Table 1
Table abbreviations: BHD, Birt-Hogg-Dube syndrome; CC3, constitutional chromosome 3 translocation; DIRC1,disrupted in renal carcinoma 1;DIRC3,disrupted in renal carcinoma 3; FCCRC, familial non-syndromic clear cell renal cell carcinoma;
FH, fumarate hydratase;FHIT, fragile histidine triad; HIF, hypoxia inducible factor;
HGF, hepatic growth factor; HLRCC, hereditary leiomyomatosis and renal cell carcinoma;HPRC, hereditary papillary renal cancer syndrome;HPT-JT, hyperparathyroidism-jaw tumor syndrome;HRPT2, hyperparathyroidism 2;
HSPBAP1, heat-shock 27-KD protein-associated protein 1;LSAMP,limbic system-associated membrane protein;MET, met proto-oncogene;NORE1, N-Oct-3 responsive element 1;Paf1, polymerase-associated factor 1;
RASSF1, Ras association domain family protein 1; RCC, renal cell carcinoma;TCA, tricarboxylic acid;TRC8, translocation in renal carcinoma 8;VHL, Von Hippel-Lindau disease
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Von Hippel-Lindau disease(VHL) / Hereditary Papillary Renal Cancer Syndrome
(HPRC) / Hereditary Leiomyomatosis and Renal Cell Carcinoma
(HLRCC) / Birt-Hogg-Dube syndrome
(BHD) / Constitutional chromosome 3 translocation
(CC3) / Hyperparathyroidism -jaw tumor syndrome
(HPT-JT) / Familial non syndromic clear cell renal cell carcinoma
(FCCRC)
OMIM / 193300 / 605074 / 605839 / 135150 / - / 145001 / -
Year of description / 1894 / 1994 / 2001 / 1977 / 1979 / 1987 / 1997
Mode of inheritance / Autosomal dominant / Autosomal dominant / Autosomal dominant / Autosomal dominant / - / Autosomal dominant / Autosomal dominant
Genes / VHL / MET / FH / BHD / Breakpoint associated genes described in some families:
FHIT-TRC8,
NORE1-LSAMP,
DIRC3-HSPBAP1, RASSF1,
DIRC1. / HRPT2 / unknown
Year of identification / 1993 / 1997 / 2002 / 2002 / 2002 / 2002 / -
Chromosomal location / 3p25-26 / 7q31.1-q34 / 1q42.3-q43 / 17p11.2 / Eight constitutional translocations described.
t(1;3) (q32;q13), t(2;3) (q33;q21), t(2;3) (q35;q21), t(3;4) (p13;p16), t(3;6) (p13;q25), t(3;6) (q12;q15), t(3;8) (p13;q24), t(3;8) (p14;q24) / 1q25-q31 / Not known
Protein / VHL protein / C-MET proto-oncogene / FH (Fumarate
Hydratase) / Folliculin / Under research, possible involvement in stress pathway.
( stress sensors) / Parafibromin,part of the Paf1 complex / Not known
Protein
Function / Regulation of transcription hypoxia inducible factor (HIF). Tumor suppressor. / Receptor
for hepatic
growth factor (HGF). Classical oncogene. / Oxidation of fumarate to malate in TCA. Tumor suppressor. / Unknown, possible tumor suppressor. / Unclear. / Not known, possible tumor suppressor / Not known
Gene frequency / One in 36,000 births per year / 10 families described / 114 families described / More than 60 families described / 8 families identified / 40 families in the literature / 34 affected individuals in 11 families.
Main clinical features / Retinal angiomas, central nervous system hemangiobla-stoma, bilateral multifocal clear type RCC, pheochromo-cytoma, pancreatic cyst, neuroendocrine tumor, cystadenomas of epididymis and broad ligaments.Endo-lymphatic sac tumors. / Bilateral, multifocal RCC of papillary type I. Typically at sixth decade. Manifestation confined to the kidney. / Aggressive unilateral RCC papillary type 2, early metastasizing with high fatality, leiomyomat-osis of the skin and uterus. No clear genotype-phenotype correlation. / Facial fibrofollicu-lomas, pulmonary cysts, spontaneous pneumothorax and bilateral RCC of different histologies. / Multiple, bilateral RCC. / Hyperparathyroidism fibroosseus tumors of maxilla and mandible and renal manifestations. / Unilateral clear type RCC, no extra renal manifestations described, age of presentation earlier than sporadic cases.
Percentage of sporadic cases that harbour a somatic mutation / 60 % / ~13 % / Not known / Identified in sporadic cases of clear RCC not known in oncocytomas chromophobe or oncocytomas / Not known / Identified in parathyroid carcinoma, not known in relation to renal manifestations. / Not known
Comment / According to genotype-phenotype correlation VHL is divided into 4 types. Type 1 low chance of developing pheochromo-cytoma, type 2 subdivided into 2A (low RCC risk) 2B (high RCC risk) and 2C associated with pheochromo-cytoma only.
Homozygotes or compound heterozygotes in C-terminal portion of VHL gene associated with autosomal recessive familial erythrocytosis (Chuvash polycythemia) / Trisomy of chromosome 7 on cytogenetic analysis of the tumors indicating duplication of the affected gene. / Homozygotes or compound heterozygotes of FH mutations are associated with autosomal recessive syndrome, FH deficiency (OMIM 606812) / Chromophobe RCC and oncocytomas are the most common types. Clear cell and papillary type are also described. / Kidney involvement is the only feature. No reported systemic manifestations of VHL disease / Renal manifestations include papillary RCC, polycystic renal disease and hamartomas resembling Wilms tumor. / No formal diagnostic criteria, exclusion of other familial causes is required namely VHL and CC3.
Incidence might be under estimated.
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