Skip to main content
SpringerLink
Log in

Histologic correlates of “Choroidal abnormalities” in Neurofibromatosis type 1 (NF1)

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disorder characterized by proliferation of cells from neural crest origin. The most common manifestations are cutaneous, neurologic, skeletal and ocular. The distinction of NF1 from other syndromes with multiple café-au-lait macules may be difficult in the pediatric age group, and ocular findings, especially Lisch nodules (i.e., melanocytic hamartomas on the irides), are a useful, early diagnostic tool. In recent years, novel ocular manifestations descriptively referred to as “choroidal abnormalities”, choroidal “hyperpigmented spots” and “retinal vascular abnormalities” have been recognized in NF1. Choroidal abnormalities (CA) appear as bright patchy nodules that can be best detected with near-infrared ocular coherence tomography imaging (NIR-OCT). Because of their high specificity and sensitivity for NF1, CA have been added as an ocular diagnostic criterion of NF1 as an alternative to Lisch nodules. Although CA are important ocular diagnostic criteria for NF1, the histologic correlates are controversial. We present the postmortem ocular pathology findings of an NF1 patient for whom clinical notes and ocular imaging were available. Findings in this patient included choroidal hyperpigmented spots on funduscopy and retinal vascular abnormalities, both of which have been reported to be closely associated with CA. Histologic examination of the eyes showed multiple clusters of melanocytes of varying sizes in the choroid. Pathologic review of 12 additional postmortem eyes from 6 NF1 patients showed multiple, bilateral choroidal melanocytic aggregates in all eyes. These findings suggest that the CA seen on NIR-OCT and the hyperpigmented spots seen clinically in NF1 patients are manifestations of multifocal choroidal melanocytic clusters, consistent with choroidal melanocytic hamartomas. Lisch nodules, often multiple, were present in all eyes with morphology that differed from the choroidal hamartomas. As such, although CA and Lisch nodules are melanocytic hamartomas, there are clear phenotypical differences in their morphologies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. (1988) Neurofibromatosis Conference statement. National Institutes of Health Consensus Development ConferenceArch Neurol 45 575

  2. Abdolrahimzadeh S, Felli L, Piraino DC, Mollo R, Calvieri S, Recupero SM (2014) Retinal microvascular abnormalities overlying choroidal nodules in neurofibromatosis type 1. BMC Ophthalmol 14:146. https://doi.org/10.1186/1471-2415-14-146

    Article  PubMed  PubMed Central  Google Scholar 

  3. Abdolrahimzadeh S, Felli L, Plateroti R, Plateroti AM, Giustini S, Calvieri S et al (2015) Morphologic and vasculature features of the choroid and associated choroid-retinal thickness alterations in neurofibromatosis type 1. Br J Ophthalmol 99:789–793. https://doi.org/10.1136/bjophthalmol-2014-306062

    Article  PubMed  Google Scholar 

  4. Battiston AJDL, Shields CL (2019) Neurofibromatosis type-1 with retinal microvascular corkscrew tortuosity. Indian J Ophthalmol 67:2054–2055

    Article  PubMed  PubMed Central  Google Scholar 

  5. Beauchamp GR (1995) Neurofibromatosis type 1 in children. Trans Am Ophthalmol Soc 93:445–472

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Cassiman C, Casteels I, Jacob J, Plasschaert E, Brems H, Dubron K et al (2017) Choroidal abnormalities in café-au-lait syndromes: a new differential diagnostic tool? Clin Genet 91:529–535. https://doi.org/10.1111/cge.12873

    Article  CAS  PubMed  Google Scholar 

  7. Cosmo E, Frizziero L, Gabbiato I, Midena G, Trevisson E, Parrozzani R (2022) Choroidal Abnormalities in Pediatric NF1: A Cohort Natural History Study. Cancers 14:1423

    Article  PubMed  PubMed Central  Google Scholar 

  8. Ferner RE, Gutmann DH (2013) Neurofibromatosis type 1 (NF1): diagnosis and management. Handb Clin Neurol 115:939–955. https://doi.org/10.1016/B978-0-444-52902-2.00053-9

    Article  PubMed  Google Scholar 

  9. Goktas S, Sakarya Y, Ozcimen M, Alpfidan I, Uzun M, Sakarya R et al (2014) Frequency of choroidal abnormalities in pediatric patients with neurofibromatosis type 1. J Pediatr Ophthalmol Strabismus 51:204–208. https://doi.org/10.3928/01913913-20140513-02

