204
Von Hippel- Lindau Disease: Analysis of two Families T. Bi/ge ' . F Ozoerenl , S. Se nol ' ; S. Bilge 2, S. Baru t ' , O. Karaka slar ' , Y. Aydin ' Department of Neurosurgery Department of Neurology Department of Ophthalmology Taksim Hospital, Istanbul - Turkey I
2 3
In this report we pres ent tWD fam ilies with von Hippel-Lindau syn drome . We operat ed on haemangioblas tomas in tWQ member s. one from eac h, in Dur clinic, In the first family w e saw 17 lesions in 9 mem ber s. Althou gh in th e first famil y carcinoma of th e kidney was often obs er ved, in the second family retinal haemangiom a was found to be pr edominant, nam ely, in eight out of nin e pati ents. In both famili es th er e wer e 11 patien ts with retin al haem angi oma. of th ese, 9 patients were blind (82 %). In 6 pati ents with retinal ha emangioblastom a blindness was unilater al and bilat eral only in one . All the patients with renal carcinoma we re male and died young . In one of Dur patient s with renal carcinoma we found metastatic lesi ons in th e distal and proximal parts of th e femur, vertebral arch, cranium and the thoracic wall. In thes e two families 23 members had 32 lesions , from whi ch eleven were retin al haem angiomas (3 + 8l. nine haem an gioblastomas of CNS (5 + 4l. one a ren al cyst (0 + l ), eight ren al ca rcino mas (7 + 1), tw o pancrea tic cysts (1 + 1) a nd one liver cyst (0 + 1).
Key-Word s
V. Htpp el-Lfndau-Syndrom: Ana lyse zw eier Familie n In diesem Bericht werden zw ei Familien vorges tellt. der en Angehörige a n von Hippel-LindauSyndrom erkrankt wa ren. Je ein Angehöriger dieser beiden Familien w urde weg en eines Hä mangioblastom operiert. In der ersten Familie wurden bei sieben Angehörigen siebzehn Läsion en festgestellt. Wahren d in der ersten Familie ein Nierenkarzinom oftmals auftrat. war in der zw eiten Familie das retina le Häm angiob lastom häufig. Es gibt In beiden Famili en elf Patienten mit einem retinalen Hämangiob lastom . von den en neun Patient en erblindeten (82 %). Bei sechs Patienten war die Blindheit unilateral und nur bei einem Patienten bilateral. Alle Patienten mit Nierenkarzinom waren männ lich und starben jung. Bei einem Patienten mit Nierenkarzinom wurden Metastasen der Wirbelsäule . des Schädels, im proximalen und distalen Oberschenkel und den Rippen gefunden . In zwei Familien hall en 23 Angehörige 32 Läsion en : von diesen waren 11 Läsio nen retinale Häm angiom e (3 + 8), 9 Häm angioblastome des ZNS (5 + 4). 8 Nierenka rzinome (7 + 1). 2 Pankraszysten (1 + 1) und eine Nierenzyste.
Von IIipp el-Lindau diseas e - Haemangioma - Renal ca rcinoma - Autosom al diso rder
Introduct ion
Von Hippel-Lindau syndrome (HLSl. is a n autoso mally domin ant inherited disorder characterise d by tumour s or tumour-like lesi ons. Amon g these lesion s, an giomatos is rctinae. haemangiobla stoma s of the CNS, ren al cysts and cancer, pan creatic cysts , and phaeochromo cytoma a re most frequ en t (15). Horton (10) reported in 1976 th at th er e could be 25 se pa ra te lesion s in von Hippel-Lindau disease, and he stated that es pecially retinal angioma tos is and haem angiob latom a of the cerebellum are the mo st frequent lesions. Although 75 % of the lesions of the CNS are located in the cerebellum, 1 % of thes e lesions are found in the cerebrum, 15 % in the sp inal cord and 9 % in th e m edulla oblongata (15).
Neurochlrurgia 35 (1992 ) 20 4 - 20 6 © Georg Thieme Verlag. Stuttgart . New York
We know now that genetic alterations on the short arm of chromos ome 3 are involved, because chromo some tr an slocations of this chromosomal reg ion have been found in ren al ca rcinoma (6, 13) and ph eoch romocytoma (12) of pati en ts with Hl.S an d loss of hete rozygosity on 3 p has been found in se veral HLS-r ela ted tumours (7. 17. 21).
