History of present illness
We present a case of a 5-year-old girl with an unremarkable past medical history referred for congenital blindness and retinopathy. There was no reported history of trauma, medication use, or premature birth. The maternal grandmother had a history of night blindness. The patient had a past medical history of positive immunoglobulin G serology for toxoplasmosis but no clinically significant infection.
Ocular examination findings
Visual acuities with correction were 20/400 in the right eye and 20/200 in the left eye. Intraocular pressures were normal. External examination revealed nystagmus. Anterior segment examination was unremarkable. Dilated fundus examination showed bilateral yellowish discoloration of the central macular region of both eyes, associated pigment clumping and mottling, diffuse pigmentary changes, and preserved paraarteriolar retinal pigment epithelium (RPE) ( Fig. 5.1 ).
Imaging
Optical coherence tomography (OCT) showed diffuse outer retinal atrophy and photoreceptor loss with extrafoveal thickened retina ( Fig. 5.2 A). Autofluorescence demonstrated diffuse hypoautofluorescence sparing periarteriolar areas, which appeared hyperautofluorescent ( Fig. 5.2 B). Full-field electroretinogram (ERG) revealed a nearly undetectable rod response and significantly reduced cone and combined rod–cone responses ( Fig. 5.3 ).
Questions to ask to aid diagnosis
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At what age did the parents first note visual impairment? Leber congenital amaurosis (LCA) is associated with visual impairment from birth or early life accompanied by nystagmus or roving eye movements.
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The parents noted decreased visual attention and nystagmus soon after birth.
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What is the patient’s refractive error? Hyperopia is commonly found in LCA, including CRB1-associated LCA, and is thought to result from impaired emmetropization, whereas myopia is characteristic of congenital stationary night blindness (CSNB).
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+3.75 + 2.00 × 085 in the right eye, +1.50 + 2.00 × 100 in the left eye
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Does the patient have a family history of ocular conditions? Inheritance patterns can aid in the diagnosis of congenital blindness and are important for genetic counseling.
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The patient’s maternal grandmother had nyctalopia.
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What is the pattern of fundus findings? Clinical phenotype can sometime correlate with the genetic mutation in LCA. GUCY2D, CEP290, CRB1, RDH12, and RPE65 are the most common LCA genotypes. RPE65-associated LCA (5–10% of LCA) typically has a blonde fundus and vascular attenuation. GUCY2D (10–20% of LCA) presents with an essentially normal fundus but is associated with significant photophobia compared with most other LCA genotypes. CEP290 (15–20% of LCA) has a relatively normal fundus in infancy with variable visual acuity progressing to severe vision loss of finger counting or worse within the first decade. CRB1 (approximately 10% of LCA) demonstrates macular atrophy and paraarteriolar sparing of RPE. RDH12 (approximately 10% of LCA) typically has widespread RPE and retinal atrophy with minimal pigmentation in early childhood, dense bone-spicule pigmentation by adulthood, and early progressive macular atrophy with pigmentation and yellowing seen as excavation on OCT. Vessel attenuation and disc pallor or drusen may also be present.
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Our patient’s fundus demonstrates macular atrophy and paraarteriolar sparing of the RPE.
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Are there any syndromic features? Hearing loss can be associated with Usher and Alström syndromes, with the latter being associated with kidney dysfunction, obesity, diabetes mellitus, and cardiomyopathy. Renal anomalies, obesity, and diabetes are also seen in Bardet-Biedl syndrome; however, the presence of postaxial polydactyly, cognitive impairment, and hypogonadism differentiate Bardet-Biedl from Alström. Renal dysfunction is also observed in Joubert, Senior-Loken, and Saldino-Mainzer syndromes. Joubert syndrome is associated with abnormal development of cerebellar vermis and brainstem resulting in the molar tooth sign on magnetic resonance imaging, whereas Saldino-Mainzer syndrome is associated with cone-shaped epiphyses of the hands, which can be seen on x-rays.
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No
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Are there any eye poking or stereotypic behaviors? Is there any presence of keratoconus from eye rubbing? Oculodigital reflex as a means of mechanically stimulating the retina is associated with LCA.
