The importance of genetic and electrophysiological studies in the differential diagnosis of acute zonal occult outer retinopathy (AZOOR)

Dear Editor, We have read with great interest the article by Roy et al.[1] entitled “Current understanding of acute zonal occult outer retinopathy (AZOOR),” a pathology first described by Gass in 1993, which currently indicates an inflammatory nature of the photoreceptors. The article focuses specifically on the inflammatory nature of AZOOR and its impact on vision, highlighting the clinical challenges associated with its diagnosis. However, we would like to emphasize that given that AZOOR is an inflammatory pathology,[2] its diagnosis must be considered in a comprehensive context, knowing its diagnosis is made by exclusion. This is due to the possibility of phenotypical overlap between multiple retinochoroidal diseases and AZOOR, making its diagnosis difficult.[1-3] Diseases such as autoimmune retinopathies (whether neoplastic or non-neoplastic), retinopathy due to phototoxicity, various choroidopathies, cone-rod dystrophy, and other late-onset hereditary retinal dystrophies may exhibit similar symptoms and clinical findings to those observed in the AZOOR. These manifestations include photopsias, myodesopsias, dyschromatopsia (generally red-green), positive scotomas, and diminished central or peripheral visual acuity, which hinders an accurate diagnosis.[4] It is essential to conduct electrophysiological studies, such as the electroretinogram (ERG), which plays a crucial role in the differential diagnosis of AZOOR. These studies enable an accurate assessment of the function of the retina as a whole, such as with full-field ERG and in specific regions with multifocal ERG.[2,3] This facilitates the identification of functional alterations that may not be evident with other types of examinations. The capability of the ERG when comparing it to other studies is advantageous in distinguishing AZOOR from multiple retinal pathologies with similar symptoms, such as hereditary retinal diseases, among others. Electrophysiological studies provide a detailed and accurate assessment of retinal activity, which is essential for planning appropriate and personalized treatment for the patient.[2-4] This phenomenon can be attributed to the absence of changes in the fundus that can be detected by multimodal structural studies, such as color retinography, autofluorescence, optical coherence tomography, or fluorescein angiography.[3-5] Other significant studies to consider include conducting genetic tests to address any of these concerns. The incorporation of genetic studies would not only help distinguish AZOOR from similar phenotypical manifestations but would also provide valuable insights into the genetic predisposition to the disease and potential pathogenic mechanisms. It has the potential to aid in making more precise therapeutic decisions and foster a more profound comprehension of the underlying etiology in certain patients. We present a series of cases with similar phenotypical characteristics to the fundus and multimodal images, whose etiology was a genetic background. Due to the bilateral and symmetric nature of the cases presented, the researchers initially aimed to make a differential diagnosis of the different hereditary retinal diseases. Furthermore, to identify potential genetic associations in the case of AZOOR [Figs. 1–3].Figure 1: A 39-year-old woman with a genetically confirmed diagnosis of retinitis pigmentosa type 69 due to a condition of the KIZ gene. The color photograph shows atrophic and pigmentary alterations of the RPE at the peridiscal level that accompany the temporal, bilateral, and symmetrical vascular arcades. These changes appear on the autofluorescence image as hypoautofluorescent lesions with a granular pattern and are associated with hyperautofluorescent lesions at the perifoveal level with an annular perifoveal shape. The HD SD-OCT image presents a series of alterations in the outer layers of the retina that are related to a decrease in the amplitudes in the multifocal ERG, indicating functional and structural macular damage. (a) right eye; (b) left eyeFigure 2: A 55-year-old man with a history of progressive decrease in visual acuity, photophobia, nyctalopia, and dyschromatopsia who, after evaluation and carrying out complementary studies, was diagnosed with Goldman-Favre disease with NR2E3 gene involvement. The color photograph shows atrophic and pigmentary changes of the RPE at the peridiscal level that accompany the temporal vascular arcades and the foveal area. These stand out in the autofluorescence image as hypoautofluorescent lesions with a granular, nummular, and annular pattern. Similarly, an annular perifoveal hypoautofluorescent area with discrete hyperautofluorescent lesions is seen at the foveolar level. In the HD SD-OCT image, alterations can be observed in the photoreceptors and outer layers of the retina that are related to a decrease in multifocal ERG amplitudes, confirming not only a structural but also a functional macular lesion. (a) right eye; (b) left eyeFigure 3: A 45-year-old woman presents with a condition of several months of evolution characterized by blurred vision, nyctalopia, and bilateral dyschromatopsia, in whom a mutation of the CRB1 gene has been detected, compatible with retinitis pigmentosa type 12. The photograph in color shows the atrophic and pigmentary changes of the RPE at the level of the middle retina, predominantly outside the vascular arcades. Furthermore, at the foveal level, some discrete changes are seen, which stand out in the autofluorescence image as hypoautofluorescent lesions with a granular, nummular, and annular pattern. There is also a discrete hyperautofluorescent area at the perifoveal level with a granular pattern. In the HD SD-OCT image, we can identify changes between the photoreceptors and outer layers of the retina. These changes are associated with a discrete cystoid macular edema that correlates with a decrease in the amplitudes in the multifocal ERG. This confirms damage in the structural and functional in the retina. (a) right eye; (b) left eyeAlthough it is important to recognize AZOOR as an inflammatory entity, the diagnostic approach should be comprehensive and consider the full spectrum of possible differential diagnoses. Genetic and electrophysiological studies should be considered necessary. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship: Nil. Conflicts of interest: There are no conflicts of interest.