Title | Optic Nerve Aplasia |
Creator | B. D. Saffren; S. H. Yassin; B. E. Geddie; J. T. H. N. de Faber; L. S. Blieden; M. Bhate; S. Gamio; T. Rutar; A. V. Levin |
OCR Text | Show Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Optic Nerve Aplasia Brooke D. Saffren, BS, Shaden H. Yassin, MD, Brooke E. Geddie, DO, Jan Tjeerd H. N. de Faber, MD, Lauren S. Blieden, MD, Manjushree Bhate, MD, Susana Gamio, MD, Tina Rutar, MD, Alex V. Levin, MD, MHSc Objective: Optic nerve aplasia (ONA) is a rare ocular anomaly. We report ophthalmologic, systemic, and genetic findings in ONA. Methods: Patients were identified through an International Pediatric Ophthalmology listserv and from the practice of the senior author. Participating Listserv physicians completed a data collection sheet. Children of all ages were included. Neuroimaging findings were also recorded. Results: Nine cases of ONA are reported. Patients’ ages ranged from 10 days to 2 years (median 9 months). Seven cases were bilateral. All patients had absence of the optic nerve and retinal vessels in the affected eye or eyes. Ophthalmologic findings included glaucoma, microcornea, persistent pupillary membrane, iris coloboma, aniridia, retinal dysplasia, retinal atrophy, chorioretinal coloboma, and persistent fetal vasculature. Systemic findings included facial dysmorphism, cardiac, genitourinary, skeletal, and developmental defects. A BCOR mutation was found in one patient. One patient had rudimentary optic nerves and chiasm on imaging. Conclusion: ONA is a unilateral or bilateral condition that may be associated with anomalies of the anterior or posterior segment with or without systemic findings. Rudimentary optic nerve on neuroimaging in one case suggests that ONA is on the continuum of optic nerve hypoplasia. Journal of Neuro-Ophthalmology 2022;42:e140–e146 doi: 10.1097/WNO.0000000000001246 © 2021 by North American Neuro-Ophthalmology Society Philadelphia College of Osteopathic Medicine (BDS), Philadelphia, Pennsylvania; Pediatric Ophthalmology and Ocular Genetics (BDS, SHY), Wills Eye Hospital, Philadelphia, Pennsylvania; Pediatric Ophthalmology (BEG), Helen DeVos Children’s Hospital, Grand Rapids, Michigan; The Rotterdam Eye Hospital (JTHNF), Rotterdam, the Netherlands; Cullen Eye Institute (LSB), Baylor College of Medicine, Houston, Texas; Department of Pediatric Ophthalmology (MB), LV Prasad Eye Institute, Hyderabad, India; Ophthalmology Unit (SG), Ricardo Gutiérrez Children Hospital, Buenos Aires, Argentina; Cataract and Laser Institute of Southern Oregon PC (TR), Medford, Oregon; Flaum Eye Institute and Golisano Children’s Hospital (AVL), University of Rochester, New York, New York. A. V. Levin is supported by the Adeline Lutz—Steven S. T. Ching, MD. Distinguished Professorship in Ophthalmology and an unrestricted grant from Research to Prevent Blindness to the Department of Ophthalmology at the University of Rochester. The remaining authors report no conflict of interest. Address correspondence to Alex V. Levin, MD, MHSc, Pediatric Ophthalmology and Ocular Genetics, Flaum Eye Institute, 601 Elmwood Avenue, Box 659, Rochester, NY 14642; E-mail: alex_levin@urmc.rochester.edu e140 O ptic nerve aplasia (ONA) is a rare anomaly, with no race or gender predilection, characterized by congenital absence of the optic nerve, retinal blood vessels, retinal ganglion cells (RGCs), and optic nerve fibers, causing lifelong visual impairment (1,2). It may affect either one eye or both eyes. Unilateral ONA is generally associated with otherwise normal brain development, whereas bilateral ONA may be accompanied by central nervous system (CNS) malformations (3). ONA may present as an isolated finding or as in association with other congenital ocular and nonocular abnormalities. Previously reported abnormal systemic findings include developmental delay, congenital cardiac disease, underdeveloped medulla and cerebellum, corpus callosum hypogenesis, and bilateral ovarian hypoplasia (3,4). In this article, we report a multicenter case series of ONA, with literature reviews. METHODS The International Pediatric Ophthalmology Listserv, hosted by UC Davis, is designed to facilitate discussion among pediatric ophthalmologists in the field of pediatric ophthalmology. Based on a call for cases put out on the listserv in December 2018, we were able to identify patients from a variety of ophthalmological centers. Diagnosis was made based on the absence of a clinically observable optic nerve head on fundus examination with or without the absence of retinal blood vessels. After the data from all the participating centers had been subjected to the oversight of their own institutional review boards, the participating centers