Von Hippel-Lindau disease

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:

angiomatosis – little knots of capillaries in the retina and various organs.
hemangioblastomas – tumors of the central nervous system (CNS, especially the cerebellum, brain stem, and spinal cord).
pheochromocytoma – tumors of the adrenal medulla that often produce catecholamines
renal cell carcinoma – in some forms
pancreas – cysts and tumors of the pancreas, which may be neuroendocrine tumors

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
Disease	Gene	Chromosome	Differentiating Features	Parathyroid	Pitutary	Pancreas	Diagnosis
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	Scoliosis Learning disabilities Vision disorders Cutaneous lesions Epilepsy.	–	–	–	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 Sarcoma Cancers of Breast Brain Adrenal glands	–	–	–	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	–	Medullary thyroid carcinoma (MTC) Pheochromocytoma Primary hyperparathyroidism	+	–	–	Hypercalcemia Hypophosphatemia, Elevated parathyroid hormone, Elevated norepinephrine Criteria Two or more specific endocrine tumors Medullary thyroid carcinoma Pheochromocytoma Parathyroid hyperplasia
Cowden syndrome	PTEN	–	Hamartomas	–	–	–	PTEN mutation probability risk calculator
Acromegaly/gigantism	–	–	Enlargement of the hands, feet, nose, lips and ears, and a general thickening of the skin Hypertrichosis Hyperpigmentation Hyperhidrosis Carpal tunnel syndrome.	–	+	–	An elevated concentration of serum growth hormone (GH) and insulin-like growth factor 1(IGF-1) levels is diagnostic of acromegaly.
Pituitary adenoma	–	–	Visual field defects classically bitemporal hemianopsia Increased intracranial pressure Migraine Lateral rectus palsy	–	+	–	Elevated serum level of prolactin Elevated or decreased serum level of adrenocorticotropic hormone (ACTH) Elevated or decreased serum level of growth hormone (GH) Elevated or decreased serum level of thyroid-stimulating hormone (TSH) Elevated or decreased serum level of follicle-stimulating hormone (FSH) Elevated or decreased serum level of luteinizing hormone (LH)
Hyperparathyroidism	–	–	– Kidney stones Hypercalcemia, Constipation Peptic ulcers Depression	+	–	–	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 Episodic hypertension Palpitations Anxiety Diaphoresis Weight loss	–	–	–	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) p57^kip2	17p, 13q	Cushing syndrome (cortisol hypersecretion) Conn syndrome (aldosterone hypersecretion) virilization (testosterone hypersecretion)	–	–	–	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]

References

↑ Von Hippel E. Ueber eine sehr seltene Erkrankung der Netzhaut. Albrecht von Graefes Arch Ophthal 1904;59:83-106.
↑ Lindau A. Zur Frage der Angiomatosis Retinae und Ihrer Hirncomplikation. Acta Ophthal 1927;4:193-226.
↑ “Hatfield-McCoy feud blamed on ‘rage’ disease“. MSNBC.com. 2007-04-05. Retrieved 2007-04-05. Check date values in: |date= (help)
↑ “‘Pheochromocytoma Information‘“. vhl.org. 2007-04-05. Retrieved 2007-04-05. Check date values in: |date= (help)
↑ 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. doi:10.6061/clinics/2013(07)24. PMC 3715026. PMID 23917672.

External links

Clinical Description of VHL
The VHL Handbook
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Von Hippel-Lindau syndrome at NLM Genetics Home Reference
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Online Mendelian Inheritance in Man (OMIM) 608537 (VHL gene)

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[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)

[pmid23917672-5] 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. doi:10.6061/clinics/2013(07)24. PMC 3715026. PMID 23917672.

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