manifestations. Hemorrhage is a frequent complication with an annual risk of 0.25–5% [226]. The diagnosis of familial cerebral cavernous malformations requires histopathologic or imaging documentation of cavernous hemangioma in at least two family members.

Diagnosis and Diagnostic Aids

FA best demonstrates the plasma-erythrocytic separation within retinal cavernous hemangioma. The fluorescein collects in the superior portion of the aneurysm with the sediment red blood cells blocking the inferior. The aneurysms fill slowly and the dye rarely extravasates from the tumor in the late phase of the angiogram.

CNS cavernous hemangioma is best visualized by MRI as a central enhancing core with a dark ring from previous hemorrhages. These lesions are not readily detected by cerebral angiography because they are venous in origin. All patients diagnosed with a retinal cavernous hemangioma should undergo detailed neuroimaging studies for possible CNS lesions [227].

Treatment

Retinal cavernous hemangioma generally does not require treatment because these lesions are relatively stable with rare complications. Photocoagulation or cryotherapy has been tried with little proven benefit [221]. Nonclearing vitreous hemorrhage can be treated with vitrectomy.

References

1.Huson, S.M., Harper, P.S., Compston, D.A.: Von Recklinghausen neurofibromatosis. A clinical and population study in south-east Wales. Brain 111(Pt 6), 1355–1381 (1988)

2.Neurofibromatosis.:Conferencestatement.NationalInstitutes of Health Consensus Development Conference. Arch. Neurol. 45(5), 575–578 (1988)

3.Ragge, N.K., et al.: Images of Lisch nodules across the spectrum. Eye 7(Pt 1), 95–101 (1993)

4.Lewis, R.A., Riccardi, V.M.: Von Recklinghausen neurofibromatosis. Incidence of iris hamartomata. Ophthalmology 88(4), 348–354 (1981)

5.Lewis, R.A., et al.: The Gardner syndrome. Significance of ocular features. Ophthalmology 91(8), 916–925 (1984)

6.Destro, M., et al.: Retinal manifestations of neurofibromatosis. Diagnosis and management. Arch. Ophthalmol. 109(5), 662–666 (1991)

7.Gutmann, D.H.: Recent insights into neurofibromatosis type 1: clear genetic progress. Arch. Neurol. 55(6), 778–780 (1998)

8.Cichowski, K., Jacks, T.: NF1 tumor suppressor gene function: narrowing the GAP. Cell 104(4), 593–604 (2001)

9.Kluwe, L., Friedrich, R., Mautner, V.F.: Loss of NF1 allele in Schwann cells but not in fibroblasts derived from an NF1-associated neurofibroma. Genes Chromosomes Cancer 24(3), 283–285 (1999)

10.Jadayel, D., et al.: Paternal origin of new mutations in von Recklinghausen neurofibromatosis. Nature 343(6258), 558–559 (1990)

11.Huson, S.M., et al.: A genetic study of von Recklinghausen neurofibromatosis in south east Wales. I. Prevalence, fitness, mutation rate, and effect of parental transmission on severity. J. Med. Genet. 26(11), 704–711 (1989)

12.Michels, V.V., et al.: Chromosome translocations in couples with multiple spontaneous abortions. Am. J. Hum. Genet. 34(3), 507–513 (1982)

13.Fahsold, R., et al.: Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. Am. J. Hum. Genet. 66(3), 790–818 (2000)

14.Messiaen, L.M., et al.: Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Hum. Mutat. 15(6), 541–555 (2000)

15.Poyhonen, M., Niemela, S., Herva, R.: Risk of malignancy and death in neurofibromatosis. Arch. Pathol. Lab. Med. 121(2), 139–143 (1997)

16.Johnson, N.S., et al.: Social and emotional problems in children with neurofibromatosis type 1: evidence and proposed interventions. J. Pediatr. 134(6), 767–772 (1999)

17.Imes, R.K., Hoyt, W.F.: Magnetic resonance imaging signs of optic nerve gliomas in neurofibromatosis 1. Am. J. Ophthalmol. 111(6), 729–734 (1991)

18.Listernick, R., et al.: Optic pathway tumors in children: the effect of neurofibromatosis type 1 on clinical manifestations and natural history. J. Pediatr. 127(5), 718–722 (1995)

19.Lund, A.M., Skovby, F.: Optic gliomas in children with neurofibromatosis type 1. Eur. J. Pediatr. 150(12), 835–838 (1991)

20.Rush, J.A., et al.: Optic glioma. Long-term follow-up of 85 histopathologically verified cases. Ophthalmology 89(11), 1213–1219 (1982)

21.Pascual-Castroviejo, I., et al.: Optic gliomas in neurofibromatosis type 1 (NF-1). Presentation of 31 cases. Neurologia 9(5), 173–177 (1994)

22.King, A.A., et al.: Malignant peripheral nerve sheath tumors in neurofibromatosis 1. Am. J. Med. Genet. 93(5), 388–392 (2000)

23.Khafaga, Y., et al.: Optic gliomas: a retrospective analysis of 50 cases. Int. J. Radiat. Oncol. Biol. Phys. 56(3), 807– 812 (2003)

24.Gayre, G.S., et al.: Long-term visual outcome in patients with anterior visual pathway gliomas. J. Neuroophthalmol. 21(1), 1–7 (2001)

25.Korf, B.R.: Plexiform neurofibromas. Am. J. Med. Genet. 89(1), 31–37 (1999)

26.Hyman, S.L., Shores, A., North, K.N.: The nature and frequency of cognitive deficits in children with neurofibromatosis type 1. Neurology 65(7), 1037–1044 (2005)

