|
© Borgis - Postępy Nauk Medycznych 11, s. 842-845
*Cezary Cybulski, Karol Krzystolik, Jan Lubiński
Von Hippel-Lindau disease
Choroba von Hippel-Lindau
International Hereditary Cancer Centre, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
Head of Department of Genetics and Pathology: prof. dr hab. med. Jan Lubiński Streszczenie
Choroba von Hippel-Lindau (VHL) jest zespołem zwiększonej genetycznej predyspozycji do nowotworów wykazującym rodowodowe cechy dziedziczenia autosomalnego dominującego. Schorzenie jest wywołane mutacjami germinalnymi genu VHL. Częstość występowania choroby ocenia się na 1/36 000 osób. Szacuje się, że w Polsce żyje około 1000 pacjentów z chorobą VHL. Nosiciele mutacji genu VHL obarczeni są ryzykiem występowania różnych nowotworów. Do istotnych z klinicznego punktu widzenia oraz charakterystycznych dla schorzenia zmian narządowych zaliczamy: naczyniaki zarodkowe ( hemangioblastoma) móżdżku i rdzenia kręgowego (OUN-HB), naczyniaki zarodkowe siatkówki (R-HB), raka jasnokomórkowego nerki (CC-RCC), guzy chromochłonne nadnerczy ( pheochromocytoma), guzy neuroendokrynne (PNET) oraz guzy worka endolimfatycznego (ELST). Zmiany takie jak torbiele i torbielakogruczolaki ( cystadenoma) nerek, trzustki, najądrza i więzadła szerokiego macicy, również często występują w przebiegu VHL, lecz zwykle są bezobjawowe i nie stanowią znaczącego problemu klinicznego (1). Nowotwory u pacjentów z chorobą VHL, rozwijają się wieloogniskowo, obustronnie oraz w młodym wieku. Rozpoznanie choroby VHL stawia się w oparciu o kryteria rodowodowo-kliniczne i/lub analizę nosicielstwa mutacji genu VHL. Opieka nad rodzinami z VHL polega na zastosowaniu programu badań profilaktyczno-diagnostycznych u osób z grupy ryzyka, który ma na celu wczesne wykrywanie i leczenie zmian nowotworowych. Ma to kluczowe znaczenie kliniczne, dlatego też wszystkie przypadki ze zmianami narządowymi charakterystycznymi dla VHL, również te, które nie spełniają klinicznych kryteriów rozpoznania VHL, powinny być poddane konsultacji genetycznej. Od 1997 roku istnieje Polski Rejestr VHL przy Międzynarodowym Ośrodku Nowotworów Dziedzicznych w Szczecinie. W ramach Rejestru prowadzona jest analiza molekularna mutacji genu VHL, badania profilaktyczno-diagnostyczne oraz leczenie pacjentów z VHL. Słowa kluczowe: VHL, choroba von Hippel-Lindau, gen VHL
Summary
Von Hippel-Lindau (VHL) disease is a rare autosomal dominant disorder. It occurs with a frequency 1/36 000 live births. We estimate that there are approximately 1000 VHL patients in Poland. VHL disease is caused by germline mutations in the VHL tumour suppressor gene. Carriers of germline mutations in VHL gene develop hemangioblastomas of the central nervous system and retina, renal cell carcinomas and pheochromocytomas, islet cell tumours of the pancreas, endolymphatic sac tumours, cysts and cystadenoma in the kidney, pancreas, epididymis and broad ligament. Tumors in VHL patients are often multifocal, bilateral and of early onset. The diagnosis of VHL is based on clinical criteria and analysis of mutations in the VHL gene. The management with VHL individuals involves clinical screening according to carefully planned surveillance schedule and early treatment of VHL tumours. The appropriate management may reduce morbidity and mortality. VHL gene testing and clinical evaluation should be performed, and family history should be obtained in all patients affected by VHL-associated lesions, also those with apparently sporadic tumours. In 1997, we established the Polish VHL Registry at the International Hereditary Cancer Center in Szczecin. The Registry provides appropriate management of patients affected with VHL disease in the Polish population, including DNA testing, surveillance and early treatment of VHL individuals. Key words: VHL, von Hippel-Lindau disease, VHL gene
GERMLINE MUTATIONS OF VHL GENE
VHL disease is caused by germline mutations in the VHL gene localised on chromosome 3p25-26 (1, 2). Coding sequence of the gene includes 3 exons, and encodes a protein containing 213 amino acids. In most cases mutation is inherited from an affected parent. 20% cases of disease are caused by de novo mutations, and in such cases family history is negative. VHL somatic mosaicism is uncommon, seen in approximately <1% of all cases (3).
