KEY TAKEAWAYS
- PRPH2-related diseases are autosomal dominant and have heterogeneous and variable presentations.
- Ocular manifestations of pseudoxanthoma elasticum include angioid streaks, peripapillary atrophy, and a high risk of choroidal neovascularization.
- Reported ophthalmic manifestations of Danon disease include peripheral salt-and-pepper retinopathy, macular atrophy, bulls-eye maculopathy, lens abnormalities, and visual field defects.
Patients are referred to retina specialists for myriad reasons, many of which are easy to diagnose. However, when a patient’s symptoms, examination, and/or imaging don’t add up, it’s the retina specialist’s job to get to the bottom of the mystery, regardless of how unlikely the diagnosis. These mystery cases are designed to test your diagnostic skills and help improve your rare and inherited disease (IRD) know-how.
- Rebecca Hepp, MA, Editor-in-Chief
MYSTERY CASE NO. 1
By Kenneth C. Fan, MD, MBA
A 47-year-old African American woman presented with a history of central vision loss that began in her 30s. She described central vision distortion that had gradually worsened, now coalescing into blind spots. Her vision was 20/40 OD and 20/40 OS with normal IOPs OU. Family history revealed that her mother had been diagnosed with AMD in her 50s. Her sister and two children have no visual symptoms. There was no evidence of consanguinity. The physical examination did not reveal any other syndromic findings.
Fundus imaging showed symmetric subtle flecks in the macula and posterior pole and a beaten-bronze appearance of central atrophy in each eye (Figure 1). Fundus autofluorescence (FAF) revealed severe central decreased autofluorescence with macular and mid-peripheral flecks (Figure 2). OCT imaging demonstrated patchy multifocal atrophy of the ellipsoid zone (EZ) and retinal pigment epithelium (RPE) in each eye (Figure 3).
Based on these findings, can you diagnose this patient?
Figure 1. Fundus photography of right (A) and left (B) eye demonstrates subtle flecks in the macula and posterior pole and beaten-bronze appearance of central atrophy.
Figure 2. FAF of right (A) and left (B) eye demonstrates severely decreased central autofluorescence with macular and midperipheral flecks.
Figure 3. OCT imaging of right (A) and left (B) eye demonstrates patchy multifocal atrophy of the EZ and retinal pigment epithelium.
MYSTERY CASE NO. 2
By Caroline C. Awh, MD, and Nimesh A. Patel, MD
A 6-year-old healthy girl was referred for bilateral retinal pigmentary changes. She was asymptomatic with a VA of 20/25 OU. The dilated fundus examination demonstrated 360° peripheral retinal hyperpigmentation (Figure 4) with normal FAF imaging (Figure 5). OCT revealed subtle outer plexiform deposits in the macula (Figure 6).
The referring ophthalmologist had ordered an autoimmune workup, an infectious and inflammatory workup, and a retinal dystrophy panel, all of which were negative. Her review of systems and family history for IRD was negative.
Based on these findings, can you diagnose this patient?
Figure 4. The fundus examination revealed 360° peripheral retinal hyperpigmentation in the right (A) and left (B) eye.
Figure 6. OCT imaging was remarkable for subtle outer plexiform deposits in the macula of the right (A) and left (B) eye.
MYSTERY CASE NO. 3
By Marta Stevanovic, MD, MSc; Maria Emfietzoglou, MD; and Demetrios Vavvas, MD, PhD
A 63-year-old man presented with a VA of counting fingers OU (Figure 7). He reported no personal medical history, and family history included an uncle and cousin (in his 40s) who also had decreased visual acuity. Dilated fundus examination revealed large areas of central atrophy with surrounding drusen. FAF showed central areas of hypoautofluorescence and OCT demonstrated significant retinal thinning and EZ loss.
Based on these findings, can you diagnose this patient?
Figure 7. Fundus photography shows central retinal atrophy with surrounding drusen. There is a corresponding area of hypoautofluorescence. OCT shows significant central retinal atrophy and drusen surrounding the atrophic region.
MYSTERY CASE NO. 4
By Mary V. Lang; Lisa A. Schimmenti, MD; and Brittni A. Scruggs, MD, PhD
A 78-year-old man presented for a second opinion regarding progressive geographic atrophy (GA). He had a 7-year diagnosis of wet AMD managed with intravitreal aflibercept (Eylea, Regeneron) every 6 weeks due to recurrent subretinal fluid accumulation with injection spacing.
A review of systems reveals long-standing leg claudication. BCVA was 20/200 OD and 20/125 OS, and Ishihara color plates are 3/14 in each eye. Fundus examination and FAF were remarkable for profound GA, peripapillary atrophy, and subtle angioid streaks (Figure 8).
Based on these findings, can you diagnose this patient?
