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BJO Online First, published on April 29, 2015 as 10.1136/bjophthalmol-2014-305897 Clinical science
Retinal degeneration in autoimmune polyglandular syndrome type 1: a case series Serge Bourgault,1,2 Catherine Baril,1,2 Ajoy Vincent,3,4 Elise Héon,3,4 Asim Ali,3,4 Ian MacDonald,5 Gregg T Lueder,6 Kevin M Colleaux,7,8 Isabelle Laliberté1,9 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ bjophthalmol-2014-305897). For numbered affiliations see end of article. Correspondence to Dr Serge Bourgault, Hôpital du Saint-Sacrement, 1050 Chemin Sainte-Foy, Québec, QC, Canada G1S 4L8; [email protected] Received 4 November 2014 Revised 8 April 2015 Accepted 12 April 2015
ABSTRACT Background Autoimmune polyglandular syndrome type 1 (APS1) is a rare autosomal recessive disorder due to mutations in the AIRE gene. Aim To report the ocular features and characterise the retinal phenotype in molecularly confirmed APS1. Method This retrospective case series reviewed five molecularly confirmed cases with APS1 known to have ocular involvement (age range: 19 months–44 years; mean follow-up of 8 years). The medical history, ocular history and evaluation, visual field testing, full-field electroretinogram (ERG) and antiretinal antibody results were reviewed. Results All but one case had decreased vision at first presentation. All cases had peripheral pigmentary retinal changes; macular atrophy was noted in 80% of cases. The most common feature on spectral-domain optical coherence tomography was a disruption of the external limiting membrane and inner segment ellipsoid band (n=3). Fundus autofluorescence imaging demonstrated a parafoveal ring of hyper-autofluorescence (n=1) or a stippled and patchy autofluorescence pattern in the macula (n=1). The visual fields were constricted in all tested patients (n=3). The rod ERG was abnormal in all cases; the relative involvement of rods and cones differed. Four patients who were tested for antiretinal antibodies were found positive by immunohistochemistry (n=3) and/or western blot (n=2). Conclusions Photoreceptor degeneration is part of APS1 phenotype and the presence of antiretinal antibodies strongly supports an aetiology similar to that of non-paraneoplastic autoimmune retinopathy. Periodic retinal evaluation and imaging, visual field testing and ERG would assist in monitoring the retinopathy in APS1-related disease.
INTRODUCTION
To cite: Bourgault S, Baril C, Vincent A, et al. Br J Ophthalmol Published Online First: [ please include Day Month Year] doi:10.1136/bjophthalmol2014-305897
Autoimmune polyglandular syndrome type 1 (APS1; OMIM 240300), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a rare autosomal recessive disorder due to mutations in the AIRE (autoimmune regulator) gene.1 2 APS1 was first described by Neufeld and colleagues in 19803 and is characterised by a triad of chronic mucocutaneous candidiasis, hypoparathyroidism and primary adrenal insufficiency, usually in the same chronological order. Ocular findings occur not infrequently, with keratopathy being the most common ophthalmic association.4 5 Isolated cases reminiscent of retinitis pigmentosa (RP) have been associated with APS1 in the literature,6–8 for which an autoimmune basis has been proposed.8 We detail the comprehensive clinical phenotype in a
molecularly confirmed cohort of five cases of APS1. To our knowledge, this is the first comprehensive characterisation of retinal degeneration in patients molecularly confirmed for APS1.
MATERIALS AND METHODS A retrospective chart review was performed on five molecularly confirmed APS1 subjects known to have ocular involvement. The study protocol adhered to the tenets of the Declaration of Helsinki and was approved by the research ethics board of all participating centres: Centre Hospitalier de l’Université Laval (Québec, Quebec, Canada), The Hospital for Sick Children (Toronto, Ontario, Canada), Royal Alexandra Hospital (Edmonton, Alberta, Canada) and St Louis Children’s Hospital (St Louis, Missouri, USA). Comprehensive eye examination, including bestcorrected visual acuity (BCVA), slit-lamp evaluation and dilated fundus examination, was performed on all five affected individuals. Spectral domain optical coherence tomography (SD-OCT) was possible in four cases (Cases 1 and 4 imaged using Cirrus, Carl Zeiss Meditec, Dublin, California, USA; Case 2 imaged using Spectralis, Heidelberg Engineering GmbH, Heidelberg, Germany; Case 3 imaged using Envisu Clinical, Bioptigen, Morrisville, North Carolina, USA). Fundus autofluorescence (FAF) imaging was performed in Cases 1 (Spectralis) and 2 (FF 450plus Fundus Camera, Carl Zeiss Meditec). Goldmann visual field (GVF) assessment was available on three patients. Full-field electroretinograms (ERGs) were recorded in all cases incorporating the International Society for Clinical Electrophysiology of Vision or similar standards.9 All five cases underwent molecular genetic screening for mutations in the AIRE gene. Four patients were also tested for retinal autoantibodies by indirect immunohistochemistry and/ or western blot; Case 2 was tested through the Immunology Laboratory of the National Eye Institute, National Institutes of Health (Chi-Chao Chan, Bethesda, Maryland, USA), Cases 3 and 4 were tested at the Ocular Immunology Laboratory at Casey Eye Institute (Portland, Oregon, USA) and Case 5 was tested at the Ocular Hypersensitivity Pathology Lab at U.C. Davis Medical Center (Charles E. Thirkill, Sacramento, California, USA).
RESULTS The patients’ ages at presentation varied from 19 months to 44 years. Patients were followed up for an average period of 8 years (range 4–13 years). BCVA was decreased at the first visit in all subjects, except for Case 1 (age 11 years) and did not
Bourgault S, et al. Br J Ophthalmol 2015;0:1–7. doi:10.1136/bjophthalmol-2014-305897
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Clinical science ERGs showed 80% reduction in the a-wave and b-wave amplitudes. Over a 6-year follow-up period, progressive peripheral RPE atrophic changes and appearance of a few frank bone spicules were noted (figure 1A, B). BCVA remained stable (20/20) during this time, but GVF showed progression of peripheral constriction to III3e stimulus (80°×50° diameter in the horizontal and vertical axes, respectively). The latest scotopic ERGs (at 16 years of age) remained non-detectable; photopic ERGs showed prolonged latencies and further reduction in the amplitudes. Macular SD-OCT demonstrated complete disruption of the external limiting membrane (ELM) and inner segment ellipsoid (ISe) band outside the fovea and small parafoveal cysts were noted in the inner nuclear layer. There was marked thinning of the outer nuclear layer beyond the fovea (figure 1C, D). A parafoveal ring of hyper-autofluorescence was noted in either eye (figure 1E, F).