Case report We examined two famili es wi th 77 mem bers a nd found 33 lesion s in 23 memb er s .
Family 1 In the pedigree of the family our 33-ycar old female patient indicated as No. 7 was exa mined on account of the complaint of headache and dizziness . Papilloedema and ataxia were present. Cranial CT sean revca led a cerebellar cystic lesion. This cystic les ion was removed totally. The res ult of the histologi-
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Summary
Von Hipp el-Lindau Diseas e
Neurochirurgia 35 (1992)
205
cal examination was a haemangioblastom a. Having leam ed that severa l members of this family had similar lesions. we examined the othe r memb ers. We found in the person who was shown on the diagram of the pedigree as No. 9 bilatera l renal tumours, a pan er eatie eyst and multiple renal eysts. There were also a great numbe r of metastati e masses of the bone, especially in the era nium, in the proxim al pa rt of the femur and in the thoracie wall. In addition to two patients examine d by us, 12 members were also exa mincd a nd 3 reti nal. 3 CNS haemangioblastomas , 7 renal carci nomas 1 pan ereati c eyst were found . In this family 6 patients with renal carcinomas did not survive. Dur patient No. 9 died two month s after our examination. All the patient s who had died of the renal twnour wer e of the 30- 35 year age group a nd died soon after our diagnosis.
The first patient we had from the seeond family was the seventh member. This forty-year old fema le patient present ed with gait disturbanees , dizziness and head aehe. Examination revea led papi lloed ema . loss of vision in the right eye and bilateral cer ebellar signs such as nystag mus and ataxia. The CT sean showed a eystie eerebellar mass. At opera tion we explored the posterior fossa while the patient was in the sitting position a nd we removed the eystie mass with a small mur al solid lesion. The pathologieal results revealed a ha emangioblastoma. Furth er exa mination showed us her loss of vision in the right eye was due to the haemorrhage eaused by the retina l ha eman gioma seven years ea rlier. Since we suspeeted von Hippel-ünd au dise ase. an ab dominal CT sea n was done revealing a liver eyst. The daughter a nd sister of the patient were examined and a retina l haemangi oma was found with the dau ghter a nd reün a l haeman gioma. multiple eysts of pa ner eas an d kidney were found in the sister, At examination of the 35 mem bers of the family simila r lesions were see n in 7. As a result 16 lesions were diagnosed in 9 membe rs of this family. These lesions were eight retinal haemangiomas. 4 eNS lesions Ione ccre bra l. two eere bellar, one spinal). one ren al cyst. one re nal car cinoma. one liver cyst, one pan ereatie eyst. Ther e were 6 eases of unilateral and one of bilateral blindness out of the eight patients with retinal haemangioma . In the patients with retina I haem angtoma only the da ughter of our first patient had no vtston loss. (The ease history of this fam ily was published in Acta Ber g Neural in 1991.)
Discus sion In von Hippe I-Lindau's syndrome angiomatosis retina e and cer ebellar ha emangioma are the most common lesion s. Retlnal ba emangiomas occur in mor e than half of the cases and becom e manifest as tbe ea rllest sign (10 , 15, 20). In Neumann 's (15) series of cas es, angi orna tosis retinae was diseover ed in 154 patients distributed almost equally between both sexes. Here 7 % unilateral blindness wa s rep ort ed and 4 % bilate ra l blindness . In our se eond family case, especially angiomatosis retinae was mor e orten present (eight out of nine patientsl. Of these 8 pati ents, one had bilateral blindness . In six patients tbere was unilateral blindness . When the ratio of blindness was compared in our series, it was found to be very high . In both families 12 patients had retinal haema ngioma an d ten out of these twelve pati ents sulTered from bllndness (83 %). This may be explaine d by Iate diagnoses after complications h ad develop ed , as well as by a lack of a suitable scre ening programme. Th e second common lesion, CNS