    Article  PubMed  Google Scholar 

  10. Kurosawa AKH (1982) Ovoid bodies in choroidal neurofibromatosis. Arch Ophthlmol 100:1939–1941

    Article  CAS  Google Scholar 

  11. Legius E, Messiaen L, Wolkenstein P, Pancza P, Avery RA, Berman Y et al (2021) Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genet Med 23:1506–1513. https://doi.org/10.1038/s41436-021-01170-5

    Article  PubMed  PubMed Central  Google Scholar 

  12. Lubs ML, Bauer MS, Formas ME, Djokic B (1991) Lisch nodules in neurofibromatosis type 1. N Engl J Med 324:1264–1266. https://doi.org/10.1056/NEJM199105023241807

    Article  CAS  PubMed  Google Scholar 

  13. Lukacs A, Junk AK, Stefani FH, Kampik A, Schirren CG, Plewig G (1997) Lisch nodules. Markers of neurofibromatosis 1 and immunohistochemical references for neuroectodermal differentiation. Hautarzt 48:38–41. https://doi.org/10.1007/s001050050544

    Article  CAS  PubMed  Google Scholar 

  14. Meyer SN, Simmons E, Studer AC, Rauen KA, Kiuru M (2023) Melanocytic neoplasms in neurofibromatosis type 1: a systematic review. Melanoma Res 33:437–446. https://doi.org/10.1097/CMR.0000000000000912

    Article  CAS  PubMed  Google Scholar 

  15. Moramarco A, Mallone F, Sacchetti M, Lucchino L, Miraglia E, Roberti V et al (2021) Hyperpigmented spots at fundus examination: a new ocular sign in Neurofibromatosis Type I. Orphanet J Rare Dis 16:147. https://doi.org/10.1186/s13023-021-01773-w

    Article  PubMed  PubMed Central  Google Scholar 

  16. Moramarco A, Miraglia E, Mallone F, Roberti V, Iacovino C, Bruscolini A et al (2019) Retinal microvascular abnormalities in neurofibromatosis type 1. Br J Ophthalmol 103:1590–1594. https://doi.org/10.1136/bjophthalmol-2018-313002

    Article  PubMed  Google Scholar 

  17. Muci-Mendoza RRM, Fuenmayor-Rivera D (2002) Corkscrew retinal vessels in neurofibromatosis type 1: Report of 12 cases. Br J Ophthlmol 86:282–284

    Article  CAS  Google Scholar 

  18. Nakakura S, Shiraki K, Yasunari T, Hayashi Y, Ataka S, Kohno T (2005) Quantification and anatomic distribution of choroidal abnormalities in patients with type I neurofibromatosis. Graefes Arch Clin Exp Ophthalmol 243:980–984. https://doi.org/10.1007/s00417-005-1184-z

    Article  PubMed  Google Scholar 

  19. Parrozzani R, Clementi M, Frizziero L, Miglionico G, Perrini P, Cavarzeran F et al (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 56:6036–6042. https://doi.org/10.1167/iovs.14-16053

    Article  PubMed  Google Scholar 

  20. Parrozzani R, Frizziero L, Trainiti S, Calciati A, Londei D, Miglionico G et al (2021) RETINAL VASCULAR ABNORMALITIES RELATED TO NEUROFIBROMATOSIS TYPE 1: natural history and classification by optical coherence tomography angiography in 473 patients. Retina 41:979–986. https://doi.org/10.1097/iae.0000000000002962

    Article  CAS  PubMed  Google Scholar 

  21. Perry HD, Font RL (1982) Iris nodules in von Recklinghausen’s Neurofibromatosis. Electron microscopic confirmation of their melanocytic origin. Arch Ophthalmol 100:1635–1640. https://doi.org/10.1001/archopht.1982.01030040613012

    Article  CAS  PubMed  Google Scholar 

  22. Pimentel MFHA, Wan MJ, Hussein R, Leahy KE, MacDonald H, Tavares E et al (2022) Prevalence of choroidal abnormalities and Lisch nodules in children meeting clinical and molecular diagnosis of neurofbromatosis type 1. Transl Vis Sci Technol 11:10