Small intragenic mutations constitute about 2/3 of all VHL mutations, and they include substitutions, small deletions and insertions. Large deletions are responsible for approximately 1/3 of VHL cases. Germline mutations of the VHL gene are present in ~100% of families with VHL (4). In our center we use sequencing, long-range PCR and multiplex PCR for testing of VHL disease. We identified germinal mutations of VHL in 34 Polish VHL families: large deletions in 13/34 families and small mutations in 21/34 families (5, 6, 7). Testing of VHL gene is performed in cases with definitive clinical diagnosis and in suspected cases. It is particularly important in cases affected with tumors associated with VHL disease, which do not fulfill clinical criteria. In such cases DNA testing enables early diagnosis of the disease.
CLINICAL CHARACTERISTICS OF VHL
There is marked clinical heterogeneity of the disease. There are two major types of VHL, type 1 and type 2. VHL type 1 is more common (90% of VHL cases) and it is characterized by the presence of retinal and central nervous system heamangioblastomas, kidney cancer, but without pheochromocytoma. VHL type 2, seen in 10% of affecetd families, is charecterised by the presence of pheochromocytoma and other VHL related tumors. VHL type 2 is further classified to 3 subtypes based on the risk of renal cancer (RCC): type 2A – low risk of RCC, type 2B – high risk of RCC, and type 2C – pheochromocytoma only phenotype.
VHL type 1 disease (without pheochromocytoma) is associated with mutations predicted to cause complete unraveling of protein structure (missense mutations mapping to VHL protein hydrophobic core, protein truncating mutations, and partial gene deletions). VHL type 2 (with phaeochromocytoma) is caused by missense mutations which map to protein binding sites of pVHL and are predicted to cause local protein defects. Specific pheochromocytoma associated missense mutations confer different risks of HAB and RCC, being responsible for the occurrence of subcategories VHL type 2A (VHL without RCC), 2B (VHL with RCC), and 2C (pheochromocytoma only). Phenotypic expression of VHL disease is also influenced by genetic modifiers (8).
Carriers of VHL mutations associated with VHL type 2 are at high risk of pheochromotoma, particularly two missense mutations, arg167trp and arg167gln, conferred a high (62%) risk for phaeochromocytoma. The positive correlation between specific missense mutations and pheochromocytoma is useful in genetic counseling. VHL kindreds with such missense mutations require careful surveillance for pheochromocytoma as this is frequently the first manifestation (8).
CLINICAL CRITERIA FOR VHL
The disease is diagnosed on the basis of clinical criteria:
1) For member of a VHL family the disease is diagnosed in the presence of a single haemangioblastoma, pheochromocytoma, multiple pancreatic cysts, or renal cell carcinoma in a patient.
2) For clinical diagnosis of isolated cases of VHL, at least two haemangioblastomas or a single haemangioblastoma in association with a visceral manifestation are required (9, 10).
CHARACTERISTICS OF VHL – RELATED TUMORS
Tumors associated with VHL are bilateral, multifocal and of early onset. Approximately 67% patients with VHL develop disease before age of 30, and 99% of patients to age of 65. First disease manifestation is retinal or CNS haemangioblastoma in about 85% of patients, kidney cancer in 10% of patients and pheochromocytoma in 5% patients (10). Clinical characteristics of VHL disease is shown in table 1.
Table 1. Clinical characteristics of VHL (1).
The most common tumors in VHL disease are retinal and CNS heamangioblastomas.Retinal lesions are most often located in the temporal periphery of the retina with feeder and draining vessels going to and from the optic disc. However, they may develop in the posterior pole (1%) and optic disc (8%). They may be asymptomatic and be detected on routine ophthalmoscopy. Others present with a visual field defect or a loss of visual activity resulting from retinal detachment, exudation, or hemorrhage. Treatment of presymtomatic retinal heamangioblastomas is recommended using lasertherapy or kriotherapy (11).