~ eNS hemangoblutoma ~ retina! anglomatosia ~ renal carclnoma ~ pancreatlc cyats
c.- -
0--
Fig. 1 Pedigree of 000 families affected with von Hippel-Lindau disease (Ahexagon indicates a non-affected memberl
haema ngiobIastoma. was pr esent in 212 of 338 Neumann 's cases . 158 of these cases wre Iocate d in the cerebellum. Th e tumour was of a cystic nature rather than being solid. It used to be located most common (74 %) in the cerebellum and least orten (1 %) in the cer ebrum (16). Haemangioblastomas located in the post erior fossa present often with inereased intracranial press ure an d cer ebe llar symptoms and cause hydrocephalus. CNS haemangioblastoma, especially cerebellar haeman gioma is a manifestation of this disorder that produces the grea test morbidity and mo rtallty (10). In recent years this rate decreases with the micros urgical operative techniqu es. Accord ing to Neumann (16), Palmer (19) and Constants (5) this rate was published as folIows: 7 %, 8 %, 10 %. It app ears, therefore, that microsurgical rem oval is the techniq ue of choice in the operative treatment of CNS haemangioblatomas. CNS haemangioblastomas a re usua lly 10cated in tbe cer ebe llum, whereas about 15 % a re loeated in the spinal cord . Subarachnoida l ha emo rrbage was never seen in cas es of intracranial haemangioblastomas, but it occurred in spina l turno urs (50 %) (16). Postoperative recurrance rate of cerebellar haemangioblastoma was mor e eommon in the family ease s (22). Fabiani (8) re ported in his two cases that the recur rent tumours in the cer ebe llum of patients were not loeated at the same sites as the initial cer ebe llar tumours. These authors consid er ed this to be a new growth of a muIticentrie tumour.
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Family II
Neurochirurgia 35 (1992)
Renal cysts, ad enom as and carcinomas are the most commo n ren allesion s of VHL (15). Ren allesion s are usually bilat eral and occasiona lly two different renallesio ns may be found (3, 9, 11). In our cases 7 patients in th e first family an d only one pa tient in the seco nd fam ily had bilat eral re na l carcinomas, all of whom were male patient s. Horton also reported th e ra te to be more cammon in males (4, 10, 11), The second most common cause of death in patients with von Hippel-Lindau disease is report ed to be renal ca rcinoma (32 %) after cere bellar haem angioblastoma (53 %) (10 , 14) . However we think th e mortality is decreasing, using pr ogressive microneuro srugery in poste rior fossa lesion s. In Dur cases WB operated on two cerebellar cystic haemangiomas and both patients are weil. Some authors indicate that the renal tum ours are rather benign (15). We think th at ren al carcinomas are highly malign ant lesions and ha ve the high est mortality rat e in pat ients with VHL syndrome. Our seven pati ents with renal carcinoma died shortly after diagnosis. Pan creatic lesions are often multip le and found In 17 % ofthe pa tien ts w ith von Hippel-Lindau ' syndrom e. In genera l, cystic pancreati c lesions in HLS are asymp tomatic or ass ociated with only mild clinical syrnptoms (18). In our three pati ents thi s lesion showed no sign or symptom.
T. Bilge et al. Deck et; ll., ll. P. ll. Neumann. T. Walt er, A. Sandberg: 3p Involvement in a re nal cell carsioma in von Hippel-Lindau syndro me : Region of tumor bre akpo int clustering on 3p. Cance r Genet. Cytoge ne t. 33 (1988) 59-65 7 Decket; 11. . R. Gemi ll. 11. P. H. Neumann. T. Walter. A. Sandberg: Loss of heterozygosty on 3p in a von Hippel-Lindau re nal cell cars inoma . Cance r Genet. Cytoge ne t. 39 (1988 ) 289 -293 8 Fobiani. A.. M. Faoero. M. Deseidlme. L. Durelli. F. 8rignolio. F. Benech: On the fam ilial occurrence of soiitary cere belJar hem a ngioblastomas. A clinicopathological study of a family with four affected me mbers. Acta Ne urol. Belg. 82 (982) 3 17 - 326 9 Frimod t-Moller. !I. M.. U. Nissen: Polycystic kidn eys as th e r enal lesion in Lindau 's disease. J. Urology 125 (1981) 868 -8 70 10 Herton. W A.. V. Wang. R. Eldr idge : Von Hippel-Lindau disease. Clin lcal and Path ological manifestati on s in nine famili es w ith 50 afTected me mbers. Arch. Intern . Med. 136 (1976) 769 -77 7 II Kadis; S .. W Kert; C. A. Athanasoulis: The ro le of arteriography in the management of re na l cell carc inoma associated with von lIippel-ündau syndrome . Hum an Genet. 