Microphthalmia, Isolated 6

A number sign (#) is used with this entry because of evidence that isolated microphthalmia-6 (MCOP6) is caused by homozygous or compound heterozygous mutation in the PRSS56 gene (613858) on chromosome 2q37.

Description

Autosomal recessive isolated posterior microphthalmos defines a rare distinct phenotype restricted to the posterior segment of the eye. In adults, it is clinically characterized by extreme hyperopia (from +7.5 to +21 diopters) due to short axial length (14 mm to 20 mm; normal is greater than 21 mm). Other features include an essentially normal anterior segment, steep corneal curvatures, shallow anterior chamber, thick lenses, and thickened scleral wall. The palpebral fissures appear narrow because of relatively deep-set eyes, visual acuity is mildly to moderately reduced, and anisometropic or strabismic amblyopia is common. The fundus of the eye shows crowded optical discs, tortuous vessels, and an abnormal foveal avascular zone; in addition, papillomacular folds are often reported. Morphometric features of the small eyes predispose to complications such as narrow-angle glaucoma and uveal effusion (summary by Gal et al., 2011).

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

Nomenclature

The term 'posterior microphthalmos' was introduced by Franceschetti and Gernet (1965) and later applied to several cases of small eyes with normal-sized anterior segments. Other authors used the designation 'nanophthalmos' (see NNO1, 600165), while Warburg (1993) preferred to label such eyes as 'partial microphthalmos' (summary by Fuchs et al., 2005).

Clinical Features

Fuchs et al. (2005) reported 2 families from the Faroe Islands, 1 of which had previously been studied by Fledelius and Rosenberg (1987), in which affected individuals exhibited a rare ocular phenotype characterized by a short axial length (less than 21 mm), mainly confined to the posterior segment of the eye; a shallow anterior chamber; a thickened eye wall; and very high hyperopia (median, +16.5 diopters (D); range, +7.75 D to +22 D). The morphologic characteristics predisposed to sight-threatening complications such as angle-closure glaucoma, chorioretinal pathology including uveal effusion, strabismus, and amblyopia. Fuchs et al. (2005) concluded that endemic high prevalence in the Faroe Islands suggested the presence of a founder effect, and that further genetic research would probably indicate pseudodominant rather than dominant transmission in these families.

Hmani-Aifa et al. (2009) studied 6 consanguineous Tunisian families segregating autosomal recessive nonsyndromic posterior microphthalmia. All affected individuals had an identical bilateral phenotype characterized by foreshortening of the eye axial length with normal corneal diameters. Findings in most patients included high hyperopia and an elevated papillomacular retinal fold; other changes included reduction of the capillary-free zone, crowded optic disc, macular pigment migration, and 2 cases of uveal effusion. Two patients developed age-related cataracts. Funduscopy and fluorescein angiography excluded other optic anomalies, and no systemic symptoms were observed in any of the affected individuals. There was no significant inter- or intrafamilial phenotypic variation.

Gal et al. (2011) studied a large consanguineous Tunisian family in which 5 of 11 children were affected. Features included nanophthalmos (see 600165) with microcornea, shallow anterior chamber and angle, extreme hyperopia, short axial length, high lens/eye volume ratio, thick sclera and choroid, and absence of overt structural defects. Fundus abnormality was seen in 5 eyes, involving a papillomacular fold in 3 eyes, choroidal neovascular membrane in 1 eye, and a central venous occlusion secondary to angle-closure glaucoma in 1 eye. The authors noted that the phenotype of the Tunisian families reported by Hmani-Aifa et al. (2009) differed from the phenotype in this family with respect to normal corneal diameters and steepness in the former. In addition, Gal et al. (2011) studied 4 Faroese patients from 2 large pedigrees, 1 originally reported by Fledelius and Rosenberg (1987) and 1 previously studied by Fuchs et al. (2005), and 23 sporadic Faroese patients, all of whom had a phenotype that was very similar to that of their Tunisian family except for having corneal diameters that were in the lower range of normal. Gal et al. (2011) suggested that a distinction between posterior microphthalmos and nanophthalmos might be artificial, and that the 2 conditions might represent a continuum of phenotypes.

