MTC: medullary thyroid carcinoma; PHEO: pheochromocytoma; PGL: paraganglioma; RCC: renal cell carcinoma; pNET: pancreatic neuroendocrine tumor; A: adrenaline; D: dopamine; IHC: immunohistochemistry; NA: noradrenaline; FH: fumarate hydratase gene; HIF2A: hypoxia-inducible factor 2 alpha gene; MAX: Myc-associated protein X gene; MEN2A: multiple endocrine neoplasia type 2A; MEN2B: multiple endocrine neoplasia type 2B; NF1: neurofibromatosis type 1 gene; PHD1: prolyl hydroxylase type 1 gene; RET: rearranged during transfection gene; SDHA: succinate dehydrogenase subunit A gene; SDHA: succinate dehydrogenase subunit A protein; SDHB: succinate dehydrogenase subunit B gene; SDHB: succinate dehydrogenase subunit B protein; SDHC: succinate dehydrogenase subunit C gene; SDHD: succinate dehydrogenase subunit D gene; VHL: von Hippel-Lindau gene; ND: not defined. Small samples in case series. Metastatic PGL: 29%.