27.Mautner, V.F., et al.: Treatment of ADHD in neurofibromatosis type 1. Dev. Med. Child. Neurol. 44(3), 164–170 (2002)

28.North, K.N., et al.: Cognitive function and academic performance in neurofibromatosis. 1: consensus statement from the NF1 cognitive disorders task force. Neurology 48(4), 1121–1127 (1997)

29.Obringer, A.C., Meadows, A.T., Zackai, E.H.: The diagnosis of neurofibromatosis-1 in the child under the age of 6 years. Am. J. Dis. Child. 143(6), 717–719 (1989)

30.Dervin, J.E., et al.: CT findings in orbital tumours of nerve sheath origin. Clin. Radiol. 40(5), 475–479 (1989)

31.DiPaolo, D.P., et al.: Neurofibromatosis type 1: pathologic substrate of high-signal-intensity foci in the brain. Radiology 195(3), 721–724 (1995)

32.DiMario Jr., F.J., Ramsby, G.: Magnetic resonance imaging lesion analysis in neurofibromatosis type 1. Arch. Neurol. 55(4), 500–505 (1998)

33.Balcer, L.J., et al.: Visual loss in children with neurofibromatosis type 1 and optic pathway gliomas: relation to tumor location by magnetic resonance imaging. Am. J. Ophthalmol. 131(4), 442–445 (2001)

34.Grill, J., et al.: When do children with optic pathway tumours need treatment? An oncological perspective in 106 patients treated in a single centre. Eur. J. Pediatr. 159(9), 692–696 (2000)

35.Cappelli, C., et al.: Long-term follow up of 69 patients treated for optic pathway tumours before the chemotherapy era. Arch. Dis. Child. 79(4), 334–338 (1998)

36.Bouzas, E.A., et al.: Lens opacities in neurofibromatosis 2: further significant correlations. Br. J. Ophthalmol. 77(6), 354–357 (1993)

37.Ragge, N.K., et al.: The ocular presentation of neurofibromatosis 2. Eye 11(Pt 1), 12–18 (1997)

38.Evans, D.G., et al.: A genetic study of type 2 neurofibromatosis in the United Kingdom. II. Guidelines for genetic counselling. J. Med. Genet. 29(12), 847–852 (1992)

39.Evans, D.G., et al.: A genetic study of type 2 neurofibromatosis in the United Kingdom. I. Prevalence, mutation rate, fitness, and confirmation of maternal transmission effect on severity. J. Med. Genet. 29(12), 841–846 (1992)

40.Kluwe, L., et al.: Molecular study of frequency of mosaicism in neurofibromatosis 2 patients with bilateral vestibular­ schwannomas. J. Med. Genet. 40(2), 109–114 (2003)

41.Ruggieri, M., Huson, S.M.: The clinical and diagnostic implications of mosaicism in the neurofibromatoses. Neurology 56(11), 1433–1443 (2001)

42.Moyhuddin, A., et al.: Somatic mosaicism in neurofibromatosis 2: prevalence and risk of disease transmission to offspring. J. Med. Genet. 40(6), 459–463 (2003)

43.Claudio, J.O., et al.: Expression of schwannomin in lens and Schwann cells. Neuroreport 8(8), 2025–2030 (1997)

44.Claudio, J.O., Lutchman, M., Rouleau, G.A.: Widespread but cell type-specific expression of the mouse neurofibromatosis type 2 gene. Neuroreport 6(14), 1942–1946 (1995)

45.Giovannini, M., et al.: Schwann cell hyperplasia and tumors in transgenic mice expressing a naturally occurring mutant NF2 protein. Genes Dev. 13(8), 978–986 (1999)

46.Kluwe, L., et al.: Identification of NF2 germ-line mutations and comparison with neurofibromatosis 2 phenotypes. Hum. Genet. 98(5), 534–538 (1996)

47.Ruttledge, M.H., et al.: Type of mutation in the neurofibromatosis type 2 gene (NF2) frequently determines severity of disease. Am. J. Hum. Genet. 59(2), 331–342 (1996)

48.Antinheimo, J., et al.: Population-based analysis of sporadic and type 2 neurofibromatosis-associated meningiomas and schwannomas. Neurology 54(1), 71–76 (2000)

49.Meyers, S.M., et al.: Retinal changes associated with neurofibromatosis 2. Trans. Am. Ophthalmol. Soc. 93, 245–252; discussion 252–257 (1995)

50.Landau, K., Yasargil, G.M.: Ocular fundus in neurofibromatosis type 2. Br. J. Ophthalmol. 77(10), 646–649 (1993)

51.Kaye, L.D., et al.: Ocular findings associated with neurofibromatosis type II. Ophthalmology 99(9), 1424–1429 (1992)

52.Ragge, N.K., et al.: Ocular abnormalities in neurofibromatosis 2. Am. J. Ophthalmol. 120(5), 634–641 (1995)

53.Evans, D.G., et al.: Management of the patient and family with neurofibromatosis 2: a consensus conference statement. Br. J. Neurosurg. 19(1), 5–12 (2005)

54.Saeed, S.R., et al.: Magnetic resonance imaging: a costeffective first line investigation in the detection of vestibular schwannomas. Br. J. Neurosurg. 9(4), 497–503 (1995)

55.Gillespie, J.E.: Imaging in neurofibromatosis type 2: screening using magnetic resonance imaging. Ear Nose Throat J. 78(2), 102–103; 106; 108–109 (1999)

