Human Molecular Genetics, 2001, Vol. 10, No. 7 763-767
© 2001 Oxford University Press
Genotype–phenotype correlation in von Hippel-Lindau syndrome
Division of Medical Genetics, Department of Preventive Medicine, University of Mississippi School of Medicine, 2500 North State Street, Jackson, MS 39216-4505, USA
Received 2 February 2001; Accepted 2 February 2001.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONCLINICAL MANIFESTATIONSGENE STRUCTURE AND PROTEIN...GENOTYPE-PHENOTYPE CORRELATIONSINCORPORATING MOLECULAR TESTING...CONCLUSIONSREFERENCES |
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The von Hippel-Lindau (VHL) syndrome (OMIM 193300) is an autosomal dominant disorder caused by deletions or mutations in a tumor suppressor gene on human chromosome 3p25. It is characterized clinically by vascular tumors including benign hemangioblastomas of the cerebellum, spine, brain stem and retina. Clear-cell renal cell carcinoma is a frequent cause of death, occurring in up to 70% of patients with VHL. Pheochromocytomas occur in association with specific alleles (usually mutations as opposed to deletions), therefore a family history of pheochromocytoma in association with VHL is an indication for thorough surveillance for pheochromocytoma in affected family members.The VHL gene coding sequence contains three exons. Two isoforms of mRNA exist, reflecting the presence or absence of exon 2. Tumors arise following the loss or inactivation of the wild-type allele in a cell. In initial studies
20% of patients had large germline mutations detectable by Southern blot analysis, 27% had missense mutations and 27% had nonsense or frameshift mutations. Advances in mutation analysis now allow for a 100% mutation detection rate in families with definite VHL. Families may be characterized by the presence [type 2 (7–20% of families)] or absence (type 1) of pheochromocytomas. Most type 2 families are affected by missense mutations, whereas most type 1 families have deletions or premature termination mutations. The prognosis for the lifetime risk of pheochromocytoma can be estimated by determination of the underlying mutation even if there is no family history of VHL. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONCLINICAL MANIFESTATIONSGENE STRUCTURE AND PROTEIN...GENOTYPE-PHENOTYPE CORRELATIONSINCORPORATING MOLECULAR TESTING...CONCLUSIONSREFERENCES |
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The von Hippel-Lindau (VHL) syndrome is a rare autosomal dominant condition characterized by the development of specific benign and malignant tumors. It is caused by point mutations or deletions in a tumor suppressor gene. Although there is great variation in the clinical presentation, those who have a mutated gene are at greatly increased risk of developing spinal hemangioblastoma, renal cell carcinoma (RCC), retinal hemangioblastoma, cerebellar hemangioblastoma, pheochromocytoma, pancreatic and renal cysts, endolymphatic sac tumors, hemangiomas of the adrenals, liver and lungs, and papillary cystadenoma of the epididymis or broad ligament, as illustrated in the Figure 1 (1–3). As many as 50% of patients in VHL families may show only one manifestation of the syndrome (4,5). Although there is variable expressivity among families, some clinical features are similar within families. Clear-cell renal RCC occurs in up to 70% of patients (5). In early studies death was often due to complications of cerebellar hemangioblastoma (53%) or metastatic RCC (32%) (5–8). The retinal lesions can cause retinal detachment or hemorrhage which lead to blindness, but usually respond to treatment with laser therapy or cryotherapy if detected early.
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Table 1 lists the age of onset of typical findings (5,9). Pheochromocytoma may be the initial presentation. A registry of 83 patients in northwest England was started in 1990 (10). Their mean age of onset at the first sign or symptom was 26.25 years, with a mean age at diagnosis of 30.87 years. Cerebellar hemangioblastoma was the most common initial manifestation (34.9%). The most common cause of death was complications of cerebellar hemangioblastoma (47.7%), and the mean age at death was 40.9 years. The cumulative occurrence of cerebellar hemangioblastoma was 60.2%, retinal hemangioblastoma (41%), RCC (25.3%), spinal hemangioblastoma (14.5%) and pheochromocytoma (14.5%).