Figure 8. Fundus photography shows bilateral parafoveal and peripapillary atrophy (A, B). FAF imaging demonstrates angioid streaks (arrows) with peripapillary and parafoveal atrophy surrounded by perifoveal hyperautofluorescence (C, D). OCT demonstrates bilateral GA with a diffuse epiretinal membrane in the right eye (E) and disorganization of the inner retinal layers in the left eye (F).
DIAGNOSIS AND DISCUSSION
Case No. 1
This patient was diagnosed with PRPH2-associated retinal dystrophy. PRPH2-related diseases are autosomal dominant (hence her mother possibly having a similar diagnosis in her 50s) and have heterogeneous and variable presentations. The scope of phenotypes can include pseudo-Stargardt (which this patient has), retinitis pigmentosa (RP), central areolar choroidal dystrophy, and Leber congenital amaurosis.1,2 PRPH-related RP is suspected in up to 8% of all autosomal-dominant RP globally.1,2 The average age of onset is approximately 40 years of age, although significant variability exists. Because wildtype PRPH2 expression is critical for the survivability of rod photoreceptors, and to some degree cone photoreceptors, molecular variants in PRPH2 can cause retinal dysfunction.3
With the increasing number of clinical trials for ABCA4-related IRD and Stargardt disease, differentiation between PRPH2- and ABCA4-related disease is paramount. A thorough family history can be immensely helpful.
Case No. 2
Prior experience led us to obtain specific genetic testing for a mutation in the lysosome-associated membrane protein-2 (LAMP2) gene, revealing a pathogenic variant (c864+1G>T) and solidifying a diagnosis of retinal dystrophy in the setting of Danon disease.
Danon disease is a rare X-linked disorder of autophagy caused by deficiency in the LAMP2 protein. LAMP2 is most heavily expressed in the myocardium, skeletal muscle, and brain, and the classic triad of Danon disease is a severe cardiomyopathy, nonprogressive skeletal myopathy, and mild neurocognitive issues.4
Reported ophthalmic manifestations of Danon disease vary and include pigmentary retinopathy, lens abnormalities, and visual field defects.5 Retinal findings, such as a peripheral salt-and-pepper retinopathy, are the most common ophthalmic manifestation. Patients may also develop severe macular atrophy, bulls-eye maculopathy, near complete pigment loss mimicking choroideremia, and pigment clumping mimicking RP.6 As survival improves with advanced cardiac care and emerging gene therapies, detecting and monitoring retinal disease is increasingly important.7,8
Our patient continues to be monitored by a multidisciplinary team including pediatric cardiology, genetics, and ophthalmology. She will need to be followed throughout childhood and adolescence, as cardiac disease may develop.
Case No. 3
Nine years prior to this presentation (54 years of age), his VA was 20/30 OD and 20/80 OS. Examination revealed a large macular elevation with yellow deposits and surrounding drusen (Figure 9).
Electrooculography (EOG) was normal (Arden ratio OD = 3.79 OD, 2.83 OS [normal ≥ 1.80]), as was full-field electroretinography (ERG). Multifocal ERG revealed diminished responses centrally (Figure 10).
Figure 9. At initial presentation nine years prior, imaging showed macular elevation with yellow subretinal deposits and surrounding drusen. On FAF, there is a hypoautofluorescent region in the superior macular and a hyperautofluorescent area in the inferior macula, corresponding to the yellow deposits. OCT shows reflective subretinal material layering in the inferior macula.
Figure 10. Multifocal ERG showed diminished central responses in each eye. In the right eye (A), the response density ring ratios are abnormally low in the central 8°, consistent with the individual traces. The timing is relatively delayed in the central three rings. In the left eye, the average ring amplitudes are abnormally low throughout, and the response density ring ratios are abnormally low in the central 10° (B). The timing is normal.
The patient underwent genetic testing, which revealed a heterozygous BEST1 5′-UTR variant, c.-8G>A, a previously undescribed mutation. Although the pathogenicity of this variant has not yet been established, it is considered the likely cause of the patient’s disease. In vitro studies have demonstrated reduced protein expression with the c.-8G>A variant compared with the wild type, suggesting that this variant impairs BEST1 expression.
Clinically, the patient exhibited vitelliform macular lesions but had a normal EOG, which is atypical for Best disease and more consistent with adult-onset foveomacular vitelliform dystrophy. Based on the clinical and genetic findings, the patient was diagnosed with BEST1-related adult-onset foveomacular vitelliform dystrophy. This case expands the BEST1 mutational spectrum and highlights the importance of examining 5′ UTR variants.
MYSTERY CASE MASQUERADE
By Yicheng Bao, MD, and Hossein Ameri, MD, PhD, FRCSI, MRCOphth
A 35-year-old man presented with a progressive nyctalopia starting 2 years prior. He reported difficulty adjusting from bright light to dark environments but noted no significant deficits in central or color vision. The patient lacked a family history of vision loss, and review of systems was negative.
