Table 1.

Genetic alterations, tumorigenesis mechanisms, clinical features and surgical management of renal lesions found in hereditary renal cell carcinoma syndromes.

Syndrome	Chromosome Localization	Gene(s)	Tumorigenesis Mechanisms:	Clinical Features	3-cm Rule Applied:
VHL	3p25	VHL	Augmented HIF Angiogenesis through VEGF lipid accumulation, β-oxidation inhibition aerobic glycolysis Augmented erythropoietin Mitochondrial lysine hyperacetylation	Brain, spine, retina and liver hemangioblastomas Pancreatic neuroendocrine tumors (NET) Endolymphatic sac tumors Clear cell renal cell carcinoma Pheochromocytoma/paragangliomas Benign cystadenomas of the epididymis or broad ligament	Yes
HPRC	7q31	MET	MET activation mutations or amplification Augmented cell growth, angiogenesis Increased motility Attenuated contact inhibition	Type 1 Papillary RCC (only finding in syndrome) Hypovascular/attenuated signal on CT/MRI	Yes
Succinate Dehydrogenase-Deficient Renal Cell Carcinoma	5p15.33-SDHA 1p36.13-SDHB 1q23.3-SDHC 11q23.1-SDHD 11q12.2-SDHAF2	SDHA, SDHB, SDHC, SDHD, SDHAF2	Defective oxidative phosphorylation with succinate acculmation (oncometabolite) Lysine succinylation of protein targets Elevated HIF1α	Pheochromocytomas Head/neck paragangliomas GIST tumors SDH-deficient RCC	No (wide local excision)
HLRCC	1q42.3-q43	Fumurate hydratase	Elevated fumurate (oncometabolite) Succination of cysteine residues on proteins Decreased mtDNA copy number Increased mtDNA mutations increased NRF2 activity (anti-oxidant system) Aerobic glycolysis	Cutaneous leiomyomas and uterine leiomyomas Hysterectomy at an early age HLRCC-associated RCC Histology: high grade tumors with large eosinophilic nucleoli and perinuclear clearing, increased S-(2-succinyl) cysteine staining (succination)	No (wide local excision)
BAP1	3p21	BAP1	Lost BAP1 deubiquitinase activity Augmented cell cycle progression (G1 to S) Inhibited DNA repair	Mesotheliomas of chest/abdomen Uveal melanoma Cutaneous melanoma Aggressive RCC	Unknown (likely not recommended)
Birt-Hogg-Dubé Syndrome (BHD)	17p11.2	Folliculin	Overactive AKT-mTOR TFEB overactivity (lost mTOR inhibition) Overative mTOR activity on p70S6K and 4E-BP	Benign painless cutaneous papules (fibrofolliculomas) Pulmonary cysts with risk for spontaneous pneumothorax Renal tumors:(oncocytoma, chromophobe, hybrid oncocytic) Possibly increased risk for colonic tumors	Yes
Tuberous Sclerosis	9q34 16p13	TSC1, TSC2	Overactive mTOR activity Augmented protein synthesis	Angiomyelolipomas RCC in ~2–4% Skin: angiofibromas, ash-leaf spots, Shagreen patches & periungual fibromas Brain: subependymal giant cell astrocytoma & cerebral cortical tubers Heart: rhabdomyoma Lung lymphangioleiomyomatosis (LAM) Epilepsy, behavioral disorder, and intellectual disabilities	Unknown for RCC AML: 4-cm rule
Translocation RCC	Xp11 t(6:11)	TFE3, TFEB also MiTF/TFEC	Elevated MiTF family activity Augmetned lysosomal biogenesis Increased autophagy Increased lysosomal exocytosis	Higher incidence in pediatric and young adults FISH, rtPCR and immunohistochemistry needed for diagnosis Histology: Xp11—increased GPNMB signal, papillary/nested ccRCC or cystic features t6:11- biphasic morphology	No (wide local excision)

Abbreviations: HIF—hypoxia inducible factor, VHL—von-Hippel Lindau, HPRC—hereditary papillary renal carcinoma, HLRCC—Hereditary leiomyomatosis and renal cell cancer, BAP1—BRCA1-associated protein 1, MET—mesenchymal-epithelial transition factor, SDH—succinate dehydrogenase, FISH—Fluorescence in situ hybridization, MITF—Microphthalmia-associated transcription factor, GIST—gastrointestinal stromal tumor, ccRCC—clear cell renal cell carcinoma, AML—angiomyelolipoma.