92 (1989) 127 -1 30 12 Kiechle-S chawarz. M.• JI. P. JI. Neuma nn . H. Decket; C. Diet ric h. 8 . w utlieb. W S chempp: Cytogene tic studies on 3 phe ochro mocytomas de rived fr om pa tients with von Hippel-Lind au syndrome. Human Genet . 92 (1 989) 127-130 13 King. C. R.. R. N. Schimke. T. Arthur: 8 . Danoren, D. Collin s: Proximal 3p deletion in ren al cell cars inoma cells from a pati ent with von Hippel-Lindau disease. Cance r Genet. Cytogenet. 27 6
(1 987) 345-348 14
15
(1987) 220-226 16
Phen ochromocytoma is often see n in HLS. It ha s been reported tha t in Neumann s (15) se ries of 338 VHL patients 69 ph eochromocytoma s were found in 46 pa tien ts (14 %). Five of these tumours wer e extraaadre na l (par ag an gliom as) . Horton et aI. (1O) re po rte d th e incide nce of ph eochrom ocytoma in VHL pati en ts to be 10 %. Although the overa ll ratio was 10 %. four of five were limited to the single family. In A tuk s series it occurred in one farnily in 12 out of 13 m embers. This findi ng suggests that on ly memb ers of cert ain families are predisp osed to develop this manifestation . In our case s it was found that the mortality and morbidity were high du e to la te diagnos is and th e lack of suitable screening . References
Mal ek. R. S . L. F Greene. Urologic as pec ts of Hippel-Lindau syn drome . J. Urology106 (1971) 800-801 Neumann. H. P. 11.: Basic criter ia for clinical d iagnosis and gen etic cou nselling in von Hippel-Lindau syn dro me . VASA 16 Neumann. H, P. H.• H. R. Eggert. K. Weigel. I/. Friedburg. 0. D. Wiest/er. P. S chollmey er: Hem an giob lastomas of th e centr al
nervous syste m. A 10 year study with special re fere nce to von Hippel-Linda u syndrome. J . Neur osurg. 70 (1989) 24 -30 17 Neumann. H. P. H . O. D. Wiest/ er: Clustering of features of von Hlppel-Linda u synd ro me: eviden ce for a complex geneuc locus.
Lancet 337 (1 991) 1052- 1054 IR Neumann. 11. P. 11. . E. Dinkel. ll. Brambs. B. Wimmer, H.
mea-
burg. B. Volk. G. Siegmund. P. Rieg ler. K. Haag. P. Schollmeyer. O. D. Wiest/er: Pancreatic lesion s in the von Hlppel-Lindau syndrom e. Gastroentro logy 101 (1991) 465 - 471 19 Palmer. J. J.: Heman gioblastomas: A review of 81 cases. Acta Neurochir. 27 (197 2) 125-148 20 S alazar. F. G.. J. M. i.amiell: Ear ly ide ntification of reti nal an giomas in a large kind red with von Hippel-Un dau disea se. Am. J.
Ophtalmo!. 89 (1980) 540- 545 21
Tory. K.. H. Brau ch. M. Llnehan; D. Barbe, E. Oldfield. M . Fillinq-Katz. B. Seizinqer; Y. Na ka m ura. R. l:Vh ite. F. F. Mar shalI. M. I. Lerman, 8 . Zber: Speciflc genetic change in tumours associated with von Hippel-Lindau disease . J . Natl. Cance r. Inst. 8 1
(1 989) 1097- 1101 I
A tuk. N. 0.. T. McDonald. T. Wood. J. T. Carpente r, M. P. Walz ak. M. Donaidson. J . Y. Gillenwater: Fa milial ph eochromocytom a. hype rcalc emi a and Von Hippel-Lindau disease. A ten year st udy
22 Yamashita. J.. JI. Han da . S. Kim: Fam ilial occurrence of cere be llar hem an giomas - Analys is of five farm lies. Neuros urge ry 11
(1 982) 761-763
of a large family. Medicine 58 (1979) 209-2 18 2 Bilge. T.. S. Bilge. S. Borut; B. Cokn eseli: Famili al hemangioblastoma and von Hippel-Lind au's disease: Case r eport . Acta
Neuro!. Belg. 91 (1991) 223-229 3 Christensen. P. J.. J . P. Crai g. M. C. Bioro . K. J. O'Connel: Cysts contai ning renal cell carcinoma in von Hlppel-Llndau's disease.
