Various Syndromes with Benign Intraocular Tumors

  • Mahesh Shanmugam Palanivelu
  • Pradeep Sagar


A selected group of benign intraocular tumors manifest as a part of neurocutaneous syndromes which are termed as phakomatoses. Most of the syndromes are caused by an underlying genetic defect that is responsible for multiple lesions involving various organ systems. Some ocular tumors are benign, asymptomatic, and serve as an indicator to the underlying disease such as astrocytic hamartoma associated with tuberous sclerosis complex. Some tumors can be locally destructive resulting in loss of vision as in von-Hippel Lindau and Sturge-Weber syndrome. Few ocular lesions may need observation alone and a few require active treatment with various modalities such as laser photocoagulation, photodynamic therapy, radiotherapy or vitreo-retinal surgery. Identification of the ocular disease would prompt periodic screening for systemic involvement to decrease morbidity and mortality associated with these syndromes.


Phakomatoses von-Hippel Lindau syndrome Wyburn-Mason syndrome Eye Sturge Weber syndrome Tuberous sclerosis Neurofibromatosis CHRPE CHRRPE 


  1. 1.
    Hardwig P, Robertson DM. Von Hippel-Lindau disease: a familial, often lethal, multi-system phakomatosis. Ophthalmology. 1984;91:263–70.PubMedCrossRefGoogle Scholar
  2. 2.
    Maher ER, Iselius L, Yates JR, Littler M, Benjamin C, Harris R, Sampson J, et al. Von Hippel-Lindau disease: a genetic study. J Med Genet. 1991;28:443–7.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, et al. von Hippel-Lindau disease. Lancet. 2003;361(9374):2059–67.PubMedCrossRefGoogle Scholar
  4. 4.
    Turturro F. Beyond the Knudson’s hypothesis in von Hippel-Lindau (VHL) disease- proposing vitronectin as a “gene modifier”. J Mol Med (Berl). 2009;87(6):591–3.CrossRefGoogle Scholar
  5. 5.
    Nordstrom-O’Brien M, van der Luijt RB, van Rooijen E, van den Ouweland AM, Majoor-Krakauer DF, Lolkema MP, et al. Genetic analysis of von Hippel-Lindau disease. Hum Mutat. 2010;31(5):521–37.PubMedGoogle Scholar
  6. 6.
    Chan CC, Vortmeyer AO, Chew EY, Green WR, Matteson DM, Shen DF, et al. VHL gene deletion and enhanced VEGF gene expression detected in the stromal cells of retinal angioma. Arch Ophthalmol. 1999;117(5):625–30.PubMedCrossRefGoogle Scholar
  7. 7.
    Kaelin WG Jr. The von Hippel-Lindau gene, kidney cancer, and oxygen sensing. J Am Soc Nephrol. 2003;14(11):2703–11.PubMedCrossRefGoogle Scholar
  8. 8.
    Maher ER, Yates JR, Harries R, Benjamin C, Harris R, Moore AT, et al. Clinical features and natural history of von Hippel-Lindau disease. MAQ. J Med. 1990;77(283):1151–63.Google Scholar
  9. 9.
    Singh A, Shields J, Shields C. Solitary retinal capillary hemangioma: hereditary (von Hippel-Lindau disease) or nonhereditary? Arch Ophthalmol. 2001;119(2):232–4.PubMedGoogle Scholar
  10. 10.
    Richard S, Chauveau D, Chrétien Y, Beigelman C, Denys A, Fendler JP, et al. Renal lesions and pheochromocytoma in von Hippel-Lindau disease. Adv Nephrol Necker Hosp. 1994;23:1–27.PubMedGoogle Scholar
  11. 11.
    Varshney N, Kebede AA, Owusu-Dapaah H, Lather J, Kaushik M, Bhullar JSJ, et al. A review of Von Hippel-Lindau syndrome. J Kidney Cancer VHL. 2017;4(3):20–9.PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Kanno H, Kobayashi N, Nakanowatari S, et al. Pathological and clinical features and management of central nervous system hemangioblastomas in von Hippel-Lindau disease. J Kidney Cancer VHL. 2014;1(4):46–55.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Maher ER, Neumann HP, Richard S. Von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet. 2011;19(6):617–23.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Wing GL, Weiter JJ, von Kelly PJ. Hippel-Lindau disease. Angiomatosis of the retina and central nervous system. Ophthalmology. 1981;88:1311–4.PubMedCrossRefGoogle Scholar
  15. 15.
