CASE REPORT

Management of Full-Thickness Macular Holein A Genetically Confirmed Case with UsherSyndrome

Evangelia S. Panagiotou . Thomas Papathomas . Konstantinos Nikopoulos .

Stavrenia Koukoula . Mathieu Quinodoz . Atta Ur Rehman .

Theodoros Giannopoulos . Carlo Rivolta . Anastasios G. Konstas

Received: May 12, 2020 / Published online: June 21, 2020� The Author(s) 2020

ABSTRACT

Introduction: Full-thickness macular hole(FTMH) formation is rarely seen in patients withretinitis pigmentosa (RP) and can have anadverse impact on their residual visual function.The underlying mechanisms are unknown, andclinical experience is limited regarding surgicaloutcomes. Here, we describe the surgical man-agement of FTMH in a young patient withgenetically confirmed Usher syndrome, themost common form of syndromic RP.Case Report: A 28-year-old woman presentedwith blurred vision in her right eye (RE). She

had a history of RP and bilateral hearingimpairment since childhood. Fundoscopy andspectral-domain optical coherence tomographyrevealed a FTMH in the RE along with typical RPfeatures bilaterally. After pars plana vitrectomy(PPV) with internal limiting membrane peeland gas tamponade, the FTMH closed. Sixmonths after PPV the patient underwent catar-act surgery in the affected eye, and the visualacuity remained stable compared to baseline.The clinical diagnosis of Usher syndrome wasgenetically confirmed by whole exomesequencing (WES), which revealed the presenceof two pathogenic nucleotide variants in trans(compound heterozygosity) in the gene USH2A.Conclusion: We report a rare case of successfulclosure of a FTMH in a patient with UsherDigital Features To view digital features for this article

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E. S. Panagiotou � T. Papathomas � T. Giannopoulos� A. G. Konstas (&)1st Department of Ophthalmology, AristotleUniversity of Thessaloniki, AHEPA Hospital,Thessaloniki, Greecee-mail: agkonstas@gmail.com

K. NikopoulosLaboratory of Oncogenomics, Department ofHematology, Lausanne University Hospital (CHUV),Lausanne, Switzerland

S. KoukoulaOphthalmica Institute, Thessaloniki, Greece

M. Quinodoz � C. RivoltaDepartment of Genetics and Genome Biology,University of Leicester, Leicester, UK

M. Quinodoz � C. RivoltaInstitute of Molecular and Clinical OphthalmologyBasel (IOB), Basel, Switzerland

M. Quinodoz � C. RivoltaDepartment of Ophthalmology, University of Basel,Basel, Switzerland

A. U. RehmanDivision of Genetic Medicine, Lausanne UniversityHospital and University of Lausanne, Lausanne,Switzerland

A. G. Konstas3rd Department of Ophthalmology, AristotleUniversity of Thessaloniki, AHEPA Hospital,Thessaloniki, Greece

Ophthalmol Ther (2020) 9:677–684

https://doi.org/10.1007/s40123-020-00276-4

https://doi.org/10.6084/m9.figshare.12459272http://crossmark.crossref.org/dialog/?doi=10.1007/s40123-020-00276-4&domain=pdfhttps://doi.org/10.1007/s40123-020-00276-4

syndrome. Surgical treatment of FTMH can helppreserve the central vision in RP patients, whoseperipheral vision is severely affected.

Keywords: Full-thickness macular hole; Parsplana vitrectomy; Retinitis pigmentosa; Ushersyndrome

Key Summary Points

Full-thickness macular hole (FTMH)formation is rarely seen in patients withretinitis pigmentosa (RP) and can have anadverse impact on their residual visualfunction, while clinical experience islimited regarding surgical outcomes.

We report a rare case of successful closureof a FTMH in a patient with Ushersyndrome, the most common form ofsyndromic RP, which was geneticallyconfirmed.

This is the first case of FTMH in Ushersyndrome reporting surgical outcomescombined with genetic data.

Vitrectomy appears to be effective in thesecases and should be performed to try topreserve the central vision of RP patientswho usually have severely impairedperipheral vision.

INTRODUCTION

Usher syndrome is an autosomal recessive dis-order characterised by retinitis pigmentosa (RP),sensorineural hearing loss and in some casesvestibular dysfunction [1] with a prevalenceestimated to be between 6.2 and 16.67/100,000[2, 3]. It is the most common form of syndromicRP and accounts for about 10% of inheritedblindness caused by retinal dystrophies andoptic neuropathies [4]. Usher syndrome isgenetically heterogeneous and to date morethan ten genes have been identified as causativeof the disease [5, 6].