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None
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Assessment
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This is a case of a 5-year-old girl with congenital blindness in association with decreased photopic and scotopic ERG amplitudes, diffuse pigmentary changes, and preserved paraarteriolar RPE.
Differential diagnosis
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LCA, which can be caused by multiple genes ,
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LCA, nonsyndromic
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LCA with nephronophthisis
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Joubert syndrome
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Senior-Loken syndrome
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Saldino-Mainzer syndrome
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Alström syndrome
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Severe early childhood–onset retinal dystrophy (SECORD): better visual function compared with LCA despite early, progressive loss
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Early-onset retinitis pigmentosa (RP): considered a milder form of LCA
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CSNB
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Achromatopsia: typically presents with day blindness, reduced visual acuity, photophobia, and nystagmus
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Blue-cone monochromatism: X-linked
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Metabolic ,
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Abetalipoproteinemia/Bassen-Kornzweig syndrome
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Zellweger syndrome
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Neonatal adrenoleukodystrophy
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Infantile Refsum disease
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Infections (i.e., rubella or syphilis)
Working diagnosis
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LCA: CRB1 phenotype given paraarteriolar RPE sparing
Multimodal testing and results
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Fundus photographs
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Disease-causing CRB1 variants have been found in a wide range of phenotypes, including early-onset LCA or SECORD, RP with or without Coats-like vasculopathy, later-onset macular dystrophy, and even isolated autosomal recessive foveal retinoschisis. , Although fundus presentation can range from initially normal to pigmentary retinopathy, the characteristic fundus findings include macular atrophy, nummular RPE pigmentation, sparing of the paraarteriolar RPE, and possible presence of Coats-like reaction. As with other LCA/RP genotypes, optic disc abnormalities such as pallor and drusen may be seen. The CRB1 protein is a component of the outer limiting membrane and is involved in retinal development.
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OCT
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Our patient’s OCT was notable for diffuse outer retinal atrophy with thickening of other retinal layers, a common finding in CRB1-associated LCA. Loss of normal retinal laminations and cystoid macular edema can also be present in a significant portion of patients.
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Autofluorescence
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Findings can vary depending on the CRB1 gene variant, with a variable amount of macular atrophy present. Widespread RPE atrophy leads to diffuse fundus hypoautofluorescence. A characteristic feature of CRB1-associated retinal dystrophy is spared RPE along the arterioles seen in our patient as preserved autofluorescence in a paraarteriolar distribution. This finding is characteristic of CRB1 mutation; however, its absence should not exclude CRB1 as a potential causative gene. ,
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ERG
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ERG was obtained, which showed nearly extinguished scotopic and severely decreased photopic responses, suggesting LCA.
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Genetic testing
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Important in diagnosis, prognosis, and identifying gene therapy candidates. Our patient had genetic testing confirming a homozygous mutation in CRB1 (p.Cys948Tyr.2843G>A).
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Management
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Our patient was entered into a gene therapy registry, referred to low-vision services, and provided with spectacle correction.
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It is also important to identify treatable conditions associated with LCA, including refractive error, cataract, keratoconus, and macular edema.
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Genetic counseling of the parents was provided considering CRB1-associated LCA is autosomal recessive and the risk of having another child with the same condition is 25%.
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The patient and family were referred to low-vision, educational, and social support resources.
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As of 2017, the U.S. Food and Drug Administration approved subretinal injection of voretigene neparvovec-rzyl (Luxturna Spark Therapeutics, Inc., Philadelphia, PA), for biallelic RPE65 mutation–associated LCA2. Numerous other clinical trials are ongoing.
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Supplements, particularly vitamin A, have not been shown to be clearly beneficial and may be harmful in some conditions (i.e., ABCA4-associated inherited retinal disease).
Follow-up care
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Although there are no established guidelines, serial examinations, imaging, and genetic counseling are recommended.
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Carrier testing for family members and prenatal testing can be considered.
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If a patient exhibits syndromic features, further workup may include labs, renal ultrasound, hand x-ray, and evaluation by an internist.
Algorithm 5.1 : Algorithm for differential diagnosis of congenital blindness and retinopathy
