Macular abnormalities are relatively frequent in RP patients, the most prevalent being cystoid macular oedema, epiretinal membrane and vitreomacular traction [7, 8, 10]. FTMH in RP has been reported to be rare (≤ 1%), although most studies have focused on non-syndromic RP patients [7, 10,11,12]. The only study including exclusively Usher patients was performed by Testa et al. [13] who demonstrated a high prevalence of macular abnormalities (47%). In this Italian cohort of 134 genetically confirmed Usher cases, FTMH was found only in one eye of a patient carrying USH2A mutations and thus showing a prevalence of 0.4% [13].
The mechanism underlying the formation of FTMH in RP remains unclear and is considered multifactorial. Principally, abnormalities of the vitreomacular interface, such as vitreomacular traction and epiretinal membrane, are considered to be a major mechanism [11, 14, 15]. Moreover, atrophy due to chronic cystoid macular oedema and macular schisis in highly myopic eyes could potentially lead to FTMH [12, 15]. Of note, our patient had posterior vitreous detachment in the affected eye, so our hypothesis is that vitreomacular traction is the underlying mechanism in this case.
The role of vitrectomy is established in the treatment of idiopathic FTMH leading to a high closure rate and significant VA improvement compared to observation [16]. However, due to the rarity of FTMH cases in the context of RP, surgical outcomes have only been reported in a few small case series including patients with heterogeneous characteristics such as RP stage, symptoms duration, baseline VA, FTMH size and ocular comorbidities [10, 12, 14, 15, 17, 18]. Eight RP cases with FTMH have been reported to have a successful anatomic outcome with seven of them showing higher post-operative VA and one of them having unaltered VA [10, 14, 15, 18]. Another four cases with high myopia have been reported, two of which were accompanied by retinal detachment. All four underwent vitrectomy resulting in successful closure, with VA improvement in three patients, while in the fourth one the VA deteriorated [12, 15, 18]. Moreover, in three patients the FTMH failed to close after one vitrectomy and resulted in worse VA [10, 14, 18]. Of note, FTMH reopening after successful surgical intervention has been reported in one patient [17]. Based on these studies, a successful closure of the macular hole is achieved in the majority of the cases, whereas the visual outcomes seem to be mostly positive but can be variable. Thus, the surgical treatment of these cases is usually considered beneficial, notwithstanding the potential risks of vitrectomy, including phototoxicity [19] and visual field defects [20]. The presence of long-standing retinal degeneration may affect the visual outcomes in RP patients. In our patient the FTMH remained closed until the most recent follow-up 11 months post-operatively and the VA remained stable compared to baseline.
Importantly, most of these studies have included patients with either non-syndromic RP or no clear clinical statement (syndromic vs. non-syndromic RP) [10, 12, 15, 18]. The only study reporting surgical outcomes of a FTMH case with Usher syndrome was performed by Vingolo et al. [21]. The authors report the results from three cases including two RP patients with lamellar holes and one Usher subject with FTMH who underwent combined microincision vitrectomy and cataract surgery. The latter case was successful showing a VA improvement from 2/20 to 4/20. However, the underlying mechanism may be different from our report because the macular holes were secondary to “chronic CMO and tangential vitreoretinal tractions”. No OCT data were presented for this patient [21].
No genetic data were presented in the aforementioned reports of similar cases. To the best of our knowledge, this is the first case of surgical management of a FTMH in a patient with genetically confirmed Usher syndrome. In our patient, WES revealed two compound heterozygous mutations in USH2A. Pathogenic variants in this gene account for the majority among the entire spectrum of genetic aberrations present in patients with Usher syndrome type 2 [4]. USH2A encodes usherin, localised to the periciliary membrane complex, a region of the photoreceptor inner segment that surrounds the connecting cilium between the outer and inner segment [22]. The stop mutation, p.(Arg34Ter), has been previously reported in several patients with Usher syndrome [23, 24]. The second pathogenic variant, p.(Arg317=), is predicted to activate a cryptic donor splice site and has also been previously reported [25, 26]. Its effect has been functionally assessed in vitro at the mRNA level [r.(949C>A, 951_1143del)], where it was shown to lead to the deletion of the last 193 bases of exon 6 and thus result in the introduction of a premature termination codon in exon 7 [9]. We recommend that the genetic defects underlying these patients’ RP should be reported, when possible. Apart from the typical benefits of genetic testing, such as obtaining an accurate diagnosis, offering genetic counselling and identifying patients eligible for gene therapy or clinical trials, it could help us establish useful genotype-phenotype correlations, e.g. while examining whether specific genes or mutations are associated with the development of macular hole in RP.