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Family studies have shown reduced penetrance of the clinical phenotype. Three obligate carriers without lesions were found in the northwest England registry (10). The prevalence of VHL disease was estimated at 1 in 53 000 in East Anglia, with an incidence of 1 in 36 000 (1), and the prevalence was 1 in 38 951 in Freiburg (4). The northwest England VHL registry estimated the prevalence at 1 in 85 000 with an incidence of 1 in 45 500 (10).
The life expectancy of those affected has been <50 years. Earlier diagnosis and the recent development of surveillance protocols emphasizing regular monitoring for predictable complications, followed by early interventions, may have improved the prognosis.
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CLINICAL MANIFESTATIONS |
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TOPABSTRACTINTRODUCTIONCLINICAL MANIFESTATIONSGENE STRUCTURE AND PROTEIN...GENOTYPE-PHENOTYPE CORRELATIONSINCORPORATING MOLECULAR TESTING...CONCLUSIONSREFERENCES |
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The diagnosis is usually made on clinical grounds. In a patient with a family history of VHL, the finding of a single retinal or cerebellar hemangioblastoma, pheochromocytoma or RCC is considered sufficient to justify the diagnosis (11). It has been argued that the presence of multiple pancreatic cysts is also sufficient. Renal or epididymal cysts alone are insufficient because of their frequent occurrence in the general population (12).
In the absence of a definite family history of VHL, two or more retinal or cerebellar hemangioblastomas, or one hemangioblastoma plus one visceral tumor must be present to make the diagnosis. New mutations account for 1–3% of VHL cases (13,14).
Symptoms and signs of cerebellar hemangioblastoma can include headache, slurred speech, nystagmus, positional vertigo, labile hypertension (without pheochromocytoma), vomiting, wide-based gait and dysmetria (15). Erythrocytosis has been reported in 5–20% of patients (16). VHL disease has been found in up to 30% of patients with cerebellar hemangioblastoma (5,17). Spinal hemangioblastomas are more specific for VHL disease, with 80% being due to VHL, and they have been found in 13–59% of VHL patients (5,7,18).
Renal cysts may give rise to renal cell carcinomas. The tumors usually grow slowly (<2 cm per year), and it has been recommended they be followed with CT scans semi-annually (19). When they are 3 cm in size nephron-sparing surgery may preserve renal function, postponing the need for dialysis (20,21).
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GENE STRUCTURE AND PROTEIN FUNCTION |
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TOPABSTRACTINTRODUCTIONCLINICAL MANIFESTATIONSGENE STRUCTURE AND PROTEIN...GENOTYPE-PHENOTYPE CORRELATIONSINCORPORATING MOLECULAR TESTING...CONCLUSIONSREFERENCES |
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Family linkage studies assigned the gene responsible for VHL disease to chromosome 3p25 (22). This was confirmed when pulsed field gel electrophoresis studies revealed nested constitutional deletions in three unrelated patients (23). Positional cloning using overlapping yeast artificial chromosomes and cosmid-phage contigs allowed identification of the VHL gene (13).
The gene coding sequence has three exons containing 712 nucleotides, including 70 bp of the 5' untranslated sequence in exon 1 (3). There are two mRNA isoforms, differing based on the presence or absence of exon 2 (24). Tumors arise from loss of heterozygosity after inactivation (e.g. deletion or hypermethylation) of the wild-type allele in a cell (25–27).
Although it was initially predicted that the VHL gene product would contain 284 amino acid residues (13) it was eventually shown that the protein contained 213 amino acids and the numbering scheme was revised (28,29). The apparent molecular weight is 28–30 kDa (28,29). The VHL gene product, pVHL, binds to two transcription factors, elongin B and C, and its binding site is mutated frequently in VHL disease (30–32). The normal function of this protein involves inhibition of transcription elongation (30,31). Introduction of wild-type, but not mutant, VHL protein into clear-cell RCC cell lines lacking functioning VHL genes suppresses the ability to form tumors in nude mouse xenograft assays, confirming that the VHL gene product functions as a tumor suppressor (29,33).
