A 40-year-old white male presented to establish care with a retina specialty clinic after recently moving to the area. He presented with history of legal level blindness from presumed choroideremia, which had been diagnosed clinically and was also based on family history. Genetic testing had not been performed. He has two siblings: an unaffected sister, and a brother who also has the condition. He also reported his maternal grandfather was blind from a retinal condition. He has three children: two daughters and a son, none of whom are known to be affected.
His visual acuity was hand motion OU. He had 360 severe constriction of his visual fields and sluggish but equal pupillary responses OU. His extraocular motilities were full OU. Intraocular pressure measured with tonopen was 18 and 18. The anterior segment was normal.
In the posterior segment, there was increased visibility of larger choroidal vessels and scleral visibility indicating outer retina/retinal pigment epithelium (RPE)/and choroidal atrophy throughout the posterior pole and mid-peripheral retina (Figure 1).
OCT showed severe atrophy of the outer retina and loss of photoreceptor integrity line even within the fovea. There was presence of outer retinal tubules in both eyes: a finding that can present in diseases that affect the outer retina and photoreceptors and is not unique to choroideremia. There was also significant choroidal thinning centrally and choroidal atrophy (Figure 2).
The fundus autofluorescence taken with the Optos Daytona showed areas of hyper-autofluorescence in regions of more significant chorioretinal atrophy. This likely represents autofluorescent properties of the scleral due to the patient’s significantly progressed disease and severe outer retina, RPE, and choroidal atrophy in these regions (Figure 3).
The patient’s clinical findings were consistent with choroideremia. A gene pedigree was constructed considering the patient’s known family history (Figure 4). This matched a pattern of x-linked recessive inheritance that is also consistent with choroideremia.
The patient was educated about findings consistent with choroideremia, and that treatment does not currently exist for the condition. He was educated that to make a definitive diagnosis, genetic testing could be performed. The patient was consented for gene testing through the Spark Therapeutics free genetic testing program. For more information visit https://sparktx.com. A saliva sample was collected and sent out for testing. The patient’s results were positive for a pathogenic gene mutation in the CHM gene: which is consistent with x-linked recessive choroideremia. (Figure 5)
The patient was advised to pursue genetic counseling: a free service also offered by Spark Therapeutics. He was counseled about the implications of this diagnosis for his daughters, who will be carriers of the condition. Their potential sons will have 50% chance of having the condition, and their potential daughters will have 50% chance of being carriers. There are also implications of this diagnosis for the patient’s sister, whose carrier status is unknown, but who has 50% chance of being a carrier. Genetic testing for potentially affected family members is also offered through the Spark Therapeutics program for many conditions.
The patient was advised of the Foundation for Fighting Blindness online gene registry program. This registry is devised to better understand prevalence and prognosis of retinal disease as well as access patients who would benefit from clinical trials. More information about this program can be found at myretinatracker.org. The patient was also advised about the Choroideremia Research Foundation, a good source of information and support for patients and families suffering from the disease (https://www.curechm.org/).
The patient was advised of low vision programs and services offered in the area but was currently doing well with his devices and use of a white cane for mobility. Due to the long-standing nature of his condition and previous work with low vision specialists, he was well adapted to efficiently perform ADLs.
The patient was advised to return to clinic for monitoring in six months to a year.
The patient and his wife were concerned about their female daughters who would be carriers of choroideremia. At the time, the couple had two daughters 10 and 11 years old who reported no visual abnormalities. While choroideremia is x-linked, female carriers have been reported to have retinal findings such as RPE mottling. They may remain asymptomatic or develop symptoms such as nyctalopia, glare sensitivity, field loss, and reduction in visual acuity. Symptoms have been reported in carriers with varying amounts of severity. In general, female carriers tend to have a much better prognosis than affected male patients. (1,2,3)
A dilated examination was performed on both daughters. Visual acuity was 20/20 OD, OS for each daughter. Both retinal exams showed diffuse mid-peripheral and peripheral pigmentary abnormalities. FAF demonstrated reticular mottling of the autofluorescent signal for both patients with the younger daughter demonstrating more alterations in the macula than the older daughter. The cross-section macular OCT of the younger daughter showed mild RPE disruption with patchy hyper-reflectivity on the infrared reflectance image. The older daughter’s macular OCT appeared fairly normal with milder alterations on the infrared reflectance image. (Figures 6 and 7)
Due to these findings, the parents wanted to pursue genetic testing on the daughters to confirm that they were carriers for choroideremia and had no other genetic mutations that could complicate their clinical course. Both daughters were confirmed to be carriers for choroideremia with genetic testing. The younger daughter had no additional genetic defects of certain significance. The older daughter was a carrier for a “likely pathogenic” variant of USH2A associated with autosomal recessive Usher Syndrome type 2A and retinitis pigmentosa (Figure 8). It is difficult to understand if this will have any clinical significance for the visual prognosis of the older daughter at this time; however, it could have significance for future offspring. Genetic counseling was advised again for the parents and children.
The parents were encouraged that while the daughters showed signs of retinal pathology, this has been previously reported in female carriers, that many remain asymptomatic, and that those who do exhibit symptoms tend to be much less severe than male patients. Further investigation with functional testing such as ERG and perimetry was considered but was not available at the satellite clinic where the patients were seen. It was ultimately decided with the parents to monitor at this time. All were advised about the rare but possible complication of choroidal neovascularization and the daughters were taught how to use an Amsler grid. The daughters will be seen every six months to a year as well.
Choroideremia is a rare x-linked recessive inherited retinal disease (IRD). Being x-linked, the condition is present most commonly in males, but some female carriers have been reported to have phenotypical retinal alterations as well. (1,2,3) Choroideremia leads to progressive and ultimately severe atrophy of the outer retina, RPE, and choroid. The earliest presenting symptom is night blindness, followed by progressive loss of the midperipheral and peripheral vision. Patients tend to maintain a central island of vision until later stages of the diseases. (4)
While there is currently no treatment for choroideremia, multiple clinical trials are underway to potentially benefit these patients. (5) As we progress closer to treatment for IRDs such as choroideremia, genetic testing to reach a definitive diagnosis becomes more clinically relevant. There are multiple avenues to pursue testing for patients, potentially at no cost to the patient with programs such as the Spark Therapeutics gene testing program.
Genetic testing can have multiple implications for not only the patient, but also for potentially affected family members, and genetic counseling should always be offered to patients in conjunction with genetic testing.
While this patient was performing ADL’s well with his current low vision devices and training, low vision services remain key in the management of patients with choroideremia and must remain a point of emphasis as the disease progresses and visual demands change over time.
- Jauregui R, Park KS, Tanaka AJ, et al. Spectrum of Disease Severity and Phenotype in Choroideremia Carriers. Am J Ophthalmol. 2019;207:77-86.
- Dugel PU, Zimmer CN, Shahidi AM. A case study of choroideremia carrier – Use of multi-spectral imaging in highlighting clinical features. Am J Ophthalmol case reports. 2016;2:18-22.
- Pidro A, Ratkovic M, Pjano MA, Biscevic A. A Case Study of Choroideremia and Choroideremia Carrier. Med Arch (Sarajevo, Bosnia Herzegovina). 2019;73(1):61-62.
- Coussa RG, Traboulsi EI. Choroideremia: A review of general findings and pathogenesis. Ophthalmic Genet. 2012;33(2):57-65.
- Pennesi ME, Birch DG, Duncan JL, Bennett J, Girach A. Choroideremia: Retinal Degeneration with an Unmet Need. Retina. 2019;39(11):2059-2069.