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Von Hippel-Lindau syndrome(VHLS)

MedGen UID:
42458
Concept ID:
C0019562
Disease or Syndrome
Synonyms: VHL syndrome; VHLS; Von Hippel-Lindau
SNOMED CT: VHL (Von Hippel-Lindau) syndrome (46659004); Lindau's disease (46659004); Von Hippel-Lindau syndrome (46659004); Familial cerebello-retinal angiomatosis (46659004); Lindau' disease (46659004); Cerebroretinal angiomatosis (46659004)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Genes (locations): CCND1 (11q13.3); VHL (3p25.3)
 
Monarch Initiative: MONDO:0008667
OMIM®: 193300
Orphanet: ORPHA892

Disease characteristics

Excerpted from the GeneReview: Von Hippel-Lindau Syndrome
Von Hippel-Lindau syndrome (VHL) is characterized by hemangioblastomas of the brain, spinal cord, and retina; renal cysts and clear cell renal cell carcinoma; pheochromocytoma and paraganglioma; pancreatic cysts and neuroendocrine tumors; endolymphatic sac tumors; and epididymal and broad ligament cystadenomas. Retinal hemangioblastomas may be the initial manifestation of VHL and can cause vision loss. Cerebellar hemangioblastomas may be associated with headache, vomiting, gait disturbances, or ataxia. Spinal hemangioblastomas and related syrinx usually present with pain. Sensory and motor loss may develop with cord compression. Renal cell carcinoma occurs in about 70% of individuals with VHL and is the leading cause of mortality. Pheochromocytomas can be asymptomatic but may cause sustained or episodic hypertension. Pancreatic lesions often remain asymptomatic and rarely cause endocrine or exocrine insufficiency. Endolymphatic sac tumors can cause hearing loss of varying severity, which can be a presenting symptom. Cystadenomas of the epididymis are relatively common. They rarely cause problems, unless bilateral, in which case they may result in infertility. [from GeneReviews]
Authors:
Rachel S van Leeuwaarde  |  Saya Ahmad  |  Bernadette van Nesselrooij, et. al.   view full author information

Additional descriptions

From OMIM
Von Hippel-Lindau syndrome (VHLS) is a dominantly inherited familial cancer syndrome predisposing to a variety of malignant and benign neoplasms, most frequently retinal, cerebellar, and spinal hemangioblastoma, renal cell carcinoma (RCC), pheochromocytoma, and pancreatic tumors. Neumann and Wiestler (1991) classified VHL as type 1 (without pheochromocytoma) and type 2 (with pheochromocytoma). Brauch et al. (1995) further subdivided VHL type 2 into type 2A (with pheochromocytoma) and type 2B (with pheochromocytoma and renal cell carcinoma). Hoffman et al. (2001) noted that VHL type 2C refers to patients with isolated pheochromocytoma without hemangioblastoma or renal cell carcinoma. McNeill et al. (2009) proposed that patients with VHL syndrome caused by large VHL deletions that include the HSPC300 gene (C3ORF10; 611183) have a specific subtype of VHL syndrome characterized by protection from renal cell carcinoma, which the authors proposed be named VHL type 1B. Nordstrom-O'Brien et al. (2010) provided a review of the genetics of von Hippel-Lindau disease.  http://www.omim.org/entry/193300
From MedlinePlus Genetics
Von Hippel-Lindau syndrome is an inherited disorder characterized by the formation of tumors and fluid-filled sacs (cysts) in many different parts of the body. Tumors may be either noncancerous or cancerous and most frequently appear during young adulthood; however, the signs and symptoms of von Hippel-Lindau syndrome can occur throughout life.

Tumors called hemangioblastomas are characteristic of von Hippel-Lindau syndrome. These growths are made of newly formed blood vessels. Although they are typically noncancerous, they can cause serious or life-threatening complications. Hemangioblastomas that develop in the brain and spinal cord can cause headaches, vomiting, weakness, and a loss of muscle coordination (ataxia). Hemangioblastomas can also occur in the light-sensitive tissue that lines the back of the eye (the retina). These tumors, which are also called retinal angiomas, may cause vision loss.

People with von Hippel-Lindau syndrome commonly develop cysts in the kidneys, pancreas, and genital tract. They are also at an increased risk of developing a type of kidney cancer called clear cell renal cell carcinoma and a type of pancreatic cancer called a pancreatic neuroendocrine tumor.

