Case of the Month

Edited by Robert N. Johnson, MD

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Case #121 July, 2019

Presented by:

Michelle Peng, MD

A 21-year-old woman presented for evaluation of retinal hemorrhages noted on routine eye examination. She had no symptoms

Case of the Month Listing

Figure 1A: Color photograph of the right eye. Note the areas of retinal hemorrhage, cotton wool spots and areas of avascular retina temporally.

Figure 1B: Color photograph of the left eye showing an apparent unremarkable macula.

Case History

A 21-year-old woman presented for evaluation of retinal hemorrhages noted on routine eye examination. She had no symptoms.

On examination visual acuity was 20/40 in both eyes. Her pupils were equal round and reactive with no afferent pupillary defect.  The intraocular pressure and anterior segment examination in both eyes were unremarkable. Fundus examination demonstrated temporal retinal hemorrhages and sclerotic vessels in both eyes (Figures 1A and B). Fluorescein angiography (FA) showed widespread ischemia extending from the temporal macula and into the periphery. There was enlargement of the foveal avascular zone with telangiectasia that leaked in the late phase of the study (Figures 2A-D). Optical coherence tomography showed retinal thinning and distortion of the outer nuclear and outer plexiform layers (Figures 3A and B).

Figures 1A-D: Fluorescein angiograms of the left and right eyes. Note the areas of telangiectasis, nonperfusion and some late leakage (more so in the right macula.

Figures 3A and B: SD-OCT horizontal scans through macula. Note areas of retinal thinning and distortion of the outer plexiform and outer nuclear layers in both eyes.

What is your Diagnosis?

Differential Diagnosis

Primary vitreovasculopathies (familial exudative retinal vasculopathy, Coats disease, Eales disease); Associated with systemic disease (Proliferative diabetic retinopathy, Radiation retinopathy); Associated with inflammatory etiologies (Multiple sclerosis, Pars planitis, Systemic lupus erythematosus, Sarcoidosis); Associated with blood dyscrasias (Sickle cell retinopathy, Polycythemia vera, Fanconi anemia, Hemoglobin C trait, Leukemia).

 

Additional History and Diagnosis

Upon further questioning she reports a history of frequent nosebleeds and easy bruising. Physical examination revealed a young frail woman with short stature and skin hyperpigmentation (Figure 4) who weighed only sixty-three pounds. She was sent to a hematologist and was found to have normocytic anemia and thrombocytopenia. Her electrolytes, liver and thyroid function, and hypercoagulability workup was otherwise unremarkable. Given her physical examination and laboratory findings a bone marrow biopsy and aspirate were performed revealing hypocellular bone marrow. Studies were negative for leukemia as well as a myelodysplastic syndrome. A diepoxybutane chromosome breakage test was positive for increased deoxyribonucleic acid (DNA) thus confirming a diagnosis of Fanconi anemia (FA). Test for FA C-mutation testing for complementation Group C was negative. Further genetic testing was not pursued.

 She was subsequently lost to follow up for three years and represented with elevated intraocular pressure, rubeosis, and progression in macular ischemia of her left eye. She underwent panretinal photocoagulation with regression in her rubeosis but her vision remained poor due to neovascular glaucoma.

 

Discussion

Fanconi anemia is the most common inherited bone marrow failure syndrome, with a prevalence of 1 case per million persons. The disorder may arise from a mutation in any one of fifteen DNA repair genes. Bone marrow failure is the presenting finding in 90% of patients, most of whom tend to be symptomatic in the first decade of life. The diagnosis is typically made by exposing a patient’s DNA to cross-linking agents ie. Diepoxybutane or mitomycin C. An increase in fragility of the DNA suggests an impaired DNA repair mechanism. Genetic testing is available but typically used in familial cases when a diagnosis is known.1 Blood transfusions provide symptomatic relief but definitive treatment requires hematopoietic stem-cell transplantation.1,2

Overall patients may present with a variety of congenital anomalies of any organ system, bone marrow failure, leukemias and myelodysplastic syndromes, solid tumors, and endocrinologic issues.3

Ophthalmic manifestations of FA are similarly diverse: reports have ranged from retinoblastoma,4 cataract and anterior ischemic syndrome5 to microphthalmia and microcornea.6,7 Reports of retinal occlusive vasculopathy and hemorrhages such as in our patient have been previously published.8,9,10

Management of the condition is directed toward addressing the specific eye issues. Advances in bone marrow transplantation has improved survival for patients; mortality is typically due to solid tumors or complications from hematopoietic stem cell transplantation11.

Take Home Points

  • Fanconi anemia is an inherited bone marrow syndrome that typically presents as bone marrow failure in the first decade of life
  • Ophthalmic and systemic manifestations are diverse, thus requiring multispecialty care

Adapted from Matthew Denny, Sara Haug, Emmett Cunningham, J. Michael Jumper. Fanconi anemia presenting as bilateral diffuse retinal occlusive vasculopathy. Retinal Cases & Brief Reports 2016 Spring;10(2):171-4.

