DICER1 Syndrome: Characterization of the Ocular Phenotype in a Family-Based Cohort Study

Abstract

Purpose: To characterize the ocular phenotype of DICER1 syndrome.

Design: Prospective, single-center, case-control study.

Participants: One hundred three patients with an identified germline pathogenic DICER1 variant (DICER1 carriers) and 69 family control participants underwent clinical and ophthalmic examination at the National Institutes of Health between 2011 and 2016.

Methods: All participants were evaluated with a comprehensive ophthalmic examination, including best-corrected visual acuity, slit-lamp biomicroscopy, and a dilated fundus examination. A subset of patients returned for a more detailed evaluation including spectral-domain OCT, color fundus photography, fundus autofluorescence imaging, visual field testing, full-field electroretinography, and genetic testing for inherited retinal degenerative diseases.

Main outcome measures: Visual acuity and examination findings.

Results: Most DICER1 carriers (97%) maintained a visual acuity of 20/40 or better in both eyes. Twenty-three DICER1 carriers (22%) showed ocular abnormalities compared with 4 family controls (6%; P = 0.005). These abnormalities included retinal pigment abnormalities (n = 6 [5.8%]), increased cup-to-disc ratio (n = 5 [4.9%]), optic nerve abnormalities (n = 2 [1.9%]), epiretinal membrane (n = 2 [1.9%]), and drusen (n = 2 [1.9%]). Overall, we observed a significant difference (P = 0.03) in the rate of retinal abnormalities in DICER1 carriers (n = 11 [11%]) versus controls (n = 1 [1.5%]). One patient demonstrated an unexpected diagnosis of retinitis pigmentosa with a novel variant of unknown significance in PRPF31, and 1 showed optic nerve elevation in the setting of increased intracranial pressure (ICP) of unclear cause. Three patients (3%) demonstrated DICER1-related ciliary body medulloepithelioma (CBME), 2 of which were identified during routine examination, a higher rate than that reported previously.

Conclusions: Ophthalmologists should be aware of the ophthalmic manifestations of DICER1 syndrome, and individuals and families should be counseled on the potential signs and symptoms. We recommend that children with a germline pathogenic variant in DICER1, especially those younger than 10 years, undergo annual dilated ophthalmic examination, looking for evidence of CBME, signs of increased ICP, and perhaps changes in the retinal pigment epithelium.

Figure 1.

7-year-old boy, DICER1 carrier with medulloepithelioma of the ciliary body. A: Macroscopic photograph of the anterior portion of the eye after sectioning demonstrating a tan-white lesion (inside square) adjacent to the ciliary body with a membrane extending around the cataractous lens (L). B: Microscopic photograph of the tumor (same site as in the previous photo inside the square) adjacent to the pigmented epithelium of ciliary body. The tumor is composed by tubular structures of neoplastic neuroepithelium seen on a basophilic loose stroma. Hematoxylin and Eosin stain. Original magnification 4X. C: T1 weighted axial image with contrast demonstrating the ciliary body tumor (dashed arrow). Note the displacement of the lens laterally.

Figure 2.

Panel A: 7-year-old boy with headaches and transient blurred vision. Examination of the fundus revealed disc elevation with retinal vascular tortuosity and no hyperautofluorecence at the nerve head (i). There was no obvious hyper- or hypo-reflective lesion in the peripapillary area on b-scan imaging in high (ii left) or low gain (ii right). OCT does not demonstrate any classic optic nerve head drusen features (iii). Panel B: 65-year-oid female with optic nerve head drusen noted on direct visualization and hyperautofluorescent lesions on imaging.

Figure 3.

37-year-old DICER1-carrier woman presenting with retinitis pigmentosa. Fundus examination revealed classic features of retinal atrophy, bony spicules and vessel attenuation (top panel A) with peripheral hypoautofluorescence with a central hyperautoflu orescent ring (lower panel A). Visual acuity was preserved at 20/20 in each eye with a constricted visual field (B) and macular cystic changes and loss of photoreceptor IS/OS band demonstrated on OCT (C). Full-field ERG showed nearly unrecordable scotopic responses with severely reduced photopic responses, consistent with a rod-cone dystrophy (D).