correlate with age. Case 5 had no light perception in both eyes at presentation (19 months). Only one patient showed a progressive vision loss during the course of the follow-up (Case 2). All patients showed fundus changes ranging from isolated patchy atrophy of the retinal pigment epithelium (RPE) to an RP-like fundus with bone spicules, waxy pallor of the optic nerve and attenuated vasculature. The macula of four patients (except Case 3) demonstrated RPE granularity or atrophy. SD-OCT showed corresponding disruption of the photoreceptor layers at the macula; Case 3 had normal macular OCT. FAF in Case 1 showed a hyper-autofluorescent ring in the parafoveal region; Case 2 with a more severe maculopathy had a patchy and stippled pattern of macular autofluorescence. The visual fields were constricted in the three patients who were tested. Full-field ERG showed wide variability, was initially normal in Case 3 (4 years of age), non-recordable in Case 5 (at 19 months of age) and showed varying degrees of rod–cone abnormality in the other three cases (Cases 1, 2 and 4; age at testing 11, 15 and 57 years respectively). Three of the four cases had positive immunohistochemistry results suggesting antibody reaction to various cell types (see table 1 for details). Case 3 had negative immunohistochemistry, but had antiretinal antibodies against 37 and 38 kDa proteins on western blot testing. AIRE gene mutations and systemic findings are also summarised in table 1. Table 2 summarises the ocular phenotypes documented.
Case 2 A 15-year-old boy was referred for progressive decrease in vision. At presentation, BCVA was 20/200 and 20/40 in the right and left eyes, respectively. The anterior segment examination was within normal limits. The retina showed irregular patches of granular RPE changes at the posterior pole extending to the equator in either eye. Bone spicule changes were noted only in the right eye. At 17 years of age, the peripheral retina of both eyes showed bone spicules. ERG showed severely reduced photopic 30 Hz flicker amplitude, whereas the standard flash scotopic ERG (mixed rod–cone response) showed moderate reduction in both a-wave and b-wave amplitudes. In an effort to preserve as much residual visual function as possible, systemic immunosuppressive therapy with ciclosporin A and mycophenolate mofetil was started at 18 years of age. One month prior to the initiation of therapy, the photopic flicker response was recordable at 5.9 μV. One month after the start of the therapy, the flicker response was measured at 6.6 μV. On four subsequent visits, each approximately 4–6 months
Case 1 An 11-year-old girl diagnosed to have APS1 at 10 years of age presented with a 20 months history of nyctalopia. BCVA was 20/20 in both eyes. Slit-lamp examination was unremarkable. Fundus examination revealed normal optic nerves, attenuated arterioles and some peripheral punctate atrophic lesions of the retina without bone spicule changes. GVF was slightly constricted to 85°×70° diameter in the horizontal and vertical axes, respectively, in either eye (III3e stimulus). Dim-light scotopic ERGs (rod response) were non-detectable; single flash photopic
Table 1 Molecular results and systemic features of patients studied Case/gender
AIRE Mutation
Systemic findings
Immunohistochemistry
Western blot
Case 1/female
P539L/P539L
Parents declined testing
Parents declined testing
Case 2/male
R257X/c.967_c.979del13
c.967_c.979del13/ c.967_c.979del13
Positive in the IPL, OPL and photoreceptors inner and outer segments Negative
NA
Case 3/female
Case 4/male
R256X/c.967_c.979del13
Positive in the photoreceptor cell layer
Positive to 23 kDa (recoverin), 80 kDa, 92 kDa and 130 kDa
Case 5/female
c.463G>A/p.G155S/p.G155S
Mucocutaneous candidiasis Hypoparathyroidism Alopecia Growth retardation Mucocutaneous candidiasis Hypoparathyroidism Acne Mucocutaneous candidiasis Hypoparathyoidism Adrenal insufficiency Osteopenia Vitiligo Sicca syndrome Multiple bacterial/fungal infections Oesophageal candidiasis/stricture Hypoparathyroidism Hypogonadism Nails dystrophy Alopecia Autoimmune hepatitis Mucocutaneous candidiasis Hypoparathyroidism Addison disease
Positive in the photoreceptor outer segments, and upon the vasculature of both the retina and the optic nerve
NA
Positive to 37 kDa and 38kDa
IPL, inner plexiform layer; kDa, kilodalton; OPL, outer plexiform layer; NA, not available.
2
Bourgault S, et al. Br J Ophthalmol 2015;0:1–7. doi:10.1136/bjophthalmol-2014-305897
Bourgault S, et al. Br J Ophthalmol 2015;0:1–7. doi:10.1136/bjophthalmol-2014-305897
20/50; 20/200
20/30; 20/80
20/80; 20/80 NA NA 20/60; 20/25
20/400; 20/400
20/200; 20/40 NA
20/20; 20/20 20/20; 20/20
BCVA OD; OS
Normal
Normal
Mild keratopathy; sub-epithelial and epithelial punctate opacities
Normal
Punctate epithelial erosions and sub-epithelial scarring Severe ocular surface disease NA Few corneal deposits and minimal corneal scarring
Normal
Normal
Normal
Normal
Normal
Anterior segment OU
Decreased calibre of retinal vessels; discrete zones of patchy RPE atrophy OU Attenuated vessels, progressive pigmentary, retinopathy with bone spicules OU
Waxy pallor of optic nerve; peripapillary atrophy; attenuated vessels; CME; macular and peripheral RPE changes OU Mid-peripheral patchy atrophy; worsened pigment clumping OU
NA Zone of patchy RPE atrophy OU NA
Normal
Atrophic macula with beaten metal appearance OU
Bone spicules OU
Patches of RPE atrophy OU; bone spicules OD
Attenuated vessels OU; peripheral retinal punctate atrophic lesions OU RPE atrophy; bone spicules OU
Fundus
NA
NA
Extensive disruption of photoreceptor layer OU
NA
NA NA Normal
NA
NA
NA
NA
NA NA NA
NA
Absence of foveal AF; residual patchy AF within the arcades; stippled pattern
Disruption of ELM and ISe; ↓ central sub-foveal thickness; hyper-reflective material in RPE NA
NA
NA
NR rod and cone responses
NR rods; moderate to severe ↓ cones
NA
Normal NA ↓ rod; cone WNL
NA
Moderately ↓ mixed rod–cone, severely ↓ cone flicker Moderately ↓ mixed rod–cone, severely ↓ cone flicker
NA
NR rod, 85% ↓ cone
Parafoveal ring of ↑ AF
NA
NR rod, 80% ↓ cone
ERG
NA
FAF
NA
NA
Complete disruption of ELM and ISe; small parafoveal cysts in INL; marked thinning of the ONL
NA
OCT
BCVA, best corrected visual acuity; CME, cystoid macular oedema; ELM, external limiting membrane; ERG, electroretinogram; FAF, fundus autofluorescence; INL, inner nuclear layer; ISe, inner segment ellipsoid; NA, not available; NLP, no light perception; NR, non-recordable; OCT, optical coherence tomography; OD, right eye; ONL, outer nuclear layer; OS, left eye; OU, both eyes; RPE, retinal pigment epithelium; WNL, within normal limits.