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References

 

  1. Auerbach A. Fanconi anemia and its diagnosis. Mutat Res 2009;668:4–10.
  2. Kupfer G. Fanconi anemia: a Signal Transduction and DNA repair Pathway. Yale J Biol Med 2013;86:491–497.
  3. Shimamura A, Alter BP. Pathophysiology and management of inherited bone marrow failure syndromes. Blood Reviews 2010; 24:101.
  4. Reddy MA, Bibby K. Vitreous haemorrhage in Fanconi’s anaemia. J R Soc Med 1998;91:540–541. Jain V, Shome D, Maiti A, Natarajan S. An unusual ocular manifestation in fanconi anaemia: anterior ischaemic syn- drome. Eye (Lond) 2007;21:1449–1450.
  5. Tsilou ET, Giri N, Weinstein S, et al. Ocular and orbital manifestations of the inherited bone marrow failure syndromes: fanconi anemia and dyskeratosis congenita. Ophthalmology 2010;117:615–622.
  6. Törnquist AL, Martin L, Winiarski J, Fahnehjelm KT. Ocular manifestations and visual functions in patients with Fanconi anaemia. Acta Ophthalmol 2014;92:171–178.
  7. Reddy MA, Bibby K. Vitreous haemorrhage in Fanconi’s anaemia. J R Soc Med 1998;91:540–541.
  8. Bahar I, Weinberger D, Kramer M, Axer-Siegel R. Retinal vasculopathy in Fanconi anemia: a case report. Retina 2005;25:799–800.
  9. Ben Yahia S, Touffahi SA, Zeghidi H, et al. Ocular neo- vascularization in a patient with Fanconi anemia. Can J Ophthalmol 2006;41:778–779.
  10. Risitano AM, Marotta S, Calzone R, et al. Twenty years of the Italian Fanconi Anemia Registry: where we stand and what remains to be learned. AU Haematologica. 2016 Mar;101(3):319-27.

Comments or Questions

Differential Diagnosis

Primary vitreovasculopathies (familial exudative retinal vasculopathy, Coats disease, Eales disease); Associated with systemic disease (Proliferative diabetic retinopathy, Radiation retinopathy); Associated with inflammatory etiologies (Multiple sclerosis, Pars planitis, Systemic lupus erythematosus, Sarcoidosis); Associated with blood dyscrasias (Sickle cell retinopathy, Polycythemia vera, Fanconi anemia, Hemoglobin C trait, Leukemia).

 

Additional History and Diagnosis

Upon further questioning she reports a history of frequent nosebleeds and easy bruising. Physical examination revealed a young frail woman with short stature and skin hyperpigmentation (Figure 4) who weighed only sixty-three pounds. She was sent to a hematologist and was found to have normocytic anemia and thrombocytopenia. Her electrolytes, liver and thyroid function, and hypercoagulability workup was otherwise unremarkable. Given her physical examination and laboratory findings a bone marrow biopsy and aspirate were performed revealing hypocellular bone marrow. Studies were negative for leukemia as well as a myelodysplastic syndrome. A diepoxybutane chromosome breakage test was positive for increased deoxyribonucleic acid (DNA) thus confirming a diagnosis of Fanconi anemia (FA). Test for FA C-mutation testing for complementation Group C was negative. Further genetic testing was not pursued.

 She was subsequently lost to follow up for three years and represented with elevated intraocular pressure, rubeosis, and progression in macular ischemia of her left eye. She underwent panretinal photocoagulation with regression in her rubeosis but her vision remained poor due to neovascular glaucoma.

 

Discussion

Fanconi anemia is the most common inherited bone marrow failure syndrome, with a prevalence of 1 case per million persons. The disorder may arise from a mutation in any one of fifteen DNA repair genes. Bone marrow failure is the presenting finding in 90% of patients, most of whom tend to be symptomatic in the first decade of life. The diagnosis is typically made by exposing a patient’s DNA to cross-linking agents ie. Diepoxybutane or mitomycin C. An increase in fragility of the DNA suggests an impaired DNA repair mechanism. Genetic testing is available but typically used in familial cases when a diagnosis is known.1 Blood transfusions provide symptomatic relief but definitive treatment requires hematopoietic stem-cell transplantation.1,2

Overall patients may present with a variety of congenital anomalies of any organ system, bone marrow failure, leukemias and myelodysplastic syndromes, solid tumors, and endocrinologic issues.3

Ophthalmic manifestations of FA are similarly diverse: reports have ranged from retinoblastoma,4 cataract and anterior ischemic syndrome5 to microphthalmia and microcornea.6,7 Reports of retinal occlusive vasculopathy and hemorrhages such as in our patient have been previously published.8,9,10

Management of the condition is directed toward addressing the specific eye issues. Advances in bone marrow transplantation has improved survival for patients; mortality is typically due to solid tumors or complications from hematopoietic stem cell transplantation11.