Although in RP the peripheral visual field istypically constricted with initial sparing of thecentral retina, macular abnormalities are oftenobserved, leading to reduction of the visualacuity (VA). Cystoid macular oedema andepiretinal membrane are the most commonmacular anomalies in these patients, while thepresence of a macular hole is rare [7, 8]. Since inRP patients the peripheral vision is affected, it isimportant to detect and treat any potentialmacular abnormalities to preserve centralvision. Due to the limited experience in cases ofmacular hole in RP, it is useful to study theoutcomes and prognosis of surgical treatment.Here, we report the anatomical and functionaloutcomes of surgical management in a youngpatient with Usher syndrome and full-thicknessmacular hole (FTMH). The genetic pathogenicvariants underlying the patient’s condition arealso presented.

CASE PRESENTATION

A 28-year-old woman was referred to ourdepartment with a complaint of blurred visionduring a period of 1 month in her right eye (RE).She reported nyctalopia and restricted visualfield in both eyes since childhood and had beendiagnosed RP with no family history. She alsohad had bilateral hearing impairment sincechildhood and wore hearing aids.

At presentation, her best-corrected VA was2.5/10 (- 1.00sph) in the RE and 3.5/10 (-1.00cyl 9 90�) in the left eye (Snellen). Anteriorsegment examination was unremarkable withbilateral clear lenses. Dilated fundoscopyrevealed a full-thickness macular hole and pos-terior vitreous detachment in the RE. In addi-tion, both eyes showed typical signs of RPincluding peripheral retinal atrophy with bonespicule-shaped pigmentation in the midperiphery, waxy pallor of the optic nerve headand attenuation of retinal vessels (Fig. 1). Spec-tral domain optical coherence tomography (SD-OCT) confirmed the presence of a FTMH stageIV in the RE along with atrophy of the outerretinal layers and absence of the ellipsoid zone(Fig. 2a). In the fellow eye, thinning of the outerretinal layers was also observed, while the

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ellipsoid zone was only preserved in the fovea(Fig. 2b, d, f).

The patient underwent 23-gauge three-portpars plana vitrectomy (PPV) with internal lim-iting membrane (ILM) peeling assisted bymembrane dual blue and tamponade with 16%hexafluoroethane (C2F6) gas. One month aftersurgery, OCT (RE) confirmed the successfulclosure of the macular hole with severe disrup-tion of the ellipsoid zone (Fig. 2c). Due to pos-terior subcapsular cataract development in theRE, the patient subsequently underwent suc-cessful uncomplicated cataract surgery withphacoemulsification and intraocular lensimplantation 6 months after PPV. At final fol-low-up, 11 months after PPV, the BCVA

remained stable at 2.5/10 (RE) while the macu-lar hole remained closed and a small part of theellipsoid zone could be seen (Fig. 2e).

The scotopic full-field electroretinogram(ffERG) was non-recordable in either of the eyesindicating mostly loss of rod system sensitivity(Fig. 3a, b). The responses obtained from thephotopic ERG, which entirely assesses conefunction, were reduced and delayed in botheyes (Fig. 3c, d). These findings are in keepingwith rod-cone dystrophy [1]. Due to the co-ex-istence of severe bilateral sensorineural hearingimpairment (data not shown), a clinical diag-nosis of Usher syndrome was made.

After written informed consent had beenobtained from the patient and family members

Fig. 1 Pre-operative fundus photographs. a, b Fundus ofthe right eye showing peripheral retinal atrophy with a fewintraretinal pigment deposits in a bone-spicule configura-tion, retinal vessel attenuation and optic nerve head pallor,while a full-thickness macular hole can be seen in the

macula. c, d The left eye also has a typical RP appearancewith multiple bone spicules in the periphery and arelatively spared macula. RE right eye, LE left eye

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(approved by the Bioethics Committee of theSchool of Medicine, Aristotle University ofThessaloniki), saliva samples were obtainedfrom the patient and family members for sub-sequent genomic DNA extraction (OrageneDNA OG-500 saliva kits, DNA Genotek).Genetic testing following whole exomesequencing (WES) analyses revealed that thepatient carried two compound heterozygous

pathogenic variants in the USH2A gene (OMIM608400, NM_007123.5) and in particular: anonsense mutation, c.100C[T, p.(Arg34Ter),and a synonymous change c.949C[A,p.(Arg317=), which has been shown to lead to anew splice site [9]. The two variants, classified aspathogenic in ClinVar by multiple submitters,segregated with the phenotype in the patient’s

