Conclusiones. Es importante para el urólogo el conocimiento básico de la enfermedad de von Hippel-Lindau porque las manifestaciones genitourinarias de ella. Von Hippel-Lindau (VHL) syndrome is characterized by hemangioblastomas of the brain, spinal cord, and retina; renal cysts and clear cell. Von Hippel-Lindau (VHL) disease is an inherited disorder characterized by the abnormal growth of both benign and cancerous tumors and cysts in many parts of .

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Von Hippel-Lindau Disease

University of Washington, Seattle; May 17, ; Last Update: Von Hippel-Lindau VHL syndrome is characterized by hemangioblastomas of the brain, spinal cord, and retina; renal cysts and clear cell renal cell carcinoma; pheochromocytoma, pancreatic cysts, and neuroendocrine tumors; endolymphatic sac tumors; and epididymal and broad ligament cysts. 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. Retinal hemangioblastomas may be the initial manifestation of VHL syndrome and can cause vision loss. 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. The diagnosis of VHL is established in a proband who fulfills existing diagnostic clinical criteria.

Identification of a heterozygous germline VHL pathogenic variant on molecular genetic testing establishes the diagnosis if clinical features are inconclusive. Prevention of secondary complications: For individuals with VHL syndrome, those with a VHL pathogenic variantand at-risk relatives of unknown genetic status:. Tobacco products should be avoided since they are considered a risk factor for kidney cancer; chemicals and industrial toxins known to affect VHL-involved organs should be avoided; contact sports should be avoided if adrenal or pancreatic lesions are present.

Evaluation of relatives at risk: If the pathogenic variant in a family is known, molecular genetic testing can be used to clarify the genetic status of at-risk family members to eliminate the need for surveillance of family members who have not inherited the pathogenic variant.

Intensified surveillance for cerebellar hemangioblastoma and pheochromocytoma during preconception and pregnancy; MRI without contrast of the cerebellum at four months’ gestation. VHL syndrome is inherited in an autosomal dominant manner.

Parental mosaicism has been described; the incidence is not known. Prenatal testing for a pregnancy at risk is possible if the pathogenic variant has been identified in a family member. Von Hippel-Lindau syndrome should be suspected in individuals with or without a family history of VHL who have:. Identification of a heterozygous germline pathogenic variant in VHL by molecular genetic testing Table 1 establishes the diagnosis and supports periodic follow up even if clinical and radiographic features are inconclusive.

ELST presents as a mass on the posterior wall of the petrous part of the temporal bone and can be missed on standard MRI. MRI with contrast and high signal intensity with T 1 using thin slices of the internal auditory canal is recommended in symptomatic individuals. Approaches can include a combination of gene -targeted testing single-gene testing, multigene panel and comprehensive genomic testing exome sequencinggenome sequencingexome array depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene s are likely involved, whereas genomic linvau does not.

Because the phenotype of VHL is broad, individuals with the distinctive features linndau in Suggestive Findings are likely to be diagnosed using gene-targeted testing see Option 1whereas those with a phenotype indistinguishable from many other inherited disorders associated with an increased risk of tumors enfermesad more likely to be diagnosed using genomic testing see Option 2.


When the phenotypic, laboratory, and radiographic findings suggest the diagnosis of VHL molecular genetic testing approaches can include single- gene testing or use of a multigene panel. A multigene panel that includes VHL and other genes of interest see Differential Diagnosis is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants voh uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype.

For an introduction to multigene panels click here. More detailed information for clinicians ordering dee tests can be found here. When the phenotype is indistinguishable from many other inherited ljndau characterized by tumors, comprehensive genomic testing which does not require the clinician to determine which gene [s] enermedad likely involved is the best option.

Exome sequencing is most commonly used; genome sequencing is also possible. Exome array when clinically available may be considered if exome sequencing is not diagnostic.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here. View enferrmedad own window. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.

Sequence analysis detects variants that are benign, likely benign, of uncertain significancelikely pathogenic, or pathogenic. For issues to consider in interpretation of sequence analysis results, click here.

Nordstrom-O’Brien et al []. See also Molecular Genetics. Methods used may include: Von Hippel-Lindau VHL syndrome is characterized by hemangioblastomas of the brain, spinal cord, and retina; renal cysts and renal cell carcinoma; pheochromocytoma and paraganglioma; pancreatic cysts and neuroendocrine tumors; endolymphatic sac tumors; and epididymal and broad ligament cysts. Some clustering of tumors occurs, resulting in the designation of specific VHL syndrome phenotypes.

The manifestations and severity are highly variable both within and between families, even among those with the same pathogenic variant. One study showed that in adulthood, men have more VHL manifestations compared to women.

They also showed that the risk for manifestations was not constant, but varied throughout the affected individual’s lifetime [ Binderup et al ]. Age was the only predictor for the number of involved organs. Multiple CNS tumors, occurring either synchronously or metachronously, are common. Peripheral nerve hemangiomas may be a rare manifestation [ Giannini et al ].

Hemangioblastomas oscillate between periods of growth and stability [ Wanebo et al ] and are generally slow growing, but on occasion include rapidly enlarging cysts that produce hydrocephaly with papilledema. Some hemangioblastomas do not cause symptoms and are discovered only on imaging.