56.Welling, D.B., et al.: Mutational spectrum in the neurofibromatosis type 2 gene in sporadic and familial schwannomas. Hum. Genet. 98(2), 189–193 (1996)

57.Merel, P., et al.: Screening for germ-line mutations in the NF2 gene. Genes Chromosomes Cancer 12(2), 117–127 (1995)

58.MacCollin, M., et al.: Mutational analysis of patients with neurofibromatosis 2. Am. J. Hum. Genet. 55(2), 314–320 (1994)

59.Abaza, M.M., et al.: Growth rate characteristics of acoustic neuromas associated with neurofibromatosis type 2. Laryngoscope 106(6), 694–699 (1996)

60.Andrews, D.W., et al.: Stereotactic radiosurgery and fractionated stereotactic radiotherapy for the treatment of acoustic schwannomas: comparative observations of 125 patients treated at one institution. Int. J. Radiat. Oncol. Biol. Phys. 50(5), 1265–1278 (2001)

61.Anand, V.T., et al.: Non-surgical management of acoustic neuromas. Clin. Otolaryngol. Allied Sci. 17(5), 406–410 (1992)

62.Gutmann, D.H., et al.: The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 278(1), 51–57 (1997)

63.Melmon, K.L., Rosen, S.W.: Lindau’s disease. Review of the Literature and Study of a Large Kindred. Am. J. Med. 36, 595–617 (1964)

64.Choyke, P.L., et al.: von Hippel-Lindau disease: genetic, clinical, and imaging features. Radiology 194(3), 629–642 (1995)

65.Manski, T.J., et al.: Endolymphatic sac tumors. A source of morbid hearing loss in von Hippel-Lindau disease. JAMA 277(18), 1461–1466 (1997)

66.Chang, J.H., et al.: The two-stage mutation model in retinal hemangioblastoma. Ophthalmic Genet. 19(3), 123–130 (1998)

67.Kaelin, W.G., et al.: Functions of the von Hippel-Lindau tumour suppressor protein. J. Intern. Med. 243(6), 535–539 (1998)

68.Webster, A.R., Maher, E.R., Moore, A.T.: Clinical characteristics of ocular angiomatosis in von Hippel-Lindau disease and correlation with germline mutation. Arch. Ophthalmol. 117(3), 371–378 (1999)

69.Webster, A.R., et al.: A clinical and molecular genetic analysis of solitary ocular angioma. Ophthalmology 106(3), 623–629 (1999)

70.Singh, A.D., et al.: Solitary retinal capillary hemangioma: lack of genetic evidence for von Hippel-Lindau disease. Ophthalmic Genet. 23(1), 21–27 (2002)

71.Stolle, C., et al.: Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. Hum. Mutat. 12(6), 417–423 (1998)

72.Grossniklaus, H.E., et al.: Retinal hemangioblastoma. A histologic, immunohistochemical, and ultrastructural evaluation. Ophthalmology 99(1), 140–145 (1992)

73.Neumann, H.P., Wiestler, O.D.: Clustering of features and genetics of von Hippel-Lindau syndrome. Lancet 338(8761), 258 (1991)

74.Maher, E.R., et al.: Von Hippel-Lindau disease: a genetic study. J. Med. Genet. 28(7), 443–447 (1991)

75.Lamiell, J.M., Salazar, F.G., Hsia, Y.E.: von Hippel-Lindau disease affecting 43 members of a single kindred. Medicine (Baltimore) 68(1), 1–29 (1989)

76.Lewis, R.A., Cohen, M.H., Wise, G.N.: Cavernous haemangioma of the retina and optic disc. A report of three cases and a review of the literature. Br. J. Ophthalmol. 59(8), 422–434 (1975)

77.Maher, E.R., et al.: Clinical features and natural history of von Hippel-Lindau disease. Q. J. Med. 77(283), 1151–1163 (1990)

78.Ehlers, N., Jensen, O.A.: Juxtapapillary retinal hemangioblastoma (angiomatosis retinae) in an infant: light microscopical and ultrastructural examination. Ultrastruct. Pathol. 3(4), 325–333 (1982)

79.Horton, W.A., Wong, V., Eldridge, R.: Von Hippel-Lindau disease: clinical and pathological manifestations in nine families with 50 affected members. Arch. Intern. Med. 136(7), 769–777 (1976)

80.Ridley, M., Green, J., Johnson, G.: Retinal angiomatosis: the ocular manifestations of von Hippel-Lindau disease. Can. J. Ophthalmol. 21(7), 276–283 (1986)

81.Salazar, F.G., Lamiell, J.M.: Early identification of retinal angiomas in a large kindred von Hippel-Lindau disease. Am. J. Ophthalmol. 89(4), 540–545 (1980)

82.Richard, S., et al.: Haemangioblastoma of the central nervous system in von Hippel-Lindau disease. French VHL Study Group. J. Intern. Med. 243(6), 547–553 (1998)

83.de Jong, P.T., et al.: Twin vessels in von Hippel-Lindau disease. Am. J. Ophthalmol. 105(2), 165–169 (1988)

84.Zbar, B., et al.: Third International Meeting on von Hippel-Lindau disease. Cancer Res. 59(9), 2251–2253 (1999)

85.Annesley Jr., W.H., et al.: Fifteen year review of treated cases of retinal angiomatosis. Trans. Sect. Ophthalmol. Am.