Alternate translation initiation, using an internal AUG codon (codon 54), produces a gene product (PVHL18) with an apparent molecular weight of 18 kDa (34). When introduced into RCC cells lacking wild-type pVHL, pVHL18 has similar effects as native pVHL (34,35).
A large number of missense mutations occur within the domain where elongin B binds, disrupting the formation of a complex which contains elongin B, elongin C, cullin (cul-2) and Rbx1, and functions as an E3 ubiquitin ligase (36–38). The multiprotein complex structure shows similarity to the Skp1-Cul1-F-box protein complex that targets proteins for degradation (37). Mutations which affect the elongin-binding domain allow the complex to be degraded by the proteasome (38).
Similarly, the pVHL-Elongin B-Elongin C complex also regulates hypoxia-inducible proteins, and requires direct binding of the ß-domain of pVHL to hypoxia-inducible factor (HIF). This targets HIF for ubiquitination catalyzed by the 
-domain (39).The VHL gene product has also been shown to be necessary for cell cycle exit after serum is withdrawn (40).
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GENOTYPE–PHENOTYPE CORRELATIONS |
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TOPABSTRACTINTRODUCTIONCLINICAL MANIFESTATIONSGENE STRUCTURE AND PROTEIN...GENOTYPE-PHENOTYPE CORRELATIONSINCORPORATING MOLECULAR TESTING...CONCLUSIONSREFERENCES |
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Mutation analysis has allowed the correlation of phenotypes with genotype. Initial reports showed
15–20% of patients had large germline deletions, 27% had missense mutations, 27% had nonsense or frameshift mutations and the remainder had no deletion or mutation detected (3). Subsequent studies using improved diagnostic techniques allowed mutation detection in 100% of patients with definite VHL (41). Analysis of five Dutch patients with sporadic pheochromocytomas showed one (20%) had a VHL mutation in tumor tissue (42). In 62 German patients with sporadic pheochromocytoma only two patients (3%) showed VHL mutations (43). A study of eight families with familial pheochromocytoma showed three had VHL mutations (44). In the same study one of two patients with bilateral pheochromocytomas had a germline VHL mutation. In six patients with multiple ectopic pheochromocytomas tumors (or single tumors with a family history of neuroectodermal tumors), none had VHL mutations (44). In 27 Israeli patients with sporadic pheochromocytomas, only one had a VHL mutation (45). An Australian study of 16 individuals with possible VHL disease revealed mutations in eight (50%), including three without family histories of VHL (46).
The identification of a mutation in a proband allows the identification of mutation carriers among family members who do not yet exhibit any clinical manifestation of VHL (47). Surveillance protocols for monitoring patients and family members at risk have been developed by several groups, and the NIH group recommendations are listed in Table 2 (16). Family members who previously had an empiric risk of 50% of being affected, but are found not to have inherited the mutation, do not need monitoring.
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Genotype–phenotype correlation studies have been useful in counseling for prognosis, especially regarding the risk of pheochromocytoma. Studies of 55 unrelated VHL kindreds showed an arg238gln mutation was present in five kindreds and an arg238trp mutation was found in four other families. Premature truncation mutations or large deletions were reported in 36 of 53 families without a history of pheochromocytoma (designated type 1 families), but in only 2 of 12 families with pheochromocytoma (type 2 families). In 10 of 12 type 2 families missense mutations were identified, whereas only 13 of 53 type 1 families had missense mutations. There was a 62% risk for pheochromocytoma associated with the arg238trp and arg238gln mutations (48).
Subsequent studies produced similar findings. In type 2 families (representing 7–20% of families) renal and pancreatic cysts are rarely present (5,49). Premature termination mutations or deletions were found in 56% of type 1 families, whereas 96% of type 2 families had missense mutations, 43% at nucleotide 238 (50). Prognostic counseling regarding pheochromocytoma may be possible based on molecular results even if there is no family history of VHL disease.
Similar results were found in 469 families from North America, Europe and Japan (51). Three additional phenotypes were studied: families with RCC but not pheochromocytoma, those with RCC and hemangioblastoma plus pheochromocytoma, and those with pheochromocytoma alone. Mutations were identified in 63% of the families. A total of 137 mutations were identified, most occurring in only one or two families.