    Singh AD, Nouri M, Shields CL, Shields JA, Smith AF. Retinal capillary hemangioma: a comparison of sporadic cases and cases associated with von Hippel-Lindau disease. Ophthalmology. 2001;108(10):1907–11.PubMedCrossRefGoogle Scholar
  16. 16.
    Shields JA, Shields CL, Deglin E. Retinal capillary haemangioma in Marshall-Stickler syndrome. Am J Ophthalmol. 1997;124:120–2.PubMedCrossRefGoogle Scholar
  17. 17.
    Shields JA, Shields CL. A textbook and atlas. Philadelphia: W. B. Saunders; 1992.Google Scholar
  18. 18.
    Saitta A, Nicolai M, Giovannini A, Mariotti C. Juxtapapillary retinal capillary hemangioma: new therapeutic strategies. Med Hypothesis Discov Innov Ophthalmol. 2014;3:71–5.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Gass JD, Braunstein R. Sessile and exophytic capillary angiomas of the juxtapapillary retina and optic nerve head. Arch Ophthalmol. 1980;98:1790–7.CrossRefGoogle Scholar
  20. 20.
    Shields CL, Materin MA, Shields JA. Review of optical coherence tomography for intraocular tumors. Curr Opin Ophthalmol. 2005;16(3):141–54.CrossRefGoogle Scholar
  21. 21.
    Chin EK, Trikha R, Morse LS, Zawadzki RJ, Werner JS, Park SS. Optical coherence tomography findings of exophytic retinal capillary hemangiomas of the posterior pole. Ophthalmic Surg Lasers Imaging. 2010;9:1–5.Google Scholar
  22. 22.
    Lang SJ, Cakir B, Evers C, Ludwig F, Lange CA, Agostini HT. Value of optical coherence tomography angiography imaging in diagnosis and treatment of hemangioblastomas in von Hippel-Lindau disease. Ophthalmic Surg Lasers Imaging Retina. 2016;47:935–46.PubMedCrossRefGoogle Scholar
  23. 23.
    Champion KJ, Guinea M, Dammai V, Hsu T. Endothelial function of von Hippel-Lindau tumor suppressor gene: control of fibroblast growth factor receptor signaling. Cancer Res. 2008;68(12):4649–57.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Frantzen C, Klasson TD, Links TP, Giles RH, Adam MP, Ardinger HH, et al. Von Hippel-Lindau syndrome. Seattle: University of Washington; 2000. p. 1993–2017.Google Scholar
  25. 25.
    Maher ER. Von Hippel-Lindau disease. Curr Mol Med. 2004;4:833–42.PubMedCrossRefGoogle Scholar
  26. 26.
    Schmidt D, Natt E, Neumann HP. Long-term results of laser treatment for retinal angiomatosis in von Hippel-Lindau disease. Eur J Med Res. 2000;28:47–58.Google Scholar
  27. 27.
    Singh AD, Nouri M, Shields CL, Shields JA, Perez N. Treatment of retinal capillary hemangioma. Ophthalmology. 2002;109:1799–806.PubMedCrossRefGoogle Scholar
  28. 28.
    Parmar DN, Mireskandari K, McHugh D. Transpupillary thermotherapy for retinal capillary hemangioma in von Hippel-Lindau disease. Ophthalmic Surg Lasers. 2000;31:334–6.PubMedGoogle Scholar
  29. 29.
    Garcia-Arumi J, Sararols LH, Cavero L, Escalada F, Corcostegui BF. Therapeutic options for capillary papillary hemangiomas. Ophthalmology. 2000;107:48–54.PubMedCrossRefGoogle Scholar
  30. 30.
    Kreusel KM, Bornfeld N, Lommatzsch A, Wessing A, Foerster MH. Ruthenium-106 brachytherapy for peripheral retinal capillary hemangioma. Ophthalmology. 1998;105:1386–92.CrossRefGoogle Scholar
  31. 31.
    Russo V, Stella A, Barone A, Scott IU, Noci ND. Ruthenium-106 brachytherapy and intravitreal bevacizumab for retinal capillary hemangioma. Int Ophthalmol. 2012;32:71–5.PubMedCrossRefGoogle Scholar
  32. 32.
    Raja D, Benz MS, Murray TG. Salvage external beam radiotherapy of retinal capillary hemangiomas secondary to von Hippel-Lindau disease: visual and anatomical outcomes. Ophthalmology. 2004;111:150–3.PubMedCrossRefGoogle Scholar
  33. 33.
