Microphthalmia, Isolated 5

A number sign (#) is used with this entry because of evidence that posterior microphthalmia with retinitis pigmentosa, foveoschisis, and optic disc drusen (MCOP5) is caused by homozygous or compound heterozygous mutation in the MFRP gene (606227) on chromosome 11q23.

For a phenotypic description and a discussion of genetic heterogeneity of isolated microphthalmia, see MCOP1 (251600).

Clinical Features

Ayala-Ramirez et al. (2006) described a 49-year-old woman, born of second-cousin Mexican parents, who presented with progressive impairment of night vision and bilateral progressive decrease in visual acuity, both starting around 24 years of age. On examination, her best-corrected visual acuity was 20/200 on the right and 20/100 on the left, and she had decreased axial length of both globes with normal-sized corneas, diffuse scleral thickening, optic disc drusen, an extinguished rod response and barely registrable cone responses on electroretinography (ERG), and retinal pigment epithelium (RPE) atrophy with areas of pigment clumping and bone-spicule pigmentation. Optical coherence tomography (OCT) showed diffuse macular thickening, schisis of the outer retinal layers with discrete bridging elements at the fovea, absence of a foveal pit, and no evidence of macular cysts. The patient had 3 affected sibs, 45- and 39-year-old brothers and a 41-year-old sister, all of whom reported a progressive decrease in visual acuity and nyctalopia with onset in the third decade of life. All had high hyperopia, normal-sized cornea, shallow anterior chamber, reduced axial eye length, increased scleral thickness, optic disc drusen, extinguished rod responses with moderate to severe damage in cone responses on ERG, and foveoschisis and absence of foveal pit on OCT. None of the sibs had additional somatic anomalies, mental retardation, or hearing loss.

Crespi et al. (2008) studied 3 affected brothers, aged 40, 54, and 60 years, from a consanguineous Spanish family with posterior microphthalmia, retinitis pigmentosa, foveoschisis, and optic disc drusen. All 3 patients had bilateral shortening of the posterior ocular segment associated with high hyperopia and normal anterior segment dimensions. Best-corrected visual acuity ranged from 20/60 to 20/200. Funduscopy, ERGs, and fluorescein angiography were compatible with advanced rod-cone dystrophy (retinitis pigmentosa); findings included patchy areas of hypopigmentation, blunted macular reflex, and midperipheral bone spicule-like pigment clumping and vascular attenuation. OCT showed outer retinal layer schisis with absence of the foveal pit. Although the ocular phenotype was remarkably similar in the 3 brothers, the older ones exhibited a more severe degree of both foveoschisis and visual function impairment, with 1 eye in the oldest brother showing no light perception. Their first-cousin parents and 6 other sibs were unaffected, and there was no family history of ocular or extraocular malformations. Crespi et al. (2008) stated that nanophthalmos was classically distinguished from posterior microphthalmia based on the presence of normal corneal size and anterior chamber dimensions in the latter, but that later clinical and genetic data indicated that the 2 malformations could be considered distinct clinical manifestations of the same anomaly. The authors noted that in their patients, although corneal diameters were normal, that 2 of the affected brothers developed angle-closure glaucoma might make the term 'nanophthalmos' a more appropriate designation for the ocular malformations in this family.

Zenteno et al. (2009) reported a Mexican sister and brother who had had progressive nyctalopia and decreasing visual acuity from infancy. The 18-year-old sister had visual acuity of 20/200 bilaterally, whereas her 16-year-old brother had 20/200 in the right eye and 20/100 in the left. Both sibs had normal intraocular pressure and corneal diameters without anterior chamber angle anomalies. Funduscopy revealed very small optic cups in the sister, and both patients exhibited macular cystic lesions as well as bilaterally diminished foveal reflex with mottling and atrophy of the RPE at the posterior pole and peripheral retina. Fluorescein angiography revealed diminished transmission in the mottled areas of RPE atrophy. ERG showed abolished scotopic and reduced photopic responses in both sibs, and their Arden ratios were reduced bilaterally. By ultrasound, axial lengths in the sibs were less than 15 mm bilaterally, and optic nerve drusen and thickened choroid were present in all eyes. OCT showed foveal thickening and hyporeflective cystic areas, with splitting of the inner retinal layers.

