Doyne honeycomb retinal dystrophy/malattia leventinese induced by EFEMP1 mutation in a Chinese family

Doyne honeycomb retinal dystrophy (DHRD)/Malattia leventinese (ML) is caused by a single mutation in EFEMP1 that encodes the epidermal growth factor-containing fibrillin-like extracellular matrix protein 1 [1]. In its early stages, the disease appears as massive drusens, while the visual acuity of the patients would decrease with the lesion progress [2]. To date, laser therapy and anti-VEGF therapy have been utilized for the treatment, but the treatment is still a challenge as there is no effective way to correct the gene mutation of such condition [3]. In this study, we reported a family with DHRD/ML disease that presented different features with the former reports. It contributed to the diversity of DHRD/ML.

A 28-year-old female patient presented to our department due to blurry visual acuity for 10 years especially in the right eye with deterioration for 5 months. The best corrected visual acuity (BCVA) in the right and left eyes was 5.0 and 5.1 (logmar visual acuity chart), respectively. The intraocular pressure (IOP) in the right and left eyes was 17 mmHg and 18 mmHg, respectively. No abnormalities were observed in the anterior segment of both eyes. Fundus examination showed that the optic disc was normal, while the remarkable diffuse pinpoint or drusen-like speckle yellow white lesions affected the posterior fundus, with varying degrees of retina/retinal pigment epithelium (RPE)/choroid atrophy around the disc. The fovea light reflex was not clear (Figs. 1 and 2). Optical coherence tomography (OCT) scan showed extensive hyperreflective thickening beneath the retinal pigment epithelium (RPE, Fig. 3). Fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA) assumed that RPE/choroidal disorder was featured by “honeycomb” appearance (Fig. 4). Visual field showed defect in the temporal sides (Fig. 5). Electrophysiological examination findings (e.g. ERG, EOG, and VEP) were normal.

Her 22-year-old brother showed BCVA of 5.0 (logmar visual acuity chart) in both eyes. Fundus examination showed diffuse pinpoint yellow white deposits throughout the macular and peripapillar area with honeycomb-like pigmentary changes around the disc (Fig. 6a and b). OCT scan showed a hyperreflective thickening beneath the pigmentary epithelium accompanied by wavy uplift (Fig. 7a and b).

Her 54-year-old mother complained of poor visual acuity for at least 20 years, especially at nighttime. The BCVA of the right eye was FC/10 cm, and the left eye was 4.0 (logmar visual acuity chart). She had corneal opacity in both eyes (Fig. 8a and b), and the fundus could not be observed clearly. Corneal scan of OCT showed granular cloudiness, and corneal endothelium detachment in the peripheral part (Fig. 8c and d). Color Doppler ultrasonography of eyeball showed thickening in the posterior wall of both eyeballs.

Her father showed no history of ocular diseases. He would not come to our hospital for the ocular examinations due to personal reasons.

After signing the informed consents, venous blood was collected from the female patient, her mother and her brother, respectively. Gene sequencing was performed by MyGenostics (Peking, China). Gene sequencing revealed heterozygous mutations in EFEMP1 gene, which was consistent with the DHRD/ML. The study protocols were approved by the Ethical Committee of Hainan General Hospital. For the gene sequencing, single heterozygous mutation (c.1033C > T) was observed in each of the three blood samples. This missense mutation triggered p.R345W (Fig. 9).

DHRD was initially reported in 1899 by Doyne, which was featured by closely-grouped white spots involving the disc-macular area in a pattern termed honeycomb [4]. Also, it is manifested as diffuse retina white spots. To our best knowledge, ML was initially described initially in inhabitants or descendants in the Leventine valley of Tessin Canton in Southern Switzerland [5]. In a previous study, Haimovici et al. [6] summarized the typical onset age and features of such condition, which was featured by drusen-like deposits in the macula and around the optic nerve that were usually apparent by the age of 20. Moreover, most of the patients were asymptomatic, and then the patients developed more numerous and larger drusen. In this literature, the authors also mentioned that the earliest visual symptoms included dyschromatopsia, metamorphopsia, or relative scotomas at the age of 30–40 yrs. Central visual acuity usually showed deterioration at the age of 40–50 yrs., however, it may occur at 30 or be delayed until 60 yrs [6]. In the later stages, the majority of patients showed loss of central vision and absolute scotomas, which was associated with the development of extensive pigmentary changes and geographic atrophy (GA) or choroidal neovascularization (CNV) in the region of the confluent macular drusen [6].