    Schmidt-Erfurth UM, Kusserow C, Barbazetto IA, Laqua H. Benefits and complications of photodynamic therapy of papillary capillary hemangiomas. Ophthalmology. 2002;109(7):1256–66.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Farah ME, Uno F, Höfling-Lima AL, Morales PH, Costa RA, Cardillo JA. Transretinal feeder vessel ligature in von Hippel-Lindau disease. Eur J Ophthalmol. 2001;11(4):386–8.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    McDonald HR, Schatz H, Johnson RN. Vitrectomy in eyes with peripheral retinal angioma associated with traction macular detachment. Ophthalmology. 1996;103:329–35.PubMedCrossRefGoogle Scholar
  36. 36.
    Ziemssen F, Voelker M, Inhoffen W, Bartz-Schmidt KU, Gelisken F. Combined treatment of a juxtapapillary retinal capillary haemangioma with intravitreal bevacizumab and photodynamic therapy. Eye (Lond). 2007;21(8):1125–6.CrossRefGoogle Scholar
  37. 37.
    Wong WT, Liang KJ, Hammel K, Coleman HR, Chew EY. Intravitreal ranibizumab therapy for retinal capillary hemangioblastoma related to von Hippel-Lindau disease. Ophthalmology. 2008;115(11):1957–64.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Muthukumar N, Sundaralingam MP. Retinocephalic vascular malformation: case report. Br J Neurosurg. 1998;12(5):458–60.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Wyburn-Mason R. Arteriovenous aneurysm of midbrain and retina, facial nevi and mental changes. Brain Dev. 1943;66:163–203.CrossRefGoogle Scholar
  40. 40.
    Ponce FA, Han PP, Spetzler RF, Canady A, Feiz-Erfan I. Associated arteriovenous malformation of the orbit and brain: a case of Wyburn-Mason syndrome without retinal involvement. Case report. J Neurosurg. 2001;95(2):346–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Albert DM, Jakobiec FA, editors. Phakomatoses. In: Principles and practice of ophthalmology, 2nd ed. Philadelphia: W. B. Saunders; 2000. p. 3779.Google Scholar
  42. 42.
    Goh D, Malik NN, Gilvarry A. Retinal racemose haemangioma directly communicating with a intramuscular facial cavernous haemangioma. Br J Ophthalmol. 2004;88(6):840–2.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Luo CB, Lasjaunias P, Bhattacharya J. Craniofacial vascular malformations in Wyburn-Mason syndrome. J Chin Med Assoc. 2006;69(12):575–80.PubMedCrossRefGoogle Scholar
  44. 44.
    Wyburn-Mason R. Arteriovenous aneurysm of mid-brain and retina, facial naevi and mental changes. Brain. 1943;66:163–203.CrossRefGoogle Scholar
  45. 45.
    Theron J, Newton TH, Hoyt WF. Unilateral retinocephalic vascular malformations. Neuroradiology. 1974;7:186–96.CrossRefGoogle Scholar
  46. 46.
    Archer DB, Deutman A, Ernest JT, et al. Arteriovenous communications of the retina. Am J Ophthalmol. 1973;75:224–41.PubMedCrossRefGoogle Scholar
  47. 47.
    Bernth-Petersen P. Racemose haemangioma of the retina. Report of three cases with long term follow-up. Acta Ophthalmol. 1979;57(4):669–78.CrossRefGoogle Scholar
  48. 48.
    Mansour AM, Wells AM, Jampol LM, et al. Ocular complications of arteriovenous communications of the retina. Arch Ophthalmol. 1989;107:232–6.PubMedCrossRefGoogle Scholar
  49. 49.
    Schatz H, Chang LF, Ober RR, et al. Central retinal vein occlusion associated with retinal arteriovenous malformation. Ophthalmology. 1993;100:24–30.PubMedCrossRefGoogle Scholar
  50. 50.
    Papageorgiou KI, Ghazi-Nouri SM, Andreou PS. Vitreous and subretinal haemorrhage; an unusual complication of retinal racemose haemangioma. Clin Exp Ophthalmol. 2006;34:176–7.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Barreira AK Jr, Nakashima AF, Takahashi VK, Marques GA, Minelli T, Santo AM. Retinal racemose hemangioma with focal macular involvement. Retin Cases Brief Rep. 2016;10:52–4.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Gass JDM. Cavernous hemangioma of the retina. A neuro-oculocutaneous syndrome. Am J Ophthalmol. 1971;71:799–814.PubMedCrossRefGoogle Scholar
  53. 53.
