Von Hippel–Lindau disease (VHL), also known as Von Hippel–Lindau syndrome, is a
rare genetic disorder
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
with multisystem involvement. It is characterized by visceral cysts and
benign tumors
A benign tumor is a mass of cells (tumor) that does not invade neighboring tissue or metastasize (spread throughout the body). Compared to malignant (cancerous) tumors, benign tumors generally have a slower growth rate. Benign tumors have rel ...
with potential for subsequent malignant transformation. It is a type of
phakomatosis
Phakomatoses, also known neurocutaneous syndromes, are a group of multisystemic diseases that most prominently affect structures primarily derived from the ectoderm such as the central nervous system, skin and eyes. The majority of phakomatoses ar ...
that results from a
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
in the
Von Hippel–Lindau tumor suppressor
) hockey league, Supreme Hockey League
The Von Hippel–Lindau tumor suppressor also known as pVHL is a protein that, in humans, is encoded by the ''VHL'' gene. Mutations of the VHL gene are associated with Von Hippel–Lindau disease.
Function ...
gene on
chromosome 3
Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 3 spans almost 200 million base pairs (the building material of DNA) and represents about 6.5 percent of the total DNA in ...
p25.3.
Signs and symptoms
![Hippel Lindau](https://upload.wikimedia.org/wikipedia/commons/b/bb/Hippel_Lindau.gif)
Signs and symptoms associated with VHL disease include headaches, problems with balance and walking, dizziness, weakness of the limbs, vision problems, and high blood pressure.
Conditions associated with VHL disease include
angiomatosis
Angiomatosis is a non-neoplastic condition characterised by nests of proliferating capillaries arranged in a lobular pattern, displacing adjacent muscle and fat. It consists of many angiomas.
These tend to be cavernous hemangiomas, which are shar ...
,
hemangioblastoma
Hemangioblastomas, or haemangioblastomas, are vascular tumors of the central nervous system that originate from the vascular system, usually during middle age. Sometimes, these tumors occur in other sites such as the spinal cord and retina. They ma ...
s,
pheochromocytoma
Pheochromocytoma (PHEO or PCC) is a rare tumor of the adrenal medulla composed of chromaffin cells, also known as pheochromocytes. When a tumor composed of the same cells as a pheochromocytoma develops outside the adrenal gland, it is referred t ...
,
renal cell carcinoma
Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cancer in adults, resp ...
,
pancreatic
The pancreas is an Organ (anatomy), organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine ...
cyst
A cyst is a closed sac, having a distinct envelope and cell division, division compared with the nearby Biological tissue, tissue. Hence, it is a cluster of Cell (biology), cells that have grouped together to form a sac (like the manner in which ...
s (
pancreatic serous cystadenoma
Pancreatic serous cystadenoma is a benign tumour of the pancreas. It is usually found in the tail of the pancreas, and may be associated with von Hippel–Lindau syndrome.
In contrast to some of the other cyst-forming tumors of the pancreas (such ...
),
endolymphatic sac tumor
An endolymphatic sac tumor (ELST) is a very uncommon papillary epithelial neoplasm arising within the endolymphatic sac or endolymphatic duct. This tumor shows a very high association with Von Hippel–Lindau syndrome (VHL).
Classification
The ...
, and bilateral papillary cystadenomas of the
epididymis
The epididymis (; plural: epididymides or ) is a tube that connects a testicle to a vas deferens in the male reproductive system. It is a single, narrow, tightly-coiled tube in adult humans, in length. It serves as an interconnection between the ...
(men) or
broad ligament of the uterus
The broad ligament of the uterus is the wide fold of peritoneum that connects the sides of the uterus to the walls and floor of the pelvis.
Structure
Subdivisions
Contents
The contents of the broad ligament include the following:
* Reprodu ...
(women).
Angiomatosis occurs in 37.2% of patients presenting with VHL disease and usually occurs in the retina. As a result, loss of vision is very common. However, other organs can be affected: strokes, heart attacks, and cardiovascular disease are common additional symptoms.
Approximately 40% of VHL disease presents with CNS hemangioblastomas and they are present in around 60-80%. Spinal hemangioblastomas are found in 13-59% of VHL disease and are specific because 80% are found in VHL disease.
Although all of these tumours are common in VHL disease, around half of cases present with only one tumour type.
Pathogenesis
The disease is caused by mutations of the
Von Hippel–Lindau tumor suppressor
) hockey league, Supreme Hockey League
The Von Hippel–Lindau tumor suppressor also known as pVHL is a protein that, in humans, is encoded by the ''VHL'' gene. Mutations of the VHL gene are associated with Von Hippel–Lindau disease.
Function ...
