Ocular surface involvement in patients with neurofibromatosis type 1 syndrome



The aim of this study is to evaluate ocular surface morphological and functional changes in patients with neurofibromatosis type 1 (NF1).


Twenty-eight patients with NF1 and 14 healthy subjects were included in this study. All participants underwent a medical history collection, a complete ophthalmological examination including slit lamp exam and assessment of best-corrected visual acuity (BCVA), corneal sensitivity, and lacrimal function (Schirmer test and fluorescein tear break-up time test). Corneal nerves’ morphology and endothelial cells density were evaluated by in vivo corneal confocal microscopy (IVCM). Tear and conjunctiva epithelium samples were collected to evaluate nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) tear levels and conjunctival expression of their receptors TrkA and p75NTR.


Patients with NF1 showed a significant decrease of FTBUT when compared with healthy subjects (p < 0.001). Corneal sensitivity was ≤ 50 mm in 46% of NF1 patients. IVCM showed a significant increase of corneal nerve branching and of corneal endothelial cells density. No significant difference was observed between the two groups on NGF and BDNF tear levels and conjunctival expression of their receptors.


This study demonstrated the presence of ocular surface changes in NF-1 patients including decrease of tear stability and of corneal sensitivity. Patients with NF1 also showed changes of corneal endothelial cells’ density.

This is a preview of subscription content, access via your institution.

Fig. 1


  1. 1.

    Anderson JL, Gutmann DH (2015) Neurofibromatosis type 1. Handb Clin Neurol 132:75–86

    PubMed  Google Scholar 

  2. 2.

    Menon AG, Anderson KM, Riccardi VM, Chung RY, Whaley JM, Yandell DW, Farmer GE, Freiman RN, Lee JK, Li FP et al (1990) Chromosome 17p deletions and p53 gene mutations associated with the formation of malignant neurofibrosarcomas in von Recklinghausen neurofibromatosis. Proc Natl Acad Sci U S A 87(14):5435–5439

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Gutmann DH, Ferner RE, Listernick RH, Korf BR, Wolters PL, Johnson KJ (2017) Neurofibromatosis type 1. Nat Rev Dis Primers 3:17004

    PubMed  Google Scholar 

  4. 4.

    Ohba Y, Mochizuki N, Yamashita S, Chan AM, Schrader JW, Hattori S, Nagashima K, Matsuda M (2000) Regulatory proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3. J Biol Chem 275(26):20020–20026

    CAS  PubMed  Google Scholar 

  5. 5.

    Viola F, Villani E, Natacci F, Selicorni A, Melloni G, Vezzola D, Barteselli G, Mapelli C, Pirondini C, Ratiglia R (2012) Choroidal abnormalities detected by near-infrared reflectance imaging as a new diagnostic criterion for neurofibromatosis 1. Ophthalmology. 119(2):369–375

    PubMed  Google Scholar 

  6. 6.

    Moramarco A, Giustini S, Nofroni I, Mallone F, Miraglia E, Iacovino C, Calvieri S, Lambiase A (2018) Near-infrared imaging: an in vivo, non-invasive diagnostic tool in neurofibromatosis type 1. Graefes Arch Clin Exp Ophthalmol 256(2):307–311

    PubMed  Google Scholar 

  7. 7.

    Richetta A, Giustini S, Recupero SM, Pezza M, Carlomagno V, Amoruso G, Calvieri S (2004) Lisch nodules of the iris in neurofibromatosis type 1. J Eur Acad Dermatol Venereol 18(3):342–344

    CAS  PubMed  Google Scholar 

  8. 8.

    Hirbe AC, Gutmann DH (2014) Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol 13(8):834–843

    PubMed  Google Scholar 

  9. 9.

    Makino S, Tampo H (2013) Optical coherence tomography imaging of choroidal abnormalities in neurofibromatosis type 1. Case Rep Ophthalmol Med 2013:292981

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Makino S, Tampo H, Arai Y, Obata H (2014) Correlations between choroidal abnormalities, Lisch nodules, and age in patients with neurofibromatosis type 1. Clin Ophthalmol 8:165–168

    PubMed  Google Scholar 

  11. 11.