    Dubovsky J, Zabramski JM, Kurth J, et al. A gene responsible for cavernous malformations of the brain maps to chromosome 7q. Hum Mol Genet. 1995;4:453–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Gunel M, Awad IA, Finberg K, et al. A founder mutation as a cause of cerebral cavernous malformation in Hispanic Americans. N Engl J Med. 1996;334:946–51.PubMedCrossRefGoogle Scholar
  55. 55.
    Gunel M, Awad IA, Finberg K, et al. Genetic heterogeneity of inherited cerebral cavernous malformation. Neurosurgery. 1996;38:1265–71.PubMedGoogle Scholar
  56. 56.
    Wallner EF, Moorman LT. Hemangioma of the optic disc. Arch Ophthalmol. 1955;53:115–7.CrossRefGoogle Scholar
  57. 57.
    Sarraf D, Payne AM, Kitchen ND, Sehmi KS, Downes SM, Bird AC. Familial cavernous hemangioma: an expanding ocular spectrum. Arch Ophthalmol. 2000;118(7):969–73.PubMedGoogle Scholar
  58. 58.
    Lewis RA, Cohen MH, Wise GN. Cavernous haemangioma of the retina and optic disc. A report of three cases and a review of the literature. Br J Ophthalmol. 1975;59(8):422–34.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Drigo P, Mammi I, Battistella PA, et al. Familial cerebral, hepatic, and retinal cavernous angiomas: a new syndrome. Childs Nerv Syst. 1994;10:205–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Weskamp C, Cotlier I. Angioma del cerebro y de la retina con malformaciones capilares de la piel. Arch Oftalmol B Aires. 1940;15:1–10.Google Scholar
  61. 61.
    Zografos L, Gonvers M. Ocular melanocytosis and cavernous haemangioma of the optic disc. Br J Ophthalmol. 1994;78:73–4.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Gunduz K, Ozbayrak N, Okka M, et al. Cavernous hemangioma with cone dysfunction. Ophthalmologica. 1996;210:367–71.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Naftchi S, la Cour M. A case of central visual loss in a child due to macular cavernous haemangioma of the retina. Acta Ophthalmol Scand. 2002;80(5):550–2.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Yamaguchi K, Tamai M. Cavernous hemangioma of the retina in a pediatric patient. Ophthalmologica. 1988;197(3):127–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Bottoni F, Canevini MP, Canger R, Orzalesi N. Twin vessels in familial retinal cavernous hemangioma. Am J Ophthalmol. 1990;15:285–9.CrossRefGoogle Scholar
  66. 66.
    Haller JA, Knox DL. Vitrectomy for persistent vitreous hemorrhage from a cavernous hemangioma of the optic disk. Am J Ophthalmol. 1993;116(1):106–7.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Shanmugam MP, Ramanjulu R, Dwivedi S, Barigali A, Havanje A. Therapeutic surprise! Photodynamic therapy for cavernous hemangioma of the disc. Indian J Ophthalmol. 2017;65:754–7.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Thomas-Sohl KA, Vaslow DF, Maria BL. Sturge-Weber syndrome: a review. Pediatr Neurol. 2004;30(5):303–10.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Shirley MD, Tang H, Gallione CJ, Baugher JD, Frelin LP, Cohen B, et al. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med. 2013;368(21):1971–9.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Rochkind S, Hoffman HJ, Hendrick EB. Sturge-Weber syndrome: natural history and prognosis. J Epilepsy. 1990;3:293–304.Google Scholar
  71. 71.
    Zanzmera P, Patel T, Shah V. Diagnostic dilemma: Sturge-Weber syndrome, without facial nevus. J Neurosci Rural Pract. 2015;6(1):105–7.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Piram M, Lorette G, Sirinelli D, Herbreteau D, Giraudeau B, Maruani A. Sturge-Weber syndrome in patients with facial port-wine stain. Pediatr Dermatol. 2012;29:32–7.PubMedCrossRefGoogle Scholar
  73. 73.
    Ch'ng S, Tan ST. Facial port-wine stains - clinical stratification and risks of neuro-ocular involvement. J Plast Reconstr Aesthet Surg. 2008;61:889–93.PubMedCrossRefGoogle Scholar
  74. 74.
    Higueros E, Roe E, Granell E, Baselga E. Sturge-Weber syndrome: a review. Actas Dermosifiliogr. 2017;108(5):407–17.PubMedCrossRefGoogle Scholar
  75. 75.