used a data collection sheet (Appendix A) to gather all relevant clinical data. All data collection conformed to the requirements of the US Health Insurance Portability and Privacy Act. We included children of any age with no demographic restrictions. Children with optic nerve hypoplasia were excluded. Saffren et al: J Neuro-Ophthalmol 2022; 42: e140-e146 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Saffren et al: J Neuro-Ophthalmol 2022; 42: e140-e146 Age/ Which CaseGender Eye Initial Presentation Ocular Examination Anterior segment Posterior segment Systemic Microcorneas, peripheral iris strand OD, and persistent pupillary membrane OD Absent right optic nerve and retinal vessels, macular hypoplasia, and disorganized choroidal vasculature Normal 1 10 d/F OD Microphthalmia 2 2 m/F OU Microphthalmia/ Microcorneas, aniridia OU, and pupil ectopia abnormality lentis OD 3 2 y/M OU Glaucoma 4 9 m/M OU Roving eye movements Absent optic nerves and retinal vessels, PFV OS retinal dysplasia OS, and macular hypoplasia OD Absent optic Variable angle nerves and ET OD, nystagmus, retinal vessels, sclerocornea OD, microcorneas, aniridia foveal OS, and infratemporal hypoplasia, and “bull’s eye” lenticular notch OS maculopathy OD Microcorneas, inferonasal iris coloboma and lens notch OD Facial dysmorphism Atrial septal defect, hypospadias, cryptorchidism, umbilical hernia, developmental delay, seizures, wide-based gait, and dysphagia, autistic spectrum Normal; endocrine Absent optic nerves and workup negative for retinal vessels hypopituitarism andinferonasal chorioretinal coloboma OD including the macula Family History/ Consanguinity Genetic Testing MRI/CT Abnormalities Absent right optic Fundus nerve, right Normal flavimaculatus/ globe smaller microarray and macular than left globe, normal degeneration (maternal great aunt sequencing WT1 normal pituitary, and diagnosed in young PAX6 infundibulum is adulthood and slightly deviated mother with toward the left anomalous branching of optic nerve vessels) Constricted genetic Not performed Absent optic pool nerves and chiasm Negative BCOR c.4870C.T (P.Q1624) Absent optic nerves and chiasm and decreased white matter volume involving the frontal lobes Negative Not performed Absent optic nerves and chiasm, cavum septum vergae, and dilated perivascular spaces bilaterally Original Contribution e141 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 1. Summary of clinical data Age/ Which CaseGender Eye Initial Presentation 5* 2 y/M OU 6 35 d/F OS Ocular Examination Anterior segment Posterior segment Systemic Saffren et al: J Neuro-Ophthalmol 2022; 42: e140-e146 No data available Microcorneas, absent Absent optic Roving eye nerves and pupillary reaction to movements/ retinal unable to track light OU, flat featureless irides OD, vasculature, or see objects scattered and roving eye fundus movements OU pigmentation, and macular hypoplasia OU* Small stature without Posterior Microphthalmia Microcorneas, iris skeletal dysplasia staphyloma coloboma OS and (2nd percentile OS, large and nonreactive pupil OS for height) and small areas of endocrine workup complete negative for chorioretinal hypopituitarism atrophy OS, some associated with hemorrhage over bare sclera following no obvious anatomical distribution (Fig. 1), retinal dysplasia OS, absence of left optic nerve and vessels, and macular hypoplasia OS Family History/ Consanguinity Genetic Testing MRI/CT Abnormalities Negative Not performed Absent optic nerves, unable to assess optic chiasm or tracts due to poor image quality Negative WES normal Slightly small left globe, absent left optic nerve from globe to optic chiasm, optic chiasm formed solely by right optic nerve, bilateral optic tracts are present, brain is otherwise normal Original Contribution e142 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (Continued ) Saffren et al: J Neuro-Ophthalmol 2022; 42: e140-e146 Age/ Which CaseGender Eye Initial Presentation 7 10 m/ OU M 8 19 m/ OU M 9 4 m/M OU Ocular Examination Anterior segment Posterior segment Mild developmental delay Umbilical hernia, mild macrocephaly without increased intracranial pressure Normal Family History/ Consanguinity Negative Negative Negative Genetic Testing MRI/CT Abnormalities Not performed Absent optic nerves, absent optic chiasm, and agenesis of the optic tracts Not performed Rudimentary optic nerves and optic chiasm, small right globe Not performed Absent optic nerves and chiasm Original Contribution Absence of Nystagmus with Absent pupillary optic nerves and no eye contact reaction to vessels, focal light OU, remnants of pupillary membrane areas of retinal dysplasia, and OU, nasal notch of macular lens OU, and hypoplasia nystagmus