Case 5 19 months NLP; NLP 12 years NLP; NLP
57 years
Case 4 44 years
4 years 7 years 9 years
Case 3 2 years
19 years
17 years
Case 2 15 years
17 years
Case 1 11 years
Age at testing
Table 2 Summary of ocular findings Downloaded from http://bjo.bmj.com/ on September 11, 2015 - Published by group.bmj.com
Clinical science
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Clinical science Figure 1 Case 1: colour fundus photographs (A and B), optical coherence tomography (C (right eye), D (left eye)) and autofluorescence (E, F) at 17 years of age.
apart, the recorded flicker amplitudes were similar (range 5.7– 10.8 μV). During this period, his vision declined to 20/400 OU in each eye and retinal examination showed an atrophic macula with beaten-metal appearance (figure 2A, B). GVF displayed a severely constricted pattern with a 50° and 5° diameter in the horizontal axes in the right eye and left eye, respectively, with preservation of a small temporal island in both eyes (V4e stimulus). SD-OCT showed disruption of the ELM and ISe band at the fovea. The central subfoveal thickness was reduced, and macular RPE showed deposition of hyper-reflective material in some areas (figure 2C, D). FAF showed absence of autofluorescence at the fovea; residual patchy autofluorescence was observed predominantly within the arcades, and some regions showed a stippled pattern (figure 2E, F).
Case 3 A 2-year-old girl was referred for management of dry eyes. BCVA was measured to be 20/80 (Lea symbols) in both eyes and her pupils were sluggishly reactive in either eye. Slit-lamp examination showed corneal punctate epithelial erosions and central subepithelial scarring secondary to aqueous tear deficiency. Fundus examination was unremarkable at the time. At 3 years of age, she was molecularly diagnosed to have APS1. An ERG 4
performed at 4 years of age was normal. She was given mycophenolate mofetil and systemic steroids (at 4 years of age). She has been on systemic immunosuppressants since then. At the age of 7 years, she was markedly photophobic. Fundus examination showed a zone of patchy atrophy of the RPE in either eye; it was mid-peripheral in the right eye and along the inferior arcades in the left eye (see online supplementary figure S1A, B). Progressive poliosis was noted. The corneal findings worsened over time, ultimately necessitating the use of the Boston Ocular Surface Prosthesis (Boston Foundation for Sight, Needham, Massachusetts, USA) at 8 years of age to manage the severe ocular surface disease. At the most recent follow-up (at 9 years of age), BCVA was 20/60 and 20/25 in the right and left eyes, respectively. There were a few corneal deposits and minimal corneal scarring in either eye. A follow-up ERG done at 9 years of age showed a decrease in the amplitude of the scotopic ERGs while the cone ERGs were similar and still within limits of normality. SD-OCT showed normal central retinal thickness and layering at the macula.
Case 4 A 44-year-old male patient was referred for decreased vision. BCVA was 20/30 and 20/80 in the right and left eyes, Bourgault S, et al. Br J Ophthalmol 2015;0:1–7. doi:10.1136/bjophthalmol-2014-305897
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Clinical science Figure 2 Case 2: colour fundus photographs (A and B), optical coherence tomography (C (right eye), D (left eye)) and autofluorescence (E, F) at 19 years of age.
respectively. He had partial upper lid madarosis and alopecia and was treated for hypoparathyroidism. Corneal examination was normal. The fundus showed waxy pallor of the optic nerve, peripapillary atrophy, attenuated vessels, cystoid macular oedema and macular and peripheral pigmentary changes suggestive of photoreceptor dysfunction (see online supplementary figure S2A). During the 13 years of follow-up, he experienced multiple episodes of anterior uveitis that were treated topically. At 54 years of age, ERG showed a non-recordable dim-light scotopic ERG and severe reduction in a-waves and b-waves of mixed rod–cone ERG (standard flash). The cone ERGs were markedly delayed and showed severe reduction in amplitudes. At 57 years of age, his BCVA was 20/50 and 20/200 in the right and left eyes, respectively. Corneal examination showed mild keratopathy with punctate epithelial erosions. On retinal evaluation, mid-peripheral patchy atrophy was noted and pigment clumping had worsened. GVF showed peripheral constriction with preservation of 70° diameter of fields in the horizontal axis (III4e stimulus). Macular SD-OCT demonstrated extensive disruption of photoreceptor layers in both eyes (see online supplementary figure S2B).
Case 5 A 19-month-old female patient presented with a 3 months history of abrupt-onset decrease in vision. Her visual behaviour and health had been normal until then, when she developed Bourgault S, et al. Br J Ophthalmol 2015;0:1–7. doi:10.1136/bjophthalmol-2014-305897
nystagmus and began bumping into things. Her development was otherwise normal. On examination, the patient was unable to fixate with either eye and showed no light perception. She had conjugate horizontal nystagmus and decreased pupillary reaction to light. Anterior segment examination was unremarkable. Fundus examination revealed decreased calibre of the retinal vessels and discrete zones of patchy atrophy of the RPE inferiorly in either eye (figure 3A, B). Full-field ERG testing revealed nonrecordable scotopic and photopic responses. At that time, the patient was screened for mutations in Leber congenital amaurosis genes, all of which was negative (Carver Laboratory for Ophthalmic Molecular diagnosis, University of Iowa Health Care, Iowa, USA). At the age of 3 years, she was diagnosed with autoimmune hepatitis and has been treated with azathioprine since that time. When last evaluated at 12 years of age, the child had no light perception in either eye. She developed progressive pigmentary retinopathy and vessel attenuation (figure 3C–F).