J. Urology 128 (1982) 798- 800 4
Chris tcfe rson. L. A.. M. B. Gustafson. A. G. Pete rson: Von Hip-
pel-Lindau's disease. JAMA 178 (1961) 280- 282 5 Cons ta ns. J. P. . F. Meder. Mau ri, F.. Donzelli, R. Spaziante. E. Dioiitls: Poste rior fossa hemangioblastomas. Surg . Neurol. 25
(1 986) 269- 275
Turgay Bilge, MD Taksim Hastan esi Nörösirü rji KJinigi Ta ksim, Ista nbul Turkey
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206
Von Hippel- Lindau Disease: Analysis of two Families T. Bi/ge ' . F Ozoerenl , S. Se nol ' ; S. Bilge 2, S. Baru t ' , O. Karaka slar ' , Y. Aydin ' Department of Neurosurgery Department of Neurology Department of Ophthalmology Taksim Hospital, Istanbul - Turkey I
2 3
In this report we pres ent tWD fam ilies with von Hippel-Lindau syn drome . We operat ed on haemangioblas tomas in tWQ member s. one from eac h, in Dur clinic, In the first family w e saw 17 lesions in 9 mem ber s. Althou gh in th e first famil y carcinoma of th e kidney was often obs er ved, in the second family retinal haemangiom a was found to be pr edominant, nam ely, in eight out of nin e pati ents. In both famili es th er e wer e 11 patien ts with retin al haem angi oma. of th ese, 9 patients were blind (82 %). In 6 pati ents with retinal ha emangioblastom a blindness was unilater al and bilat eral only in one . All the patients with renal carcinoma we re male and died young . In one of Dur patient s with renal carcinoma we found metastatic lesi ons in th e distal and proximal parts of th e femur, vertebral arch, cranium and the thoracic wall. In thes e two families 23 members had 32 lesions , from whi ch eleven were retin al haem angiomas (3 + 8l. nine haem an gioblastomas of CNS (5 + 4l. one a ren al cyst (0 + l ), eight ren al ca rcino mas (7 + 1), tw o pancrea tic cysts (1 + 1) a nd one liver cyst (0 + 1).
Key-Word s
V. Htpp el-Lfndau-Syndrom: Ana lyse zw eier Familie n In diesem Bericht werden zw ei Familien vorges tellt. der en Angehörige a n von Hippel-LindauSyndrom erkrankt wa ren. Je ein Angehöriger dieser beiden Familien w urde weg en eines Hä mangioblastom operiert. In der ersten Familie wurden bei sieben Angehörigen siebzehn Läsion en festgestellt. Wahren d in der ersten Familie ein Nierenkarzinom oftmals auftrat. war in der zw eiten Familie das retina le Häm angiob lastom häufig. Es gibt In beiden Famili en elf Patienten mit einem retinalen Hämangiob lastom . von den en neun Patient en erblindeten (82 %). Bei sechs Patienten war die Blindheit unilateral und nur bei einem Patienten bilateral. Alle Patienten mit Nierenkarzinom waren männ lich und starben jung. Bei einem Patienten mit Nierenkarzinom wurden Metastasen der Wirbelsäule . des Schädels, im proximalen und distalen Oberschenkel und den Rippen gefunden . In zwei Familien hall en 23 Angehörige 32 Läsion en : von diesen waren 11 Läsio nen retinale Häm angiom e (3 + 8), 9 Häm angioblastome des ZNS (5 + 4). 8 Nierenka rzinome (7 + 1). 2 Pankraszysten (1 + 1) und eine Nierenzyste.
Von IIipp el-Lindau diseas e - Haemangioma - Renal ca rcinoma - Autosom al diso rder
Introduct ion
Von Hippel-Lindau syndrome (HLSl. is a n autoso mally domin ant inherited disorder characterise d by tumour s or tumour-like lesi ons. Amon g these lesion s, an giomatos is rctinae. haemangiobla stoma s of the CNS, ren al cysts and cancer, pan creatic cysts , and phaeochromo cytoma a re most frequ en t (15). Horton (10) reported in 1976 th at th er e could be 25 se pa ra te lesion s in von Hippel-Lindau disease, and he stated that es pecially retinal angioma tos is and haem angiob latom a of the cerebellum are the mo st frequent lesions. Although 75 % of the lesions of the CNS are located in the cerebellum, 1 % of thes e lesions are found in the cerebrum, 15 % in the sp inal cord and 9 % in th e m edulla oblongata (15).
