Nanophthalmos, a severe form of microphthalmia, is a rare structural eye disease which can be inherited or develop through sporadic mutations. The disorder is characterized by an axial length that is less than 20.5 mm [1]. Affected patients are prone to developing ophthalmological complications including angle closure glaucoma, uveal effusion, retinal detachment, or chorioretinal folds [2]. Several genes including BEST1, CRB1, FAM111A, MFRP, MYRF, PRSS56, and TMEM98 have been implicated in syndromic or nonsyndromic nanophthalmos [3], and most cases have been reported to occur within European or consanguineous South Asian families. Herein, we report a case of nanophthalmos and foveal hypoplasia with retinal wrinkling in a patient harboring two novel PRSS55 variants. Written informed consent for publication of the research details and clinical images was obtained from the patient’s parent.

A 4-year-old boy with normal skin and hair coloration presented at our hospital with poor visual acuity and high hyperopia. He was born at full term and no perinatal medical history was noted. Cycloplegic refraction revealed +9.50 − 0.50 × 180 and +10.50 − 0.50 × 180 in his right and left eye, respectively. The best-corrected visual acuity was 20/60 and 20/100 in his right and left eye, respectively. Analysis of extraocular motility examination revealed full duction with no evidence of nystagmus. Slit-lamp examination showed normal configuration of the iris and no transillumination defects. Evaluation of the dilated fundi revealed wrinkling of the macular mound in both eyes (Fig. 1A, 1B), and the axial length was 17.90 mm in the right eye and 17.86 mm in the left eye. Optical coherence tomography demonstrated bilateral grade 1b foveal hypoplasia with wrinkling of the retinal nerve fiber layers (Fig. 1C, 1D). Targeted panel next-generation sequencing (595 genes) identified two novel heterozygous variants in PRSS56 (NM_001195129.1), namely c.875G>A:p.(Cys292Tyr) and c.1618G>A:p.(Val540Met), that were presented in trans (Fig. 1E). Of these, c.875G>A:p.(Cys292Tyr) variant has been listed with a frequency of 2/40490 in gnomAD East Asian v4.1 and is predicted to be deleterious in silico (CADD:25.5, SIFT:0.01, Polyphen2:0.744). The second variant, c.1618G>A:p.(Val540Met) variant has a frequency of 4/40570 in gnomAD East Asian v4.1 and is also predicted to be deleterious in silico (CADD:25.4, SIFT:0.01, Polyphen2:0.988).

PRSS56 (OMIM *613858) encodes a 603-amino acid protein that belongs to the chymotrypsin serine protease family. To date, six genes, namely BEST1, CRB1, MFRP, MYRF, PRSS56, and TMEM98 have been found to play a role in non-syndromic familial forms of microphthalmos, of which PRSS56 and MFRP variants are the most prevalent in multiple ethnicities. In PRSS56 gene, 65 single nucleotide and indels variants have been reported in literatures and ClinVar (assessed March 24, 2022) (Fig. 1F) as causative for microphthalmia and hyperopia. Given that eye development is tightly regulated by genetic and environmental factors, appropriate expression of proteins involved in ocular growth is of paramount importance. A previous study found that PRSS56 of Muller glial cell origin contributes to ocular axial length elongation, and its persistent activity is essential for sustenance of ocular growth during the entire duration of pre- and post-eye opening periods in mice [4]. However, the exact molecular and cellular mechanisms involved in refractive development remain unelucidated.

Several retinal abnormalities including retinal cysts, foveal hypoplasia, retinoschisis, papillomacular folds, retinal dystrophies, and disc drusen have been reported to be associated with microphthalmos [5]. The present case had grade 1b foveal hypoplasia and papillomacular wrinkling that were noted on fundus examination. Low-grade foveal hypoplasia has been previously reported in cases of nanophthalmos, albeit with intact outer nuclear layer widening and photoreceptor outer segment lengthening. This implies that foveal hypoplasia associated with nanophthalmos may be a consequence of the centripedal force effect of the inner retinal layers owing to extremely small eye size and not arrested foveal development. Therefore, while foveal hypoplasia is commonly associated with either albinism, PAX6-related phenotype, or SLC38A8 foveal hypoplasia, the differential diagnosis should include nanophthalmos.

We identified two novel PRSS56 variants that are responsible for the development of nanophthalmos and foveal hypoplasia. Although these two variants were classified as variant of uncertain significance, it could be reclassified as pathogenic in the future. A confirmed genetic diagnosis will help prevent future surgical complications related to intraocular surgery in the patient. Early detection of genetic conditions will aid provision of genetic counseling services including family planning and future gene-based therapeutic strategies.