DISCUSSION We describe a cohort of five patients with molecularly confirmed APS1 disease in whom central vision loss and photoreceptor dysfunction showed a wide spectrum of severity that did not correlate with age. This is the first report to characterise structural and functional features in APS1-related retinopathy. All tested patients were positive for antiretinal antibodies, 5
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Clinical science Figure 3 Case 5: colour fundus photographs of the right (A) and left eye (B) at 19 months of age. Colour fundus photographs of the right (C, E) and left eye (D, F) at the age of 12 years.
suggesting a non-paraneoplastic form of autoimmune retinopathy (npAIR) in the disease. Autoimmune retinopathy (AIR) encompasses a spectrum of diseases that includes npAIR, cancer-associated retinopathy and melanoma-associated retinopathy.10 A presumptive diagnosis of AIR can be made when a combination of clinical and electrophysiological evidence of retinal degeneration occurs in a patient who tests positive for serum retinal autoantibodies.11 The clinical spectrum of AIR is quite variable. The fundus may be normal or display heterogeneous changes, such as waxy disc pallor, attenuated vessels and RPE atrophy or clumping.11 12 Electrophysiological anomalies may precede retinal changes. All the patients in this study showed peripheral RPE changes, either patchy atrophy or pigment clumping. A variable degree of macular atrophy was found in 80% of cases. ERG findings previously reported in AIR include an electronegative waveform and extremely variable cone and rod response abnormalities.11 13 In our series, involvement of both rod and cone ERGs was the most common pattern observed. Visual fields in AIR defects could be variable; generalised constriction, blind spot enlargement, central and peri-central scotoma, and peripheral field constriction have been reported.13 All tested patients in our study showed peripheral field constriction. Decrease in central retinal thickness at the macula, loss of the photoreceptor outer segment layer and disruption of the photoreceptor inner and outer segment junction (now known as the ISe band) are the most common OCT findings in patients with 6
AIR.14 Three of the four cases in the study (75%) showed macular thinning with disruption of the ELM, ISe band and photoreceptor layers. Previously in AIR, studies have described a parafoveal hyper-autofluorescent ring on FAF that corresponds to the junction of the loss of the inner and outer photoreceptor segment junction on SD-OCT.15 16 One of the two cases in this series showed a hyper-AF ring in the parafoveal region. The precise pathogenesis of AIR remains unknown and little is known about the actual trigger. Adamus et al17 report that in npAIR, antiretinal antibodies can be found in about 41% of the patients. Antibodies against the retina and optic nerve have previously been documented in one patient with APS1.8 In this series, immunoreactivity was detected against one or more retinal components in 75% of tested cases. The sole case that had negative immunohistochemistry tested positive to antiretinal antibodies against 37 and 38 kDa proteins on western blot testing. Of interest, Case 4 showed autoantibodies against recoverin (23 kDa), which had been frequently linked to AIR. Phenotypical heterogeneity among patients with APS1 has been documented by several authors.18 19 Such variability was noted in the present series and suggests a role for additional disease-modifying factors (genetic and environmental).11 Some of the autoimmune features in APS1 that are caused by pathogenic autoantibodies include Addison disease, hypoparathyroidism, diabetes mellitus, vitiligo, autoimmune hepatitis, intestinal dysfunction, pernicious anaemia, alopecia and autoimmune thyroid disease.20 Autoimmunity in patients with APECED is likely due to the crucial role AIRE plays in central Bourgault S, et al. Br J Ophthalmol 2015;0:1–7. doi:10.1136/bjophthalmol-2014-305897
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Clinical science and peripheral immune tolerance.21 AIRE is expressed in the thymus and in secondary lymphoid organs, where it modulates the expression of peripheral antigens.22 AIRE has a key role in preventing organ-specific autoimmunity involving autoantibodies.23 Pathogenic mutations in the AIRE gene lead to a perturbation of the immunological tolerance and hence give rise to autoimmune subversive processes against many target organs.20 22 23 Immunomodulatory treatment of patients with APS1 has been historically reserved for life-threatening clinical manifestations.20 In our report, the response to immunosuppressive treatment was variable. Three cases received different immunosuppressants at various stages in the disease, with all of them showing progressive worsening of the retinopathy, vision and/or ERG. Case 2 demonstrated stable ERG parameters over a 20-month period while on immunosuppressant therapy; however, the maculopathy worsened during this time.
CONCLUSION This study highlights the clinical, imaging and electrophysiological findings in five molecularly confirmed patients with APS1. Photoreceptor degeneration, presumably autoimmune, is part of the disease phenotype and the presence of antiretinal antibodies strongly supports an aetiology similar to npAIR. Ophthalmologists, paediatricians and endocrinologists should be aware of the possibility of progressive retinopathy in patients with APS1, and a baseline ERG is recommended. This condition requires long-term multidisciplinary management. The role of immunosuppression in the treatment of APS1-associated AIR remains unclear and requires further evaluation.
Provenance and peer review Not commissioned; externally peer reviewed.
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Author affiliations 1 Département d’ophtalmologie et ORL-Chirurgie cervico-faciale, Faculté de médecine, Université Laval, Québec, Quebec, Canada 2 Centre universitaire d’ophtalmologie, Hôpital du Saint-Sacrement, CHU de Québec, Québec, Quebec, Canada 3 Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada 4 Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada 5 Department of Ophthalmology and Visual Sciences, University of Alberta, Edmonton, Canada 6 Departments of Ophthalmology and Visual Sciences and Pediatrics, Washington University School of Medicine, St Louis, Missouri, USA 7 Department of Ophthalmology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada 8 Saskatoon Retina Consultants, Saskatoon, Saskatchewan, Canada 9 Centre mére-enfant Soleil, CHUL, CHU de Québec, Québec, Quebec, Canada Contributors All authors have contributed to the acquisition, analysis and interpretation of data. All authors have drafted, revised and approved the manuscript. Funding SB is supported in part by the “Programme des bourses McLaughlin du doyen de la Faculté de médecine de l’Université Laval”, the CNIB Baker Fellowship Fund and the William H. Ross Fellowship in Vitreo-Retinal Excellence.
14 15 16 17 18
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Competing interests None declared. Patient consent Obtained. Ethics approval Research ethics board of all participating centres: Centre Hospitalier de l’Université Laval (Québec, Quebec, Canada), The Hospital for Sick Children (Toronto, Ontario, Canada), Royal Alexandra Hospital (Edmonton, Alberta, Canada) and St Louis Children’s Hospital (St Louis, Missouri, USA).