Fig. 2 SD-OCT of the macula of both eyes. a Pre-operatively, in the right eye a FTMH (width 401 lm) anda few intraretinal cystic spaces can be seen. There is alsothinning of the outer retinal layers and no ellipsoid zonecan be seen. b, d, f In the left eye, thinning of the outerretinal layers is observed, while only the foveal part of theellipsoid zone is preserved. c One month after vitrectomy,

the FTMH is closed in the right eye. e Eleven months aftervitrectomy, the macular hole in the right eye remainsclosed with only few photoreceptors remaining in thetemporal part of the fovea. RE right eye, LE left eye

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family (Fig. 4). Genetic counselling was given tothe patient and family members.

DISCUSSION

Macular abnormalities are relatively frequent inRP patients, the most prevalent being cystoidmacular oedema, epiretinal membrane and vit-reomacular traction [7, 8, 10]. FTMH in RP hasbeen reported to be rare (B 1%), although moststudies have focused on non-syndromic RPpatients [7, 10–12]. The only study includingexclusively Usher patients was performed byTesta et al. [13] who demonstrated a highprevalence of macular abnormalities (47%). Inthis Italian cohort of 134 genetically confirmedUsher cases, FTMH was found only in one eye ofa patient carrying USH2A mutations and thusshowing a prevalence of 0.4% [13].

The mechanism underlying the formation ofFTMH in RP remains unclear and is consideredmultifactorial. Principally, abnormalities of thevitreomacular interface, such as vitreomaculartraction and epiretinal membrane, are consid-ered to be a major mechanism [11, 14, 15].Moreover, atrophy due to chronic cystoidmacular oedema and macular schisis in highlymyopic eyes could potentially lead to FTMH[12, 15]. Of note, our patient had posterior vit-reous detachment in the affected eye, so ourhypothesis is that vitreomacular traction is theunderlying mechanism in this case.

Fig. 3 Full-field ERG findings indicating the presence ofrod-cone dystrophy. a, b Under scotopic conditions, theERG is non-detectable in both eyes. c, d Under photopicconditions, the responses are reduced and delayed bilater-ally. The x axis represents time in ms (20 ms/div). The

y axis represents potential in lV (a, b 50 lV/div, c-d20 lV/div). DA dark-adapted, LA light-adapted, ERGelectroretinogram, RE right eye, LE left eye, N normal

Fig. 4 Genetic analysis of the patient’s family showing thepedigree and segregation data for the pathogenic variantsin USH2A. The genotypes for all tested family membersare shown below each individual, with M1 representing thefirst mutant allele, c.100C[T, p.(Arg34Ter), M2 thesecond mutant allele, c.949C[A, p.(Arg317=) and ? rep-resenting the wild-type allele. The affected individual isshaded black

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The role of vitrectomy is established in thetreatment of idiopathic FTMH leading to a highclosure rate and significant VA improvementcompared to observation [16]. However, due tothe rarity of FTMH cases in the context of RP,surgical outcomes have only been reported in afew small case series including patients withheterogeneous characteristics such as RP stage,symptoms duration, baseline VA, FTMH sizeand ocular comorbidities [10, 12, 14, 15, 17, 18].Eight RP cases with FTMH have been reported tohave a successful anatomic outcome with sevenof them showing higher post-operative VA andone of them having unaltered VA[10, 14, 15, 18]. Another four cases with highmyopia have been reported, two of which wereaccompanied by retinal detachment. All fourunderwent vitrectomy resulting in successfulclosure, with VA improvement in threepatients, while in the fourth one the VA dete-riorated [12, 15, 18]. Moreover, in three patientsthe FTMH failed to close after one vitrectomyand resulted in worse VA [10, 14, 18]. Of note,FTMH reopening after successful surgical inter-vention has been reported in one patient [17].Based on these studies, a successful closure ofthe macular hole is achieved in the majority ofthe cases, whereas the visual outcomes seem tobe mostly positive but can be variable. Thus, thesurgical treatment of these cases is usuallyconsidered beneficial, notwithstanding thepotential risks of vitrectomy, including photo-toxicity [19] and visual field defects [20]. Thepresence of long-standing retinal degenerationmay affect the visual outcomes in RP patients.In our patient the FTMH remained closed untilthe most recent follow-up 11 months post-op-eratively and the VA remained stable comparedto baseline.