Acad. Ophthalmol. Otolaryngol. 83(3 Pt 1), OP446–QP453 (1977)

86.Carr,R.E.,Noble,K.G.:Retinalangiomatosis.Ophthalmology 87(9), 956–959; 961 (1980)

87.Schmidt, D.: Ocular massage in a case of central retinal artery occlusion the successful treatment of a hitherto undescribed type of embolism. Eur. J. Med. Res. 5(4), 157–164 (2000)

88.Oosterhuis, J.A., Rubinstein, K.: Haemangioma at the optic disc. Ophthalmologica 164(5), 362–374 (1972)

89.Gass, J.D., Braunstein, R.: Sessile and exophytic capillary angiomas of the juxtapapillary retina and optic nerve head. Arch. Ophthalmol. 98(10), 1790–1797 (1980)

90.Darr, J.L., Hughes Jr., R.P., McNair, J.N.: Bilateral peripapillary­ retinal hemangiomas. A case report. Arch. Ophthalmol. 75(1), 77–81 (1966)

91.Schindler, R.F., Sarin, L.K., MacDonald, P.R.: Hemangiomas of the optic disc. Can. J. Ophthalmol. 10(3), 305–318 (1975)

92.Gass, J.D.: Treatment of retinal vascular anomalies. Trans. Sect. Ophthalmol. Am. Acad. Ophthalmol. Otolaryngol. 83(3 Pt 1), OP432–OP442 (1977)

93.Schmidt, D., Neumann, H.P.: Retinal vascular hamartoma in von Hippel-Lindau disease. Arch. Ophthalmol. 113(9), 1163–1167 (1995)

94.Neumann, H.P., et al.: Hemangioblastomas of the central nervous system. A 10-year study with special reference to von Hippel-Lindau syndrome. J. Neurosurg. 70(1), 24–30 (1989)

95.Filling-Katz, M.R., et al.: Central nervous system involvement in Von Hippel-Lindau disease. Neurology 41(1), 41–46 (1991)

96.Wizigmann-Voos, S., Plate, K.H.: Pathology, genetics and cell biology of hemangioblastomas. Histol. Histopathol. 11(4), 1049–1061 (1996)

97.Maher, E.R., Yates, J.R., Ferguson-Smith, M.A.: Statistical analysis of the two stage mutation model in von Hippel-Lindau disease, and in sporadic cerebellar haemangioblastoma and renal cell carcinoma. J. Med. Genet. 27(5), 311–314 (1990)

98.Neumann, H.P.: Basic criteria for clinical diagnosis and genetic counselling in von Hippel-Lindau syndrome. Vasa 16(3), 220–226 (1987)

99.Choyke, P.L., et al.: The natural history of renal lesions in von Hippel-Lindau disease: a serial CT study in 28 patients. AJR Am. J. Roentgenol. 159(6), 1229–1234 (1992)

100. Kragel, P.J., et al.: Simple renal cysts, atypical renal cysts, and renal cell carcinoma in von Hippel-Lindau disease: a lectin and immunohistochemical study in six patients. Mod. Pathol. 4(2), 210–214 (1991)

101. Gardner Jr., K.D., Evan, A.P.: Cystic kidneys: an enigma evolves. Am. J. Kidney. Dis. 3(6), 403–413 (1984)

102. Fill, W.L., Lamiell, J.M., Polk, N.O.: The radiographic manifestations of von Hippel-Lindau disease. Radiology 133(2), 289–295 (1979)

103. Malek, R.S., et al.: Renal cell carcinoma in von HippelLindau syndrome. Am. J. Med. 82(2), 236–238 (1987)

104. Green, J.S., Bowmer, M.I., Johnson, G.J.: Von HippelLindau disease in a Newfoundland kindred. CMAJ 134(2), 133–138; 146 (1986)

105. Walther, M.M., 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. 162(3 Pt 1), 659–664 (1999)

106. Neumann, H.P., et al.: Adrenal-sparing surgery for phaeochromocytoma. Br. J. Surg. 86(1), 94–97 (1999)

107. Witten, F.R., et al.: Bilateral clear cell papillary cystadenoma of the epididymides presenting as infertility: an early manifestation of von Hippel-Lindau’s syndrome. J. Urol. 133(6), 1062–1064 (1985)

108. Shields, C.L., et al.: Vasoproliferative tumors of the ocular fundus. Classification and clinical manifestations in 103 patients. Arch. Ophthalmol. 113(5), 615–623 (1995)

109. Lieb, W.E., et al.: Color Doppler imaging in the management of intraocular tumors. Ophthalmology 97(12), 1660– 1664 (1990)

110. Balazs, E., et al.: Hemodynamic changes after ruthenium irradiation of Hippel’s angiomatosis. Ophthalmologica 200(3), 128–132 (1990)

111. Probst, A., Lotz, M., Heitz, P.: Von Hippel-Lindau’s disease, syringomyelia and multiple endocrine tumors: a complex neuroendocrinopathy. Virchows Arch. A Pathol. Anat. Histol. 378(3), 265–272 (1978)

112.Cardoso, R.D., Brockhurst, R.J.: Perforating diathermy coagulation for retinal angiomas. Arch. Ophthalmol. 94(10), 1702–1715 (1976)

113.Welch, R.B.: Von Hippel-Lindau disease: the recognition

and treatment of early angiomatosis retinae and the use of cryosurgery as an adjunct to therapy. Trans. Am. Ophthalmol. Soc. 68, 367–424 (1970)

114. Neame, H.: Angiomatosis retinae, with report of pathological examination. Br. J. Ophthalmol. 32(9), 677–689 (1948)

115. Straatsma, B.R.: Angiomatosis retinae. N. Engl. J. Med. 250(8), 314–317 (1954)

116. Schmidt, D., Natt, E., Neumann, H.P.: Long-term results of laser treatment for retinal angiomatosis in von HippelLindau disease. Eur. J. Med. Res. 5(2), 47–58 (2000)