Choroidal vessels Cloudy corneas Nystagmus, entered through microcorneas, lamina cribosa, aniridia OD, and peripheral elevated IOP OS posterior staphyloma temporally in both eyes (bare sclera with some outpouching), no recognizable retina or retinal vessels; only bare choroid, absent optic nerves Absent red reflex Microcornea OD Retinal detachment OD, absent optic nerves OU, absent retinal vessels OU, and macular hypoplasia OD Systemic CT, computed tomography; d, days; ET, esotropia; F, female; IOP, intraocular pressure; m, months; M, male; OD, right eye; OS, left eye; OU, both eyes; PFV, persistent fetal vasculature; Y, year; WES; whole exome sequencing. *Data obtained during examination under general anesthesia. e143 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (Continued ) Original Contribution FIG. 1. Fundus photograph of the left eye of case 6 showing large and small areas of complete chorioretinal atrophy, some associated with hemorrhage over bare sclera, following no obvious anatomical distribution. RESULTS We report 9 cases of ONA. Ages of the patients ranged from 10 days to 2 years (median 9 months). Six were male patients. Seven had bilateral involvement. Clinical, genetic, and systemic findings are summarized in Table 1. Fundus photographs from case 6 and 7 are shown in Figures 1 and 2, respectively. The most common initial presentations were abnormal eye movements (3) or microcornea (3). On examination, the most frequent anterior segment finding was iris malformations including aniridia (3), 2 of which had glaucoma. On fundus examination, all patients had absence of the optic nerve and retinal vessels in the affected eye or eyes, 3 had retinal dysplasia, and 2 had retinal absence or atrophy. One case had a “bull’s eye” maculopathy; one case had a coloboma extending over the macular area, and there was no identifiable macular architecture in 7 cases. One case had ipsilateral persistent fetal vasculature. Five cases had systemic involvement, of which 4 had bilateral ONA. Abnormal systemic findings included skeletal abnormalities, umbilical hernia, and developmental delay (2 cases each). Endocrine testing was performed on 2 patients, neither of them showing evidence of hypopituitarism. Genetic testing was performed on 3 patients; 2 of which had negative results and one had a mutation in BCOR. Neuroimaging was performed on all patients. All but one showed absent optic nerve and, in bilateral cases, absent chiasm (in case 5 the optic chiasm could not be assessed). One case reported rudimentary optic nerves and optic chiasm despite no visible optic nerve on fundus examination. Agenesis of the optic tracts was reported in one case. No other brain abnormalities were found. MRI images are shown in Fig. 3–5 for cases 2, 3, and 6, respectively. FIG. 2. Fundus photograph of case 7 showing focal area of retinal dysplasia in midperiphery. include microphthalmia, esotropia, and afferent pupillary defect (4,6,7). To the best of our knowledge, less than 50 cases have been reported. Unilateral disease is reported to be more common (6,7), although our cases were more commonly bilateral. In general, unilateral cases have normal brain development, whereas bilateral cases often have brain malformations. Common ocular findings include microcornea, pupillary membrane, iris hypoplasia, chorioretinal coloboma, and chorioretinal atrophy (4,6–10). We also CONCLUSION ONA is characterized by the absence of an optic disc, retinal vessels, and RGCs (5). Common initial presentations e144 FIG. 3. T1 axial MRI image of case 2 showing absent optic nerves and chiasm. Saffren et al: J Neuro-Ophthalmol 2022; 42: e140-e146 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 5. T2 axial image of case 6 showing absent left optic nerve. FIG. 4. T2 axial image of case 3 showing absent optic nerves and chiasm. observed 2 cases with glaucoma, both with aniridia and microcornea. All of our cases had absent retinal vessels. Retinal dysplasia and macular hypoplasia have been reported by others (4,6,7,9). Microcornea, which was seen in 3 of our cases, is not typically seen in optic nerve hypoplasia but has been reported (3,11,12). Other concomitant genetic syndromes, such as Aicardi syndrome, were ruled out based on clinical presentation. The embryologic precursor of the optic nerve is the optic stalk, which connects the optic vesicle to the forebrain. Outpouching of the stalk occurs in response to expression of SHH and PAX2 (13). As the ventral embryologic fissure of the optic vesicle and stalk closes, it encompasses the hyaloid vascular system that provides vascular supply to the lens, iris, and anterior chamber. Closure of the fissure begins at 5 weeks and is completed