Recently, DHRD and ML are considered as the same disease because of similar clinical symptoms. In a previous study, Stone et al. revealed a single non-conservative mutation (Arg345Trp) in EFEMP1 gene that was associated with the pathogenesis of ML and DHRD [1]. EFEMP1 gene, localized on chromosome 2p16–21, encodes an extracellular matrix protein expressed in the retina, RPE and choroid [7]. Besides, it showed homology among the protein members [8]. EFEMP1-encoded protein may interact with the other extracellular matrix proteins such as connexin, collagen, fibronectin, and laminin, which contributed to the formation of drusen [1]. The clinical symptoms and pathogenesis of DHRD/ML are similar with that of age-related macular degeneration (AMD), which is featured by soft drusen, external RPE structure loss, RPE vacuolation and atrophy, as well as the final neovascularization at the age of less than 40 yrs. [9]. However, they are indeed different diseases. The mutation (Arg345Trp) of EFEMP1 was reported to show no association with the drusen related lesions such as AMD [10]. Meanwhile, no Arg345Trp mutation was identified in the cases with dispersed or familial AMD [11]. Thus far, the Arg345Trp mutation is the only mutation identified in the coding or adjacent intronic regions of EFEMP1 gene in familial or sporadic early onset drusen. This suggests that the Arg345Trp mutation is responsible for producing a specific drusen phenotype (drusen around the optic nerve head in DHRD and radial drusen in ML) [12]. In a previous study aimed to distinguish DHRD apart from ML, DHRD patients were considered to present comby drusen in the posterior fundus, while smaller discrete drusen radially distributed around the macula in ML patients [13].

To date, there were few reports of ML/DHRD. In China mainland, there was only one case report of R345W mutation in EFEMP1 caused ML/DHRD in a family [14]. In that report, 6 members of one family at the age of 37–61 yrs., and the proband was 43 yrs., all of whom showed drusen distributed in the fundus, 2 had RPE disorders and CNV. In this study, we identified a heterozygous mutation of EFEMP1 in a family with a 28-yrs sister of proband, a 22-yrs brother, and their mother. Our clinical findings were not similar with previously reported cases, despite some similarities [11‐15]. Firstly, the young proband in this study presented clustered drusen reaching the equator of fundus with no CNV in the macula, while all previous cases showed drusen only localized in the macular region not exceeding the vascular arch. Secondly, besides remarkable drusen, there were large dark gray lesions originated from RPE/choroid atrophy in the posterior pole around the disc. No such feature was reported in the previous literature, even a few cases presented pigment proliferation in the macula [11‐14]. Thirdly, the vision of the patient and her brother was not significantly impaired despite of the wide damages in the fundus. Some reports [4, 12] showed declined vision if there were densely large drusen in the macular area, which may deteriorate when combing with CNV and RPE disorder. However, in the 5-yr follow-up [16] of a Japanese female patient with DHRD/ML, one eye of BCVA remained normal in spite of aggravation of drusen and pigmentation in the macula, and the other eye showed vision loss due to CNV of macula. Furthermore, the brother present remarkable diffused drusen, while milder RPE /choroid damages of honeycomb-like appearance were noticed in the posterior pole around the disc. Nevertheless, it showed no clinical symptoms at present. The sister presented visual field defects corresponding to the peripapillary RPE/choroid damages. Thus, we deduced the pinpoint, yellowish, white drusen might represent the early stage of this disease, which then fused to patchy drusen. However, the dark gray lesions of RPE/choroid atrophy around the optic disc might imply progress of the disease with following vision loss. Multifocal ERG, OCT or FFA/ICGA examinations and visual field examinations may contribute to long-term follow-up [16‐18].

For the treatment, Lenassi et al. [19] reported that low-energy laser treatment was safe and might be effective for treating autosomal dominant drusen induced by EFEMP1 mutation. In 11 patients with autosomal dominant drusen and confirmed with disease-causing EFEMP1 mutation, the eyes with poor vision were treated with Argon green laser. The untreated eyes lost an average of 0.8 letters, whereas, the treated eyes gained an average of 4.9 letters. The average thickness of the drusen in the untreated eyes showed increase, while no changes were noticed in the treated eyes. Meanwhile, Sohn et al. [20] showed that CNV in DHRD was sensitive to treatment with intravitreal bevacizumab which was featured by absorption of subretinal fluid and improvement of visual acuity in two cases.

In this study, the patient and her brother had almost normal central vision, which might the associated with the fact that the lesion did not involve the fovea. We implied that there would be a vision loss when the RPE/choroid atrophy invaded the macula. Anyway, long-term follow up was still required, and immediate treatment was recommended in cases of deterioration of drusen or CNV formation, in order to keep the vision. On the other hand, her mother showed long-term corneal opacity with granular cloudiness. Up to now, we are not sure whether these lesions are associated with the DHRD/ML. In the future, we hope to find out the exact relations between them.