Neurochlrurgia 35 (1992 ) 20 4 - 20 6 © Georg Thieme Verlag. Stuttgart . New York
We know now that genetic alterations on the short arm of chromos ome 3 are involved, because chromo some tr an slocations of this chromosomal reg ion have been found in ren al ca rcinoma (6, 13) and ph eoch romocytoma (12) of pati en ts with Hl.S an d loss of hete rozygosity on 3 p has been found in se veral HLS-r ela ted tumours (7. 17. 21).
Case report We examined two famili es wi th 77 mem bers a nd found 33 lesion s in 23 memb er s .
Family 1 In the pedigree of the family our 33-ycar old female patient indicated as No. 7 was exa mined on account of the complaint of headache and dizziness . Papilloedema and ataxia were present. Cranial CT sean revca led a cerebellar cystic lesion. This cystic les ion was removed totally. The res ult of the histologi-
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Summary
Von Hipp el-Lindau Diseas e
Neurochirurgia 35 (1992)
205
cal examination was a haemangioblastom a. Having leam ed that severa l members of this family had similar lesions. we examined the othe r memb ers. We found in the person who was shown on the diagram of the pedigree as No. 9 bilatera l renal tumours, a pan er eatie eyst and multiple renal eysts. There were also a great numbe r of metastati e masses of the bone, especially in the era nium, in the proxim al pa rt of the femur and in the thoracie wall. In addition to two patients examine d by us, 12 members were also exa mincd a nd 3 reti nal. 3 CNS haemangioblastomas , 7 renal carci nomas 1 pan ereati c eyst were found . In this family 6 patients with renal carcinomas did not survive. Dur patient No. 9 died two month s after our examination. All the patient s who had died of the renal twnour wer e of the 30- 35 year age group a nd died soon after our diagnosis.
The first patient we had from the seeond family was the seventh member. This forty-year old fema le patient present ed with gait disturbanees , dizziness and head aehe. Examination revea led papi lloed ema . loss of vision in the right eye and bilateral cer ebellar signs such as nystag mus and ataxia. The CT sean showed a eystie eerebellar mass. At opera tion we explored the posterior fossa while the patient was in the sitting position a nd we removed the eystie mass with a small mur al solid lesion. The pathologieal results revealed a ha emangioblastoma. Furth er exa mination showed us her loss of vision in the right eye was due to the haemorrhage eaused by the retina l ha eman gioma seven years ea rlier. Since we suspeeted von Hippel-ünd au dise ase. an ab dominal CT sea n was done revealing a liver eyst. The daughter a nd sister of the patient were examined and a retina l haemangi oma was found with the dau ghter a nd reün a l haeman gioma. multiple eysts of pa ner eas an d kidney were found in the sister, At examination of the 35 mem bers of the family simila r lesions were see n in 7. As a result 16 lesions were diagnosed in 9 membe rs of this family. These lesions were eight retinal haemangiomas. 4 eNS lesions Ione ccre bra l. two eere bellar, one spinal). one ren al cyst. one re nal car cinoma. one liver cyst, one pan ereatie eyst. Ther e were 6 eases of unilateral and one of bilateral blindness out of the eight patients with retinal haemangioma . In the patients with retina I haem angtoma only the da ughter of our first patient had no vtston loss. (The ease history of this fam ily was published in Acta Ber g Neural in 1991.)