117. Kremer, I., Gilad, E., Ben-Sira, I.: Juxtapapillary exophytic retinal capillary hemangioma treated by yellow krypton (568 nm) laser photocoagulation. Ophthalmic. Surg. 19(10), 743–747 (1988)

118. Gorin, M.B.: Von Hippel-Lindau disease: clinical considerations and the use of fluorescein-potentiated argon laser therapy for treatment of retinal angiomas. Semin. Ophthalmol. 7(3), 182–191 (1992)

119. Lane, C.M., et al.: Laser treatment of retinal angiomatosis. Eye 3(Pt 1), 33–38 (1989)

120. Bonnet, M., Garmier, G.: Treatment of retinal capillary angiomas of von Hippel’s disease. J. Fr. Ophtalmol. 7(8–9), 545–555 (1984)

121. Apple, D.J., Goldberg, M.F., Wyhinny, G.J.: Argon laser treatment of von Hippel-Lindau retinal angiomas. II. Histopathology of treated lesions. Arch. Ophthalmol. 92(2), 126–130 (1974)

122. Goldberg, M.F., Koenig, S.: Argon laser treatment of von Hippel-Lindau retinal angiomas. I. Clinical and angiographic findings. Arch. Ophthalmol. 92(2), 121–125 (1974)

123.Blodi, C.F., et al.: Direct and feeder vessel photocoagulation of retinal angiomas with dye yellow laser. Ophthalmology 97(6), 791–795; discussion 796–797 (1990)

124. Meyer-Schwickerath, G.: The preservation of vision by treatment of intraocular tumors with light coagulation. Arch. Ophthalmol. 66, 458–466 (1961)

125. Ginzburg, B.M., et al.: Diagnosis of von Hippel-Lindau disease in a patient with blindness resulting from bilateral optic nerve hemangioblastomas. AJR Am. J. Roentgenol. 159(2), 403–405 (1992)

126. Barbazetto, I.A., Schmidt-Erfurth, U.: Photodynamic Therapy in the Treatment of Intraocular Angioma, in Presented at the American Academy of Ophthalmology. Orlando, FL, USA (1999)

127. Rohrschneider, K., et al.: Capillary hemangioma of the retina. Laser scanning tomography follow-up after radiotherapy. Fortschr. Ophthalmol. 88(6), 623–628 (1991)

128. Kreusel, K.M., et al.: Ruthenium-106 brachytherapy for peripheral retinal capillary hemangioma. Ophthalmology 105(8), 1386–1392 (1998)

129.Palmer, J.D., Gragoudas, E.S.: Advances in treatment of retinal angiomas. Int. Ophthalmol. Clin. 37(4), 159–170 (1997)

130. Machemer, R., Williams Sr., J.M.: Pathogenesis and therapy of traction detachment in various retinal vascular diseases. Am. J. Ophthalmol. 105(2), 170–181 (1988)

131. Johnson, M.W., Flynn Jr., H.W., Gass, J.D.: Pars plana vitrectomy and direct diathermy for complications of multiple retinal angiomas. Ophthalmic Surg. 23(1), 47–50 (1992)

132. Gomez, M.R.: History of the tuberous sclerosis complex. Brain Dev. 17 Suppl, 55–57 (1995)

133. Kwiatkowski, D.J., Short, M.P.: Tuberous sclerosis. Arch. Dermatol. 130(3), 348–354 (1994)

134. Roach, E.S., Delgado, M.R.: Tuberous sclerosis. Dermatol. Clin. 13(1), 151–161 (1995)

135. Avellino, A.M., et al.: Surgical management and seizure outcome in patients with tuberous sclerosis. J. Neurosurg. 87(3), 391–396 (1997)

136. Schillinger, F., Montagnac, R.: Chronic renal failure and its treatment in tuberous sclerosis. Nephrol. Dial. Transplant. 11(3), 481–485 (1996)

137. Webb, D.W., Fryer, A.E., Osborne, J.P.: Morbidity associated with tuberous sclerosis: a population study. Dev. Med. Child. Neurol. 38(2), 146–155 (1996)

138. Uzzo, R.G., et al.: Coexisting lymphangioleiomyomatosis and bilateral angiomyolipomas in a patient with tuberous sclerosis. J. Urol. 151(6), 1612–1615 (1994)

139. Jones, A.C., et al.: Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis. Hum. Mol. Genet. 6(12), 2155–2161 (1997)

140. Dabora, S.L., et al.: Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am. J. Hum. Genet. 68(1), 64–80 (2001)

141.Roach, E.S., et al.: Detection of tuberous sclerosis in parents by magnetic resonance imaging. Neurology 41(2 (Pt 1)), 262–265 (1991)

142. Osborne, J.P., Fryer, A., Webb, D.: Epidemiology of tuberous sclerosis. Ann. N. Y. Acad. Sci. 615, 125–127 (1991)

143.Povey, S., et al.: Two loci for tuberous sclerosis: one on 9q34 and one on 16p13. Ann. Hum. Genet. 58(Pt 2), 107–127 (1994)

144.Kozlowski, P., et al.: Identification of 54 large deletions/ duplications in TSC1 and TSC2 using MLPA, and genotype-

phenotype correlations. Hum. Genet. 121(3–4), 389–400 (2007)

