medRxiv : the preprint server for health sciences · 2026
Neuro-Ocular Vasculopathy Associated with Fanconi Anemia: A Clinical-Radiologic Phenotypic Case Series.
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Waldrop Greer, Pandya Darshan, Smith Bryan R, Soldatos Ariane, Abdelhak Ahmed, Rasool Nailyn, Mina Yair, Friend Christopher, Goldbach-Mansky Raphaela, Zhang Kevin Y, Lucas Calixto-Hope G, Zorn Kelsey C, Sidhu Sukhman, Green Ari J, Tilton Iris, Pleasure Samuel J, Giri Neelam, Toro Camilo, Nath Avindra, Wilson Michael R, Ramachandran Prashanth S
Аннотация
OBJECTIVE: To characterize the clinical, radiological, and pathological features of Neuro-Ocular Vasculopathy Associated with Fanconi Anemia (NOVA-FA).
METHODS: Six patients with FA and neurological symptoms were phenotyped using retrospective chart review of clinical notes, neuroimaging, fluorescein angiogram, CSF analysis, and advanced research techniques including extensive infectious testing. Biopsies were reviewed in two patients.
RESULTS: NOVA-FA is defined by neurological symptoms, retinal vasculopathy, accumulation of punctate cerebellar lesions and/or large mass-like lesions with surrounding vasogenic edema. Histopathology showed vasculopathy without inflammation. Treatments with immunosuppressants appeared largely ineffective. Imaging and pathology suggest a non-inflammatory small vessel vasculopathy as the primary pathology.
INTERPRETATION: NOVA-FA is a recently identified condition that affects a subset of patients with FA and results in significant disability, including death. The etiology remains unknown, although the condition mimics features of the syndrome "retinal vasculopathy and cerebral leukodystrophy" which is due to dysfunction in DNA repair mechanisms. There is currently no known effective treatment.
KEY MESSAGES: What is already known on this topic: Fanconi anemia is an inherited DNA-repair disorder, and only scattered case reports and small series have described an acquired neurological and ocular condition in a subset of these patients, and often presumed to be inflammatory. A consistent clinical-radiological definition, an understanding of the underlying mechanism, and evidence to guide treatment have been lacking.What this study adds: This series of six patients provides the most detailed clinical, radiological and pathological characterization of the syndrome to date, proposes the name Neuro-Ocular Vasculopathy Associated with Fanconi Anemia (NOVA-FA) with provisional diagnostic criteria, and shows that histopathology, CSF and serum biomarkers, infectious testing and treatment response together point to a non-inflammatory small vessel vasculopathy rather than a primary immune-mediated or infectious process, closely mirroring the DNA-repair disorder RVCL.How this study might affect research, practice or policy: The findings argue against reflexive immunosuppression, support earlier recognition of NOVA-FA through defined criteria, and reframe it as a DNA-repair-driven vasculopathy, motivating natural-history and mechanistic studies and the evaluation of vascular-targeted therapies as FA life expectancy rises and this phenotype becomes more common.
SOCIAL MEDIA SUMMARY IF PUBLISHED: None of the co-authors have a X handle that we would like to be tagged. There are scant case reports about this emerging neurologic syndrome in patients with Fanconi Anemia. This study contains the most robust neurological phenotyping of these patients and explores in-depth evaluations for molecular presence of inflammation.Draft: A novel progressive neuro-ocular vasculopathy in Fanconi Anemia (NOVA-FA) presents with enhancing brain lesions and retinal changes. Likely due to microvascular DNA repair failure, not inflammation. #FanconiAnemia #Neurovascular #RareDisease.
METHODS: Six patients with FA and neurological symptoms were phenotyped using retrospective chart review of clinical notes, neuroimaging, fluorescein angiogram, CSF analysis, and advanced research techniques including extensive infectious testing. Biopsies were reviewed in two patients.
RESULTS: NOVA-FA is defined by neurological symptoms, retinal vasculopathy, accumulation of punctate cerebellar lesions and/or large mass-like lesions with surrounding vasogenic edema. Histopathology showed vasculopathy without inflammation. Treatments with immunosuppressants appeared largely ineffective. Imaging and pathology suggest a non-inflammatory small vessel vasculopathy as the primary pathology.
INTERPRETATION: NOVA-FA is a recently identified condition that affects a subset of patients with FA and results in significant disability, including death. The etiology remains unknown, although the condition mimics features of the syndrome "retinal vasculopathy and cerebral leukodystrophy" which is due to dysfunction in DNA repair mechanisms. There is currently no known effective treatment.
KEY MESSAGES: What is already known on this topic: Fanconi anemia is an inherited DNA-repair disorder, and only scattered case reports and small series have described an acquired neurological and ocular condition in a subset of these patients, and often presumed to be inflammatory. A consistent clinical-radiological definition, an understanding of the underlying mechanism, and evidence to guide treatment have been lacking.What this study adds: This series of six patients provides the most detailed clinical, radiological and pathological characterization of the syndrome to date, proposes the name Neuro-Ocular Vasculopathy Associated with Fanconi Anemia (NOVA-FA) with provisional diagnostic criteria, and shows that histopathology, CSF and serum biomarkers, infectious testing and treatment response together point to a non-inflammatory small vessel vasculopathy rather than a primary immune-mediated or infectious process, closely mirroring the DNA-repair disorder RVCL.How this study might affect research, practice or policy: The findings argue against reflexive immunosuppression, support earlier recognition of NOVA-FA through defined criteria, and reframe it as a DNA-repair-driven vasculopathy, motivating natural-history and mechanistic studies and the evaluation of vascular-targeted therapies as FA life expectancy rises and this phenotype becomes more common.
SOCIAL MEDIA SUMMARY IF PUBLISHED: None of the co-authors have a X handle that we would like to be tagged. There are scant case reports about this emerging neurologic syndrome in patients with Fanconi Anemia. This study contains the most robust neurological phenotyping of these patients and explores in-depth evaluations for molecular presence of inflammation.Draft: A novel progressive neuro-ocular vasculopathy in Fanconi Anemia (NOVA-FA) presents with enhancing brain lesions and retinal changes. Likely due to microvascular DNA repair failure, not inflammation. #FanconiAnemia #Neurovascular #RareDisease.