(VHL) gene on the short arm of
chromosome 3
Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 3 spans almost 200 million base pairs (the building material of DNA) and represents about 6.5 percent of the total DNA in ...
(3p25-26). There are over 1500
germline mutation
A germline mutation, or germinal mutation, is any detectable variation within germ cells (cells that, when fully developed, become sperm and ova). Mutations in these cells are the only mutations that can be passed on to offspring, when either a mu ...
s and
somatic mutation
A somatic mutation is a change in the DNA sequence of a somatic cell of a multicellular organism with dedicated reproductive cells; that is, any mutation that occurs in a cell other than a gamete, germ cell, or gametocyte. Unlike germline mutatio ...
s found in VHL disease.
Every cell in the body has 2 copies of every gene (bar those found in the sex chromosomes, X and Y). In VHL disease, one copy of the VHL gene has a mutation and produces a faulty VHL protein (pVHL). However, the second copy still produces a functional protein. The condition is inherited in an autosomal dominant manner - one copy of the faulty gene is sufficient to increase the risk of developing tumours.
Approximately 20% of cases of VHL disease are found in individuals without a family history, known as ''
de novo'' mutations. An inherited mutation of the VHL gene is responsible for the remaining 80 percent of cases.
30-40% of mutations in the VHL gene consist of 50-250kb
deletion mutation
In genetics, a deletion (also called gene deletion, deficiency, or deletion mutation) (sign: Δ) is a mutation (a genetic aberration) in which a part of a chromosome or a sequence of DNA is left out during DNA replication. Any number of nucleoti ...
s that remove either part of the gene or the whole gene and flanking regions of DNA. The remaining 60-70% of VHL disease is caused by the truncation of pVHL by
nonsense mutation
In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a ''nonsense codon'' in the transcribed mRNA, and in leading to a truncated, incomplete, and usually nonfunctional protein produc ...
s,
indel mutations or
splice site mutation
A splice site mutation is a genetic mutation that inserts, deletes or changes a number of nucleotides in the specific site at which splicing takes place during the processing of precursor messenger RNA into mature messenger RNA. Splice site co ...
s.
VHL protein
![HIF and pVHL](https://upload.wikimedia.org/wikipedia/commons/5/58/HIF_and_pVHL.png)
The VHL protein (pVHL) is involved in the regulation of a protein known as
hypoxia inducible factor 1α (HIF1α). This is a subunit of a
heterodimeric
In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' has ...
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
that at normal
cellular oxygen levels is highly regulated. In normal physiological conditions, pVHL recognizes and binds to HIF1α only when oxygen is present due to the
post translational hydroxylation
In chemistry, hydroxylation can refer to:
*(i) most commonly, hydroxylation describes a chemical process that introduces a hydroxyl group () into an organic compound.
*(ii) the ''degree of hydroxylation'' refers to the number of OH groups in a ...
of 2
proline
Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...
residues within the HIF1α protein. pVHL is an
E3 ligase
A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin ...
that
ubiquitin
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
ates HIF1α and causes its degradation by the
proteasome
Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.
Proteasomes are part of a major mechanism by w ...
. In low oxygen conditions or in cases of VHL disease where the VHL gene is mutated, pVHL does not bind to HIF1α. This allows the subunit to dimerise with HIF1β and activate the transcription of a number of genes, including
vascular endothelial growth factor
Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...
,
platelet-derived growth factor B,
erythropoietin
Erythropoietin (; EPO), also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production (erythropoiesis) in the bo ...
and genes involved in glucose uptake and metabolism.
A new novel missense mutation in VHL genes c.194 C>T, c.239 G>A, c.278 G>A, c.319 C>G, c.337 C>G leading to the following variations p.Ala 65 Val, p.Gly 80 Asp, p.Gly 93 Glu, p.Gln 107 Glu, p.Gln 113 Glu in the protein contributed to renal clear cell carcinoma.
Diagnosis
The detection of tumours specific to VHL disease is important in the disease's diagnosis. In individuals with a family history of VHL disease, one hemangioblastoma,
pheochromocytoma
Pheochromocytoma (PHEO or PCC) is a rare tumor of the adrenal medulla composed of chromaffin cells, also known as pheochromocytes. When a tumor composed of the same cells as a pheochromocytoma develops outside the adrenal gland, it is referred t ...
or
renal cell carcinoma
Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cancer in adults, resp ...
may be sufficient to make a diagnosis. As all the tumours associated with VHL disease can be found sporadically, at least two tumours must be identified to diagnose VHL disease in a person without a family history.
