Stair-Case/Honeycomb Maculopathy in Alport Syndrome: A Case Report

Abstract

Introduction

Alport syndrome is an inherited disease caused by mutations in COL4A5, COLA3, or COL4A4 resulting in kidney failure, hearing loss, and ocular symptoms. We report a patient with Alport syndrome who has a “stair-case/honeycomb” maculopathy, a rare but distinctive finding in this disease.

Case Presentation

A 53-year-old man with Alport syndrome was referred for gradual decrease in vision. His ocular history was remarkable for intraocular lens implantation secondary to lenticonus in each eye. Fundus photography showed rare white dots in the temporal mid-periphery in each eye and fundus autofluorescence was normal. Optical coherence tomography (OCT) B-scans through the fovea showed irregular thinning of the inner retina with peaks and valleys in the macula of each eye. The ellipsoid zone was intact except for mild patchiness centrally. En face retinal structural OCT angiography (OCTA) images showed a mosaic-like honeycomb pattern in the macular region in both eyes, with hyporeflective depressions in areas of focal retinal atrophy. Retinal OCTA scans showed irregular foveal avascular zone (FAZ) areas with capillaries crossing the FAZ in the left eye, corresponding to islands of preserved retinal tissue. There was predominance of capillaries in the deeper retinal layers centrally.

Conclusion

While severe irregular thinning of the macula is not a common feature in Alport syndrome, when it is present in patients who have not been previously diagnosed, particularly in patients with renal disease, it should suggest the diagnosis of Alport syndrome. Its occurrence can be the cause of vision loss which is not commonly associated with Alport central maculopathy.

Introduction

Alport syndrome is an inherited disease characterized by abnormal basement membranes due to a mutation in COL4A5, COLA3, or COL4A4 [1, 2]. The basement membrane abnormalities have the greatest clinical impact in the kidney, often resulting in renal insufficiency and renal failure [3]. There is also frequent sensorineural hearing loss and ocular findings including posterior polymorphous corneal dystrophy, anterior lenticonus, peripheral retinopathy, and central retinopathy. The central retinopathy has several possible features including yellow or white dots and flecks in the temporal macula [4], a perimacular annulus of densely packed dots causing a tapetal reflex [5], maculoschisis, and rarely, a macular hole [6]. An unusual but quite distinctive finding is irregular thinning in the macula that has been labeled “stair-case” foveal sign [7]. Herein, we report a patient with Alport Syndrome who has “stair-case” maculopathy with corresponding honeycomb appearance on en face OCT images, and OCTA showing irregular foveal avascular zone (FAZ) areas in each eye.

Case Presentation

A 53-year-old man with Alport syndrome was referred because of gradually decreasing vision in each eye. He was diagnosed with Alport syndrome as a teenager based upon distinctive findings on renal biopsy which was done because of hematuria and sensorineural hearing loss. The diagnosis was later confirmed by genetic testing. He developed renal failure and had a renal transplant in 1994. He developed graft rejection and recurrent renal failure and had a second renal transplant in 2010. Since then, he has been managed with immunosuppressives and antihypertensives and his general health has been stable. His ocular history was remarkable for lenticonus in both eyes for which he had lens removal and intraocular lens implantation in each eye. The patient was medicated with latanoprost in each eye for ocular hypertension. Visual acuity was 20/50 in the right eye (OD) and 20/63 in the left eye (OS) and intraocular pressure was 18 mm Hg OD and 19 mm Hg OS. Slit lamp examination showed well-positioned posterior chamber intraocular lens in each eye. Indirect ophthalmoscopy and wide-angle fundus photography showed normal-appearing optic nerves, vessels, maculae, and peripheral retina except for rare white dots in the temporal mid-periphery of each eye (Fig. 1a, b). Fundus autofluorescence was normal in each eye (Fig. 1c, d). Optical coherence tomography (OCT) showed irregular thinning of the inner retina with peaks and valleys in the macula of each eye and with the underlying ellipsoid zone mostly intact except for some mild patchiness centrally (Fig. 2a, b). There was also thinning of the choroid. En face retinal structural OCT angiography (OCTA) images showed a symmetrical, mosaic-like, honeycomb pattern in the macular region in both eyes. This was characterized by hyporeflective depressions in areas of focal retinal atrophy, with alternating zones/islands of preserved and thinned neurosensory retina, creating a well-demarcated honeycomb pattern on en face imaging. Depth-encoded retinal OCTA scans showed irregular FAZ areas bilaterally, with capillaries crossing the FAZ in the OS, corresponding to islands of preserved retinal tissue. Pseudocoloring demonstrated predominance of capillaries in the deep retinal layers (green) centrally that was more pronounced in the OD than OS. This is presumably due to atrophy of the inner retinal layers (Fig. 3a–d). Corresponding B-scans through the macula demonstrated several small defects hollowed out from the surface of the internal limiting membrane (ILM), with disruption and collapse of the inner retinal layers, representing partial atrophy of the neurosensory retina. The fovea was indistinct in both eyes with a loss of its normal contour, characteristic of temporal retinal thinning in Alport syndrome. The external limiting membrane appeared to be intact, with preservation of the photoreceptor layer, except for mild patchiness in the ellipsoid zone (EZ) in both eyes (Fig. 3e, f). A CARE Checklist is provided as supplementary material (for all online suppl. material, see https://doi.org/10.1159/000546567).

