Ocular alterations, molecular findings, and three novel pathological mutations in a series of NF2 patients

  • Vanessa WaisbergEmail author
  • Luiz Oswaldo Carneiro Rodrigues
  • Márcio Bittar Nehemy
  • Luciana Bastos-Rodrigues
  • Débora Marques de Miranda



To evaluate ophthalmological and molecular findings in eight patients with a clinical diagnosis of neurofibromatosis type 2 (NF2). New pathological mutations are described and variability in the ophthalmic phenotype and NF2 allelic heterogeneity are discussed.


Eye examination was performed in eight NF2 patients, and it included the measurement of the visual acuity, biomicroscopy, dilated fundus examination, color fundus photography, infrared photography, and spectral domain optical coherence tomography (SD-OCT). Molecular analysis was performed with whole-exome sequencing using DNA derived from peripheral blood mononuclear cells from each individual.


Ophthalmological features were present in all patients, ranging from subtle retinal alterations identified only using SD-OCT to severe ocular damage present at birth. Six mutations were observed: two patients with stop codon mutation as shown on table 1 and result section, three patients with frameshift mutation as shown on table 1 and result section. Three novel mutations were found among them.


It is a descriptive study of a rare disease, with poor previous literature. Clinical and genetic data are shown, reviving the need to further studies to clarify the genotype-phenotype correlations in NF2.


Hamartoma Mutation Neurofibromatosis type 2 Optical coherence tomography Retina Vestibular schwannoma 



This research was partially supported by Federal University of Minas Gerais, Brazil.


This study was partially funded by FAPEMIG (Grupos Emergentes).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

