Von Hippel-Lindau disease

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Von Hippel-Lindau disease
ICD-10 Q85.8
ICD-9 759.6
OMIM 193300
DiseasesDB 14000
eMedicine ped/2417  oph/354
MeSH C10.562.400

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Overview

Von Hippel-Lindau disease (VHL) is a rare inherited genetic condition involving the abnormal growth of tumors in parts of the body which are particularly rich in blood supply.

Features

Features of VHL are:

Untreated, VHL may result in blindness and permanent brain damage; death is usually caused by complications of malignant tumors in the brain or kidney, cardiovascular disease secondary to pheochromocytoma. With early detection and appropriate treatment, there is more hope today for people with VHL than ever before.

Types

There are various subtypes:

  • Type 1 (angiomatosis without pheochromocytoma)
  • Type 2 (angiomatosis with pheochromocytoma)
    • Type 2A (with renal cell carcinoma)
    • Type 2B (without renal cell carcinoma)
    • Type 2C (only pheochromocytoma and no angiomatosis or renal cell carcinoma)

Genetics

The disease is caused by mutations of the Von Hippel-Lindau tumor suppressor (VHL) gene on the short arm of third chromosome.

Von Hippel-Lindau disease is inherited in an autosomal dominant pattern.

VHL is an autosomal dominant disorder, but there is a wide variation in the age of onset of the disease, the organ system affected and the severity of effect. Most people with von Hippel-Lindau syndrome inherit an altered copy of the gene from one parent. In about 20 percent of cases, however, the altered gene is the result of a new mutation that occurred during the formation of reproductive cells (eggs or sperm) or early in fetal development.

As long as one copy of the VHL gene is producing functional VHL protein in each cell, tumors do not form. If a mutation occurs in the second copy of the VHL gene during a person's lifetime, the cell will have no working copies of the gene and will produce no functional VHL protein. A lack of this protein allows tumors characteristic of von Hippel-Lindau syndrome to develop.

History

Eugen von Hippel described the angiomas in the eye in 1904.[1]. Arvid Lindau described the angiomas of the cerebellum and spine in 1927.[2]

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-Landau disease. The article suggests that the McCoy family was pre-disposed to bad tempers because many of them had a pheochomocytoma, which produced excess adrenaline and a tendency toward explosive tempers.[3] Pheochromocytomas produce surges of adrenaline which are more often perceived as panic attacks than rage attacks. Left untreated, they will cause serious cardiovascular disease, heart attack, and stroke. Only about 20% of people with VHL get pheochromocytomas.[4]

Nomenclature

Other names are: angiomatosis retinae, angiophakomatosis retinae et cerebelli, familial cerebello-retinal angiomatosis, cerebelloretinal hemangioblastomatosis, Hippel Disease, Hippel-Lindau syndrome, HLS, Lindau disease or retinocerebellar angiomatosis.

DIfferentiating Von Hippel-Lindau disease from other diseases

Disease Gene Chromosome Differentiating Features Components of MEN Diagnosis
Parathyroid Pitutary Pancreas
von Hippel-Lindau syndrome Von Hippel–Lindau tumor suppressor 3p25.3
  • Angiomatosis, 
  • Hemangioblastomas,
  • Pheochromocytoma, 
  • Renal cell carcinoma,
  • Pancreatic cysts (pancreatic serous cystadenoma)
  • Endolymphatic sac tumor,
  • Bilateral papillary cystadenomas of the epididymis (men) or broad ligament of the uterus (women)
- - +
  • Clinical diagnosis
  • In hereditary VHL, disease techniques such as Southern blotting and gene sequencing can be used to analyse DNA and identify mutations.
Carney complex  PRKAR1A 17q23-q24
  • Myxomas of the heart
  • Hyperpigmentation of the skin (lentiginosis)
  • Endocrine (ACTH-independent Cushing's syndrome due to primary pigmented nodular adrenocortical disease)
- - -
  • Clinical diagnosis
Neurofibromatosis type 1 RAS 17 - - - Prenatal
  • Chorionic villus sampling or amniocentesis can be used to detect NF-1 in the fetus.

