foveal dysplasia

Foveal Hypoplasia 1

Clinical Characteristics
Ocular Features: 

This is a poorly defined syndrome with features overlapping aniridia, hereditary keratitis, ocular albinism, and iris anomalies as in Peters anomaly.  However, presenile cataracts seem to be unique to this disorder.  The foveal hypoplasia may occur without other anomalies although the fundus is usually lightly pigmented.  As expected, acuity is subnormal from birth, in the range of 20/50, and dyschromatopsia may be present.  Some patients have nystagmus.  Weak iris transillumination has been reported and a small limbal pannus may be present. Lens opacities may become visually significant in the third to fourth decade of life.  OCT has shown abnormal foveal thickness with multiple inner retinal layers somewhat similar to the situation in oculocutaneous albinism (203100) and it has been suggested that 'foveal dysplasia' is a better description than 'foveal hypoplasia'. 

Systemic Features: 

No systemic disease is present. 

Genetics

This disorder is associated with mutations in the PAX6 gene (11p13) and inherited as an autosomal dominant.

The protein product of the PAX6 gene is a transcription factor that attaches to DNA and regulates the expression of other genes.  PAX6 plays a major role primarily in development of the eye and central nervous system but evidence suggests it is also active postnatally.  Hundreds of mutations have been found in disorders such as hereditary keratitis, aniridia, Peters anomaly, hypoplasia and colobomas of the optic nerve.  This database contains 8 conditions in which mutations in PAX6 seem to be responsible, including syndromal conditions such as Stromme and Gillespie syndromes in which there may be cognitive disabilities. 

True isolated foveal hypoplasia without lens or corneal disease does exist as well but this condition (FVH2) is not well defined.  Homozygous mutations in SLC38A8 have been found to cosegregate with this form of foveal hypoplasia among families of Jewish Indian ancestry.  Hypopigmentation is not a feature of isolated foveal hypoplasia secondary to such mutations but misrouting of optic nerve axons may be present.  Nystagmus and reduced vision but no anterior segment abnormalities were present.

With the widespread utilization of OCT measurements, we have learned that underdevelopment of the fovea can be a feature of numerous ocular disorders (more than 20 in this database).  In most conditions, the foveal dysplasia is part of a disease complex as in foveal hypoplasia with anterior segment dysgenesis (609218).

 

Pedigree: 
Autosomal dominant
Treatment
Treatment Options: 

Cataract surgery is indicated when lens opacities become visually significant. 

References
Article Title: 

Recessive Mutations in SLC38A8 Cause Foveal Hypoplasia and Optic Nerve Misrouting without Albinism

Poulter JA, Al-Araimi M, Conte I, van Genderen MM, Sheridan E, Carr IM, Parry DA, Shires M, Carrella S, Bradbury J, Khan K, Lakeman P, Sergouniotis PI, Webster AR, Moore AT, Pal B, Mohamed MD, Venkataramana A, Ramprasad V, Shetty R, Saktivel M, Kumaramanickavel G, Tan A, Mackey DA, Hewitt AW, Banfi S, Ali M, Inglehearn CF, Toomes C. Recessive Mutations in SLC38A8 Cause Foveal Hypoplasia and Optic Nerve Misrouting without Albinism. Am J Hum Genet. 2013 Dec 5;93(6):1143-50.

PubMed ID: 
24290379

Nanophthalmos 2

Clinical Characteristics
Ocular Features: 

In this condition the axial length of the globe is often only 14-16 mm (normal >20 mm) resulting in extreme hyperopia of +8-25 diopters.  Corrected vision is usually 20/40 to 20/80 but 20/200 is not uncommon.  The choroid and sclera are thickened in nanophthalmos to a greater degree than seen in common mild hyperopia.  While all ocular structures are small in microphthalmia, in nanophthalmos the lens dimensions are generally normal.  In a small globe this causes ‘crowding’ of the anterior chamber angles and angle closure glaucoma is a major risk.

Folds in the choroid and retina are common.  Choroidal effusions, retinal edema and retinal detachments are not uncommon.  The retinal pigment epithelial may have mild window defects.  Hypoplasia, cysts, yellowish discoloration, and horizontal striae of the macula have been reported.  The foveal reflex is frequently absent corresponding to the lack of a normal foveal pit as revealed by OCT.  The foveal avascular zone may be small or absent.  The disks often appear crowded.  ERGs and VEPs are usually normal.   Scleral collagen is abnormal and thickened, leading to the postulation that this interferes with suprachoroidal drainage resulting in effusion and non-rhegmatogenous retinal detachments.

Systemic Features: 

No systemic disease has been consistently associated with simple nanophthalmos. Individuals with Kenny’s syndrome, Hallerman-Streiff-Francois (234100) syndrome and oculodentodigital dysplasia syndrome (164200) with nanophthalmos have been reported.

Genetics

Nanophthalmos may result from several mutations. Most cases occur sporadically but familial cases suggesting autosomal recessive inheritance (NNO2, 609549) have been reported. The mutation is a frameshift insertion, 1143C, in the MFRP gene on chromosome 11 (11q23.3) and has been found in the homozygous configuration in several families. The protein product has a domain that may be related to the Frizzled family of transmembrane  cell-cell signaling molecules responsible for regulation of growth and differentiation. In this connection, it is of interest that this gene is highly expressed in the retinal pigment epithelium.

It seems that at least two dominant mutations can also cause nanophthalmos. One (NNO3, 611897), located on chromosome 2 (2q11-q14), has been identified in a large Chinese pedigree although the molecular mutation remains unknown. Another, NNO1, (600165), has also been mapped to chromosome 11 but at 11p.  The molecular mutations also remain unknown.

Homozygous mutations in serine protease PR2258 have also been reported in several families with nanophthalmos.

Pedigree: 
Autosomal dominant
Autosomal recessive
Treatment
Treatment Options: 

Prophylactic iridotomies should be considered.
 

References
Article Title: 

Familial nanophthalmos

Cross HE, Yoder F. Familial nanophthalmos. Am J Ophthalmol. 1976 81(3):300-6.

PubMed ID: 
1258954

The nanophthalmic macula

Serrano JC, Hodgkins PR, Taylor DS, Gole GA, Kriss A. The nanophthalmic macula. Br J Ophthalmol. 1998 Mar;82(3):276-9.

PubMed ID: 
9602624

Mutations in a novel serine protease PRSS56 in families with nanophthalmos

Orr A, Dub?(c) MP, Zenteno JC, Jiang H, Asselin G, Evans SC, Caqueret A, Lakosha H, Letourneau L, Marcadier J, Matsuoka M, Macgillivray C, Nightingale M, Papillon-Cavanagh S, Perry S, Provost S, Ludman M, Guernsey DL, Samuels ME. Mutations in a novel serine protease PRSS56 in families with nanophthalmos. Mol Vis. 2011;17:1850-61.  PubMed PMID: 21850159.

PubMed ID: 
21850159
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