Genetic diagnosis is also useful in VHL disease diagnosis. In hereditary VHL disease, techniques such as the
Southern blot
A Southern blot is a method used in molecular biology for detection of a specific DNA sequence in DNA samples. Southern blotting combines transfer of electrophoresis-separated DNA fragments to a filter membrane and subsequent fragment detecti ...
and
gene sequencing can be used to analyse DNA and identify mutations. These tests can be used to screen family members of those afflicted with VHL disease; ''de novo'' cases that produce
genetic mosaicism are more difficult to detect because mutations are not found in the white blood cells that are used for genetic analysis.
Classification
VHL disease can be subdivided according to the clinical manifestations, although these groups often correlate with certain types of mutations present in the VHL gene.
Treatment
Early recognition and treatment of specific manifestations of VHL can substantially decrease complications and improve quality of life. For this reason, individuals with VHL disease are usually screened routinely for retinal angiomas, CNS hemangioblastomas, clear-cell renal carcinomas and pheochromocytomas. CNS hemangioblastomas are usually surgically removed if they are symptomatic.
Photocoagulation and
cryotherapy
Cryotherapy, sometimes known as cold therapy, is the local or general use of low temperatures in medical therapy. Cryotherapy may be used to treat a variety of tissue lesions. The most prominent use of the term refers to the surgical treatment, s ...
are usually used for the treatment of symptomatic retinal angiomas, although anti-angiogenic treatments may also be an option. Renal tumours may be removed by a partial
nephrectomy
A nephrectomy is the surgical removal of a kidney, performed to treat a number of kidney diseases including kidney cancer. It is also done to remove a normal healthy kidney from a living or deceased donor, which is part of a kidney transplant pro ...
or other techniques such as
radiofrequency ablation
Radiofrequency ablation (RFA), also called fulguration, is a medical procedure in which part of the electrical conduction system of the heart, tumor or other dysfunctional tissue is ablated using the heat generated from medium frequency alternat ...
.
Belzutifan is a drug under investigation for the treatment of von Hippel–Lindau disease-associated
renal cell carcinoma
Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cancer in adults, resp ...
.
Epidemiology
VHL disease has an incidence of one in 36,000 births. There is over 90%
penetrance
Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (the genotype) that also express an associated trait (the phenotype). In medical genetics, the penetrance of a disease-causing mutation is t ...
by the age of 65. Age at diagnosis varies from infancy to age 60–70 years, with an average patient age at clinical diagnosis of 26 years.
History
![Hippel](https://upload.wikimedia.org/wikipedia/commons/b/b0/Hippel.JPG)
The German ophthalmologist
Eugen von Hippel first described angiomas in the eye in 1904.
Arvid Lindau described the angiomas of the
cerebellum
The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebel ...
and
spine
Spine or spinal may refer to:
Science Biology
* Vertebral column, also known as the backbone
* Dendritic spine, a small membranous protrusion from a neuron's dendrite
* Thorns, spines, and prickles, needle-like structures in plants
* Spine (zoolog ...
in 1927. The term Von Hippel–Lindau disease was first used in 1936; however, its use became common only in the 1970s.
Notable cases
Some descendants of the McCoy family (involved in the
Hatfield-McCoy feud of
Appalachia
Appalachia () is a cultural region in the Eastern United States that stretches from the Southern Tier of New York State to northern Alabama and Georgia. While the Appalachian Mountains stretch from Belle Isle in Newfoundland and Labrador, Ca ...
, USA) are presumed to have VHL. In an article appearing in the Associated Press, it has been speculated by a Vanderbilt University endocrinologist that the hostility underlying the Hatfield–McCoy feud may have been partly due to the consequences of Von Hippel–Lindau disease. The article suggests that the McCoy family was predisposed to bad tempers because many of them had a pheochromocytoma which produced excess adrenaline and a tendency toward explosive tempers.
Nomenclature
Other uncommon names are: angiomatosis retinae, familial cerebello-retinal angiomatosis, cerebelloretinal hemangioblastomatosis, Hippel Disease, Hippel–Lindau syndrome, HLS, VHL, Lindau disease or retinocerebellar angiomatosis.
See also
*
Haemangioblastoma
*
epithelial sodium channel
The epithelial sodium channel (ENaC), (also known as amiloride-sensitive sodium channel) is a membrane-bound ion channel that is selectively permeable to sodium ions (). It is assembled as a heterotrimer composed of three homologous subunits α ...
*
Nephron
The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structure ca ...
*
proximal convoluted tubule
The proximal tubule is the segment of the nephron in kidneys which begins from the renal pole of the Bowman's capsule to the beginning of loop of Henle. It can be further classified into the proximal convoluted tubule (PCT) and the proximal straig ...
References
External links
GeneReviews/NCBI/NIH/UW entry on Von Hippel-Lindau Syndrome*
*
*
* (VHL gene)
{{DEFAULTSORT:Von Hippel-Lindau disease
Autosomal dominant disorders
Rare diseases
Hereditary cancers
Genodermatoses
Syndromes