    Zhao Y, Tu P, Zhou G, Zhou Z, Lin X, Yang H, et al. Hemoporfin photodynamic therapy for port-wine stain: a randomized controlled trial. PLoS One. 2016;11:e0156219.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Enjolras O, Riche MC, Merland JJ. Facial port-wine stains and Sturge-Weber syndrome. Pediatrics. 1985;76(1):48–51.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Mantelli F, Bruscolini A, La Cava M, Abdolrahimzadeh S, Lambiase A. Ocular manifestations of Sturge-Weber syndrome: pathogenesis, diagnosis, and management. Clin Ophthalmol. 2016;10:871–8.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Weiss JS, Richt R. Glaucoma in phakomatoses. The glaucomas. St. Louis: C. V. Mosby; 1996. p. 899–924.Google Scholar
  79. 79.
    Stevenson RF, Morin JD. Ocular findings in nevus flammeus. Can J Ophthalmol. 1975;10:136–9.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Sullivan TJ, Clarke MP, Morin JD. The ocular manifestations of the Sturge-Weber syndrome. J Pediatr Ophthalmol Strabismus. 1992;29(6):349–56.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Susac JO, Smith JL, Scufo RJ. The “tomato catsup fundus” in the Sturge Weber syndrome. Arch Ophthalmol. 1974;92:69–70.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Addison PK, Papadopoulos M, Nischal KK, Hykin PG. Serous retinal detachment induced by topical bimatoprost in a patient with Sturge Weber syndrome. Eye (Lond). 2011;25:124–5.CrossRefGoogle Scholar
  83. 83.
    Tsipursky MS, Golchet PR, Jampol LM. Photodynamic therapy of choroidal hemangioma in Sturge-Weber syndrome, with a review of treatments for diffuse and circumscribed choroidal hemangioma. Surv Ophthalmol. 2011;56:68–85.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Alberti W. Radiotherapy of choroidal haemangioma. Int J Radiat Oncol Biol Phys. 1986;12:122–3.CrossRefGoogle Scholar
  85. 85.
    Arepalli S, Shields CL, Kaliki S, Emrich J, Komamicky L, Shields JA. Diffuse choroidal hemangioma management with plaque radiotherapy in 5 cases. Ophthalmology. 2013;120:2358–9.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Arevalo JF, Arias JD, Serrano MA. Oral propranolol for exudative retinal detachment in diffuse choroidal hemangioma. Arch Ophthalmol. 2011;129:1373–5.CrossRefGoogle Scholar
  87. 87.
    Shoeibi N, Ahmadieh H, Abrishami M, Poorzand H. Rapid and sustained resolution of serous retinal detachment in Sturge-Weber syndrome after single injection of intravitreal bevacizumab. Ocul Immunol Inflamm. 2011;19:358–60.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Garcia-Arumi J, Ramsay LS, Guraya BC. Trans pupillary thermotherapy for circumscribed choroidal hemangiomas. Ophthalmology. 2000;107:351–7.PubMedCrossRefGoogle Scholar
  89. 89.
    Kamal A, Watts AR, Rennie IG. Indocyanine green enhanced transpupillary thermotherapy of circumscribed choroidal haemangioma. Eye (Lond). 2000;5:701–5.CrossRefGoogle Scholar
  90. 90.
    Gunduz K. Transpupillary thermotherapy in the management of circumscribed choroidal hemangioma. Surv Ophthalmol. 2004;49(3):316–27.PubMedCrossRefGoogle Scholar
  91. 91.
    Ong T, Chia A, Nischal KK. Latanoprost in port wine stain related paediatric glaucoma. Br J Ophthalmol. 2003;87:1091–3.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Yang CB, Freedman SF, Myers JS, et al. Use of latanoprost in the treatment of glaucoma associated with Sturge-Weber syndrome. Am J Ophthalmol. 1998;126:600–2.PubMedCrossRefGoogle Scholar
  93. 93.
    Sakai H, Sakima N, Nakamura Y, Nakamura Y, Hayakawa K, Sawaguchi S. Ciliochoroidal effusion induced by topical latanoprost in a patient with Sturge-Weber syndrome. Jpn J Ophthalmol. 2002;46(5):553–5.PubMedCrossRefGoogle Scholar
  94. 94.
    Gambrelle J, Denis P, Kocaba V, Grange JD. Uveal effusion induced by topical travoprost in a patient with Sturge-Weber-Krabbe syndrome. J Fr Ophtalmol. 2008;31(9):e19.PubMedCrossRefGoogle Scholar
  95. 95.