Most (80%) of CNS hemangioblastomas develop in the brain and 20% in the spinal cord. Within the brain the vast majority are infratentorial, mainly in the cerebellar hemispheres. Spinal hemangioblastomas are generally intradural, most commonly occur in the cervical or thoracic regions, and occasionally may involve the entire cord. Clinical symptoms depend upon the site of the tumor. With infratentorial tumors, headache, vomiting, and gait disturbances or ataxia predominate. With tumors above the tentorium, symptoms depend on the location of the lesion. Hemangioblastomas are generally slow growing, but on occasion include rapidly enlarging cysts that produce hydrocephaly with papilledema. Spinal hemangioblastomas usually present with pain, but sensory and motor loss may develop with cord compression. Most symptom-producing spinal hemangioblastomas are associated with syringomyelia. Some hemangioblastomas are not symptomatic and are discovered only with MRI. Asymptomatic CNS lesions may be observed with yearly imaging studies. Symptomatic CNS lesions require intervention, most commonly surgical removal (1).
Multiple renal cysts are common in VHL syndrome. Renal cell carcinoma (RCC), specifically of the clear cell type developing either within a cyst or in the surrounding parenchyma occurs in about 40% of affected individuals. Typically VHL – associated RCC produces metastases late, when tumor size exceeds 3 cm. Depending on the size and location of the tumor, nephron-sparing surgery or partial nephrectomy is recommended. Cryoablation is being increasingly used for small lesions or in individuals at high risk for a surgical procedure (12, 13).
Most pancreatic lesions in VHL are asymptomatic, simple or multiple cysts. Rarely, solid neuroendocrine tumors of the pancreas develop in the course of VHL. Usually, they are hormonally inactive (14).
The endolymphatic sac and duct are ectodermal extensions of the membranous labyrinth. Tumors of the sac cause deafness of varying severity, often severe to profound and of sudden onset. Endolymphatic sac tumors are seen in approximately 10% of individuals with VHL syndrome. Treatment of choise is surgical removal of tumors. Early intervention with small tumors has been shown to preserve hearing and vestibular function (15).
Epididymal or papillary cystadenomas are relatively common in males with VHL syndrome. The equivalent lesion in women is papillary cystadenoma of the broad ligament (1). These lesions are usually asymptomatic.
Pheochromocytoma may present with sustained or episodic hypertension or be asymptomatic, being detected incidentally by an abdominal imaging procedure. Pheochromocytomas in the VHL disease are usually located in one or both adrenal glands, but may present along the sympathetic axis in the abdomen or thorax (paragangliomas) or head and neck (chemodectomas). Pheochromocytomas in the VHL disease are usually benign. Small and inactive tumors may be observed. Symptomatic tumors should be surgically removed using adrenal sparing surgery. Laparoscopic approaches have been shown to be effective. Preoperative treatment with alpha-adrenergic blockade for seven to ten days is appropriate even in individuals with no known hypertension (16, 17, 18, 19).
Surveillance for families with VHL
The management with VHL individuals involves clinical screening according to carefully planned surveillance schedule and early treatment of VHL tumors. Surveillance schedule for VHL patients is shown in table 2. The appropriate management reduces morbidity and mortality (20).
Table 2. Surveillance for VHL.
IN WHOME VHL DISEASE SCHOULD BE CONSIDERED?
VHL disease should be considered in each patient with CNS hemangioblastoma, retinal angioma, pheochromocytoma, early onset CC-RCC (age <40). Genetic counseling should be recommended for such patients. In 1997, we established the Polish VHL Registry at the International Hereditary Cancer Center in Szczecin. The Registry provides management for patients with VHL disease, including DNA testing, surveillance and early treatment of VHL individuals. Piśmiennictwo
1. Krzystolik K, Cybulski C, Lubiński J: Choroba Hippel-Lindau. Neur i Neurochir Pol 1998; 32 (XLVIII): 5.
2. Latif F, Tory K, Gnarra J et al.: Identification of the von Hippel-Lindau tumor suppressor gene. Science 1993; 260: 1317-20.