Postnatal Cardinal Clinical Features" are required for positive diagnosis.

  • Six or more café-au-lait spots over 5 mm in greatest diameter in pre-pubertal individuals and over 15 mm in greatest diameter in post-pubertal individuals.
  • Two or more neurofibromas of any type or 1 plexiform neurofibroma
  • Freckling in the axillary (Crowe sign) or inguinal regions
  • Optic glioma
  • Two or more Lisch nodules (pigmented iris hamartomas)
  • A distinctive osseous lesion such as sphenoid dysplasia, or thinning of the long bone cortex with or without pseudarthrosis.
Li-Fraumeni syndrome TP53 17 Early onset of diverse amount of cancers such as - - -

Criteria

  • Sarcoma at a young age (below 45)
  • A first-degree relative diagnosed with any cancer at a young age (below 45)
  • A first or second degree relative with any cancer diagnosed before age 60.
Gardner's syndrome APC  5q21
  • Multiple polyps in the colon 
  • Osteomas of the skull
  • Thyroid cancer,
  • Epidermoid cysts,
  • Fibromas
  • Desmoid tumors
- - -
  • Clinical diagnosis
  • Colonoscopy
Multiple endocrine neoplasia type 2 RET - + - -

Criteria Two or more specific endocrine tumors

Cowden syndrome PTEN -  Hamartomas - - -
  • PTEN mutation probability risk calculator
Acromegaly/gigantism - - - + -
Pituitary adenoma - - - + -
Hyperparathyroidism - - - + - -
  • An elevated concentration of serum calcium with elevated parathyroid hormone level is diagnostic of primary hyperparathyroidism.
  • Most consistent laboratory findings associated with the diagnosis of secondary hyperparathyroidism include elevated serum parathyroid hormone level and low to normal serum calcium.
  • An elevated concentration of serum calcium with elevated parathyroid hormone level in post renal transplant patients is diagnostic of tertiary hyperparathyoidism.
Pheochromocytoma/paraganglioma

VHL RET NF1   SDHB  SDHD

- Characterized by - - -
  • Increased catecholamines and metanephrines in plasma (blood) or through a 24-hour urine collection.
Adrenocortical carcinoma
  • p53
  • Retinoblastoma h19
  • Insulin-like growth factor II (IGF-II)
  • p57kip2
17p, 13q  - - -
  • Increased serum glucose
  • Increased urine cortisol
  • Serum androstenedione and dehydroepiandrosterone
  • Low serum potassium
  • Low plasma renin activity
  • High serum aldosterone.
  • Excess serum estrogen.
Adapted from Toledo SP, Lourenço DM, Toledo RA. A differential diagnosis of inherited endocrine tumors and their tumor counterparts, journal=Clinics (Sao Paulo), volume= 68, issue= 7, 07/24/2013[5]

See also

References

  1. Von Hippel E. Ueber eine sehr seltene Erkrankung der Netzhaut. Albrecht von Graefes Arch Ophthal 1904;59:83-106.
  2. Lindau A. Zur Frage der Angiomatosis Retinae und Ihrer Hirncomplikation. Acta Ophthal 1927;4:193-226.
  3. "Hatfield-McCoy feud blamed on ‘rage’ disease". MSNBC.com. 2007-04-05. Retrieved 2007-04-05.  Check date values in: |date= (help)
  4. "'Pheochromocytoma Information'". vhl.org. 2007-04-05. Retrieved 2007-04-05.  Check date values in: |date= (help)
  5. Toledo SP, Lourenço DM, Toledo RA (2013). "A differential diagnosis of inherited endocrine tumors and their tumor counterparts.". Clinics (Sao Paulo). 68 (7): 1039–56. PMC 3715026Freely accessible. PMID 23917672. doi:10.6061/clinics/2013(07)24. 

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da:Von Hippel-Lindaus sygdom de:Morbus Hippel-Lindaunl:Ziekte van Von Hippel-Lindaufi:Von Hippel-Lindaun oireyhtymä


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