    Wiederholt WC, Gomez MR, Kurland LT. Incidence and prevalence of tuberous sclerosis in Rochester, Minnesota, 1950 through 1982. Neurology. 1985;35(4):600–3.PubMedCrossRefGoogle Scholar
  96. 96.
    Huang J, Manning BD. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J. 2008;412(2):179–90.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Cohen MM, Pollock-BarZiv S, Johnson SR. Emerging clinical picture of lymphangioleiomyomatosis. Thorax. 2005;60(10):875–9.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Cohen MM, Pollock-BarZiv S, Johnson SR. Tuberous sclerosis complex-associated kidney angiomyolipoma: from contemplation to action. Nephrol Dial Transplant. 2013;28(7):1680–5.CrossRefGoogle Scholar
  99. 99.
    Pirson Y. Cutaneous manifestations of tuberous sclerosis. Ochsner J. 2010;10:200–4.Google Scholar
  100. 100.
    Franz DN, Bissler JJ, McCormack FX. Tuberous sclerosis complex: neurological, renal and pulmonary manifestations. Neuropediatrics. 2010;41(5):199–208.PubMedCrossRefGoogle Scholar
  101. 101.
    Krueger DA, Northrup H, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49(4):255–65.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Rowley SA, O’Callaghan FJ, Osborne JP. Ophthalmic manifestations of tuberous sclerosis: a population based study. Br J Ophthalmol. 2001;85(4):420–3.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Nyboer JH, Robertson DM, Gomez MR. Retinal lesions in tuberous sclerosis. Arch Ophthalmol. 1976;94(8):1277–80.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Brown CG, Shields JA. Tumors of the optic nerve head. Surv Ophthalmol. 1985;29:239–64.PubMedCrossRefGoogle Scholar
  105. 105.
    Atkinson A, Sanders MD, Wong V. Vitreous haemorrhage in tuberous sclerosis. Br J Ophthalmol. 1973;57:773–9.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Lopez JP, Ossandón D, Miller P, Sánchez L, Winter A. Unilateral eyelid angiofibroma with complete blepharoptosis as the presenting sign of tuberous sclerosis. J AAPOS. 2009;13(4):413–4.PubMedCrossRefGoogle Scholar
  107. 107.
    Robertson DM. Ophthalmic manifestations of tuberous sclerosis. Ann N Y Acad Sci. 1991;615:17–25.PubMedCrossRefGoogle Scholar
  108. 108.
    Shields CL, Benevides R, Materin MA, Shields JA. Optical coherence tomography of retinal astrocytic hamartoma in 15 cases. Ophthalmology. 2006;113(9):1553–7.PubMedCrossRefGoogle Scholar
  109. 109.
    Soliman W, Larsen M, Sander B, Wegener M, Milea D. Optical coherence tomography of astrocytic hamartomas in tuberous sclerosis. Acta Ophthalmol Scand. 2007;85(4):454–5.PubMedCrossRefGoogle Scholar
  110. 110.
    Xu L, Burke TR, Greenberg JP, Mahajan VB, Tsang SH. Infrared imaging and optical coherence tomography reveal early-stage astrocytic hamartomas not detectable by fundoscopy. Am J Ophthalmol. 2012;153(5):883–9.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Vrabec TR, Augsburger JJ. Exudative retinal detachment due to small noncalcified retinal astrocytic hamartoma. Am J Ophthalmol. 2003;136(5):952–4.PubMedCrossRefGoogle Scholar
  112. 112.
    Bloom SM, Mahl CF. Photocoagulation for serous detachment of the macula secondary to retinal astrocytoma. Retina. 1991;11:416–22.PubMedCrossRefGoogle Scholar
  113. 113.
    Mennel S, Hausmann N, Meyer CH, Peter S. Photodynamic therapy for exudative hamartoma in tuberous sclerosis. Arch Ophthalmol. 2006;124(4):597–9.CrossRefGoogle Scholar
  114. 114.
    Saito W, Kase S, Ohgami K, Mori S, Ohno S. Intravitreal anti-vascular endothelial growth factor therapy with bevacizumab for tuberous sclerosis with macular oedema. Acta Ophthalmol. 2010;88(3):377–80.PubMedCrossRefGoogle Scholar
  115. 115.