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

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

Informed consent

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


  1. 1.
    NIH conference statement (1990) Neurofibromatosis 1 (von Recklinghausen disease) and neurofibromatosis 2 (bilateral acoustic neurofibromatosis). Ann Intern Med 113:39–52CrossRefGoogle Scholar
  2. 2.
    Seizinger BR, Rouleau GA, Ozelius LJ et al (1987) Genetic linkage of von Recklinghausen neurofibromatosis to the nerve growth factor receptor gene. Cell 49:589–594CrossRefGoogle Scholar
  3. 3.
    Roleau G, Seizinger BR, Ozelius LG et al (1987) Genetic linkage analysis of bilateral acoustic neurofibromatosis to a DNA marker on chromosome 22. Nature 329:246–248CrossRefGoogle Scholar
  4. 4.
    Cooper J, Giancotti FG (2014) Molecular insights into NF2/Merlin tumor suppressor function. FEBS Lett 16:2743–2752CrossRefGoogle Scholar
  5. 5.
    Rodrigues LO, Batista PB, Goloni-Bertollo EM et al (2014) Neurofibromatosis part 1 – diagnosis and differential diagnosis. Arq Neuropsiquiatr 72:241–250CrossRefGoogle Scholar
  6. 6.
    Basser ME, Kuramoto L, Woods R et al (2005) The location of constitutional neurofibromatosis 2 (NF2) splice site mutations is associated with the severity of NF2. J Med Genet 42:540–546CrossRefGoogle Scholar
  7. 7.
    Evans DG, Howard E, Giblin C et al (2010) Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet 152A:327–332CrossRefGoogle Scholar
  8. 8.
    Antinheimo J, Sankila R, Carpén O, Pukkala E, Sainio M, Jääskeläinen J (2000) Population-based analysis of sporadic and type 2 neurofibromatosis-associated meningiomas and schwannomas. Neurology 54:71–76CrossRefGoogle Scholar
  9. 9.
    Evans DGR (2009) Neurofibromatosis type 2 (NF2): a clinical and molecular review. Orphanet J Rare Dis 4:16CrossRefGoogle Scholar
  10. 10.
    Feucht M, Kluwe L, Mautner VF, Richard G (2008) Correlation of nonsense and frameshift mutations with severity of retinal abnormalities in neurofibromatosis 2. Arch Ophthalmol 126:1376–1380CrossRefGoogle Scholar
  11. 11.
    Parry DM, MacCollin MM, Kaiser-Kupfer MI et al (1996) Germ-line mutations in the neurofibromatosis 2 gene: correlations with disease severity and retinal abnormalities. Am J Hum Genet 59:529–539Google Scholar
  12. 12.
    Moon KH, Kim HT, Lee D, Rao MB, Levine EM, Lim DS, Kim JW (2018) Differential expression of NF2 in neuroepithelial compartments is necessary for mammalian eye development. Dev Cell 44:13–28CrossRefGoogle Scholar
  13. 13.
    Kaye LD, Rothner AD, Beauchamp GR, Meyers SM, Estes ML (1992) Ocular findings associated with neurofibromatosis type II. Ophthalmology 99:1424–1429CrossRefGoogle Scholar
  14. 14.
    Bosch MM, Boltshauser E, Harpes P, Landau K (2006) Ophthalmologic findings and a long-term course in patients with neurofibromatosis type 2. Am J Ophthalmol 141:1068–1077CrossRefGoogle Scholar
  15. 15.
    Feucht M, Griffiths B, Niemüller I, Haase W, Richard G, Mautner VF (2008) Neurofibromatosis 2 leads to higher incidence of strabismological and neuro-ophthalmological disorders. Acta Ophthalmol 86:882–886CrossRefGoogle Scholar
  16. 16.
    Waisberg V, Rodrigues LO, Nehemy MB, Frassom M, De Miranda DM (2016) Spectral-domain optical coherence tomography findings in neurofibromatosis type 2. Inves Ophthalmol Vis Sci 57:OCT262–OCT267CrossRefGoogle Scholar
  17. 17.
    Schwede T (2003) SWISS-MODEL: an automated protein homology-modeling server. Nucleic Acids Res 31(13):3381–3385CrossRefGoogle Scholar
  18. 18.
    Ahronowitz I, Xin W, Kiely R, Sims K, Maccollin M, Nunes FP (2007) Mutational spectrum of the NF2 gene: a meta-analysis of 12 years of research and diagnostic laboratory findings. Hum Mutat 28:1–12CrossRefGoogle Scholar
  19. 19.
    Kluwe L, Mautner V, Heinrich B et al (2003) Molecular study of frequency of mosaicism in neurofibromatosis 2 patients with bilateral vestibular schwannomas. J Med Genet 40:109–114CrossRefGoogle Scholar
  20. 20.
    Kluwe L, Mautner VF (1998) Mosaicism in sporadic neurofibromatosis 2 patients. Hum Mol Genet 7:2051–2055CrossRefGoogle Scholar
  21. 21.
    Chan C, Koch CA, Kaiser-Kupfer MI et al (2002) Loss of heterozygosity for the NF gene in retinal and optic nerve lesions of patients with neurofibromatosis 2. J Pathol 198:14–20CrossRefGoogle Scholar
  22. 22.
    Viola F, Villani E, Natacci F et al (2012) Choroidal abnormalities detected by near-infrared reflectance imaging as a new diagnostic criterion for neurofibromatosis 1. Ophthalmology 119:369–375CrossRefGoogle Scholar
  23. 23.
    Moramarco A, Giustini S, Nofroni I, Mallone F, Miraglia E, Lacovino 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 256:307–311CrossRefGoogle Scholar
  24. 24.
    Landau K, Yasargil GM (1993) Ocular fundus in neurofibromatosis type 2. Br J Ophthalmol 77:646–649CrossRefGoogle Scholar
  25. 25.
    Meyers SM, Gutman FA, Kaye LD, Rothner AD (1995) Retinal changes associated with neurofibromatosis 2. Trans Am Ophthalmol Soc 93:245–257Google Scholar
  26. 26.
    Sisk RA, Berrocal AM, Schefler AC, Dubovy SR, Bauer MS (2010) Epirretinal membranes indicate a severe phenotype of neurofibromatosis type 2. Retina 30:51–58CrossRefGoogle Scholar
  27. 27.
    McLaughlin ME, Pepin SM, MacCollin MM, Choopong P, Lessell S (2007) Ocular pathologic findings of neurofibromatosis type 2. Arch Ophthalmol 125:389–394CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of OphthalmologyFederal University of Minas GeraisBelo HorizonteBrazil
  2. 2.Department of Clinical Medicine and Neurofibromatosis Reference CenterFederal University of Minas GeraisBelo HorizonteBrazil
  3. 3.Department of NutritionFederal University of Minas GeraisBelo HorizonteBrazil
  4. 4.Department of Pediatrics and Molecular ScienceFederal University of Minas GeraisBelo HorizonteBrazil

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