Nair et al. (2011) restudied the 6 Tunisian families originally reported by Hmani-Aifa et al. (2009), including 25 patients with posterior microphthalmia and 88 unaffected relatives. They observed that 4 affected individuals from 2 of the families (PM2 and PM3) had elevated intraocular pressure, with levels ranging from 26 mmHg to 30 mmHg. In addition, 2 affected individuals from another family (PM1) displayed optic nerve excavation.

Orr et al. (2011) ascertained 3 families, 2 from Maritime Canada and 1 from Mexico, segregating an autosomal recessive ocular phenotype of nonsyndromic nanophthalmos. In the first Canadian family, the 4 affected sibs had very small eyes that ranged from approximately 15 to 16 mm in axial length, with correspondingly severe hyperopia. Anterior chambers appeared shallow in all sibs, with angles rated as 'narrow, but not occludable.' The crystalline lenses were large, displacing the iris anteriorly, but there were no instances of angle-closure glaucoma, and intraocular pressures remained normal. Three sibs underwent dilated examinations, which showed small and congested optic nerves without a discernible cup and grossly normal maculae, although no foveal reflex was seen. Further evaluation in 1 sib showed normal color vision and thinning of the central cornea. Electrodiagnostics performed in that sib showed normal visual evoked potentials with nonspecific reduction in the amplitude of electroretinography (ERG) potentials. Ultrasound showed diffuse thickening of the choroid in all 4 quadrants. Optical coherence tomography (OCT) revealed a grossly normal macula that lacked a foveal depression. In the second Canadian family, an affected sister and brother had longer axial lengths than those in the first family (17 mm), and less severe hyperopia. Both had glaucoma. The brother showed thinning of the central cornea; his optic nerves were small and congested, but the posterior pole was morphologically normal. There were 3 affected sibs in the Mexican family. The proband presented with features of chronic angle closure, retinal vascular tortuosity, asteroid hyalosis, small optic nerve, absence of macular reflex, and choroidal thickening. Another sib had a shallow anterior chamber but declined further examination. No obvious phenotypic carrier state was observed in any of the relatives in the 3 families.

Nowilaty et al. (2013) examined the eyes of 25 patients from 13 families diagnosed with posterior microphthalmia, including 7 families previously studied by Aldahmesh et al. (2011). All affected individuals had high hyperopia of 8 diopters or more, normal-appearing anterior segment, anterior chamber of normal dimensions, normal corneal thickness, posterior chamber foreshortening, and characteristic papillomacular folds/wrinkles. None of the patients had glaucoma, night blindness, clinical signs of retinal degeneration, developmental ocular malformations, or syndromic disease. Nowilaty et al. (2013) also observed corneal steepening proportional to the degree of axial foreshortening. The authors 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 6 consanguineous Tunisian families segregating autosomal recessive nonsyndromic posterior microphthalmia (MCOP6), Hmani-Aifa et al. (2009) performed sequencing and haplotype analysis to exclude known genes and loci for posterior microphthalmos and other developmental eye defects, including the MFRP (606227) and SOX2 (184429) genes and the MCOP1 (251600) and NNO1 (600165) loci. A genomewide scan in a subfamily from 1 extended pedigree revealed 8 homozygous candidate regions; haplotype analysis confirmed linkage to chromosome 2q37.1, with a maximum lod score of 8.85 for D2S2344 (theta = 0.00). Genotyping of parents and all available family members revealed that 4 more families were linked to this region, and an ancient recombination event in 1 family defined a 2.35-Mb critical interval. A shared haplotype suggested the presence of a founder mutation responsible for the posterior microphthalmia phenotype in the families under study; 5 candidate genes were screened but no disease-causing mutation was found.

Gal et al. (2011) genotyped all available members of 2 large Faroese families with autosomal recessive posterior microphthalmia for 9 markers on chromosome 2q37.1, in an approximately 25-cM region between D2S427 and D2S395. Close linkage without recombination was observed between MCOP6 and D2S2344, with a maximum lod score of 4.79 (theta = 0.0). Analysis of multiple informative meioses in the 2 Faroese families assigned MCOP6 to an approximate 1.5-Mb region between D2S2193 and D2S206.

Nair et al. (2011) restudied the 6 Tunisian families with posterior microphthalmia originally reported by Hmani-Aifa et al. (2009) and further refined the linkage interval to a 0.93-Mb critical region on chromosome 2q37.