    Shields JA, Eagle RC Jr, Shields CL, Marr BP. Aggressive retinal astrocytomas in 4 patients with tuberous sclerosis complex. Arch Ophthalmol. 2005;123(6):856–63.PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Eskelin S, Tommila P, Palosaari T, Kivelä T. Photodynamic therapy with verteporfin to induce regression of aggressive retinal astrocytomas. Acta Ophthalmol. 2008;86(7):794–9.PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Tomida M, Mitamura Y, Katome T, Eguchi H, Naito T, Harada T. Aggressive retinal astrocytoma associated with tuberous sclerosis. Clin Ophthalmol. 2012;6:715–20.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Jett K, Friedman JM. Clinical and genetic aspects of neurofibromatosis 1. Genet Med. 2010;12(1):1–11.PubMedCrossRefGoogle Scholar
  119. 119.
    Riccardi VM. Neurofibromatosis: past, present, and future. N Engl J Med. 1991;324(18):1283–5.PubMedCrossRefGoogle Scholar
  120. 120.
    Hirbe AC, Gutmann DH. Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol. 2014;13(8):834–43.PubMedCrossRefGoogle Scholar
  121. 121.
    Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol. 1988;45(5):575–8.Google Scholar
  122. 122.
    Carey JC. Neurofibromatosis-Noonan syndrome. Am J Med Genet. 1998;75(3):263–4.PubMedCrossRefGoogle Scholar
  123. 123.
    Huson MS, Hughes CRA. The neurofibromatoses: a pathogenetic and clinical overview. London: Chapman & Hall; 1994.Google Scholar
  124. 124.
    Abdolrahimzadeh S, Felli L, Plateroti R, Plateroti AM, Giustini S, Calvieri S, et al. Morphologic and vasculature features of the choroid and associated choroid-retinal thickness alterations in neurofibromatosis type 1. Br J Ophthalmol. 2015;99(6):789–93.PubMedCrossRefGoogle Scholar
  125. 125.
    Recupero SM, Plateroti R, Abdolrahimzadeh S, et al. Lisch nodules in neurfibromatosis type 1: relationship to age and cutaneous neurfibromas. Ann Ophthalmol Glaucoma. 1996;28(3):178–83.Google Scholar
  126. 126.
    Ragge NK, Falk RE, Cohen WE, Murphree AL. Images of Lisch nodules across the spectrum. Eye (Lond). 1993;7:95–101.CrossRefGoogle Scholar
  127. 127.
    Cassiman C, Legius E, Spileers W, Casteels I. Ophthalmological assessment of children with neurofibromatosis type 1. Eur J Pediatr. 2013;172(10):1327–33.PubMedCrossRefGoogle Scholar
  128. 128.
    Destro M, D’Amico DJ, Gragoudas ES, Brockhurst RJ, Pinnolis MK, Albert DM, et al. Retinal manifestations of neurofibromatosis. Diagnosis and management. Arch Ophthalmol. 1991;109(5):662–6.PubMedCrossRefGoogle Scholar
  129. 129.
    Ruggieri M, Pavone P, Polizzi A, Di Pietro M, Scuderi A, Gabriele A, et al. Ophthalmological manifestations in segmental neurofibromatosis type 1. Br J Ophthalmol. 2004;88(11):1429–33.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Abdolrahimzadeh S, Piraino DC, Plateroti R, Scuderi G, Recupero SM. Ocular alterations in a rare case of segmental neurofibromatosis type 1 with a non-classified mutational variant of the NF-1 gene. Ophthalmic Genet. 2016;37(2):214–6.PubMedCrossRefGoogle Scholar
  131. 131.
    Font RL, Moura RA, Shetlar DJ, Martinez JA, McPherson AR. Combined hamartoma of sensory retina and retinal pigment epithelium. Retina. 1989;9(4):302–11.PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Helbig H, Niederberger H. Presumed combined hamartoma of the retina and retinal pigment epithelium with preretinal neovascularization. Am J Ophthalmol. 2003;136(6):1157–9.PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Moschos M, Ladas ID, Zafirakis PK, Kokolakis SN, Theodossiadis GP. Recurrent vitreous hemorrhages due to combined pigment epithelial and retinal hamartoma: natural course and indocyanine green angiographic findings. Ophthalmologica. 2001;215(1):66–9.PubMedCrossRefPubMedCentralGoogle Scholar
  134. 134.
    Kahn D, Goldberg MF, Jednock N. Combined retinal-retina pigment epithelial hamartoma presenting as a vitreous hemorrhage. Retina. 1984;4:40–3.PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Schachat AP, Shields JA, Fine SL, et al. Combined hamartomas of the retina and retinal pigment epithelium. Ophthalmology. 1984;91:1609–15.PubMedCrossRefGoogle Scholar
  136. 136.
