Foveal Hypoplasia 2
A number sign (#) is used with this entry because of evidence that foveal hypoplasia-2 with or without optic nerve misrouting and/or anterior segment dysgenesis (FVH2) is caused by homozygous or compound heterozygous mutation in the SLC38A8 gene (615585) on chromosome 16q23.
DescriptionFoveal hypoplasia is defined as the lack of foveal depression with continuity of all neurosensory retinal layers in the presumed foveal area. Foveal hypoplasia as an isolated entity is a rare phenomenon; it is usually described in association with other ocular disorders, such as aniridia (106210), microphthalmia (see 251600), albinism (see 203100), or achromatopsia (see 216900). All reported cases of foveal hypoplasia have been accompanied by decreased visual acuity and nystagmus (summary by Perez et al., 2014).
For a discussion of genetic heterogeneity of foveal hypoplasia, see FVH1 (136520).
Clinical FeaturesPal et al. (2004) described foveal hypoplasia and anterior segment dysgenesis in a large consanguineous pedigree. Five members of the pedigree presented with nystagmus and poor vision. The parents were unaffected. The combination of developmental abnormalities in both anterior and posterior eye structures suggested a defect in early ocular development and morphogenesis.
Van Genderen et al. (2006) reported 2 Afghan sisters and a Dutch girl with foveal hypoplasia and optic chiasm misrouting, but no albinism. The Dutch girl had previously been diagnosed with Kartagener syndrome (see 244400). All 3 patients exhibited nystagmus, and fundus examination showed absence of the usual foveal hyperpigmentation, foveal avascular zone, and macular and foveal reflexes, with small retinal vessels extending through the presumed macular area. The exit angles of the main temporal arteries were below the mean -2 SD of those seen in albino patients and well within the range of angles in controls. Optical coherence tomography (OCT) in the Dutch girl showed extension of all neurosensory retinal layers through the area in which the fovea would normally be located; no clivus, anticlivus, or foveal pit could be seen. Visual evoked potential (VEP) recordings yielded chiasmal coefficients significantly indicative of misrouting in all 3 patients. The affected girls were all dark haired with dark brown eyes and no iris transillumination; the Dutch girl tanned normally and the Afghan sisters had skin color similar to that of other family members. Parents and sibs in both families were unaffected.
Vincent et al. (2009) described a father and 2 daughters with foveal hypoplasia from a highly consanguineous Indian family. All 3 patients had poor vision, horizontal pendular nystagmus, and alternating esotropia, with normal color vision. Fundus examination of the 40-year-old father showed a poorly defined foveal zone in both eyes and a large typical inferior chorioretinal coloboma in the right eye; in addition, the axial length in both eyes was less than 19 mm, consistent with microphthalmia. In his 9-year-old and 6-year-old daughters, fundus examination showed bilateral absence of foveal reflex, and OCT demonstrated absence of foveal pits bilaterally; electroretinographic recordings were normal in both. The older daughter was also diagnosed with bilateral microphthalmia, with axial lengths less than 20 mm in both eyes, whereas in the younger daughter, axial lengths were 20.70 mm and 20.54 mm in the right and left eyes, respectively. The father was born of a consanguineous marriage, and was married to his unaffected niece; there was 1 unaffected daughter. The father's older sister and a paternal aunt and uncle were reported to have poor vision, esotropia, and nystagmus.
Perez et al. (2014) studied 9 patients from 3 apparently unrelated nonconsanguineous Israeli families of Jewish Indian (Mumbai region) ancestry with nystagmus and subnormal vision from infancy. Visual acuities ranged between 20/50 and 20/200; refractive errors were found in all patients and varied between moderate hypermetropia and high myopia. All patients had astigmatism, and 3 had strabismus. All had normal cutaneous and ocular pigmentation and no iris transillumination, and full-field electroretinography and flash VEP testing in 6 patients were within normal limits. Fundus examination in all patients revealed foveal hypoplasia; OCT, performed in 1 patient, showed absence of the normal foveal pit. The 3 affected sisters in 1 family also had mild developmental delay and pervasive developmental disorder-like features.