Discus sion In von Hippe I-Lindau's syndrome angiomatosis retina e and cer ebellar ha emangioma are the most common lesion s. Retlnal ba emangiomas occur in mor e than half of the cases and becom e manifest as tbe ea rllest sign (10 , 15, 20). In Neumann 's (15) series of cas es, angi orna tosis retinae was diseover ed in 154 patients distributed almost equally between both sexes. Here 7 % unilateral blindness wa s rep ort ed and 4 % bilate ra l blindness . In our se eond family case, especially angiomatosis retinae was mor e orten present (eight out of nine patientsl. Of these 8 pati ents, one had bilateral blindness . In six patients tbere was unilateral blindness . When the ratio of blindness was compared in our series, it was found to be very high . In both families 12 patients had retinal haema ngioma an d ten out of these twelve pati ents sulTered from bllndness (83 %). This may be explaine d by Iate diagnoses after complications h ad develop ed , as well as by a lack of a suitable scre ening programme. Th e second common lesion, CNS
~ eNS hemangoblutoma ~ retina! anglomatosia ~ renal carclnoma ~ pancreatlc cyats
c.- -
0--
Fig. 1 Pedigree of 000 families affected with von Hippel-Lindau disease (Ahexagon indicates a non-affected memberl
haema ngiobIastoma. was pr esent in 212 of 338 Neumann 's cases . 158 of these cases wre Iocate d in the cerebellum. Th e tumour was of a cystic nature rather than being solid. It used to be located most common (74 %) in the cerebellum and least orten (1 %) in the cer ebrum (16). Haemangioblastomas located in the post erior fossa present often with inereased intracranial press ure an d cer ebe llar symptoms and cause hydrocephalus. CNS haemangioblastoma, especially cerebellar haeman gioma is a manifestation of this disorder that produces the grea test morbidity and mo rtallty (10). In recent years this rate decreases with the micros urgical operative techniqu es. Accord ing to Neumann (16), Palmer (19) and Constants (5) this rate was published as folIows: 7 %, 8 %, 10 %. It app ears, therefore, that microsurgical rem oval is the techniq ue of choice in the operative treatment of CNS haemangioblatomas. CNS haemangioblastomas a re usua lly 10cated in tbe cer ebe llum, whereas about 15 % a re loeated in the spinal cord . Subarachnoida l ha emo rrbage was never seen in cas es of intracranial haemangioblastomas, but it occurred in spina l turno urs (50 %) (16). Postoperative recurrance rate of cerebellar haemangioblastoma was mor e eommon in the family ease s (22). Fabiani (8) re ported in his two cases that the recur rent tumours in the cer ebe llum of patients were not loeated at the same sites as the initial cer ebe llar tumours. These authors consid er ed this to be a new growth of a muIticentrie tumour.
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Family II
Neurochirurgia 35 (1992)
Renal cysts, ad enom as and carcinomas are the most commo n ren allesion s of VHL (15). Ren allesion s are usually bilat eral and occasiona lly two different renallesio ns may be found (3, 9, 11). In our cases 7 patients in th e first family an d only one pa tient in the seco nd fam ily had bilat eral re na l carcinomas, all of whom were male patient s. Horton also reported th e ra te to be more cammon in males (4, 10, 11), The second most common cause of death in patients with von Hippel-Lindau disease is report ed to be renal ca rcinoma (32 %) after cere bellar haem angioblastoma (53 %) (10 , 14) . However we think th e mortality is decreasing, using pr ogressive microneuro srugery in poste rior fossa lesion s. In Dur cases WB operated on two cerebellar cystic haemangiomas and both patients are weil. Some authors indicate that the renal tum ours are rather benign (15). We think th at ren al carcinomas are highly malign ant lesions and ha ve the high est mortality rat e in pat ients with VHL syndrome. Our seven pati ents with renal carcinoma died shortly after diagnosis. Pan creatic lesions are often multip le and found In 17 % ofthe pa tien ts w ith von Hippel-Lindau ' syndrom e. In genera l, cystic pancreati c lesions in HLS are asymp tomatic or ass ociated with only mild clinical syrnptoms (18). In our three pati ents thi s lesion showed no sign or symptom.