    Mason JO, Kleiner R. Combined hamartoma of the retina and retinal pigment epithelium associated with epiretinal membrane and macular hole. Retina. 1997;17:160–2.PubMedPubMedCentralGoogle Scholar
  137. 137.
    Verma L, Venkatesh P, Lakshmaiah CN, Tewari HK. Combined hamartoma of the retina and retinal pigment epithelium with full thickness retinal hole and without retinoschisis. Ophthalmic Surg Lasers. 2000;31(5):423–6.PubMedGoogle Scholar
  138. 138.
    Ryan SJ. Combined hamartoma of the retina and retinal pigment epithelium. In: Retina. St. Louis: Mosby; 2001. p. 640–6.Google Scholar
  139. 139.
    McDonald HR, Abrams GW, Burke JM, Neuwirth J. Clinicopathologic results of vitreous surgery for epiretinal membranes in patients with combined retinal and retinal pigment epithelial hamartomas. Am J Ophthalmol. 1985;100:806–13.PubMedCrossRefPubMedCentralGoogle Scholar
  140. 140.
    Sappenfield DL, Gitter KA. Surgical intervention for combined retinal-retinal pigment epithelial hamartoma. Retina. 1990;10(2):119–24.PubMedCrossRefGoogle Scholar
  141. 141.
    Stallman JB. Visual improvement after pars plana vitrectomy and membrane peeling for vitreoretinal traction associated with combined hamartoma of the retina and retinal pigment epithelium. Retina. 2002;22(1):101–4.PubMedCrossRefGoogle Scholar
  142. 142.
    Kushner BJ. Functional amblyopia associated with organic ocular disease. Am J Ophthalmol. 1981;91:39–45.PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    Inoue M, Noda K, Ishida S, Yamaguchi T, Nagai N, Shinoda K, et al. Successful treatment of subfoveal choroidal neovascularization associated with combined hamartoma of the retina and retinal pigment epithelium. Am J Ophthalmol. 2004;138(1):155–6.PubMedCrossRefPubMedCentralGoogle Scholar
  144. 144.
    Vianna RN, Pacheco DF, Vasconcelos MM, de Laey JJ. Combined hamartoma of the retina and retinal pigment epithelium associated with neurofibromatosis type-1. Int Ophthalmol. 2001;24(2):63–6.PubMedCrossRefPubMedCentralGoogle Scholar
  145. 145.
    De Potter P, Stanescu D, Caspers-Velu L, Hofmans A. Photo essay: combined hamartoma of the retina and retinal pigment epithelium in Gorlin syndrome. Arch Ophthalmol. 2000;118(7):1004–5.PubMedPubMedCentralGoogle Scholar
  146. 146.
    Stupp T, Pavlidis M, Bochner T, Thanos S. Poland anomaly associated with ipsilateral combined hamartoma of retina and retinal pigment epithelium. Eye (Lond). 2004;18(5):550–2.CrossRefGoogle Scholar
  147. 147.
    Demirci H, Shields CL, Shields JA. New ophthalmic manifestations of branchio-oculo-facial syndrome. Am J Ophthalmol. 2005;139(2):362–4.PubMedCrossRefPubMedCentralGoogle Scholar
  148. 148.
    Arepalli S, Pellegrini M, Ferenczy SR, Shields CL. Combined hamartoma of the retina and retinal pigment epithelium: findings on enhanced depth imaging optical coherence tomography in eight eyes. Retina. 2014;34(11):2202–7.PubMedCrossRefPubMedCentralGoogle Scholar
  149. 149.
    Fonseca RA, Dantas MA, Kaga T, Spaide RF. Combined hamartoma of the retina and retinal pigment epithelium associated with juvenile nasopharyngeal angiofibroma. Am J Ophthalmol. 2001;132(1):131–2.PubMedCrossRefPubMedCentralGoogle Scholar
  150. 150.
    Tulchinsky H, Keidar A, Strul H, et al. Extracolonic manifestations of familial adenomatous polyposis after proctocolectomy. Arch Surg. 2005;140(2):159–63.PubMedCrossRefPubMedCentralGoogle Scholar
  151. 151.
    Amin AR, Jakobiec FA, Dreyer EB. Ocular syndromes associated with systemic malignancy. Int Ophthalmol Clin. 1997;37:281–302.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  • Mahesh Shanmugam Palanivelu
    • 1
  • Pradeep Sagar
    • 1
  1. 1.Department of Vitreo-Retina and Ocular OncologySankara Eye HospitalBangaloreIndia

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