Mukhopadhyay et al. (2010) ascertained 7 patients from 4 families with a phenotype similar to that previously described for MFRP-associated disease. All 7 patients were highly hypermetropic, 5 had night blindness, and 1 was photophobic. All 3 patients who were tested for color vision failed to read the test plate. Two patients, aged 47 and 58 years, had undergone surgery for bilateral cataracts, and 1 patient lost central vision at age 42 years due to bilateral progressive serous retinal detachments. Funduscopy revealed arteriolar attenuation and extensive midperipheral retinal pigment epithelial changes with relative preservation of the central macular reflex in all patients, corresponding to an ellipsoid preserved region of autofluorescence on fluorescein angiography. Optic nerve head drusen were present in only 1 of the 7 patients. All ERGs showed a rod-cone pattern of dysfunction, with severe rod involvement. OCT examination of 3 patients showed thickening of the inner layers and cystic spaces at the fovea, with relative preservation of the photoreceptor-RPE complex. Over a 30-year follow-up period in 1 patient, visual acuity and hypermetropia remained stable.

In a 10-year-old Saudi Arabian boy with posterior microphthalmia, Nowilaty et al. (2013) identified homozygosity for a frameshift mutation in the MFRP gene. The patient had axial lengths of 15.65 mm and extreme hyperopia (+15.75 diopters) as well as a thick papillomacular fold, but exhibited no night blindness or clinical signs of retinal degeneration, developmental ocular malformations, or syndromic disease. The authors observed corneal steepening that was proportional to the degree of axial foreshortening in this and other patients with posterior microphthalmia, including the patients previously studied by Aldahmesh et al. (2011). Nowilaty et al. (2013) stated that the fact that corneal diameter decreases with decreasing axial length provides further evidence that posterior microphthalmia and nanophthalmos represent a spectrum of high hyperopia rather than distinct phenotypes.

Mapping

In a consanguineous southern Indian family with extreme hyperopia and retinitis pigmentosa, Kannabiran et al. (2012) performed genomewide homozygosity mapping and identified an 8.5-Mb homozygous region on chromosome 11 that included the MFRP gene locus.

Molecular Genetics

In a consanguineous Mexican family with posterior microphthalmia, retinitis pigmentosa, foveoschisis, and optic disc drusen, Ayala-Ramirez et al. (2006) analyzed the MFRP (606227) and CHX10 (142993) genes, which cause autosomal recessive forms of nanophthalmos (NNO2; 609549) and microphthalmia (see, e.g., MCOPCB3; 610092), respectively. In the 4 affected members of the family, the authors identified homozygosity for a 1-bp insertion in the MFRP gene (606227.0005), predicted to result in complete loss of functional protein. Both parents were heterozygous for the mutation. No deleterious mutations were detected in CHX10.

In 3 brothers from a consanguineous Spanish family with posterior microphthalmia, retinitis pigmentosa, foveoschisis, and optic disc drusen, Crespi et al. (2008) analyzed the MFRP gene and identified homozygosity for a 1-bp deletion (498delC; 606227.0003). An unaffected sister was heterozygous for the deletion.

In a Mexican sister and brother with posterior microphthalmia, retinitis pigmentosa, foveoschisis, and optic disc drusen, Zenteno et al. (2009) identified compound heterozygosity for the 498delC mutation and a nonsense mutation in the MFRP gene (Y317X; 606227.0006).

In 7 patients from 4 families with high hypermetropia and retinal dystrophy, Mukhopadhyay et al. (2010) identified homozygosity or compound heterozygosity for mutations in the MFRP gene (606227.0001, 606227.0003, and 606227.0007-606227.0009). Refractive analysis of obligate carriers revealed that only 1 of 15 was hypermetropic, indicating that haploinsufficiency for MFRP does not play a significant role in physiologic hypermetropia.

In 2 brothers from a South African family of Indian ancestry with 'typical' posterior microphthalmia, Aldahmesh et al. (2011) identified homozygosity for a missense mutation in the MFRP gene (R518W; 606227.0010). The patients exhibited an abnormally short axial length by standardized ultrasonography, normal corneal diameters and anterior segment appearance, high hyperopia, and an abnormal papillomacular retinal fold on ophthalmoscopy.

In 3 sibs from a consanguineous southern Indian family with extreme hyperopia and retinitis pigmentosa mapping to chromosome 11, Kannabiran et al. (2012) identified homozygosity for the 498delC mutation in the MFRP gene. Their unaffected parents were heterozygous for the mutation, which was not found in 100 controls. All 3 sibs had onset of symptoms in the first decade of life, with progressively decreasing night vision. Funduscopy showed some degree of arterial narrowing, disc pallor, and confluent RPE degeneration that included perifoveal pigments. Bright flash ERGs were subnormal and severely diminished with a rod-cone pattern. Kannabiran et al. (2012) noted that all 3 affected individuals exhibited clinically atypical retinitis pigmentosa, with the 2 younger sibs having high hyperopia of +11 and +13 diopters, respectively, and the oldest sib having slightly more pigments and macular involvement.