T. Bilge et al. Deck et; ll., ll. P. ll. Neumann. T. Walt er, A. Sandberg: 3p Involvement in a re nal cell carsioma in von Hippel-Lindau syndro me : Region of tumor bre akpo int clustering on 3p. Cance r Genet. Cytoge ne t. 33 (1988) 59-65 7 Decket; 11. . R. Gemi ll. 11. P. H. Neumann. T. Walter. A. Sandberg: Loss of heterozygosty on 3p in a von Hippel-Lindau re nal cell cars inoma . Cance r Genet. Cytoge ne t. 39 (1988 ) 289 -293 8 Fobiani. A.. M. Faoero. M. Deseidlme. L. Durelli. F. 8rignolio. F. Benech: On the fam ilial occurrence of soiitary cere belJar hem a ngioblastomas. A clinicopathological study of a family with four affected me mbers. Acta Ne urol. Belg. 82 (982) 3 17 - 326 9 Frimod t-Moller. !I. M.. U. Nissen: Polycystic kidn eys as th e r enal lesion in Lindau 's disease. J. Urology 125 (1981) 868 -8 70 10 Herton. W A.. V. Wang. R. Eldr idge : Von Hippel-Lindau disease. Clin lcal and Path ological manifestati on s in nine famili es w ith 50 afTected me mbers. Arch. Intern . Med. 136 (1976) 769 -77 7 II Kadis; S .. W Kert; C. A. Athanasoulis: The ro le of arteriography in the management of re na l cell carc inoma associated with von lIippel-ündau syndrome . Hum an Genet. 92 (1989) 127 -1 30 12 Kiechle-S chawarz. M.• JI. P. JI. Neuma nn . H. Decket; C. Diet ric h. 8 . w utlieb. W S chempp: Cytogene tic studies on 3 phe ochro mocytomas de rived fr om pa tients with von Hippel-Lind au syndrome. Human Genet . 92 (1 989) 127-130 13 King. C. R.. R. N. Schimke. T. Arthur: 8 . Danoren, D. Collin s: Proximal 3p deletion in ren al cell cars inoma cells from a pati ent with von Hippel-Lindau disease. Cance r Genet. Cytogenet. 27 6
(1 987) 345-348 14
15
(1987) 220-226 16
Phen ochromocytoma is often see n in HLS. It ha s been reported tha t in Neumann s (15) se ries of 338 VHL patients 69 ph eochromocytoma s were found in 46 pa tien ts (14 %). Five of these tumours wer e extraaadre na l (par ag an gliom as) . Horton et aI. (1O) re po rte d th e incide nce of ph eochrom ocytoma in VHL pati en ts to be 10 %. Although the overa ll ratio was 10 %. four of five were limited to the single family. In A tuk s series it occurred in one farnily in 12 out of 13 m embers. This findi ng suggests that on ly memb ers of cert ain families are predisp osed to develop this manifestation . In our case s it was found that the mortality and morbidity were high du e to la te diagnos is and th e lack of suitable screening . References
Mal ek. R. S . L. F Greene. Urologic as pec ts of Hippel-Lindau syn drome . J. Urology106 (1971) 800-801 Neumann. H. P. 11.: Basic criter ia for clinical d iagnosis and gen etic cou nselling in von Hippel-Lindau syn dro me . VASA 16 Neumann. H, P. H.• H. R. Eggert. K. Weigel. I/. Friedburg. 0. D. Wiest/er. P. S chollmey er: Hem an giob lastomas of th e centr al
nervous syste m. A 10 year study with special re fere nce to von Hippel-Linda u syndrome. J . Neur osurg. 70 (1989) 24 -30 17 Neumann. H. P. H . O. D. Wiest/ er: Clustering of features of von Hlppel-Linda u synd ro me: eviden ce for a complex geneuc locus.
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A tuk. N. 0.. T. McDonald. T. Wood. J. T. Carpente r, M. P. Walz ak. M. Donaidson. J . Y. Gillenwater: Fa milial ph eochromocytom a. hype rcalc emi a and Von Hippel-Lindau disease. A ten year st udy
22 Yamashita. J.. JI. Han da . S. Kim: Fam ilial occurrence of cere be llar hem an giomas - Analys is of five farm lies. Neuros urge ry 11
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Neuro!. Belg. 91 (1991) 223-229 3 Christensen. P. J.. J . P. Crai g. M. C. Bioro . K. J. O'Connel: Cysts contai ning renal cell carcinoma in von Hlppel-Llndau's disease.
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pel-Lindau's disease. JAMA 178 (1961) 280- 282 5 Cons ta ns. J. P. . F. Meder. Mau ri, F.. Donzelli, R. Spaziante. E. Dioiitls: Poste rior fossa hemangioblastomas. Surg . Neurol. 25
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Turgay Bilge, MD Taksim Hastan esi Nörösirü rji KJinigi Ta ksim, Ista nbul Turkey
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