Al-Araimi et al. (2013) restudied the Pakistani family with foveal hypoplasia and anterior segment dysgenesis originally reported by Pal et al. (2004). Flash VEP in 2 affected family members showed contralateral predominance, indicating increased crossover at optic chiasm. Reexamination of the 2 Afghan sisters who were originally described by van Genderen et al. (2006) revealed posterior embryotoxon in both. Al-Araimi et al. (2013) concluded that both families had the same clinical phenotype, which they designated 'FHONDA' syndrome, representing foveal hypoplasia, optic nerve decussation defects, and anterior segment dysgenesis in the absence of albinism.
InheritanceThe transmission pattern of foveal hypoplasia and anterior segment dysgenesis in the family reported by Pal et al. (2004) was consistent with autosomal recessive inheritance.
MappingBy linkage analysis in a consanguineous family segregating foveal hypoplasia and anterior segment dysgenesis, Pal et al. (2004) identified a region on 16q23.2-q24.2 that showed highly significant cosegregation with the disease. Multipoint linkage analysis generated a lod score of 5.51 at D16S511. Recombination events defined a 22.1-cM/6.5-Mb interval between markers D16S3098 and D16S2621, which included the transcription factor FOXC2 (602402); however, sequencing of this single-exon gene in patients' DNA revealed no mutations.
In an Israeli family of Jewish Indian ancestry in which 3 sisters had isolated foveal hypoplasia, Perez et al. (2014) performed homozygosity-by-descent analysis and identified a 3.4-Mb homozygous segment on chromosome 16q23.3-q24.1, between SNPs rs4888203 and rs6419428, that was common to the affected individuals. Fine mapping and haplotype reconstruction in this family and 2 additional families of similar ancestry with isolated foveal hypoplasia narrowed the region of shared homozygosity to an 830-kb interval between chr16:83,885 (GRCh37) and D16S2625, supporting a common ancestral origin for this locus. A maximum lod score of 3.5 was obtained for the 3 pedigrees combined at chr16:84,282.
In 2 Afghan sisters with foveal hypoplasia and anterior segment defects who were originally described by van Genderen et al. (2006), Al-Araimi et al. (2013) genotyped 12 microsatellites spanning the locus on chromosome 16q23.2-q24.2 and found that the sisters shared a region of homozygosity from marker D16S402 to the end of the 16q telomere. A maximum lod score of 2.0 was obtained with the telomeric 7 markers. Whole-genome SNP analysis of DNA from 1 Afghan sister and 1 member of the Pakistani family with foveal hypoplasia and anterior segment defects originally studied by Pal et al. (2004) refined the locus to a 3.1-Mb interval at chr16:83,639,061-86,716,445 (GRCh37).
Molecular GeneticsIn an Israeli family of Jewish Indian ancestry in which 3 sisters had isolated foveal hypoplasia mapping to chromosome 16q23, Perez et al. (2014) performed whole-exome sequencing and found no mutations in any genes previously associated with foveal hypoplasia. However, within the 830-kb mapped locus, they identified a homozygous missense mutation in the SLC38A8 gene (I32S; 615585.0001) that segregated with disease in each of the families. The mutation, which was not reported in the 1000 Genomes Project, was detected in heterozygosity in 5 of 50 unrelated Jews of Mumbai ancestry.
In 2 unrelated individuals with foveal hypoplasia, optic nerve misrouting, and anterior segment dysgenesis mapping to chromosome 16q23.3-q24.1, 1 from a Pakistani family originally studied by Pal et al. (2004) and 1 from an Afghan family originally described by van Genderen et al. (2006), Poulter et al. (2013) performed Sanger sequencing of the 33 candidate genes within the 3.1-Mb locus and identified homozygosity for a missense mutation (V236D; 615585.0002) and a 1-bp deletion (615585.0003) in the SLC38A8 gene, respectively. Sequencing SLC38A8 in 12 additional probands with foveal hypoplasia with or without other eye defects revealed homozygous or compound heterozygous mutations in 5 more cases (see, e.g., 615585.0002-615585.0007), including a Dutch girl previously reported by van Genderen et al. (2006) and an Indian family reported by Vincent et al. (2009). All mutations segregated with disease in the respective families and were not found in ethnically matched controls.