Fig. 1.

Wide-angle fundus color and autofluorescence images of the OD and OS. Wide-angle color fundus image of the OD (a) and OS (b), showing normal-appearing optic nerves, vessels, maculae, and peripheral retina except for rare white dots in the temporal mid-periphery of each eye. Ultrawide field autofluorescence fundus image of the OD (c) and OS (d), demonstrating normal anatomy and autofluorescence.

Fig. 2.

Spectral domain optical coherence tomography (SD-OCT) images of the OD and OS. a, b OCT images reveal irregular inner retinal thinning characterized by peaks and valleys in the macula. The ellipsoid zone (EZ) width was largely intact, although there is some patchiness in the central region. Additionally, there is evidence of choroidal thinning.

Fig. 3.

Swept-Source optical coherence tomography angiography (SS-OCTA, PlexElite 9000, Carl Zeiss Meditec) images of the OD and OS, displaying the 12 × 12 mm² and 3 × 3 mm² OCTA scans, with corresponding B-scans. These findings illustrate the chorioretinal anatomy in this patient with Alport syndrome. a En face retinal structural images of the 12 × 12 mm² scans, showing a symmetrical mosaic-like honeycomb pattern in the macular region in both eyes. A more detailed view on the 3 × 3 mm² in b demonstrates hyporeflective depressions in areas of focal retinal atrophy with alternating zones of preserved and thinned neurosensory retina. c Depth-encoded retinal OCTA scans showing irregular foveal avascular zone (FAZ) areas, with a more detailed view of the capillaries and FAZ in the next panel. d There are capillaries crossing the FAZ in the OS, corresponding to islands of preserved retinal tissue. Pseudocoloring demonstrates predominance of capillaries in the deeper retinal layers (green) centrally that is more pronounced in the OD than OS. This is presumably due to atrophy of the inner retinal layers. e Corresponding B-scans through the macula, demonstrating irregular retinal thinning in a staircase pattern, with choroidal thinning, which is more apparent in the 3 × 3 mm² scans as shown in f. The fovea is indistinct in both eyes with a loss of its normal contour, characteristic of temporal retinal thinning in Alport syndrome. There are several small defects hollowed out from the surface of the internal limiting membrane, with disruption and collapse of the inner retinal layers, representing partial atrophy of the neurosensory retina. The external limiting membrane appears to be intact, with preservation of the photoreceptor layer, except for mild patchiness in the ellipsoid zone.