Aldahmesh et al. (2011) studied 6 consanguineous unrelated Saudi families with posterior microphthalmia. Twenty affected individuals had eyes with 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. Linkage to MFRP was excluded in all 6 consanguineous families; however, a single run of homozygosity on chromosome 2q37 was shared among 5 of the 6 families, for which a lod score of 5.73 was obtained. The 17.2-Mb locus was flanked by SNPs rs6716235 and rs13009438. No pathogenic sequence variants were identified in any of the 8 genes contained in this interval.

In a family from the Maritime provinces of Canada segregating autosomal recessive nonsyndromic nanophthalmos, Orr et al. (2011) performed a whole-genome scan using microsatellite markers; homozygosity mapping suggested linkage to chromosome 2q. Whole-genome genotyping with SNP markers in this family and a second affected family from Maritime Canada identified the same region at 2q37, yielding a combined multipoint heterogeneity lod score of 4.7.

Molecular Genetics

In a large consanguineous Tunisian family segregating autosomal recessive posterior microphthalmos, Gal et al. (2011) analyzed the candidate gene PRSS56 and identified a homozygous 1-bp duplication that segregated with the disease (613858.0001). Analysis of PRSS56 in 27 Faroese patients from 25 families revealed that all but 1 patient were homozygous or compound heterozygous for 2 mutations, W309S (613858.0002) and R176G (613858.0003), respectively. None of the mutations was found in 100 German controls, but 3 of 94 Faroese controls were heterozygous for W309S, corresponding to a heterozygote frequency of 3.2%. Genealogic studies identified a married couple from the 1600s as ancestors of the parents of all affected Faroese individuals carrying W309S in homozygous or heterozygous state. No PRSS56 mutation was detected in 1 patient from the Faroe Islands or in 1 patient from Turkey, suggesting genetic heterogeneity for posterior microphthalmia.

In 6 Tunisian families with posterior microphthalmia mapping to chromosome 2q37, originally reported by Hmani-Aifa et al. (2009), Nair et al. (2011) screened 18 candidate genes and identified homozygosity for a 1-bp insertion in the PRSS56 gene (1066insC; 613858.0001) in 5 of the 6 families. In the sixth family (PM6), they identified homozygosity for a missense mutation in PRSS56 (P599A; 613858.0004). Neither mutation was found in population-matched controls.

In affected members of 2 unrelated families from Maritime Canada segregating autosomal recessive nanophthalmos mapping to chromosome 2q37, who were negative for mutations in the MFRP (606227) and BEST1 (607854) genes, Orr et al. (2011) identified homozygosity for a missense mutation in the PRSS56 gene (G320R; 613858.0005) and compound heterozygosity for a missense (V302F; 613858.0006) and a frameshift (c.833insG; 613858.0007) mutation in PRSS56, respectively. Affected sibs from a Mexican family with nanophthalmos were found to be compound heterozygous for missense mutations in PRSS56 (G237R, 613858.0008; C395R, 613858.0009). The mutations segregated with disease in the 2 Canadian families; family members were unavailable for study in the Mexican family. Orr et al. (2011) analyzed the PRSS56 and MFRP genes in a second Mexican family with nanophthalmos but did not find any mutations, suggesting the possibility of additional genetic heterogeneity.

In affected individuals from 5 Saudi Arabian families with posterior microphthalmia, including 3 families previously mapped to chromosome 2q37 by Aldahmesh et al. (2011), Nowilaty et al. (2013) identified homozygosity for the 1066insC mutation in the PRSS56 gene. In patients from 3 more Saudi families, they identified homozygosity for missense mutations in PRSS56 (see, e.g., 613858.0010). Another Saudi family was homozygous for a frameshift mutation in the MFRP gene, whereas in 3 families with posterior microphthalmia, no pathogenic variants were found in either PRSS56 or MFRP. The authors observed that truncating mutations were associated with a more severe phenotype (greater axial foreshortening) than nontruncating mutations. Noting that recessive mutations in MFRP and PRSS56 cause posterior microphthalmia or nanophthalmos, Nowilaty et al. (2013) suggested that these phenotypes represent a spectrum of hyperopia rather than 2 distinct conditions.