    Vagge A, Camicione P, Capris C, Sburlati C, Panarello S, Calevo MG, Traverso CE, Capris P (2015) Choroidal abnormalities in neurofibromatosis type 1 detected by near-infrared reflectance imaging in paediatric population. Acta Ophthalmol 93(8):e667–e671

    PubMed  Google Scholar 

  12. 12.

    Parrozzani R, Clementi M, Frizziero L, Miglionico G, Perrini P, Cavarzeran F, Kotsafti O, Comacchio F, Trevisson E, Convento E, Fusetti S, Midena E (2015) In vivo detection of choroidal abnormalities related to NF1: feasibility and comparison with standard NIH diagnostic criteria in pediatric patients. Invest Ophthalmol Vis Sci 56(10):6036–6042

    PubMed  Google Scholar 

  13. 13.

    Vagge A, Capris P, Traverso CE (2016) Choroidal abnormalities detected by near-infrared imaging (NIR) in pediatric patients with neurofibromatosis type 1 (NF1). Invest Ophthalmol Vis Sci 57(3):774

    CAS  PubMed  Google Scholar 

  14. 14.

    Cassiman C, Casteels I, Jacob J, Plasschaert E, Brems H, Dubron K, Keer KV, Legius E (2017) Choroidal abnormalities in café-au-lait syndromes: a new differential diagnostic tool? Clin Genet 91(4):529–535

    CAS  PubMed  Google Scholar 

  15. 15.

    Parrozzani R, Pilotto E, Clementi M, Frizziero L, Leonardi F, Convento E, Miglionico G, Pulze S, Perrini P, Trevisson E, Cassina M, Midena E (2018) Retinal vascular abnormalities in a large cohort of patients affected by neurofibromatosis type 1: a study using optical coherence tomography angiography. Retina. 38(3):585–593

    PubMed  Google Scholar 

  16. 16.

    Barnett C, Alon T, Abraham A, Kim RH, McCuaig JM, Kongkham P, Maurice C, Suppiah S, Zadeh G, Bril V (2019) Evidence of small-fiber neuropathy in neurofibromatosis type 1. Muscle Nerve 60(6):673–678

    CAS  PubMed  Google Scholar 

  17. 17.

    Neurofibromatosis. Paper presented at the National Institutes of Health Consensus Development Conference, Bethesda, 13–15 July, 1987

  18. 18.

    Wolffsohn JS, Arita R, Chalmers R, Djalilian A, Dogru M, Dumbleton K, Gupta PK, Karpecki P, Lazreg S, Pult H, Sullivan BD, Tomlinson A, Tong L, Villani E, Yoon KC, Jones L, Craig JP (2017) TFOS DEWS II diagnostic methodology report. Ocul Surf 15(3):539–574

    PubMed  Google Scholar 

  19. 19.

    Lambiase A, Sacchetti M, Mastropasqua A, Bonini S (2013) Corneal changes in neurosurgically induced neurotrophic keratitis. JAMA Ophthalmol 131(12):1547–1553

    PubMed  Google Scholar 

  20. 20.

    Bruscolini A, Lambiase A, Segatto M, La Cava M, Nebbioso M, Sacchetti M (2019) Evaluation of IL8 pathway on the ocular surface: new insights in patients with ocular mucous membrane pemphigoid. Acta Ophthalmol 98(2):e173–e177

    PubMed  Google Scholar 

  21. 21.

    Sacchetti M, Bruscolini A, Lambiase A (2019) Neurotrophic factors and nerve growth factor in ocular allergy. Paper presented at the Curr Opin Allergy Clin Immunol 19(5):510–516

  22. 22.

    Sacchetti M, Macchi I, Tiezzi A, La Cava M, Massaro-Giordano G, Lambiase A (2016) Pathophysiology of corneal dystrophies: from cellular genetic alteration to clinical findings. J Cell Physiol 231(2):261–269

    CAS  PubMed  Google Scholar 

  23. 23.