by 7 weeks. The optic nerve is populated by the axons from RGCs that begin differentiating at 6 weeks, making their first connection with the brain. The optic nerve is initially overpopulated with RGCs, which then decreases by 70% by the 30th week of gestation (14). The etiology of ONA remains unclear. It may be due to failure of RGC development, RGC axonal development to reach optic disc, or initiation or guidance of RGCs to migrate through the axon (15). Alternatively, there could be excessive “die-back” of axons during the period of axon reduction (5). The process of axon reduction occurs because of programmed apoptosis. BCOR, which was mutated in one of our patients, has a role in apoptosis Saffren et al: J Neuro-Ophthalmol 2022; 42: e140-e146 (16). One of our other patients did show residual optic nerve on neuroimaging. This suggests that ONA may be a severe form of optic nerve hypoplasia. ONA cannot be a primary failure of optic nerve formation as the presence of a globe necessarily implies that an optic stalk was at some time present, although that stalk may have failed to populate with axons. Another theory is that aplasia may result from abnormal vasculature secondary to defective formation of the fetal fissure. This theory is supported by the presence of fundus coloboma in some cases including one in our series but also in some cases of severe optic nerve hypoplasia (2). The presence of retinal dysplasia and macular hypoplasia in some of our patients could be a primary failure of retinal differentiation, including ganglion cells, which are also responsible for the induction of retinal vasculature (17). Vascular abnormalities may also explain, in part, the iris abnormalities seen in some patients. Iris abnormalities may also be due to abnormal expression of PAX6 in response to abnormalities in PAX2 that is responsible for the activation of PAX6 (18). Mutations in PAX6 can result in aniridia that can be associated with optic nerve hypoplasia (19) and has been reported in ONA (20). Mutations in CYP26A1, CYP26C1 (21), SOX2 (22), and OTX2 have also been reported in ONA (23). Each of these genes has been shown to play a role in the development of RGCs (24–26). Mutations in OTX2 and SOX2 have also been reported in optic nerve hypoplasia (27), further suggesting that ONA is likely a severe manifestation on the optic nerve hypoplasia spectrum, with severity possibly related to the timing and localization of the embryologic defect. e145 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Neurohypophyseal structures were normal in all patients. Neurohypophyseal abnormalities are seen in up to 64% of patients with optic nerve hypoplasia (28). Short stature was seen in 3 of our patients, raising the possibility of hypopituitarism despite normal neuroimaging, which has been reported in optic nerve hypoplasia (29). We have described the clinical manifestations of ONA. Limitations of our study include small sample size and a possible selection bias as some cases were collected from those who voluntarily responded to a pediatric ophthalmology listserv request. However, our case series is similar in size to the largest previous reports and our findings very similar (1,2,7). Collecting larger samples of patients with rare disorders is challenging. It is recommended that all patients with ONA are referred for neuroimaging. Further studies could include targeted genetic testing for optic nerve hypoplasia to further elucidate the etiology of ONA. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: A. V. Levin; b. Acquisition of data: S. H. Yassin; B. E. Geddie, J. T. H. N. de Faber, L. S. Blieden, M. Bhate, S. Gamio, and T. Rutar; c. Analysis and interpretation of data: A. V. Levin and B. Saffren. Category 2: a. Drafting the manuscript: B. Saffren and S. Yassin; b. Revising it for intellectual content: A. V. Levin, B. E. Geddie, J. T. H. N. de Faber, L. S. Blieden, M. Bhate, S. Gamio, and T. Rutar. Category 3: a. Final approval of the completed manuscript: A. V. Levin, S. H. Yassin, B. Saffren, B. E. Geddie, J. T. H. N. de Faber, L. S. 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Date | 2022-03 |
Language | eng |
Format | application/pdf |
Type | Text |
Publication Type | Journal Article |
Source | Journal of Neuro-Ophthalmology, March 2022, Volume 42, Issue 1 |
Publisher | Lippincott, Williams & Wilkins |
Holding Institution | Spencer S. Eccles Health Sciences Library, University of Utah, 10 N 1900 E SLC, UT 84112-5890 |
Rights Management | © North American Neuro-Ophthalmology Society |
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Setname | ehsl_novel_jno |
ID | 2197507 |
Reference URL | https://collections.lib.utah.edu/ark:/87278/s66a9782 |