Von Hippel-Lindau syndrome is associated with a type of tumor called a pheochromocytoma, which most commonly occurs in the adrenal glands (small hormone-producing glands located on top of each kidney). Pheochromocytomas are usually noncancerous. They may cause no symptoms, but in some cases they are associated with headaches, panic attacks, excess sweating, or dangerously high blood pressure that may not respond to medication. Pheochromocytomas are particularly dangerous in times of stress or trauma, such as when undergoing surgery or in an accident, or during pregnancy.

About 10 percent of people with von Hippel-Lindau syndrome develop endolymphatic sac tumors, which are noncancerous tumors in the inner ear. These growths can cause hearing loss in one or both ears, as well as ringing in the ears (tinnitus) and problems with balance. Without treatment, these tumors can cause sudden profound deafness.

Noncancerous tumors may also develop in the liver and lungs in people with von Hippel-Lindau syndrome. These tumors do not appear to cause any signs or symptoms.  https://medlineplus.gov/genetics/condition/von-hippel-lindau-syndrome

Clinical features

From HPO
Renal cell carcinoma
MedGen UID:
766
Concept ID:
C0007134
Neoplastic Process
A type of carcinoma of the kidney with origin in the epithelium of the proximal convoluted renal tubule.
Paraganglioma
MedGen UID:
10571
Concept ID:
C0030421
Neoplastic Process
A carotid body tumor (also called paraganglionoma or chemodectoma) is a tumor found in the upper neck at the branching of the carotid artery. They arise from the chemoreceptor organ (paraganglion) located in the adventitia of the carotid artery bifurcation.
Pheochromocytoma
MedGen UID:
18419
Concept ID:
C0031511
Neoplastic Process
Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas (tumors that arise from neuroendocrine tissues distributed along the paravertebral axis from the base of the skull to the pelvis) and pheochromocytomas (paragangliomas that are confined to the adrenal medulla). Sympathetic paragangliomas cause catecholamine excess; parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the skull base and neck (referred to as head and neck PGL [HNPGL]) and sometimes in the upper mediastinum; approximately 95% of such tumors are nonsecretory. In contrast, sympathetic extra-adrenal paragangliomas are generally confined to the lower mediastinum, abdomen, and pelvis, and are typically secretory. Pheochromocytomas, which arise from the adrenal medulla, typically lead to catecholamine excess. Symptoms of PGL/PCC result from either mass effects or catecholamine hypersecretion (e.g., sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, forceful palpitations, pallor, and apprehension or anxiety). The risk for developing metastatic disease is greater for extra-adrenal sympathetic paragangliomas than for pheochromocytomas.
Hepatic hemangioma
MedGen UID:
66765
Concept ID:
C0238246
Neoplastic Process
A congenital vascular malformation in the liver composed of masses of blood vessels that are atypical or irregular in arrangement and size.
Pulmonary capillary hemangiomatosis
MedGen UID:
87404
Concept ID:
C0340548
Disease or Syndrome
Papillary cystadenoma of the epididymis
MedGen UID:
869791
Concept ID:
C4024221
Neoplastic Process
A cystadenoma, an epithelial tumor, that originates within the head of the epididymis.
Multiple renal cysts
MedGen UID:
140917
Concept ID:
C0431718
Disease or Syndrome
The presence of many cysts in the kidney.
Epididymal cyst
MedGen UID:
1778106
Concept ID:
C5442141
Anatomical Abnormality
A smooth, extratesticular, spherical cyst in the head of the epididymis.
Hypertensive disorder
MedGen UID:
6969
Concept ID:
C0020538
Disease or Syndrome
The presence of chronic increased pressure in the systemic arterial system.
Pancreatic cysts
MedGen UID:
45293
Concept ID:
C0030283
Disease or Syndrome
A cyst of the pancreas that possess a lining of mucous epithelium.
Neoplasm of the pancreas
MedGen UID:
18279
Concept ID:
C0030297
Neoplastic Process
A tumor (abnormal growth of tissue) of the pancreas.
Sensorineural hearing loss disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Tinnitus
MedGen UID:
52760
Concept ID:
C0040264
Disease or Syndrome
Tinnitus is an auditory perception that can be described as the experience of sound, in the ear or in the head, in the absence of external acoustic stimulation.
Vertigo
MedGen UID:
53006
Concept ID:
C0042571
Sign or Symptom
An abnormal sensation of spinning while the body is actually stationary.
Retinal capillary hemangioma
MedGen UID:
152677
Concept ID:
C0730303
Neoplastic Process
A benign vascular tumor of the retina without any neoplastic characteristics.
Cerebellar hemangioblastoma
MedGen UID:
234108
Concept ID:
C1332900
Neoplastic Process
A hemangioblastoma of the cerebellum.
Spinal hemangioblastoma
MedGen UID:
869793
Concept ID:
C4024223
Neoplastic Process
A hemangioblastoma of the spinal cord.
Polycythemia
MedGen UID:
18552
Concept ID:
C0032461
Disease or Syndrome
Polycythemia is diagnosed if the red blood cell count, the hemoglobin level, and the red blood cell volume all exceed the upper limits of normal.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVVon Hippel-Lindau syndrome
Follow this link to review classifications for Von Hippel-Lindau syndrome in Orphanet.