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Retinal degeneration in autoimmune polyglandular syndrome type 1: a case series Serge Bourgault, Catherine Baril, Ajoy Vincent, Elise Héon, Asim Ali, Ian MacDonald, Gregg T Lueder, Kevin M Colleaux and Isabelle Laliberté Br J Ophthalmol published online April 29, 2015
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BJO Online First, published on April 29, 2015 as 10.1136/bjophthalmol-2014-305897 Clinical science
Retinal degeneration in autoimmune polyglandular syndrome type 1: a case series Serge Bourgault,1,2 Catherine Baril,1,2 Ajoy Vincent,3,4 Elise Héon,3,4 Asim Ali,3,4 Ian MacDonald,5 Gregg T Lueder,6 Kevin M Colleaux,7,8 Isabelle Laliberté1,9 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ bjophthalmol-2014-305897). For numbered affiliations see end of article. Correspondence to Dr Serge Bourgault, Hôpital du Saint-Sacrement, 1050 Chemin Sainte-Foy, Québec, QC, Canada G1S 4L8; [email protected] Received 4 November 2014 Revised 8 April 2015 Accepted 12 April 2015
ABSTRACT Background Autoimmune polyglandular syndrome type 1 (APS1) is a rare autosomal recessive disorder due to mutations in the AIRE gene. Aim To report the ocular features and characterise the retinal phenotype in molecularly confirmed APS1. Method This retrospective case series reviewed five molecularly confirmed cases with APS1 known to have ocular involvement (age range: 19 months–44 years; mean follow-up of 8 years). The medical history, ocular history and evaluation, visual field testing, full-field electroretinogram (ERG) and antiretinal antibody results were reviewed. Results All but one case had decreased vision at first presentation. All cases had peripheral pigmentary retinal changes; macular atrophy was noted in 80% of cases. The most common feature on spectral-domain optical coherence tomography was a disruption of the external limiting membrane and inner segment ellipsoid band (n=3). Fundus autofluorescence imaging demonstrated a parafoveal ring of hyper-autofluorescence (n=1) or a stippled and patchy autofluorescence pattern in the macula (n=1). The visual fields were constricted in all tested patients (n=3). The rod ERG was abnormal in all cases; the relative involvement of rods and cones differed. Four patients who were tested for antiretinal antibodies were found positive by immunohistochemistry (n=3) and/or western blot (n=2). Conclusions Photoreceptor degeneration is part of APS1 phenotype and the presence of antiretinal antibodies strongly supports an aetiology similar to that of non-paraneoplastic autoimmune retinopathy. Periodic retinal evaluation and imaging, visual field testing and ERG would assist in monitoring the retinopathy in APS1-related disease.
INTRODUCTION
To cite: Bourgault S, Baril C, Vincent A, et al. Br J Ophthalmol Published Online First: [ please include Day Month Year] doi:10.1136/bjophthalmol2014-305897
Autoimmune polyglandular syndrome type 1 (APS1; OMIM 240300), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a rare autosomal recessive disorder due to mutations in the AIRE (autoimmune regulator) gene.1 2 APS1 was first described by Neufeld and colleagues in 19803 and is characterised by a triad of chronic mucocutaneous candidiasis, hypoparathyroidism and primary adrenal insufficiency, usually in the same chronological order. Ocular findings occur not infrequently, with keratopathy being the most common ophthalmic association.4 5 Isolated cases reminiscent of retinitis pigmentosa (RP) have been associated with APS1 in the literature,6–8 for which an autoimmune basis has been proposed.8 We detail the comprehensive clinical phenotype in a
molecularly confirmed cohort of five cases of APS1. To our knowledge, this is the first comprehensive characterisation of retinal degeneration in patients molecularly confirmed for APS1.
MATERIALS AND METHODS A retrospective chart review was performed on five molecularly confirmed APS1 subjects known to have ocular involvement. The study protocol adhered to the tenets of the Declaration of Helsinki and was approved by the research ethics board of all participating centres: Centre Hospitalier de l’Université Laval (Québec, Quebec, Canada), The Hospital for Sick Children (Toronto, Ontario, Canada), Royal Alexandra Hospital (Edmonton, Alberta, Canada) and St Louis Children’s Hospital (St Louis, Missouri, USA). Comprehensive eye examination, including bestcorrected visual acuity (BCVA), slit-lamp evaluation and dilated fundus examination, was performed on all five affected individuals. Spectral domain optical coherence tomography (SD-OCT) was possible in four cases (Cases 1 and 4 imaged using Cirrus, Carl Zeiss Meditec, Dublin, California, USA; Case 2 imaged using Spectralis, Heidelberg Engineering GmbH, Heidelberg, Germany; Case 3 imaged using Envisu Clinical, Bioptigen, Morrisville, North Carolina, USA). Fundus autofluorescence (FAF) imaging was performed in Cases 1 (Spectralis) and 2 (FF 450plus Fundus Camera, Carl Zeiss Meditec). Goldmann visual field (GVF) assessment was available on three patients. Full-field electroretinograms (ERGs) were recorded in all cases incorporating the International Society for Clinical Electrophysiology of Vision or similar standards.9 All five cases underwent molecular genetic screening for mutations in the AIRE gene. Four patients were also tested for retinal autoantibodies by indirect immunohistochemistry and/ or western blot; Case 2 was tested through the Immunology Laboratory of the National Eye Institute, National Institutes of Health (Chi-Chao Chan, Bethesda, Maryland, USA), Cases 3 and 4 were tested at the Ocular Immunology Laboratory at Casey Eye Institute (Portland, Oregon, USA) and Case 5 was tested at the Ocular Hypersensitivity Pathology Lab at U.C. Davis Medical Center (Charles E. Thirkill, Sacramento, California, USA).
RESULTS The patients’ ages at presentation varied from 19 months to 44 years. Patients were followed up for an average period of 8 years (range 4–13 years). BCVA was decreased at the first visit in all subjects, except for Case 1 (age 11 years) and did not
Bourgault S, et al. Br J Ophthalmol 2015;0:1–7. doi:10.1136/bjophthalmol-2014-305897
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Clinical science ERGs showed 80% reduction in the a-wave and b-wave amplitudes. Over a 6-year follow-up period, progressive peripheral RPE atrophic changes and appearance of a few frank bone spicules were noted (figure 1A, B). BCVA remained stable (20/20) during this time, but GVF showed progression of peripheral constriction to III3e stimulus (80°×50° diameter in the horizontal and vertical axes, respectively). The latest scotopic ERGs (at 16 years of age) remained non-detectable; photopic ERGs showed prolonged latencies and further reduction in the amplitudes. Macular SD-OCT demonstrated complete disruption of the external limiting membrane (ELM) and inner segment ellipsoid (ISe) band outside the fovea and small parafoveal cysts were noted in the inner nuclear layer. There was marked thinning of the outer nuclear layer beyond the fovea (figure 1C, D). A parafoveal ring of hyper-autofluorescence was noted in either eye (figure 1E, F).