BCVA was 20/40 OD and 20/25 OS. IOP was 9 OD and 12 OS. Dilated fundus examination revealed bilateral, symmetric fine granular pigmentary changes across the mid-periphery (Figure 1), which was supported by fundus autofluorescence imaging (Figure 2). Spectral-domain OCT showed parafoveal inner retinal atrophy. Functional testing provided evidence of severe photoreceptor dysfunction. Electroretinography (ERG) demonstrated a profound loss of rod function and significantly reduced cone responses (Figure 3). The clinical picture was complicated by a significant systemic history, including ANCA-positive vasculitis, focal segmental glomerulosclerosis, and chronic pancreatitis.
Figure 1. Ultra-widefield fundus photography showed a bilateral, symmetric distribution of fine granular pigmentary changes across the midperiphery.
Figure 2. Fundus autofluorescence showed bilateral stippled hypoautofluorescence in the midperiphery.
Figure 4. ERG performed less than 2 months after the start of vitamin A treatment demonstrates a remarkable improvement in rod function and a modest improvement in cone function.
DISCUSSION
Genetic testing yielded a likely pathogenic heterozygous mutation in PEX10 and five variants of uncertain significance. Further laboratory evaluation revealed a markedly low serum vitamin A level of 0.12 µg/mL (Reference: 0.30–0.80 µg/mL). The patient was treated with intravenous vitamin A and started noting improvement in night vision 6 days later. Subsequently, his night vision returned to normal, and his VA improved to 20/25 OU. ERG showed a remarkable improvement in rod function and a modest improvement in cone function.
This case illustrates that pigmentary retinopathy is not always synonymous with an inherited dystrophy. Vitamin A is essential for the visual cycle; its deficiency leads to a functional failure of photoreceptors, manifesting as nyctalopia and peripheral vision loss that can masquerade as retinitis pigmentosa. Of note, genetic testing results demonstrating a pathogenic mutation should not automatically lead the physician to a diagnosis of inherited retinal degeneration without clinical correlation. In this case, the patient did not exhibit any systemic features of Zellweger syndrome. Moreover, a heterozygous mutation in PEX10 would not be expected to be disease-causing in an autosomal recessive disorder.
In patients with pigmentary changes, especially those with conditions predisposing to malabsorption, nutritional deficiencies must be ruled out immediately. Unlike many progressive inherited dystrophies, retinal dysfunction due to vitamin A deficiency is often reversible.
Yicheng Bao, MD
Vitreoretinal Surgery Fellow, USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles
yicheng.bao@med.usc.edu
Financial disclosure: None
Hossein Ameri, MD, PhD, FRCSI, MRCOphth
Associate Professor of Clinical Ophthalmology and Director, USC Retinal Degeneration Center, Department of Ophthalmology, USC Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles
ameri@med.usc.edu
Financial disclosure: Consultant Consultant (Beyang Therapeutics); Scientific Advisor (Eye Kleur)
Case No. 4
Genetic testing revealed a pathogenic deletion involving exon 9 of ABCC6, (c.(998+1_999 1) (1176+1_1177 1)del) and a variant of uncertain significance, ABCC6 c.3001G>A (p.Gly1001Arg). This patient’s clinical presentation and genetic variants are characteristic of pseudoxanthoma elasticum (PXE), a heritable disorder of elastic fiber mineralization affecting the skin, vasculature, and Bruch membrane.
PXE is an autosomal recessive condition caused by loss of function variants in ABCC6, leading to aberrant calcification of elastic tissues. Patients typically present with cutaneous laxity and lesions, premature peripheral vascular disease, and gastrointestinal bleeding, often beginning in early- to mid-adulthood. Ocular manifestations arise from progressive mineralization and fragmentation of Bruch membrane, resulting in angioid streaks, peripapillary atrophy, and a high risk of choroidal neovascularization (CNV).9,10
This patient’s initial diagnosis of wet AMD is a common misattribution, as the two conditions share overlapping features such as CNV, GA, and drusen-like deposits. The key distinguishing finding in this case was the presence of angioid streaks. While angioid streaks are not pathognomonic for PXE, they are present in nearly every affected individual and should prompt systemic evaluation. The differential diagnosis of angioid streaks includes Paget disease of bone, sickle cell disease, Ehlers-Danlos syndrome, and hyperphosphatemia, although PXE accounts for most cases when patients are examined closely.11,12
In a landmark report, Lebwohl et al demonstrated that young patients (n = 4) with angioid streaks presenting with premature cardiovascular disease were found to have histologic evidence of PXE5.13 The most frequent cause of disability in PXE is reduced vision from macular hemorrhage and disciform scarring. Given the risk of cardiovascular complications, early diagnosis and multidisciplinary management are crucial in optimizing patient outcomes.9,10,13,14
This case demonstrates the importance of recognizing PXE as both a systemic disorder and a mimicker of AMD. The combination of angioid streaks, progressive GA, chronic CNV, and vascular disease should prompt systemic evaluation, including genetic testing.
How did you do? If you have your own mystery case, we would love to share it in Retina Today! Send your case and images to rhepp@bmctoday.com.
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