Importantly, most of these studies haveincluded patients with either non-syndromic RPor no clear clinical statement (syndromic vs.non-syndromic RP) [10, 12, 15, 18]. The onlystudy reporting surgical outcomes of a FTMHcase with Usher syndrome was performed byVingolo et al. [21]. The authors report theresults from three cases including two RPpatients with lamellar holes and one Ushersubject with FTMH who underwent combinedmicroincision vitrectomy and cataract surgery.

The latter case was successful showing a VAimprovement from 2/20 to 4/20. However, theunderlying mechanism may be different fromour report because the macular holes were sec-ondary to ‘‘chronic CMO and tangential vitre-oretinal tractions’’. No OCT data were presentedfor this patient [21].

No genetic data were presented in theaforementioned reports of similar cases. To thebest of our knowledge, this is the first case ofsurgical management of a FTMH in a patientwith genetically confirmed Usher syndrome. Inour patient, WES revealed two compoundheterozygous mutations in USH2A. Pathogenicvariants in this gene account for the majorityamong the entire spectrum of genetic aberra-tions present in patients with Usher syndrometype 2 [4]. USH2A encodes usherin, localised tothe periciliary membrane complex, a region ofthe photoreceptor inner segment that sur-rounds the connecting cilium between theouter and inner segment [22]. The stop muta-tion, p.(Arg34Ter), has been previously reportedin several patients with Usher syndrome[23, 24]. The second pathogenic variant,p.(Arg317=), is predicted to activate a crypticdonor splice site and has also been previouslyreported [25, 26]. Its effect has been function-ally assessed in vitro at the mRNA level[r.(949C[A, 951_1143del)], where it was shownto lead to the deletion of the last 193 bases ofexon 6 and thus result in the introduction of apremature termination codon in exon 7 [9]. Werecommend that the genetic defects underlyingthese patients’ RP should be reported, whenpossible. Apart from the typical benefits ofgenetic testing, such as obtaining an accuratediagnosis, offering genetic counselling andidentifying patients eligible for gene therapy orclinical trials, it could help us establish usefulgenotype-phenotype correlations, e.g. whileexamining whether specific genes or mutationsare associated with the development of macularhole in RP.

CONCLUSION

We report a rare case of FTMH in a patient withgenetically confirmed Usher syndrome that was

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treated successfully with surgery. Our casereport supports the notion that vitrectomy is aneffective approach in these cases as demon-strated by the successful anatomical outcome,which stabilised central vision. Surgical man-agement should therefore be selected to try topreserve the central vision of these patients whoalready may have severely impaired peripheralvision. Further research is needed to enrich ourunderstanding and surgical experience in suchcases and potentially identify clinical and/orgenetic features related to the development andprognosis of FTMH in the context of RP.

ACKNOWLEDGEMENTS

Funding. Genetic analyses were supportedby the Swiss National Science Foundation(Berne, Switzerland), grant no. 176097, to CarloRivolta. No funding or sponsorship was receivedfor the publication of this article.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Prior Presentation. This manuscript is basedon work that was presented at the 15th Meetingof the Greek Vitreoretinal Society, 30 January-1February 2020, Athens, Greece.

Disclosures. Evangelia S. Panagiotou, Tho-mas Papathomas, Konstantinos Nikopoulos,Stavrenia Koukoula, Mathieu Quinodoz, Atta UrRehman, Theodoros Giannopoulos and CarloRivolta declare that they have no conflict ofinterest. Anastasios G. Konstas is a member ofthe journal’s Editorial Board.

Compliance with Ethics Guidelines. Writ-ten informed consent for the publication of thisreport and for genetic testing was obtained fromthe patient and family members (approved bythe Bioethics Committee of the School ofMedicine, Aristotle University of Thessaloniki).

Data Availability. Data sharing is notapplicable to this article as no datasets weregenerated or analyzed during the current study.

Open Access. This article is licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permitsany non-commercial use, sharing, adaptation,distribution and reproduction in any mediumor format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not includedin the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, youwill need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.

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Management of Full-Thickness Macular Hole in A Genetically Confirmed Case with Usher SyndromeAbstractIntroductionCase ReportConclusion

IntroductionCase PresentationDiscussionConclusionAcknowledgementsReferences