correlate with age. Case 5 had no light perception in both eyes at presentation (19 months). Only one patient showed a progressive vision loss during the course of the follow-up (Case 2). All patients showed fundus changes ranging from isolated patchy atrophy of the retinal pigment epithelium (RPE) to an RP-like fundus with bone spicules, waxy pallor of the optic nerve and attenuated vasculature. The macula of four patients (except Case 3) demonstrated RPE granularity or atrophy. SD-OCT showed corresponding disruption of the photoreceptor layers at the macula; Case 3 had normal macular OCT. FAF in Case 1 showed a hyper-autofluorescent ring in the parafoveal region; Case 2 with a more severe maculopathy had a patchy and stippled pattern of macular autofluorescence. The visual fields were constricted in the three patients who were tested. Full-field ERG showed wide variability, was initially normal in Case 3 (4 years of age), non-recordable in Case 5 (at 19 months of age) and showed varying degrees of rod–cone abnormality in the other three cases (Cases 1, 2 and 4; age at testing 11, 15 and 57 years respectively). Three of the four cases had positive immunohistochemistry results suggesting antibody reaction to various cell types (see table 1 for details). Case 3 had negative immunohistochemistry, but had antiretinal antibodies against 37 and 38 kDa proteins on western blot testing. AIRE gene mutations and systemic findings are also summarised in table 1. Table 2 summarises the ocular phenotypes documented.
Case 2 A 15-year-old boy was referred for progressive decrease in vision. At presentation, BCVA was 20/200 and 20/40 in the right and left eyes, respectively. The anterior segment examination was within normal limits. The retina showed irregular patches of granular RPE changes at the posterior pole extending to the equator in either eye. Bone spicule changes were noted only in the right eye. At 17 years of age, the peripheral retina of both eyes showed bone spicules. ERG showed severely reduced photopic 30 Hz flicker amplitude, whereas the standard flash scotopic ERG (mixed rod–cone response) showed moderate reduction in both a-wave and b-wave amplitudes. In an effort to preserve as much residual visual function as possible, systemic immunosuppressive therapy with ciclosporin A and mycophenolate mofetil was started at 18 years of age. One month prior to the initiation of therapy, the photopic flicker response was recordable at 5.9 μV. One month after the start of the therapy, the flicker response was measured at 6.6 μV. On four subsequent visits, each approximately 4–6 months
Case 1 An 11-year-old girl diagnosed to have APS1 at 10 years of age presented with a 20 months history of nyctalopia. BCVA was 20/20 in both eyes. Slit-lamp examination was unremarkable. Fundus examination revealed normal optic nerves, attenuated arterioles and some peripheral punctate atrophic lesions of the retina without bone spicule changes. GVF was slightly constricted to 85°×70° diameter in the horizontal and vertical axes, respectively, in either eye (III3e stimulus). Dim-light scotopic ERGs (rod response) were non-detectable; single flash photopic
Table 1 Molecular results and systemic features of patients studied Case/gender
AIRE Mutation
Systemic findings
Immunohistochemistry
Western blot
Case 1/female
P539L/P539L
Parents declined testing
Parents declined testing
Case 2/male
R257X/c.967_c.979del13
c.967_c.979del13/ c.967_c.979del13
Positive in the IPL, OPL and photoreceptors inner and outer segments Negative
NA
Case 3/female
Case 4/male
R256X/c.967_c.979del13
Positive in the photoreceptor cell layer
Positive to 23 kDa (recoverin), 80 kDa, 92 kDa and 130 kDa
Case 5/female
c.463G>A/p.G155S/p.G155S
Mucocutaneous candidiasis Hypoparathyroidism Alopecia Growth retardation Mucocutaneous candidiasis Hypoparathyroidism Acne Mucocutaneous candidiasis Hypoparathyoidism Adrenal insufficiency Osteopenia Vitiligo Sicca syndrome Multiple bacterial/fungal infections Oesophageal candidiasis/stricture Hypoparathyroidism Hypogonadism Nails dystrophy Alopecia Autoimmune hepatitis Mucocutaneous candidiasis Hypoparathyroidism Addison disease
Positive in the photoreceptor outer segments, and upon the vasculature of both the retina and the optic nerve
NA
Positive to 37 kDa and 38kDa
IPL, inner plexiform layer; kDa, kilodalton; OPL, outer plexiform layer; NA, not available.
2
Bourgault S, et al. Br J Ophthalmol 2015;0:1–7. doi:10.1136/bjophthalmol-2014-305897
Bourgault S, et al. Br J Ophthalmol 2015;0:1–7. doi:10.1136/bjophthalmol-2014-305897
20/50; 20/200
20/30; 20/80
20/80; 20/80 NA NA 20/60; 20/25
20/400; 20/400
20/200; 20/40 NA
20/20; 20/20 20/20; 20/20
BCVA OD; OS
Normal
Normal
Mild keratopathy; sub-epithelial and epithelial punctate opacities
Normal
Punctate epithelial erosions and sub-epithelial scarring Severe ocular surface disease NA Few corneal deposits and minimal corneal scarring
Normal
Normal
Normal
Normal
Normal
Anterior segment OU
Decreased calibre of retinal vessels; discrete zones of patchy RPE atrophy OU Attenuated vessels, progressive pigmentary, retinopathy with bone spicules OU
Waxy pallor of optic nerve; peripapillary atrophy; attenuated vessels; CME; macular and peripheral RPE changes OU Mid-peripheral patchy atrophy; worsened pigment clumping OU
NA Zone of patchy RPE atrophy OU NA
Normal
Atrophic macula with beaten metal appearance OU
Bone spicules OU
Patches of RPE atrophy OU; bone spicules OD
Attenuated vessels OU; peripheral retinal punctate atrophic lesions OU RPE atrophy; bone spicules OU
Fundus
NA
NA
Extensive disruption of photoreceptor layer OU
NA
NA NA Normal
NA
NA
NA
NA
NA NA NA
NA
Absence of foveal AF; residual patchy AF within the arcades; stippled pattern
Disruption of ELM and ISe; ↓ central sub-foveal thickness; hyper-reflective material in RPE NA
NA
NA
NR rod and cone responses
NR rods; moderate to severe ↓ cones
NA
Normal NA ↓ rod; cone WNL
NA
Moderately ↓ mixed rod–cone, severely ↓ cone flicker Moderately ↓ mixed rod–cone, severely ↓ cone flicker
NA
NR rod, 85% ↓ cone
Parafoveal ring of ↑ AF
NA
NR rod, 80% ↓ cone
ERG
NA
FAF
NA
NA
Complete disruption of ELM and ISe; small parafoveal cysts in INL; marked thinning of the ONL
NA
OCT
BCVA, best corrected visual acuity; CME, cystoid macular oedema; ELM, external limiting membrane; ERG, electroretinogram; FAF, fundus autofluorescence; INL, inner nuclear layer; ISe, inner segment ellipsoid; NA, not available; NLP, no light perception; NR, non-recordable; OCT, optical coherence tomography; OD, right eye; ONL, outer nuclear layer; OS, left eye; OU, both eyes; RPE, retinal pigment epithelium; WNL, within normal limits.
