<i>MFRP</i>-Associated Retinopathy and Nanophthalmos in Two Irish Probands: A Case Report

Abstract

The conjunction of nanophthalmos (NO) and retinitis pigmentosa (RP) provides challenges to effective clinical management while narrowing the genetic spectrum for targeted molecular diagnostics. This case study describes two not knowingly related adult cases of &lt;i&gt;MFRP&lt;/i&gt;-associated retinopathy and nanophthalmos (MARN). Structural features including short axial lengths (mean 16.4 mm), steep keratometry (mean 49.98 D), adult-onset signs, and symptoms of retinal dystrophy and acquired disease (i.e., cataract, angle-closure glaucoma) were evident in both cases. Pathogenic variants in the &lt;i&gt;MFRP&lt;/i&gt; gene impair both prenatal eye growth and childhood emmetropization while also leading to RPE/outer retinal degeneration in 75% of cases. We discuss the “small-eye” phenotype spectrum and associated defining characteristics, molecular mechanisms with particular focus on MFRP-associated NO with RP features (MARN), the spectrum of visual morbidities (e.g., extreme refractive error, amblyopia, cystoid macular lesions, early cataract) and the challenges of their treatment/surgical management.

Surgical Approaches to Serous Retinal Detachment With Retina–Lens Touch in Eyes With Nanophthalmos

“…Patients with nanophthalmos who have intraocular surgery often present with abnormal ciliary zonules. [21][22][23][24][25][26][27][28] A mutation in myelin regulatory factor (MYRF) has been implicated in the pathogenesis of many cases of familial nanophthalmos in humans. 28 A nanophthalmos frameshift mutation of MYRF in mice 25 showed ocular phenotypes similar to their human counterpart, [26][27][28] including a shallow AC and reduced zonular fiber density and structural dehiscence of zonular fibers.…”

“…[21][22][23][24][25][26] Embryonic function of the MFRP gene is necessary for the eye to achieve normal dimensions by the third trimester, and a mutation in this or related genes would halt ocular development, leading to a lack of ciliary ring expansion, a thick crystalline lens, and dwarf zonules. [26][27][28] It is critical to avoid a sudden drop in IOP during any intraocular surgery in nanophthalmos because it will exacerbate suprachoroidal fluid accumulation. Slow release of choroidal fluid via a nondrainage technique (very deep sclerotomy) allows for more controlled passive decompression of the choroidal detachment.…”

“…Patients with nanophthalmos who have intraocular surgery often present with abnormal ciliary zonules. 21–28 A mutation in myelin regulatory factor (MYRF) has been implicated in the pathogenesis of many cases of familial nanophthalmos in humans. 28 A nanophthalmos frameshift mutation of MYRF in mice 25 showed ocular phenotypes similar to their human counterpart, 26–28 including a shallow AC and reduced zonular fiber density and structural dehiscence of zonular fibers.…”

“…Zonular dialysis was noted in several case series (Table 2). 21–26 Embryonic function of the MFRP gene is necessary for the eye to achieve normal dimensions by the third trimester, and a mutation in this or related genes would halt ocular development, leading to a lack of ciliary ring expansion, a thick crystalline lens, and dwarf zonules. 26–28…”

The Role of the Ophthalmic Genetics Multidisciplinary Team in the Management of Inherited Retinal Degenerations—A Case-Based Review

“…MFRP encodes a frizzled-related protein which is involved in wingless related integration site signalling, a process implicated with both normal retinal function (post-natal) and ocular growth (embryologically and during childhood) [17,18]. This variant has been previously reported alongside another unrelated Irish patient with a consistent phenotype, together representing 0.2% of genotyped IRD pedigrees in Ireland [19]. Biallelic MFRP variants are associated with microphthalmia/nanophthalmia, RP, foveoshisis and optic disc drusen of variable severity (OMIM#611040) [20].…”