Central nervous system CNS hemangioblastoma growth appears to be associated with male sex and partial germline deletions [ Lonser et alHuntoon et al ]. Increased growth was associated with male sex, symptomatic tumors, and hemangioblastoma-associated cysts. CNS hemangioblastomas remain the main cause of death, although VHL-related survival has improved over the years [ Binderup et al b ]. Pheochromocytomas are usually located in one or both adrenal glands. They are usually benign, but malignant behavior has been reported [ Chen et alJimenez et al ].

Similar in etiology, paragangliomas can develop along the sympathetic axis in the abdomen or thorax [ Schimke et alBoedeker et al ]; these tumors are often nonfunctional i. The onset of hearing loss is typically sudden; severity varies, but it is often severe to profound [ Choo et alKim et al ].

Vertigo or tinnitus is the presenting complaint. More significant hearing loss and larger tumor size at presentation was reported in individuals with endolymphatic sac tumors not related to VHL than in individuals with VHL-related endolymphatic sac tumors [ Nevoux et al ]. Large endolymphatic sac tumors can involve other cranial nerves. Endolymphatic sac tumors are rarely malignant [ Muzumdar et al ].

Epididymal and broad ligament cystadenomas. Epididymal or papillary cystadenomas are relatively common in males with VHL syndrome.

The equivalent, much less common, lesion in women is a papillary cystadenoma of the broad ligament.


Orphanet: Diagn stico de la enfermedad de Von Hippel Lindau gen VHL

Both tissues are mesonephric in origin and are likely a developmental remnant of somatic VHL loss. Four general VHL syndrome phenotypes type 1, type 2A, type 2B, type 2C have been suggested based on the likelihood of pheochromocytoma or renal cell carcinoma.

Many lines of research support the conclusion that the molecular etiology of pheochromocytomas appears to be distinct from other VHL lesions. The hippsl discussion summarizes the genotype-phenotype studies published to date, with the cautionary note that further investigation is needed. Patterns are not clear-cut, and genotype-phenotype correlations have no current diagnostic or therapeutic value and are used for academic purposes only. Retinal angioma, CNS hemangioblastoma, renal cell carcinoma, pancreatic cysts and neuroendocrine tumors.

VHL type 1 is characterized by a low risk for pheochromocytoma. Pathogenic truncating or missense variants that are predicted to grossly disrupt the folding of the VHL protein [ Stebbins et al ] are associated with VHL type 1.

Pheochromocytoma, retinal angiomas and CNS hemangioblastoma. VHL type 2 is characterized by a high risk for pheochromocytoma.

Individuals with VHL type 2 commonly have a hipppel missense variant. Pathogenic missense variants stratified by multiple in silico computational models found that variants with a high predicted risk of pathogenicity were predictive of pancreatic lesion progression in an NIH patient series [ Tirosh et al ].

In contrast, genotype did not appear to influence the growth of renal cell carcinomas in individuals with VHL [ Farhadi et al ]. Several groups report a reduced risk for renal cell carcinoma in individuals with a deletion of VHL [ Cybulski et alMaranchie et alMcNeill et al ]. In particular, individuals with a complete or partial deletion that extends 5′ of VHL to include BRK1 previously C3orf10 have a significantly reduced risk of renal cell carcinoma [ Maranchie et alMcNeill et al ].

This genotype may constitute a distinct phenotypeVHL type 1B, characterized by a reduced risk for both renal cell carcinoma and pheochromocytoma. VHL pathogenic variants are highly penetrant. Almost all individuals who have a pathogenic variant in VHL are symptomatic by age 65 years [ Maher et al ].

Obsolete terms for VHL syndrome include: The incidence of VHL syndrome is thought to be about one in 36, births with an estimated de novo mutation rate of 4. Familial erythrocytosis type 2 OMIM is characterized by increased circulating red blood cell mass, increased serum levels of erythropoietin, and normal oxygen affinity. Familial erythrocytosis type 2 is caused by biallelic pathogenic variants in VHL resulting in retention of a cryptic exon in linda 1 [ Lenglet et al ].

Congenital erythrocytosis is endemic in subpopulations worldwide; pathogenic variants in VHL are ejfermedad most common cause of congenital erythrocytosis [ Pastore et al ]. In the Chuvash Republic of the Russian Federation, where this condition is endemic, Ang et al [] identified homozygosity for a VHL pathogenic missense variant.

Isolated hemangioblastoma, retinal angioma, or clear cell renal cell carcinoma.

Von Hippel-Lindau Disease: MedlinePlus

The clinical sensitivity of molecular genetic testing of VHL makes it possible to effectively rule out von Hippel-Lindau VHL syndrome with a high degree of certainty in individuals with 1 isolated hemangioblastoma, retinal angioma, or clear hipple renal cell carcinoma and 2 no detectable germline VHL pathogenic variant. Somatic mosaicism for a VHL pathogenic variant could still be considered in such individuals.

A younger individual, especially one with multiple lesions, ejfermedad more likely to have a germline VHL pathogenic variant than an older individual with a single lesion [ Binderup et al a ].