    Edward DP, Morales J, Bouhenni RA, Patil J, Edward PR, Cummings TJ, Chaudhry IA, Alkatan H (2012) Congenital ectropion uvea and mechanisms of glaucoma in neurofibromatosis type 1: new insights. Ophthalmology. 119(7):1485–1494

    PubMed  Google Scholar 

  24. 24.

    Rasmussen SA, Friedman JM (2000) NF1 gene and neurofibromatosis 1. Am J Epidemiol 151(1):33–40

    CAS  PubMed  Google Scholar 

  25. 25.

    Brownstein S, Little JM (1983) Ocular neurofibromatosis. Ophthalmology. 90(12):1595–1599

    CAS  PubMed  Google Scholar 

  26. 26.

    Vogel KS, Brannan CI, Jenkins NA, Copeland NG, Parada LF (1995) Loss of neurofibromin results in neurotrophin-independent survival of embryonic sensory and sympathetic neurons. Cell. 82(5):733–742

    CAS  PubMed  Google Scholar 

  27. 27.

    Fabricant RN, Todaro GJ (1981) Increased serum levels of nerve growth factor in von Recklinghausen's disease. Arch Neurol 38(7):401–405

    CAS  PubMed  Google Scholar 

  28. 28.

    Fell SM, Li S, Wallis K, Kock A, Surova O, Rraklli V, Höfig CS, Li W, Mittag J, Henriksson MA, Kenchappa RS, Holmberg J, Kogner P, Schlisio S (2017) Neuroblast differentiation during development and in neuroblastoma requires KIF1Bβ-mediated transport of TRKA. Genes Dev 31(10):1036–1053

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Powers JF, Evinger MJ, Tsokas P, Bedri S, Alroy J, Shahsavari M, Tischler AS (2000) Pheochromocytoma cell lines from heterozygous neurofibromatosis knockout mice. Cell Tissue Res 302(3):309–320

    CAS  PubMed  Google Scholar 

  30. 30.

    Pincelli C (2017) p75 neurotrophin receptor in the skin: beyond its neurotrophic function. Front Med (Lausanne) 4:22

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Lambiase A, Manni L, Bonini S, Rama P, Micera A, Aloe L (2000) Nerve growth factor promotes corneal healing: structural, biochemical, and molecular analyses of rat and human corneas. Invest Ophthalmol Vis Sci 41(5):1063–1069

    CAS  PubMed  Google Scholar 

  32. 32.

    Lambiase A, Rama P, Bonini S, Caprioglio G, Aloe L (1998) Topical treatment with nerve growth factor for corneal neurotrophic ulcers. N Engl J Med 338(17):1174–1180

    CAS  PubMed  Google Scholar 

  33. 33.

    Bruscolini A, Amorelli GM, Rama P, Lambiase A, La Cava M, Abbouda A (2017) Involvement of the anterior segment of the eye in patients with mucopolysaccharidoses: A review of reported cases and updates on the latest diagnostic instrumentation. Semin Ophthalmol 32(6):707–714

    CAS  PubMed  Google Scholar 

  34. 34.

    Tavakoli M, Mitu-Pretorian M, Petropoulos IN, Fadavi H, Asghar O, Alam U, Ponirakis G, Jeziorska M, Marshall A, Efron N, Boulton AJ, Augustine T, Malik RA (2013) Corneal confocal microscopy detects early nerve regeneration in diabetic neuropathy after simultaneous pancreas and kidney transplantation. Diabetes. 62(1):254–260

    CAS  PubMed  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Antonietta Moramarco.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee of Sapienza University of Rome and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Moramarco, A., Sacchetti, M., Franzone, F. et al. Ocular surface involvement in patients with neurofibromatosis type 1 syndrome. Graefes Arch Clin Exp Ophthalmol 258, 1757–1762 (2020). https://doi.org/10.1007/s00417-020-04717-5

Download citation


  • Neurofibromatosis type 1
  • Ocular surface
  • Break up time
  • Neurotrophins
  • Corneal endothelial cells