145. Bebin, E.M., Kelly, P.J., Gomez, M.R.: Surgical treatment for epilepsy in cerebral tuberous sclerosis. Epilepsia 34(4), 651–657 (1993)

146. Catania, M.G., Mischel, P.S., Vinters, H.V.: Hamartin and tuberin interaction with the G2/M cyclin-dependent kinase CDK1 and its regulatory cyclins A and B. J. Neuropathol. Exp. Neurol. 60(7), 711–723 (2001)

147. Johnson, M.W., et al.: Hamartin and tuberin expression in human tissues. Mod. Pathol. 14(3), 202–210 (2001)

148. Rok, P., et al.: Clinical symptoms of tuberous sclerosis complex in patients with an identical TSC2 mutation. Med. Sci. Monit. 11(5), CR230–CR234 (2005)

149. Devlin, L.A., et al.: Tuberous sclerosis complex: clinical features, diagnosis, and prevalence within Northern Ireland. Dev. Med. Child. Neurol. 48(6), 495–499 (2006)

150. Lendvay, T.S., Marshall, F.F.: The tuberous sclerosis complex and its highly variable manifestations. J. Urol. 169(5), 1635–1642 (2003)

151. Choi, J.E., et al.: Mutational analysis of TSC1 and TSC2 in Korean patients with tuberous sclerosis complex. Brain Dev. 28(7), 440–446 (2006)

152. Jones, A.C., et al.: Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. Am. J. Hum. Genet. 64(5), 1305–1315 (1999)

153.Verhoef, S., et al.: High rate of mosaicism in tuberous sclerosis complex. Am. J. Hum. Genet. 64(6), 1632–1637 (1999)

154.Wiederholt, W.C., Gomez, M.R., Kurland, L.T.: Incidence and prevalence of tuberous sclerosis in Rochester, Minnesota, 1950 through 1982. Neurology 35(4), 600–603 (1985)

155. Shepherd, C.W., et al.: Tuberous sclerosis complex in Olmsted County, Minnesota, 1950–1989. Arch. Neurol. 48(4), 400–401 (1991)

156. Robertson, D.M.: Ophthalmic manifestations of tuberous sclerosis. Ann. N. Y. Acad. Sci. 615, 17–25 (1991)

157.Zimmer-Galler, I.E., Robertson, D.M.: Long-term observationofretinallesionsintuberoussclerosis.Am.J.Ophthalmol. 119(3), 318–324 (1995)

158. Gunduz, K., et al.: Invasive giant cell astrocytoma of the retina in a patient with tuberous sclerosis. Ophthalmology 106(3), 639–642 (1999)

159. Rowley, S.A., O’Callaghan, F.J., Osborne, J.P.: Ophthalmic manifestations of tuberous sclerosis: a population based study. Br. J. Ophthalmol. 85(4), 420–423 (2001)

160. Williams, R., Taylor, D.: Tuberous sclerosis. Surv. Ophtha­ lmol. 30(3), 143–154 (1985)

161.Nyboer, J.H., Robertson, D.M., Gomez, M.R.: Retinal lesions in tuberous sclerosis. Arch. Ophthalmol. 94(8), 1277–1280 (1976)

162. Webb, D.W., Fryer, A.E., Osborne, J.P.: On the incidence of fits and mental retardation in tuberous sclerosis. J. Med. Genet. 28(6), 395–397 (1991)

163. Jozwiak, S., et al.: Skin lesions in children with tuberous sclerosis complex: their prevalence, natural course, and diagnostic significance. Int. J. Dermatol. 37(12), 911–917 (1998)

164. Roach, E.S., Gomez, M.R., Northrup, H.: Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J. Child. Neurol. 13(12), 624–628 (1998)

165. Webb, D.W., et al.: The cutaneous features of tuberous sclerosis: a population study. Br. J. Dermatol. 135(1), 1–5 (1996)

166. Roszkowski, M., et al.: Surgical treatment of intraventricular tumors associated with tuberous sclerosis. Childs Nerv. Syst. 11(6), 335–339 (1995)

167. Roach, E.S.: Diagnosis and management of neurocutaneous syndromes. Semin. Neurol. 8(1), 83–96 (1988)

168. Goodman, M., et al.: Cortical tuber count: a biomarker indicating neurologic severity of tuberous sclerosis complex. J. Child. Neurol. 12(2), 85–90 (1997)

169. Castro, M., et al.: Pulmonary tuberous sclerosis. Chest 107(1), 189–195 (1995)

170. van Baal, J.G., Fleury, P., Brummelkamp, W.H.: Tuberous sclerosis and the relation with renal angiomyolipoma. A genetic study on the clinical aspects. Clin. Genet. 35(3), 167–173 (1989)

171. Seki, I., Singh, A.D., Longo, S.: Pathological case of the month. Congenital cardiac rhabdomyoma. Arch. Pediatr. Adolesc. Med. 150(8), 877–878 (1996)

172.Shepherd, C.W., et al.: Causes of death in patients with tuberous sclerosis. Mayo. Clin. Proc. 66(8), 792–796 (1991)

173. Sturge, W.: A case of partial epilepsy apparently due lesion of one of the vasomotor center of the brain. Trans. Clin. Soc. Lond. 12, 162–167 (1879)

174. Chapieski, L., Friedman, A., Lachar, D.: Psychological functioning in children and adolescents with Sturge-Weber syndrome. J. Child. Neurol. 15(10), 660–665 (2000)

175. Tallman, B., et al.: Location of port-wine stains and the likelihood of ophthalmic and/or central nervous system complications. Pediatrics 87(3), 323–327 (1991)

