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Young child referred for difficulty seeing in the dark
Diffuse pigmentary changes were seen throughout the mid-peripheral retina.
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A 5-year-old boy was referred to the retina service for progressively worsening night vision that began approximately 6 months before presentation. He denied changes in vision in well-lit settings, eye pain, redness, new floaters, photopsias and headaches. He had no history of trauma.
His ocular history was remarkable for mild astigmatism not requiring correction. His medical history was remarkable for asthma, sinusitis and an equivocal work-up thus far for von Willebrand’s disease, which his mother has. He was born full-term without complications during the pregnancy or delivery. There was a family history of night vision difficulties, including his mother and grandmother. His maternal uncle was legally blind.
Examination
On examination, the patient’s best corrected visual acuity was 20/25 in each eye. Pupils were round, equal and reactive. Confrontational visual fields and extraocular motility were full, and he had no pain with eye movements. IOP was within normal limits. Eyelids were normal, and the anterior segment exam revealed white and quiet eyes with clear lenses and no evidence of previous inflammation or trauma. Dilated fundus exam revealed healthy, pink optic nerves, and the vasculature was of normal course and caliber bilaterally. Macular sheen and foveal pigmentation were normal bilaterally. Peripheral retinal exam was remarkable for blonde fundi and diffuse pigmentary changes throughout the periphery and encroaching upon the maculae (Figure 1). General physical exam revealed a well-appearing and developmentally appropriate child with no discernible neurological or physical abnormalities (Figure 2).
Images: Baumal C, Lewen M
What is your diagnosis?
Nyctalopia
The history and presentation of this young, healthy patient with nyctalopia and bilateral pigmentary retinopathy are suggestive of an inherited retinal degeneration, although acquired etiologies must be considered. Congenital rubella is a well-known cause of pigmentary retinopathy, and other ophthalmic manifestations of this infection include microphthalmia, cataract, glaucoma and uveitis. Other infectious causes of pigmentary retinopathy include congenital syphilis as well as measles, mumps and herpes. Medications such as thioridazine, chlorpromazine, chloroquine, hydroxychloroquine and deferoxamine have demonstrated toxicity to the retina, evident as pigmentary changes. Trauma and prior retinal detachments might also result in retinal pigmentation; however, these aforementioned acquired causes are inconsistent with the patient’s medical history.
Retinal pigmentation is associated with a host of syndromes including Kearns-Sayre, Bardet-Biedl, Alagille, Batten, Usher, Zellweger and many others. The patient’s history was not suspicious for a syndromic etiology, and his exam did not reveal associated features such as ptosis and ophthalmoplegia in Kearns-Sayre syndrome or developmental delay and polydactyly in Bardet-Biedl syndrome, to name a few.
The patient’s symptoms and exam findings were consistent with a process affecting the peripheral retina and preserving macular function. The most likely inherited retinal degenerations in this case are retinitis pigmentosa and choroideremia. Inheritance patterns of retinitis pigmentosa include autosomal dominant, autosomal recessive and X-linked recessive. The classic manifestations of retinitis pigmentosa include peripheral pigmentary changes resembling bone spicules, waxy pallor of the optic disc and attenuation of the retinal vasculature. Choroideremia is inherited in X-linked recessive fashion and demonstrates progressive and extensive loss of the choroid, choriocapillaris and retinal pigment epithelium (RPE), typically beginning in the mid-periphery and advancing both anteriorly and posteriorly. The process of diffusely deteriorating RPE can manifest as scattered pigmentation. In both conditions, nyctalopia is a common initial symptom.
Diagnosis and management
The patient and his mother were referred to the electroretinography service. The patient’s ERG was remarkable for significantly attenuated rod responses, and cone function was reduced but still within normal limits (Figure 3). On examination, the patient’s mother demonstrated peripheral retinal pigmentary changes that were not as extensive as her son’s. The patient’s mother had ERG testing as well, which revealed normal rod and cone activity and no evidence of retinal dysfunction.
Further discussion with the family revealed that the patient’s great-uncle on his mother’s side had poor peripheral vision as a young adult and subsequently lost central vision bilaterally during middle age. The inheritance is consistent with an X-linked recessive pattern, with the patient’s mother and grandmother as carriers.
X-linked retinitis pigmentosa is a particularly severe form of the disease characterized by loss of central vision as early as the first decade of life. ERG recordings in X-linked retinitis pigmentosa typically demonstrate significantly reduced function of both rods and cones, accounting for the decrease in visual acuity. The patient’s fundus exam did not demonstrate the classic findings of retinitis pigmentosa. While the presentation may indeed be too early for findings such as optic nerve pallor, vascular attenuation and bone spicule pigmentary changes, the exam findings and ERG recording are less likely to be due to retinitis pigmentosa in the setting of an X-linked inheritance pattern.
Choroideremia is known to cause peripheral pigmentary changes indicative of dysfunction of the RPE. Rods are characteristically affected early with relative preservation of cone function centrally until late-stage disease. Additionally, further investigation revealed that the patient’s great-uncle had been diagnosed with choroideremia. Due to the established family history of choroideremia and an exam consistent with this diagnosis, genetic testing of the patient was not obtained. He and his mother were counseled on the anticipated course of the degenerative condition, and he was started on lutein and zeaxanthin supplementation.
Discussion
The term “choroideremia” refers to the absence of choroid observed in end-stage disease. It is a rare disorder with a prevalence estimated to be between one in 50,000 to 100,000 individuals. Mutations in the CHM gene on the X chromosome result in the absence of Rab escort protein-1 (REP-1) and the disease manifestations of choroideremia. REP-1 is involved in intracellular transport and expressed in tissues throughout the body, although the eye is the only clinically affected site. While the exact mechanism of tissue deterioration remains unclear, the early stages of the disease are characterized by degeneration of the choriocapillaris, RPE and loss of photoreceptors beginning in the mid-peripheral retina. This results in the early symptoms of nyctalopia and progressive loss of the peripheral visual field. Despite extensive degeneration of the choroid and RPE ultimately resulting in visible sclera on fundus exam, the macula, and thus central visual acuity, is typically preserved until the end stage of the disease, which tends to occur in the fifth decade of life. As an X-linked recessive disease, choroideremia affects males almost exclusively, although female carriers might demonstrate pigmentary changes or patchy areas of RPE atrophy and decreased night vision. Definitive diagnosis is established by genetic testing for the CHM gene.
Currently there are no effective therapies for choroideremia. Supplementation with lutein and zeaxanthin may be helpful in supporting or increasing macular pigmentation. Multiple studies are investigating gene therapy for patients with choroideremia. Mice models of choroideremia have been shown to express REP-1 after administration of the exogenous CHM gene. More recently, MacLaren and colleagues reported a phase 1/2 study evaluating the safety and efficacy of submacular injection of adenovirus vectors containing the CHM gene in six adult patients with advanced disease. At the 6-month postoperative mark, no adverse events were reported and maximal retinal sensitivity had improved in the treated eyes compared with the fellow untreated eyes in all six patients. As the safety and efficacy profile of gene therapy for choroideremia advances, early preventive treatment may very well become a reality for these patients.
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- For more information:
- Caroline Baumal, MD, and Michael Lewen, MD, can be reached at New England Eye Center, Tufts University School of Medicine, 750 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.
- Edited by Kristen E. Dunbar, MD, and Kendra Klein, MD. They can be reached at New England Eye Center, Tufts University School of Medicine, 750 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.