Case 5 19 months NLP; NLP 12 years NLP; NLP
57 years
Case 4 44 years
4 years 7 years 9 years
Case 3 2 years
19 years
17 years
Case 2 15 years
17 years
Case 1 11 years
Age at testing
Table 2 Summary of ocular findings Downloaded from http://bjo.bmj.com/ on September 11, 2015 - Published by group.bmj.com
Clinical science
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Clinical science Figure 1 Case 1: colour fundus photographs (A and B), optical coherence tomography (C (right eye), D (left eye)) and autofluorescence (E, F) at 17 years of age.
apart, the recorded flicker amplitudes were similar (range 5.7– 10.8 μV). During this period, his vision declined to 20/400 OU in each eye and retinal examination showed an atrophic macula with beaten-metal appearance (figure 2A, B). GVF displayed a severely constricted pattern with a 50° and 5° diameter in the horizontal axes in the right eye and left eye, respectively, with preservation of a small temporal island in both eyes (V4e stimulus). SD-OCT showed disruption of the ELM and ISe band at the fovea. The central subfoveal thickness was reduced, and macular RPE showed deposition of hyper-reflective material in some areas (figure 2C, D). FAF showed absence of autofluorescence at the fovea; residual patchy autofluorescence was observed predominantly within the arcades, and some regions showed a stippled pattern (figure 2E, F).
Case 3 A 2-year-old girl was referred for management of dry eyes. BCVA was measured to be 20/80 (Lea symbols) in both eyes and her pupils were sluggishly reactive in either eye. Slit-lamp examination showed corneal punctate epithelial erosions and central subepithelial scarring secondary to aqueous tear deficiency. Fundus examination was unremarkable at the time. At 3 years of age, she was molecularly diagnosed to have APS1. An ERG 4
performed at 4 years of age was normal. She was given mycophenolate mofetil and systemic steroids (at 4 years of age). She has been on systemic immunosuppressants since then. At the age of 7 years, she was markedly photophobic. Fundus examination showed a zone of patchy atrophy of the RPE in either eye; it was mid-peripheral in the right eye and along the inferior arcades in the left eye (see online supplementary figure S1A, B). Progressive poliosis was noted. The corneal findings worsened over time, ultimately necessitating the use of the Boston Ocular Surface Prosthesis (Boston Foundation for Sight, Needham, Massachusetts, USA) at 8 years of age to manage the severe ocular surface disease. At the most recent follow-up (at 9 years of age), BCVA was 20/60 and 20/25 in the right and left eyes, respectively. There were a few corneal deposits and minimal corneal scarring in either eye. A follow-up ERG done at 9 years of age showed a decrease in the amplitude of the scotopic ERGs while the cone ERGs were similar and still within limits of normality. SD-OCT showed normal central retinal thickness and layering at the macula.
Case 4 A 44-year-old male patient was referred for decreased vision. BCVA was 20/30 and 20/80 in the right and left eyes, Bourgault S, et al. Br J Ophthalmol 2015;0:1–7. doi:10.1136/bjophthalmol-2014-305897
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Clinical science Figure 2 Case 2: colour fundus photographs (A and B), optical coherence tomography (C (right eye), D (left eye)) and autofluorescence (E, F) at 19 years of age.
respectively. He had partial upper lid madarosis and alopecia and was treated for hypoparathyroidism. Corneal examination was normal. The fundus showed waxy pallor of the optic nerve, peripapillary atrophy, attenuated vessels, cystoid macular oedema and macular and peripheral pigmentary changes suggestive of photoreceptor dysfunction (see online supplementary figure S2A). During the 13 years of follow-up, he experienced multiple episodes of anterior uveitis that were treated topically. At 54 years of age, ERG showed a non-recordable dim-light scotopic ERG and severe reduction in a-waves and b-waves of mixed rod–cone ERG (standard flash). The cone ERGs were markedly delayed and showed severe reduction in amplitudes. At 57 years of age, his BCVA was 20/50 and 20/200 in the right and left eyes, respectively. Corneal examination showed mild keratopathy with punctate epithelial erosions. On retinal evaluation, mid-peripheral patchy atrophy was noted and pigment clumping had worsened. GVF showed peripheral constriction with preservation of 70° diameter of fields in the horizontal axis (III4e stimulus). Macular SD-OCT demonstrated extensive disruption of photoreceptor layers in both eyes (see online supplementary figure S2B).
Case 5 A 19-month-old female patient presented with a 3 months history of abrupt-onset decrease in vision. Her visual behaviour and health had been normal until then, when she developed Bourgault S, et al. Br J Ophthalmol 2015;0:1–7. doi:10.1136/bjophthalmol-2014-305897
nystagmus and began bumping into things. Her development was otherwise normal. On examination, the patient was unable to fixate with either eye and showed no light perception. She had conjugate horizontal nystagmus and decreased pupillary reaction to light. Anterior segment examination was unremarkable. Fundus examination revealed decreased calibre of the retinal vessels and discrete zones of patchy atrophy of the RPE inferiorly in either eye (figure 3A, B). Full-field ERG testing revealed nonrecordable scotopic and photopic responses. At that time, the patient was screened for mutations in Leber congenital amaurosis genes, all of which was negative (Carver Laboratory for Ophthalmic Molecular diagnosis, University of Iowa Health Care, Iowa, USA). At the age of 3 years, she was diagnosed with autoimmune hepatitis and has been treated with azathioprine since that time. When last evaluated at 12 years of age, the child had no light perception in either eye. She developed progressive pigmentary retinopathy and vessel attenuation (figure 3C–F).
