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Mutations in the transcription factor gene PAX6 interfere with DNA information transfer to mRNA causing developmental defects.
Mutations in the transcription factor gene PAX6 interfere with DNA information transfer to mRNA causing developmental defects.

Foveal Hypoplasia

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 Str√∏mme 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 is not well defined.  Homozygous mutations in SLC38A8 have been found to cosegregate with 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).

 

Treatment Options

Cataract surgery is indicated when lens opacities become visually significant. 

References

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. doi: 10.1016/j.ajhg.2013.11.002. Epub 2013 Nov 27. PubMed PMID: 24290379;

PubMed ID: 
24290379

Perez Y, Gradstein L, Flusser H, Markus B, Cohen I, Langer Y, Marcus M, Lifshitz T, Kadir R, Birk OS. Isolated foveal hypoplasia with secondary nystagmus and low vision is associated with a homozygous SLC38A8 mutation. Eur J Hum Genet. 2013 Sep 18.  [Epub ahead of print].

PubMed ID: 
24045842

Thomas S, Thomas MG, Andrews C, Chan WM, Proudlock FA, McLean RJ, Pradeep A, Engle EC, Gottlob I. Autosomal-dominant nystagmus, foveal hypoplasia and presenile cataract associated with a novel PAX6 mutation. Eur J Hum Genet. 2013 Aug 14. [Epub ahead of print].

PubMed ID: 
23942204

Saffra N, Agarwal S, Chiang JP, Masini R, Bertolucci A. Spectral-domain optical coherence tomographic characteristics of autosomal recessive isolated foveal hypoplasia. Arch Ophthalmol. 2012 Oct 1;130(10):1324-7.  PubMed PMID: 23044950.

PubMed ID: 
23044950

Recchia FM, Carvalho-Recchia CA, Trese MT. Optical coherence tomography in the diagnosis of foveal hypoplasia. Arch Ophthalmol. 2002 Nov;120(11):1587-8.

PubMed ID: 
12427081

Azuma N, Nishina S, Yanagisawa H, Okuyama T, Yamada M. PAX6 missense mutation in isolated foveal hypoplasia. Nat Genet. 1996 Jun;13(2):141-2.

PubMed ID: 
8640214

O'Donnell FE Jr, Pappas HR. Autosomal dominant foveal hypoplasia and presenile cataracts. A new syndrome. Arch Ophthalmol. 1982 Feb;100(2):279-81.

PubMed ID: 
7065945