176. Sullivan, T.J., Clarke, M.P., Morin, J.D.: The ocular manifestations of the Sturge-Weber syndrome. J. Pediatr. Ophthalmol. Strabismus 29(6), 349–356 (1992)

177. Amirikia, A., Scott, I.U., Murray, T.G.: Bilateral diffuse choroidal hemangiomas with unilateral facial nevus flammeus in Sturge-Weber syndrome. Am. J. Ophthalmol. 130(3), 362–364 (2000)

178. Schilling, H., et al.: Long-term results after low dose ocular irradiation for choroidal haemangiomas. Br. J. Ophthalmol. 81(4), 267–273 (1997)

179.Zografos, L., et al.: Proton beam irradiation of choroidal hemangiomas. Am. J. Ophthalmol. 126(2), 261–268 (1998)

180. van Emelen, C., et al.: Treatment of glaucoma in children with Sturge-Weber syndrome. J. Pediatr. Ophthalmol. Strabismus 37(1), 29–34 (2000)

181. Phelps, C.D.: The pathogenesis of glaucoma in SturgeWeber syndrome. Ophthalmology 85(3), 276–286 (1978)

182.Budenz, D.L., et al.: Two-staged Baerveldt glaucoma implant for childhood glaucoma associated with Sturge-Weber syndrome. Ophthalmology 107(11), 2105–2110 (2000)

183. Mandal, A.K.: Primary combined trabeculotomy-trabe- culectomy for early-onset glaucoma in Sturge-Weber syndrome. Ophthalmology 106(8), 1621–1627 (1999)

184. Ali, M.A., Fahmy, I.A., Spaeth, G.L.: Trabeculectomy for glaucoma associated with Sturge-Weber syndrome. Ophthalmic Surg. 21(5), 352–355 (1990)

185. Enjolras, O., Riche, M.C., Merland, J.J.: Facial port-wine stains and Sturge-Weber syndrome. Pediatrics 76(1), 48–51 (1985)

186. Sujansky, E., Conradi, S.: Sturge-Weber syndrome: age of onset of seizures and glaucoma and the prognosis for affected children. J. Child. Neurol. 10(1), 49–58 (1995)

187. Arzimanoglou, A.A., et al.: Sturge-Weber syndrome: indications and results of surgery in 20 patients. Neurology 55(10), 1472–1479 (2000)

188. Sujansky, E., Conradi, S.: Outcome of Sturge-Weber syndrome in 52 adults. Am. J. Med. Genet. 57(1), 35–45 (1995)

189. Kramer, U., et al.: Outcome of infants with unilateral Sturge-Weber syndrome and early onset seizures. Dev. Med. Child. Neurol. 42(11), 756–759 (2000)

190. Arzimanoglou, A., Aicardi, J.: The epilepsy of Sturge-Weber syndrome: clinical features and treatment in 23 patients. Acta. Neurol. Scand. Suppl. 140, 18–22 (1992)

191. Uram, M., Zubillaga, C.: The cutaneous manifestations of Sturge-Weber syndrome. J. Clin. Neuroophthalmol. 2(4), 245–248 (1982)

192.Marti-Bonmati, L., et al.: Diagnosis of Sturge-Weber syndrome: comparison of the efficacy of CT and MR imaging in 14 cases. AJR Am. J. Roentgenol. 158(4), 867–871 (1992)

193. Wyburn-Mason, R.: Arteriovenous aneurysm of midbrain and retina, facial naevi and mental changes. Brain 66, 163–190 (1943)

194. Theron, J., Newton, T.H., Hoyt, W.F.: Unilateral retinocephalic vascular malformations. Neuroradiology 7(4), 185–196 (1974)

195. Archer, D.B., et al.: Arteriovenous communications of the retina. Am. J. Ophthalmol. 75(2), 224–241 (1973)

196. Shah, G.K., Shields, J.A., Lanning, R.C.: Branch retinal vein obstruction secondary to retinal arteriovenous communication. Am. J. Ophthalmol. 126(3), 446–448 (1998)

197. Effron, L., Zakov, Z.N., Tomsak, R.L.: Neovascular glaucoma as a complication of the Wyburn-Mason syndrome. J. Clin. Neuroophthalmol. 5(2), 95–98 (1985)

198. Ponce, F.A., et al.: Associated arteriovenous malformation of the orbit and brain: a case of Wyburn-Mason syndrome without retinal involvement. Case report. J. Neurosurg. 95(2), 346–349 (2001)

199. Kim, J., et al.: Wyburn-Mason syndrome: an unusual presentation of bilateral orbital and unilateral brain arteriovenous malformations. Pediatr. Radiol. 28(3), 161 (1998)

200. Farrell, B., Gerard, P.S.: Imaging of parietal thinning. N. Y. State J. Med. 91(11), 509–510 (1991)

201. Hopen, G., et al.: The Wyburn-Mason syndrome. Concomi­ tant chiasmal and fundus vascular malformations. J. Clin. Neuroophthalmol. 3(1), 53–62 (1983)

202. Augsburger, J.J., et al.: Changing appearance of retinal arteriovenous malformation. Albrecht Von Graefes Arch. Klin. Exp. Ophthalmol. 215(1), 65–70 (1980)

203. Louis-Bar, D.: Sur un syndrome progressif comprenant des telangiectasies capillaires cutanees et conjonctivales symetriques, a disposition naevoide et des trobles cerebelleux. Confin. Neurol. 4, 32–42 (1941)