Discussion

Patients with Alport syndrome are most impacted by renal disease, but ocular findings are common, can assist in making the diagnosis, and sometimes have visual consequences. Lenticonus is quite common and often requires cataract surgery as was the case in this patient [8]. Peripheral retinal changes consisting of white dots, flecks, and/or pigmentary changes, and central retinal changes consisting of perimacular white dots or flecks and temporal macular thinning are common and have little or no effect on vision [9–11]. More severe irregular thinning of the macula was described in 2 case reports of a single patient showing dramatic changes referred to as “stair-case” foveal sign and visual acuity of 20/30 in one eye and 20/100 in the other [7, 12, 13]. In a case series of 14 patients with Alport syndrome, the stair-case foveal sign, or similar but milder changes of inner retinal dimples, were found in 7 eyes of four patients with X-linked Alport syndrome [13]. Visual acuity was not reported for these patients, but mean visual acuity in the series was 20/40. Our patient exhibited dramatic irregular thinning of the inner retina in the macula in each eye with peaks and valleys on each side of the fovea, findings similar to those seen in OCT images of the initial case described as stair-case foveal sign in an Alport syndrome patient [7, 12] and more severe than those in the case series [13]. En face OCT images showed a very distinctive honeycomb appearance due to the irregular thinning in the macula. These changes were associated with moderate reduced vision of 20/50 in the OD and 20/63 in the OS. OCTA scans showed an irregular and enlarged FAZ in each eye and vessels crossing the FAZ in the OS. This raises the question, did the macular thinning lead to loss of superficial capillaries or did capillary drop out lead to areas of macular thinning? There is no way to determine between these alternatives by observations made at a single time point in our patient, but there is reason to believe that the inner retinal thinning was the primary event. In Alport syndrome, there are abnormalities in the α3(IV)–α5(IV) collagen network which is not part of vascular basement membranes, but is present in the basement membrane in glomeruli and in the ILM of the retina and basement membrane of the retinal pigment epithelium [14]. While mild thinning of the retina, particularly in the temporal macula, is frequently seen in patients with Alport syndrome, retinal capillary drop out is not commonly seen. Interestingly, Hess et al. [13] (2020) noted foveal hypoplasia with reduced or absent FAZ in patients with autosomal recessive Alport syndrome and enlarged FAZ in 3 eyes of patients with X-linked recessive Alport syndrome. The mechanism by which abnormalities in collagen IV in the ILM cause changes in retinal vessels and alterations in retinal thickness are unknown, but it appears to differ based upon whether there are abnormalities in the α3 or α4 subunits, which may alter development of the fovea and FAZ, versus abnormalities in the α5 subunit which may cause progressive, irregular thinning of the macula and enlargement of the FAZ [13]. While we cannot say for certain that the irregular thinning of the macula is progressive, the reduction in vision over time in our patient and the range of severity in reported cases are suggestive. Perhaps progressive thinning is the cause of macular holes that have been observed in some patients with Alport syndrome [6, 14].

In conclusion, while severe irregular thinning of the macula is not a common feature in Alport syndrome, when it is present in patients who have not been previously diagnosed and have not had prior retinal surgery, particularly in patients with renal disease, it should suggest the diagnosis of Alport syndrome. Its occurrence can be the cause of vision loss which is not commonly associated with Alport central maculopathy. It may also be a precursor of macular hole formation. It has previously been referred to as “Stair Case Foveal Sign,” but based upon the distinctive appearance on en face OCT and its presence throughout the macula rather than limited to the fovea, we propose the moniker “Stair Case/Honeycomb Maculopathy.”

Statement of Ethics

This study was performed in accordance with the Declaration of Helsinki. Ethics approval for this human study was waived by Johns Hopkins IRB3 committee because Johns Hopkins policy is that case reports of 1, 2, or 3 patients does not constitute research and are not subject to IRB approval. The one adult participant provided written informed consent to participate in this study and for the study to provide the details of the participants’ medical case and the accompanying images.

Conflict of Interest Statement

P.A.C. has received grant support from RegenxBio, Genentech, Cove, Sanofi, Celanese, Regeneron, ExgenesisBio, Ocular Therapeutics and received consulting fees from Allegro, Boehringer Ingelheim Pharmaceuticals, Inc, Bausch and Lomb, Clearside, Cove, ExgenesisBio, Exonate, Ltd, Janssen Research and Development, Llc, Merck and Co, Inc, Perfuse, Wave Life Sciences and Genentech. No direct financial support was received for the publication and authorship of this article. A.H.K. has received grant support and honoraria from Carl Zeiss Meditec. Carl Zeiss Meditec did not have any role in the design, execution or data analysis of the study. A.H.K. has received consulting fees from Regenxbio, Aspen Biosciences and Alcon Research Institute unrelated to the topic of this manuscript. All other authors have no conflicts to disclose.

Funding Sources

A.H.K: research supported by grant (R01EY030564) from the National Eye Institute. P.A.C: supported by a grant from Shirley and David Affens.

Author Contributions

Z.R. reviewed and searched medical records and revised intellectual content. Z.R. and P.A.C. wrote the first draft of the manuscript. N.S. and R.T. were involved in data and image acquisition. S.A. and A.H.K. critically edited and revised the manuscript. All authors contributed to the revision, approved the submitted version and met authorship criteria.

Funding Statement

A.H.K: research supported by grant (R01EY030564) from the National Eye Institute. P.A.C: supported by a grant from Shirley and David Affens.

Data Availability Statement

All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.