Table 3.

Molecular classification of head and neck paragangliomas (HNPs).

Syndrome	VHL	PGL1	PGL2	PGL3	PGL4	TMEM127
MIM ID	193300	168000	60650	605373	115310	613903
Inheritance	AutosomalDominant	AutosomalDominant withparent-of-origin effect	AutosomalDominant withparent-of-origin effect	AutosomalDominant	AutosomalDominant	Autosomaldominant
Gene name	VHL	SDHD	SDHAF2	SDHC	SDHB	TMEM127
Protein function	An ubiquitin ligase protein; it plays a role in the oxygen-sensing pathway	One of two membrane-anchoring subunits of complex II (SDH)	Mitochondrial assembly factorfor complex II—interactsdirectly with SDHA	One of two membrane-anchoring subunits of complex II (SDH)	The iron-sulfur protein that form together with SDHA, the main catalytic domainof complex II	Endosomal trafficking?; mTOR regulation?
Locus	3p25-26	11q23	11q13.1	1q21	1p36	2q11
Age at diagnosis of Pheochromocytoma mean and range, in years	22 (5–67)	27 (5–65)	unknown	Extremely rare	34 (12–66)	43 (34–54)
Exons (n)//amino acids (n)	3/213	4/159	4/166	6/169	8/280	3/238
HNP (%)	0,5	41	73–86	100	8	1–2
Age at diagnosis HNPMedian (range, in years)	23 (7-39)	40 (12–74)	45 (15–65)	46 (13–73)	42 (9–75)	34
Pheo risk (%)	10-34	53	0	<3	28	25
PG Abdominal extraadrenal (%)	17	59	0	0	62	1–2
Multifocality (%)	56	55	0	9	11	33
Malignant (%)	4%	0	0	0	32	5
Clinical Phenotype	SympatheticNoradrenergic	Parasympathetic, occasionally noradrenergic	Parasympa thetic	Parasympa thetic	Noradrenergic	SympatheticNoradrenergic
Associated tumors	Eye and CNS hemangioblastomas, clear cellrenal cancer, islet cell tumors,endolymphatic sac tumorsof the inner ear	Rarely Papillary thyroid cancer, GIST	GIST	GIST	Rarely renal cell cancer GIST

Adapted from Bausch et al. (73), Hensen et al. (74) and Neumann and Eng (75).

CNS  =  central nervous system; GIST  =  gastrointestinal stromal tumor, mTOR  =  mammalian target of rapamycin; PGL  =  Paraganglioma syndrome; SDHAF2  =  succinate dehydrogenase complex assembly factor 2; TMEN127  =  transmembrane protein 127.