Professional guidelines

PubMed

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Recent clinical studies

Etiology

Corral de la Calle MA, Encinas de la Iglesia J, Fernández-Pérez GC, Repollés Cobaleda M, Fraino A
Radiologia (Engl Ed) 2022 Jul-Aug;64(4):348-367. doi: 10.1016/j.rxeng.2022.07.002. PMID: 36030082
Qu L, Lv C, Ji T, Wang Y, Yu J
Int J Surg Pathol 2021 Apr;29(2):129-134. Epub 2020 Jun 14 doi: 10.1177/1066896920933998. PMID: 32538251
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Turchini J, Cheung VKY, Tischler AS, De Krijger RR, Gill AJ
Histopathology 2018 Jan;72(1):97-105. doi: 10.1111/his.13402. PMID: 29239044

Diagnosis

Li S, Li W, Yuan J, Bullova P, Wu J, Zhang X, Liu Y, Plescher M, Rodriguez J, Bedoya-Reina OC, Jannig PR, Valente-Silva P, Yu M, Henriksson MA, Zubarev RA, Smed-Sörensen A, Suzuki CK, Ruas JL, Holmberg J, Larsson C, Christofer Juhlin C, von Kriegsheim A, Cao Y, Schlisio S
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Therapy

Grimes JM, Gershkovich A, Bogomolny D, Marr BP
Retin Cases Brief Rep 2024 May 1;18(3):319-322. doi: 10.1097/ICB.0000000000001376. PMID: 36730578
Ruggeri RM, Benevento E, De Cicco F, Fazzalari B, Guadagno E, Hasballa I, Tarsitano MG, Isidori AM, Colao A, Faggiano A; NIKE Group
J Endocrinol Invest 2023 Feb;46(2):213-234. Epub 2022 Aug 30 doi: 10.1007/s40618-022-01905-4. PMID: 36038743
Russell JF, Villegas VM, Schwartz SG, Weng CY, Davis JL, Flynn HW Jr, Harbour JW
Am J Ophthalmol 2021 May;225:128-136. Epub 2021 Jan 12 doi: 10.1016/j.ajo.2021.01.002. PMID: 33450232
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Prognosis

Qu L, Lv C, Ji T, Wang Y, Yu J
Int J Surg Pathol 2021 Apr;29(2):129-134. Epub 2020 Jun 14 doi: 10.1177/1066896920933998. PMID: 32538251
Turchini J, Cheung VKY, Tischler AS, De Krijger RR, Gill AJ
Histopathology 2018 Jan;72(1):97-105. doi: 10.1111/his.13402. PMID: 29239044
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Horm Res Paediatr 2015;84(3):145-52. Epub 2015 Aug 5 doi: 10.1159/000431323. PMID: 26279462
Bhavsar AS, Verma S, Lamba R, Lall CG, Koenigsknecht V, Rajesh A
Radiographics 2013 Jan-Feb;33(1):135-53. doi: 10.1148/rg.331125097. PMID: 23322834
Lenders JW, Eisenhofer G, Mannelli M, Pacak K
Lancet 2005 Aug 20-26;366(9486):665-75. doi: 10.1016/S0140-6736(05)67139-5. PMID: 16112304

Clinical prediction guides

Russell JF, Villegas VM, Schwartz SG, Weng CY, Davis JL, Flynn HW Jr, Harbour JW
Am J Ophthalmol 2021 May;225:128-136. Epub 2021 Jan 12 doi: 10.1016/j.ajo.2021.01.002. PMID: 33450232
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Pathology 2018 Feb;50(2):238-256. Epub 2018 Jan 17 doi: 10.1016/j.pathol.2017.10.009. PMID: 29373116
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Lam AK
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Recent systematic reviews

Grossen A, Gavula T, Chrusciel D, Evans A, McNall-Knapp R, Taylor A, Fossey B, Brakefield M, Carter C, Schwartz N, Gross N, Jea A, Desai V
Neurosurg Focus 2022 May;52(5):E2. doi: 10.3171/2022.2.FOCUS21776. PMID: 35535824

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