3. Sgambati MT, Stolle C, Choyke PL et al.: Mosaicism in von Hippel-Lindau disease: lessons from kindreds with germline mutations identified in offspring with mosaic parents. Am J Hum Genet 2000; 66: 84-91.
4. Stolle C, Glenn G, Zbar B et al.: Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum Mutat 1998; 12: 417-23.
5. Cybulski C, Krzystolik K, Maher ER et al.: Long polymerase chain reaction in detection of germline deletions in the von Hippel-Lindau tumour suppressor gene. Hum Genet 1999; 105: 333-6.
6. Cybulski C, Krzystolik K, Murgia A et al.: Germline mutations in von Hippel-Lindau (VHL) gene in patients from Poland: disease presentation in patients with deletions of the entire VHL gene. J Med Genet 2002; 39: E38.
7. Cybulski C, Krzystolik K, Lubiński J: Gene symbol VHL, Disease: von Hippel-Lindau syndrome. Hum Genet 1999; 104: 194.
8. Chen F, Kishida T, Yao M et al.: Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. Hum Mutat 1995; 5: 66-75.
9. Maher ER, Iselius L, Yates JR et al.: Von Hippel-Lindau disease: a genetic study. J Med Genet 1991; 28: 443-7.
10. Maher ER, Yates JR, Harries R et al.: Clinical features and natural history of von Hippel-Lindau disease. Q J Med 1990; 77: 1151-63.
11. Krzystolik K, Cybulski C, Lubiński J et al.: Choroba von Hippel-Lindau, Okulistyka 2000; 1: 60-5.
12. Krzystolik K, Cybulski C, Lubiński J et al.: Wczesna diagnostyka bezobjawowych raków nerek w rodzinach z zespołem von Hippel-Lindau w Polsce. Urol Pol 1998; 51: 171-81.
13. Słojewski M, Gliniewicz B, Sikorski A et al.: Zastosowanie techniki nephron-sparing burgery (NSS) w leczeniu nowotworów nerek w przebiegu zespołu von Hippel-Lindau. Urol Pol 1998; 51: 182-90.
14. Bickler S, Wile AG, Melicharek M et al.: Pancreatic involvement in Hippel-Lindau disease. West J Med 1984; 140: 280-2.
15. Manski TJ, Heffner DK, Glenn GM et al.: Endolymphatic sac tumors. A source of morbid hearing loss in von Hippel-Lindau disease. JAMA 1997; 277: 1461-6.
16. Manger T, Piatek S, Klose S et al.: Bilateral laparoscopic transperitoneal adrenalectomy in pheochromocytoma. Langenbecks Arch Chir 1997; 382: 37-42.
17. Walther MM, Keiser HR, Choyke PL et al.: Management of hereditary pheochromocytoma in von Hippel-Lindau kindreds with partial adrenalectomy. Urol 1999; 161: 395-8.
18. Walther MM, Linehan WM: Von Hippel-Lindau disease and pheochromocytoma. JAMA 1996; 275: 839-40.
19. Walther MM, Reiter R, Keiser HR et al.: Clinical and genetic characterization of pheochromocytoma in von Hippel-Lindau families: comparison with sporadic pheochromocytoma gives insight into natural history of pheochromocytoma. J Urol 1999; 162: 659-64.
20. Maddock IR, Moran A, Maher ER et al.: A genetic register for von Hippel-Lindau disease. J Med Genet 1996; 33: 120-7.
otrzymano/received: 2010-10-01 zaakceptowano/accepted: 2010-10-29 Adres/address: *Cezary Cybulski International Hereditary Cancer Centre Department of Genetics and Pathology, Pomeranian Medical University ul. Połabska 4, 70-115 Szczecin tel.: (91) 466-15-32 e-mail: cezarycy@sci.pam.szczecin.pl Artykuł Von Hippel-Lindau disease w Czytelni Medycznej Borgis. |
  Proszę kliknąć w wybraną okładkę aby przejść na stronę czasopisma
 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Chcesz być na bieżąco? Polub nas na Facebooku: strona Wydawnictwa na Facebooku |