Nanophthalmos patient with a THR518MET mutation in MYRF, a case report

A 3-year-old male (Nan3) presented to the emergency department with a frontal headache, eye pain, emesis, and lethargy. Physical exam was essentially normal with no focal neurologic deficits. Work up included a CT scan and MRI, which identified increased posterior fossa fluid. A lumbar puncture was also performed with normal opening pressure. Eye examination was limited due to patient agitation, but did not reveal any abnormal findings; his visual acuity was at least fix and follow OU, and the dilated eye exam was only notable for peripheral geographic chorioretinal scars OU. Toxoplasmosis serology was obtained, which was negative, and follow-up was arranged with ophthalmology. Both neurology and neurosurgery were following on an as needed basis.

At follow up eye examination, Nan3’s symptoms had resolved. His visual acuities were 2.4cy/cm (20/260) OD and 6.5cy/cm (20/94) OS by Teller cards, and intraocular pressure (IOP) was 7 mmHg OD and 8 mmHg OS by iCare tonometer. Cycloplegic refraction revealed high hyperopia (+ 7.00 + 0.50 × 090 OD and +  7.00 + 0.50 × 090 OS). On subsequent exam under anesthesia, his pachymetry readings were thick at 640 μm OD and 616 μm OS, and the horizontal white-to-white measures were small at 10.5 mm OD and 10.6 mm OS. Gonioscopy showed angles open to the scleral spur OD and with 2 clock-hours of angle closure OS. The anterior segment examination was otherwise normal. The optic nerves OU had mild pallor and cup-to-disc ratios of 0.4 OD and 0.3 OS respectively (Fig. 1a and b). As previously noted, there were chorioretinal scars in the periphery of both eyes (Fig. 1c and d). A-scan ultrasound measured short axial eye lengths of 18.1 mm OD and 18.3 mm OS), a thick sclera (2.0 mm OU), and a relatively large lens (4.3 mm OD and 4.1 mm OS). CT and MRI scans also demonstrate short axial eye lengths and thick sclera (Fig. 2). He did not show any signs of primary congenital glaucoma, including buphthalmos, Haab’s striae, or corneal edema and was diagnosed with nanophthalmos based on axial eye length measurements.

At subsequent follow-up appointments during the next year, Nan3 had several episodes of unilateral high IOPs (once in the right eye to 53 mmHg, three times in the left ranging from 42 to 60 mmHg). Topical medications (timolol-dorzolamide and latanoprost) were successful in lowering intraocular pressure during 9 months of follow-up. Based on his clinical course and measurements, Nan3 was diagnosed with nanophthalmos, microcornea, and likely intermittent angle-closure glaucoma. Close follow-up was arranged to monitor his IOP and iridocorneal angles and the need for surgical intervention. Unfortunately, he was lost to follow-up.

Nan3 has no known family history of nanophthalmos. His parents were unavailable for examination, but are not known to be highly hyperopic or have a history of angle closure glaucoma.

We tested Nan3’s DNA for coding sequence variants in TMEM98 and MYRF using standard Sanger sequencing, and MFRP was also tested by a commercial laboratory (Bayler Miraca, Houston, TX). No variants were detected in TMEM98 or MFRP, however, we detected two heterozygous variants in MYRF, a synonymous change (rs149803 - Pro263Pro) and a missense change (Thr518Met - rs562652459).

We evaluated the potential pathogenicity of the Thr518Met variant in the MYRF gene by assessing its prevalence in control subjects with normal eyes. No instances of the Thr518Met variant were detected in the exomes of 362 normal control subjects from the University of Iowa. Moreover, the Thr518Met variant was only rarely observed in the gnomAD database at an allele frequency of 0.000024 in a non-Finnish European population (n = 61,642, gnomad.​broadinstitute.​org) as would be expected for a variant that causes nanophthalmos. Parental samples were not available for segregation studies or to determine if Thr518Met was a de novo variant in the MYRF gene. Nan3’s parents reported no history of high hyperopia or angle closure glaucoma, which would be consistent with a de novo MYRF variant in Nan3. We further explored the pathogenicity of Thr518Met with a homology analysis. The Thr518Met variant alters an amino acid in a DNA-binding domain of MYRF that has been conserved across a diverse range of mammals and vertebrate animals (Fig. 3a). We also investigated the pathogenesis of Thr518Met with variant analysis algorithms. Three of four algorithms suggested that the Thr518Met variant is deleterious (Table 1). Finally, we modeled the tertiary structure of the MYRF protein with and without the Thr518Met variant using its solved crystal structure (PDB ID: 5YHU) [11] and refinement algorithms based on the polarizable AMOEBA force field as we have previously described [12]. Our analysis showed that the Thr518Met variant replaces a polar amino acid (threonine) with a larger, hydrophobic amino acid (methionine), which results in the loss of a hydrogen bond between two MYRF DNA-binding domain β-strands (Fig. 3b). Together these data suggest that the Thr518Met variant in MYRF may cause nanophthalmos by destabilizing the fold of its DNA-binding domain and altering its function as a transcription factor.