Table 1 Table abbreviations



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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





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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