204. Boder, E., Sedgwick, R.P.: Ataxia-telangiectasia; a familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasia and frequent pulmonary infection. Pediatrics 21(4), 526–554 (1958)

205. Boder, E.: Ataxia-telangiectasia: some historic, clinical and pathologic observations. Birth Defects Orig. Artic. Ser. 11(1), 255–270 (1975)

206. Boder, E.: Ataxia-telangiectasia: an overview. Kroc. Found Ser. 19, 1–63 (1985)

207. Woods, C.G., Bundey, S.E., Taylor, A.M.: Unusual features in the inheritance of ataxia telangiectasia. Hum. Genet. 84(6), 555–562 (1990)

208. Savitsky, K., et al.: A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268(5218), 1749– 1753 (1995)

209. Kastan, M.: Ataxia-telangiectasia–broad implications for a rare disorder. N. Engl. J. Med. 333(10), 662–663 (1995)

210. Laake, K., et al.: Characterization of ATM mutations in 41 Nordic families with ataxia telangiectasia. Hum. Mutat. 16(3), 232–246 (2000)

211. Swift, M., et al.: The incidence and gene frequency of ataxia-telangiectasia in the United States. Am. J. Hum. Genet. 39(5), 573–583 (1986)

212. Woods, C.G., Taylor, A.M.: Ataxia telangiectasia in the British Isles: the clinical and laboratory features of 70 affected individuals. Q. J. Med. 82(298), 169–179 (1992)

213. Ersoy, F., et al.: Twenty-year follow-up of 160 patients with ataxia-telangiectasia. Turk. J. Pediatr. 33(4), 205–215 (1991)

214. Bundey, S.: Clinical and genetic features of ataxia-telang- iectasia. Int. J. Radiat. Biol. 66(6 Suppl), S23–S29 (1994)

215. Stell, R., et al.: Ataxia telangiectasia: a reappraisal of the ocular motor features and their value in the diagnosis of atypical cases. Mov. Disord. 4(4), 320–329 (1989)

216. Gatti, R.A.: Ataxia-telangiectasia. Dermatol. Clin. 13(1), 1–6 (1995)

217. Taylor, A.M., et al.: Leukemia and lymphoma in ataxia telangiectasia. Blood 87(2), 423–438 (1996)

218. Swift, M., Chase, C.L., Morrell, D.: Cancer predisposition of ataxia-telangiectasia heterozygotes. Cancer Genet. Cytogenet. 46(1), 21–27 (1990)

219. Swift, M., et al.: Breast and other cancers in families with ataxia-telangiectasia. N. Engl. J. Med. 316(21), 1289–1294 (1987)

220. Easton, D.F.: Cancer risks in A-T heterozygotes. Int. J. Radiat. Biol. 66(6 Suppl), S177–S182 (1994)

221. Gass, J.D.: Cavernous hemangioma of the retina. A neuro- oculo-cutaneous syndrome. Am. J. Ophthalmol. 71(4), 799–814 (1971)

222. Dobyns, W.B., et al.: Familial cavernous malformations of the central nervous system and retina. Ann. Neurol. 21(6), 578–583 (1987)

223.Sahoo, T., et al.: Mutations in the gene encoding KRIT1, a Krev-1/rap1a binding protein, cause cerebral cavernous malformations­ (CCM1). Hum. Mol. Genet. 8(12), 2325– 2333 (1999)

224. Scheyhing, H.: Ein seltner Fall von angiomatosen Veraderungen der Netzhaut. Klin. Mbl. Augnheilk 99, 362 (1937)

225. Gautier-Smith, P.C., Sanders, M.D., Sanderson, K.V.: Ocular and nervous system involvement in angioma serpiginosum. Br. J. Ophthalmol. 55(7), 433–443 (1971)

226. Raychaudhuri, R., Batjer, H.H., Awad, I.A. Intracranial cavernous angioma: a practical review of clinical and biological aspects. Surg. Neurol. 63(4), 319–328; discussion 328 (2005)

227. Dellemijn, P.L., Vanneste, J.A.: Cavernous angiomatosis of the central nervous system: usefulness of screening the family. Acta. Neurol. Scand. 88(4), 259–263 (1993)

228. Singh, A.D., Traboulsi, E., Schoenfield, L.: Neurooculocutaneous syndromes (phakomatoses). In: Singh, A.D., Damato, B.E., Pe’er, J., Murphree, A.L., Perry, J.D. (eds.) Clinical Ophthalmic Oncology, pp. 385–402. Saunders-Elsevier, Philadelphia (2007)

229. Singh, A.D., Shields, C.L., Shields, J.A.: Von HippelLindau disease. Surv. Ophthalmol. 46, 117–142 (2001)

230. Giles, J., Singh, A.D., Rundle, P.A., Noe, K.P., Rennie, I.G.: Retinal astrocytic hamartoma with exudation. Eye 19, 724–725 (2005)

231.Singh, A.D., Rundle, P.A., Rennie, I.G., Vardy, S.J.: Photodynamic therapy of choroidal hemangioma associated

with Sturge-Weber syndrome. Eye 19, 365–367 (2005) 232. Singh, A.D., Rundle, P.A., Rennie, I.: Retinal vascular

tumors. In: Singh, A.D., Damato, B.E., Pe’er, J., Murphree, A.L., Perry, J.D. (eds.) Clinical Ophthalmic Oncology,

pp. 341–347. Saunders-Elsevier, Philadelphia (2007)

233.Patikulsila, D., Visaetsilpanonta, S., Sinclair, S.H., et al.: Cavernous hemangioma of the optic disk. Retina 27, 391–392 (2007)