Studies of five families with full or partial deletions of a VHL allele showed a prevalence of central nervous system hemangioblastoma with a low likelihood of pheochromocytoma (52).
Studies of ocular lesions in VHL disease found no correlation between the type of germline mutation and the severity of ocular angiomatosis (53). However, a study of retinal hemangioblastomas in 36 Finnish patients showed that visual prognosis was worse in those with VHL (diagnosed either clinically or by mutation analysis) (54).
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INCORPORATING MOLECULAR TESTING INTO CLINICAL PRACTICE |
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TOPABSTRACTINTRODUCTIONCLINICAL MANIFESTATIONSGENE STRUCTURE AND PROTEIN...GENOTYPE-PHENOTYPE CORRELATIONSINCORPORATING MOLECULAR TESTING...CONCLUSIONSREFERENCES |
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Molecular testing is now considered standard for the evaluation of patients and families with suspected VHL (55). One study has shown a generally high level of interest in pre-symptomatic testing among families affected by cancer susceptibility genes (including VHL), with a much larger percentage of women (93%) interested than men (77%) (56).
The standard of care is for patients or family members to receive genetic counseling before and after undergoing molecular testing. The person providing the counseling must ensure a person considering being tested is aware of the potential benefits and disadvantages of learning they have a gene mutation which places them at high risk for developing tumors. This includes preparing them for common reactions which other patients and families have experienced after receiving a diagnosis, including anxiety, isolation, denial, guilt and over-protectiveness (57). Some may be concerned about the potential effect of carrying such a gene on their ability to obtain insurance or employment, or a similar effect on the patient’s relatives.
In one study of 24 women and 17 men with VHL, representing a total of 34 French kindreds, only 34% had had children. More men (82%) than women (54%) were childless. Half of these subjects did not understand completely the inherited nature of their condition, and two-thirds of the pregnancies occurred when the parent was not ill, or before the diagnosis had been made. Of the 14 subjects with children, most had asked for molecular testing for their children, or were willing to have their children tested. When questioned about whether they would request prenatal diagnosis of VHL in a fetus, neither the patients own perception of the physical, social, financial or psychological burdens of VHL, nor their attitude towards termination of pregnancy for any medical cause, predicted whether they would terminate a pregnancy if the fetus carried a VHL mutation (58).
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONCLINICAL MANIFESTATIONSGENE STRUCTURE AND PROTEIN...GENOTYPE-PHENOTYPE CORRELATIONSINCORPORATING MOLECULAR TESTING...CONCLUSIONSREFERENCES |
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The protein encoded by the VHL gene is unique and inhibits transcription elongation. Unregulated growth of vascular tumors in multiple tissues follows the loss of this function. Patients with rare tumors characteristic of VHL (e.g. retinal or cerebellar hemangioblastomas) should be evaluated clinically and molecularly for VHL. This includes reviewing a detailed family history focused on characteristic tumors. In almost all patients with VHL a deletion or significant mutation can be identified, confirming the diagnosis. The prognosis can be affected by mutation analysis results, especially regarding the risk of developing pheochromocytoma. Relatives may benefit from presymptomatic detection of increased tumor susceptibility, followed by regular surveillance for tumor development. Relatives who did not inherit the mutation will be spared anxiety and the need for regular monitoring. Those who are found to carry a mutation may suffer psychological and financial difficulties (e.g. insurability, employability) because of the likelihood they will develop clinical disease in the future. All patients and family members being tested for VHL gene mutations should receive genetic counseling before testing and after test results return, and give informed consent prior to being tested.
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FOOTNOTES |
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+ Tel: +1 601 984 1900; Fax: +1 601 984 1916; Email: cfriedrich@prevmed.umsmed.edu
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REFERENCES |
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TOPABSTRACTINTRODUCTIONCLINICAL MANIFESTATIONSGENE STRUCTURE AND PROTEIN...GENOTYPE-PHENOTYPE CORRELATIONSINCORPORATING MOLECULAR TESTING...CONCLUSIONSREFERENCES |
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