DISCUSSION We describe a cohort of five patients with molecularly confirmed APS1 disease in whom central vision loss and photoreceptor dysfunction showed a wide spectrum of severity that did not correlate with age. This is the first report to characterise structural and functional features in APS1-related retinopathy. All tested patients were positive for antiretinal antibodies, 5
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Clinical science Figure 3 Case 5: colour fundus photographs of the right (A) and left eye (B) at 19 months of age. Colour fundus photographs of the right (C, E) and left eye (D, F) at the age of 12 years.
suggesting a non-paraneoplastic form of autoimmune retinopathy (npAIR) in the disease. Autoimmune retinopathy (AIR) encompasses a spectrum of diseases that includes npAIR, cancer-associated retinopathy and melanoma-associated retinopathy.10 A presumptive diagnosis of AIR can be made when a combination of clinical and electrophysiological evidence of retinal degeneration occurs in a patient who tests positive for serum retinal autoantibodies.11 The clinical spectrum of AIR is quite variable. The fundus may be normal or display heterogeneous changes, such as waxy disc pallor, attenuated vessels and RPE atrophy or clumping.11 12 Electrophysiological anomalies may precede retinal changes. All the patients in this study showed peripheral RPE changes, either patchy atrophy or pigment clumping. A variable degree of macular atrophy was found in 80% of cases. ERG findings previously reported in AIR include an electronegative waveform and extremely variable cone and rod response abnormalities.11 13 In our series, involvement of both rod and cone ERGs was the most common pattern observed. Visual fields in AIR defects could be variable; generalised constriction, blind spot enlargement, central and peri-central scotoma, and peripheral field constriction have been reported.13 All tested patients in our study showed peripheral field constriction. Decrease in central retinal thickness at the macula, loss of the photoreceptor outer segment layer and disruption of the photoreceptor inner and outer segment junction (now known as the ISe band) are the most common OCT findings in patients with 6
AIR.14 Three of the four cases in the study (75%) showed macular thinning with disruption of the ELM, ISe band and photoreceptor layers. Previously in AIR, studies have described a parafoveal hyper-autofluorescent ring on FAF that corresponds to the junction of the loss of the inner and outer photoreceptor segment junction on SD-OCT.15 16 One of the two cases in this series showed a hyper-AF ring in the parafoveal region. The precise pathogenesis of AIR remains unknown and little is known about the actual trigger. Adamus et al17 report that in npAIR, antiretinal antibodies can be found in about 41% of the patients. Antibodies against the retina and optic nerve have previously been documented in one patient with APS1.8 In this series, immunoreactivity was detected against one or more retinal components in 75% of tested cases. The sole case that had negative immunohistochemistry tested positive to antiretinal antibodies against 37 and 38 kDa proteins on western blot testing. Of interest, Case 4 showed autoantibodies against recoverin (23 kDa), which had been frequently linked to AIR. Phenotypical heterogeneity among patients with APS1 has been documented by several authors.18 19 Such variability was noted in the present series and suggests a role for additional disease-modifying factors (genetic and environmental).11 Some of the autoimmune features in APS1 that are caused by pathogenic autoantibodies include Addison disease, hypoparathyroidism, diabetes mellitus, vitiligo, autoimmune hepatitis, intestinal dysfunction, pernicious anaemia, alopecia and autoimmune thyroid disease.20 Autoimmunity in patients with APECED is likely due to the crucial role AIRE plays in central Bourgault S, et al. Br J Ophthalmol 2015;0:1–7. doi:10.1136/bjophthalmol-2014-305897
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Clinical science and peripheral immune tolerance.21 AIRE is expressed in the thymus and in secondary lymphoid organs, where it modulates the expression of peripheral antigens.22 AIRE has a key role in preventing organ-specific autoimmunity involving autoantibodies.23 Pathogenic mutations in the AIRE gene lead to a perturbation of the immunological tolerance and hence give rise to autoimmune subversive processes against many target organs.20 22 23 Immunomodulatory treatment of patients with APS1 has been historically reserved for life-threatening clinical manifestations.20 In our report, the response to immunosuppressive treatment was variable. Three cases received different immunosuppressants at various stages in the disease, with all of them showing progressive worsening of the retinopathy, vision and/or ERG. Case 2 demonstrated stable ERG parameters over a 20-month period while on immunosuppressant therapy; however, the maculopathy worsened during this time.
CONCLUSION This study highlights the clinical, imaging and electrophysiological findings in five molecularly confirmed patients with APS1. Photoreceptor degeneration, presumably autoimmune, is part of the disease phenotype and the presence of antiretinal antibodies strongly supports an aetiology similar to npAIR. Ophthalmologists, paediatricians and endocrinologists should be aware of the possibility of progressive retinopathy in patients with APS1, and a baseline ERG is recommended. This condition requires long-term multidisciplinary management. The role of immunosuppression in the treatment of APS1-associated AIR remains unclear and requires further evaluation.
Provenance and peer review Not commissioned; externally peer reviewed.
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Author affiliations 1 Département d’ophtalmologie et ORL-Chirurgie cervico-faciale, Faculté de médecine, Université Laval, Québec, Quebec, Canada 2 Centre universitaire d’ophtalmologie, Hôpital du Saint-Sacrement, CHU de Québec, Québec, Quebec, Canada 3 Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada 4 Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada 5 Department of Ophthalmology and Visual Sciences, University of Alberta, Edmonton, Canada 6 Departments of Ophthalmology and Visual Sciences and Pediatrics, Washington University School of Medicine, St Louis, Missouri, USA 7 Department of Ophthalmology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada 8 Saskatoon Retina Consultants, Saskatoon, Saskatchewan, Canada 9 Centre mére-enfant Soleil, CHUL, CHU de Québec, Québec, Quebec, Canada Contributors All authors have contributed to the acquisition, analysis and interpretation of data. All authors have drafted, revised and approved the manuscript. Funding SB is supported in part by the “Programme des bourses McLaughlin du doyen de la Faculté de médecine de l’Université Laval”, the CNIB Baker Fellowship Fund and the William H. Ross Fellowship in Vitreo-Retinal Excellence.
14 15 16 17 18
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Competing interests None declared. Patient consent Obtained. Ethics approval Research ethics board of all participating centres: Centre Hospitalier de l’Université Laval (Québec, Quebec, Canada), The Hospital for Sick Children (Toronto, Ontario, Canada), Royal Alexandra Hospital (Edmonton, Alberta, Canada) and St Louis Children’s Hospital (St Louis, Missouri, USA).
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Retinal degeneration in autoimmune polyglandular syndrome type 1: a case series Serge Bourgault, Catherine Baril, Ajoy Vincent, Elise Héon, Asim Ali, Ian MacDonald, Gregg T Lueder, Kevin M Colleaux and Isabelle Laliberté Br J Ophthalmol published online April 29, 2015
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