Nanophthalmos is characterized by reduced age-adapted axial length of the eye leading to high hyperopia ranging from +8.00 to +25.00 dioptres. Primary or associated findings in the nanophthalmic eye may include a thickened and hardened sclera, reduced anterior chamber depth, steep or irregular corneas, disproportionally large lens, foveal hypoplasia, absent foveal avascular zone, papillomacular folds, foveoschisis, optic disc drusen and retinal dystrophy.

Seven patients with nanophthalmos and available family members from 5 families received a comprehensive ophthalmological examination. Genetic analysis was based on whole exome sequencing (WES) and variant calling in core genes including MFRP, BEST1, TMEM98, PRSS56, CRB1, GJA1, C1QTNF5, MYRF and FAM111A.

Novel pathogenic variants in MFRP and PRSS56 as well as a recurrent de novo variant in FAM111A in a patient with Kenny–Caffey syndrome type 2 were identified. In addition, we observed co-inheritance of MFRP-related nanophthalmos and ADAR-related Aicardi–Goutieres syndrome.

Nanophthalmos is a genetically heterogeneous condition, and the severity of ocular manifestations appears not to correlate with variants in a specific gene. However, retinal dystrophy is only observed in patients harbouring pathogenic MFRP variants. Furthermore, heterozygous carriers of MFRP and PRSS56 should be screened for the presence of high hyperopia. Identifying nanophthalmos as an isolated condition or as part of a syndrome has implications for counselling and can accelerate the interdisciplinary care of patients.

Luzy Baehr
Wolfgang Berger (PhD)
Silke Feil
David Grubich Atac (MD/PhD)
Samuel Koller (PhD)
Jordi Maggi (PhD)

Daniel Barthelmes (MD), Dept. Ophthalmology, University Hospital Zurich
Christina Gerth-Kahlert (MD), Dept. Ophthalmology, University Hospital Zurich
James V. M. Hanson, Dept. Ophthalmology, University Hospital Zurich
Elena Lang (MD), Dept. Ophthalmology, University Hospital Zurich