    Article  Google Scholar 

  23. Rodriguez FJ, Folpe AL, Giannini C, Perry A (2012) Pathology of peripheral nerve sheath tumors: diagnostic overview and update on selected diagnostic problems. Acta Neuropathol 123:295–319. https://doi.org/10.1007/s00401-012-0954-z

    Article  PubMed  PubMed Central  Google Scholar 

  24. Shiurba RA, Eng LF, Urich H (1984) The structure of pseudomeissnerian corpuscles. An immunohistochemical study Acta Neuropathol 63:174–176. https://doi.org/10.1007/BF00697200

    Article  CAS  PubMed  Google Scholar 

  25. Tucci A, Saletti V, Menni F, Cesaretti C, Scuvera G, Esposito S et al (2017) The absence that makes the difference: choroidal abnormalities in Legius syndrome. J Hum Genet 62:1001–1004. https://doi.org/10.1038/jhg.2017.78

    Article  CAS  PubMed  Google Scholar 

  26. Ueda-Consolvo T, Miyakoshi A, Ozaki H, Houki S, Hayashi A (2012) Near-infrared fundus autofluorescence-visualized melanin in the choroidal abnormalities of neurofibromatosis type 1. Clinical ophthalmology (Auckland, NZ) 6:1191–1194. https://doi.org/10.2147/opth.s35321

    Article  CAS  Google Scholar 

  27. 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 57:774. https://doi.org/10.1167/iovs.15-18603

    Article  CAS  PubMed  Google Scholar 

  28. Vagge A, Corazza P, Ferro Desideri L, Camicione P, Agosto G, Vagge R et al (2021) Ocular biometric parameters changes and choroidal vascular abnormalities in patients with neurofibromatosis type 1 evaluated by OCT-A. PLoS ONE 16:e0251098. https://doi.org/10.1371/journal.pone.0251098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Viola F, Villani E, Natacci F, Selicorni A, Melloni G, Vezzola D et al (2012) Choroidal abnormalities detected by near-infrared reflectance imaging as a new diagnostic criterion for neurofibromatosis 1. Cancers 119:369–375. https://doi.org/10.3390/cancers14061423

    Article  Google Scholar 

  30. Viola F, Villani E, Natacci F, Selicorni A, Melloni G, Vezzola D et al (2012) Choroidal abnormalities detected by near-infrared reflectance imaging as a new diagnostic criterion for neurofibromatosis 1. Ophthalmology 119:369–375. https://doi.org/10.1016/j.ophtha.2011.07.046

    Article  PubMed  Google Scholar 

  31. Williamson TH, Garner A, Moore AT (1991) Structure of Lisch nodules in neurofibromatosis type 1. Ophthalmic Paediatr Genet 12:11–17. https://doi.org/10.3109/13816819109023079

    Article  CAS  PubMed  Google Scholar 

  32. Wolter J (1965) Nerve fibrils in ovoid bodies. Arch Opthal 73:696–699

    Article  CAS  Google Scholar 

  33. Yasunari T, Shiraki K, Hattori H, Miki T (2000) Frequency of choroidal abnormalities in neurofibromatosis type 1. Lancet 356:988–992. https://doi.org/10.1016/S0140-6736(00)02716-1

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 20114, USA

    Anat O. Stemmer-Rachamimov & Liana Kozanno

  2. Harvard Medical School, 25 Shattuck Street, Boston, MA, 02115, USA

    Anat O. Stemmer-Rachamimov, Liana Kozanno, Scott R. Plotkin, Justin T. Jordan & Joseph F. 3rd Rizzo

  3. Department of Neurology and Cancer Center, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 20114, USA

    Scott R. Plotkin & Justin T. Jordan

  4. Neuro-Ophthalmology Service, Massachusetts Eye and Ear Infirmary, 243 Charles St, Boston, MA, 02114, USA

    Joseph F. 3rd Rizzo

Authors
  1. Anat O. Stemmer-Rachamimov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Liana Kozanno
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Scott R. Plotkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Justin T. Jordan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Joseph F. 3rd Rizzo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anat O. Stemmer-Rachamimov.

Additional information

Publisher's Note

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Stemmer-Rachamimov, A.O., Kozanno, L., Plotkin, S.R. et al. Histologic correlates of “Choroidal abnormalities” in Neurofibromatosis type 1 (NF1). Acta Neuropathol 147, 71 (2024). https://doi.org/10.1007/s00401-024-02724-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00401-024-02724-y

Keywords

Search

Navigation