LETTER TO JMG A new phenotype of recessively inherited foveal hypoplasia and anterior segment dysgenesis maps to a locus on chromosome 16q23.2–24.2

T he phrase anterior segment dysgenesis (ASD), also sometimes known as anterior segment ocular or mesenchymal dysgenesis (ASOD or ASMD, OMIM #107250), was first used in 1981 by Hittner and colleagues to describe a range of developmental defects in structures at the front of the eye. These defects are thought to result from abnormal migration or differentiation of the neural crest derived mesenchymal cells that give rise to the cornea, iris, and other components of the anterior chamber during eye development. 3 Conditions falling within the ASD spectrum include aniridia, posterior embryotoxon, Axenfeld’s anomaly, Reiger’s anomaly/syndrome, Peters’ anomaly, and iridogoniodysgenesis. Aniridia (OMIM #106210) ranges from almost complete absence of the iris, through enlargement and irregularity of the pupil mimicking a coloboma, to small slit-like defects in the anterior layer visible only with a slit lamp. In Axenfeld’s anomaly (OMIM #109120), the Schwalbe’s line is prominent and centrally displaced (posterior embryotoxon) with peripheral iris strands fused to it. Eye signs in Rieger’s anomaly (OMIM #109120) patients may include malformations of the anterior chamber angle and aqueous drainage structures (iridogoniodysgenesis), microcornea, iris hypoplasia, eccentric pupil (corectopia), iris tears (polycoria), and iridocorneal tissue adhesions traversing the anterior chamber angle. 5 In Reiger’s syndrome (OMIM #180500), patients have ASD in association with underdeveloped or misshapen teeth (hypodontia) and may also have hearing loss, heart defects and skeletal abnormalities. Peters’ anomaly (OMIM #604229) consists of a central corneal leucoma, absence of the posterior corneal stroma and Descemet membrane, and varying degrees of iris and lenticular attachment to the posterior cornea. All of these conditions carry with them an increased risk of glaucoma owing to abnormalities in the Schlemm’s canal and trabecular meshwork. Human ASD phenotypes are genetically heterogeneous, resulting from mutations in seven different transcription factor genes (PAX6, PITX2, PITX3, FOXC1, FOXE3, LXM1B, and MAF) a cytochrome enzyme gene (CYP1B1), and the human homologue of the Drosophila ‘‘eyes absent’’ gene (EYA1), 7 the exact function of which is not yet known. Mutations in two further genes, Bmp4 and Rxr-alpha, cause ASD in mice, and linkage studies in families have implicated further, as yet unidentified, genes in human ASD. However, genetic analysis has also shown that the same mutation in different patients can cause different forms of ASD, suggesting that the different clinical categories of ASD represent a spectrum of severity in what is essentially the same underlying condition. Furthermore, specific phenotypes are not the result of mutations in only a single gene. Peters’ anomaly can result from a mutation in any one of four different genes, PAX6, PITX2, CYP1B1, or FOXC1, and each of these have also been implicated in other ASD phenotypes. One consistent finding is that, as a cause of human inherited eye disease, these conditions are almost always inherited in a dominant fashion. The only clear exception is mutations in the CYP1B1 gene, which lead to Peters’ anomaly and primary congenital glaucoma. In mice, homozygosity for mutations in these genes generally results in more severe phenotypes such as anophthalmia or microphthalmia, suggesting an additive rather than a truly dominant effect. By contrast, foveal hypoplasia is a less well documented condition affecting the retina. It is characterised by an absent or abnormal foveomacular reflex, unclear definition of the foveomacular area, and presence of capillaries running abnormally close to the macula. Patients have decreased visual acuity and congenital nystagmus. When associated with other eye conditions such as albinism, incontinentia pigmenti, trisomy 8 mosaic syndrome, or Goldenhar-Gorlin syndrome, foveal hypoplasia is a recognised cause of poor vision in early childhood. It has also been documented in patients with mutations in PAX6, both in isolation, and in