Anterior Segment Developmental Anomalies (ASDA)
Introduction
The anterior segment of the eye encompasses the cornea, iris, lens, and the aqueous humor, which provides nutrients to the avascular cornea and lens. Developmental disorders of the eye related to this anatomical section of the eye are grouped under the term Anterior Segment Developmental Anomalies (ASDA) and referred to as Anterior Segment Dysgenesis (ASD). These disorders show vast phenotypic and genetic heterogeneity and thus outlined here but described in detail separately. Some symptoms overlap, such as the tendency to develop increased intraocular pressure (IOP). The ciliary body of the iris produces the aqueous humor which must be drained via the trabecular meshwork into Schlemm's canal and by the uveoscleral outflow pathway. Disruptions in this process are frequent in ASD, and thus secondary glaucoma is a common complication.[1] ASD includes Posterior embryotoxon, Axenfeld-Rieger syndrome, Peters anomaly/Peters Plus syndrome, primary congenital glaucoma, Aniridia, Congenital hereditary endothelial dystrophy, Posterior Polymorphous Corneal Dystrophy, Sclerocornea, Megalocornea, Iridocorneal Endothelial Syndrome, Iridogoniodysgenesis syndrome, Congenital Iris Ectropion Syndrome, and Posterior Keratoconus. These specific disorders are further described in separate EyeWiki articles.
Associated Syndromes
Posterior embryotoxon (PE)
Posterior embryotoxon (PE) refers to an anteriorly displaced and thickened Schwalbe’s line. As seen on slit-lamp biomicroscopy, the grey-white Schwalbe’s line is concentric with and anterior to the limbus. PE most often occurs with Axenfeld-Rieger syndrome and arterio-hepatic dysplasia (Alagille’s syndrome).[2]
Molecular and Developmental mechanisms
Alagille syndrome along with posterior embryotoxon have been associated with mutations in the JAG1 gene on locus 20p12.[3]
Inheritance
Autosomal dominant
Axenfeld-Rieger syndrome
Axenfeld-Rieger syndrome (ARS) is an autosomal dominant disorder that presents with both ocular and systemic symptoms. Symptoms are very penetrant varied; they can range from iris hypoplasia and polycoria to microdontia.[1]
Molecular and Developmental mechanisms
Axenfeld Rieger syndrome shows genetic heterogeneity and has been associated with loci on chromosomes 4,6,13, and 16.[1][4][5] Mutations in transcription factors PITX2 (chromosome 4) and FOXC1 (chromosome 6) have been associated with the ocular and hearing symptoms found in ARS.[3]
Inheritance
Autosomal dominant
Peters anomaly and Peters Plus syndrome
Peters anomaly is a congenital disease heterogeneously affecting the anterior segment, often presenting with a central corneal opacity and a defect in the endothelium and Descemet’s membrane of the cornea; the presence of a central corneal opacity is required for diagnosis but the extent of the opacity varies among patients.[1][6] Peters anomaly has been shown to have an autosomal dominant or autosomal recessive mode of inheritance, or even appear sporadically.[1][7] Peters plus syndrome is an autosomal recessive disease that is characterized by defects in the anterior chamber as well as systemic abnormalities, such as cleft lip, growth and mental delay and short stature.[1]
Molecular and Developmental mechanisms
Peters anomaly shows genetic and phenotypic heterogeneity, and is associated with mutations in PAX6, PITX2 and CYP1B1.[1] Peters plus syndrome is an autosomal recessive disease and is associated in defects in glycosylation and mutations in the B3GLCT gene.[8]
Inheritance
Peters anomaly: sporadic, autosomal dominant, or autosomal recessive; Peters Plus syndrome: autosomal recessive
Primary congenital glaucoma (PCG)
PCG is an autosomal recessive disorder defined as having elevated IOP at or within 2 years of birth. It is considered to be a part of ASD as it frequently involves malformations of the structures involved in aqueous humor outflow, such as Schlemm's canal and the trabecular meshwork.
Molecular and Developmental mechanisms
PCG shows genetic heterogeneity, but has been linked to mutations at the GLC3A locus (2p21) involving the gene CYP1B1, which produces a member of the cytochrome P450 family of enzymes.[9] Other genetic loci include GLC3B (1p36), GLC3C (14q24.3), and more recently GLC3D (14q24), involving the gene LTBP2. The gene myocilin (MYOC) has also been implicated PCG.[10][11]
Inheritance
Autosomal Recessive
Aniridia (Iris Hypoplasia)
Aniridia is an autosomal dominant disorder that involves a variety of ocular manifestations, usually without systemic symptoms, that include but are not limited to: iris hypoplasia, lens dislocation, and corneal opacity.[1] It is primarily a posterior iris defect that can lead to vision loss.[1][5]
Molecular and Developmental mechanisms
Aniridia is primarily associated with the PAX6 gene on chromosome 11.[1][3] Mutations in the genes FOXC1 and CYP1B1 (chromosomes 6 and 2 respectively) have also been linked to aniridia.[3]
Inheritance
Autosomal Dominant
Congenital hereditary endothelial dystrophy (CHED)
Congenital hereditary endothelial dystrophy (CHED) is an autosomal recessive (CHED Type 2) disease that often presents as congenital corneal edema with bilateral corneal opacifications.[12]
Molecular and Developmental mechanisms
CHED has been mapped to chromosome 20p13 and mutations in the ZEB1 gene in PPCD3 and SLC4A11 are associated with CHED Type 2.[13]
Inheritance
Autosomal recessive
Posterior Polymorphous Corneal Dystrophy (PPMD, formerly CHED Type 1)
Posterior Polymorphous Corneal Dystrophy (PPMD) is an autosomal dominant disease of the corneal endothelium and Descemet’s membrane, which can present with bilateral corneal opacities and corneal edema in severe cases.[14][15]
Molecular and Developmental mechanisms
Several loci on chromosomes 1, 8, 10 and 20 have been identified that may affect embryological development of the cornea; mutations in the PPCD1 locus on chromosome 20q11, PPCD2 locus on chromosome 1p34.3 and PPCD3 on chromosome 10p have been associated with PPMD.[13][15] These mutations result in a wide variability in clinical presentation but the disease is associated with a thickened Descemet’s membrane and epithelialization of endothelial cells of the lesion.[16]
Inheritance
Autosomal dominant
Sclerocornea
Sclerocornea is a type of congenital corneal opacification (CCO) that is defined by non-inflammatory, non-progressive ingrowth of vascularized, opaque scleral tissue extending into the peripheral cornea, causing indistinct borders between the sclera and cornea. This disorder can be seen with other ASD syndromes (i.e. Peter’s Anomaly) or as its own entity.[17]
Molecular and Developmental mechanisms
Genes that are implicated in sclerocornea have significant overlap with other forms of ASD, including lens abnormalities like congenital cataracts. Genes that have been linked to sclerocornea include FOXE3, RAX, SOX2, PITX3, PAX6, and PXDN.[17]
Inheritance
Genetic heterogeneity
Megalocornea
Megalocornea is most commonly seen as an X-linked disorder presenting with an enlarged cornea of 12.5 mm or greater.[1][18] The other ocular finding generally includes deep anterior chambers with normal intraocular pressure and normal endothelial cells.[1][18]
Molecular and Developmental mechanisms
CHRDL1 mutations have been shown to cause X-linked megalocornea. The gene has been linked to development of the corneal stroma and endothelium.[19]
Inheritance
X-linked recessive, with a few cases of autosomal recessive inheritance
Iridocorneal Endothelial (ICE) Syndrome
Iridocorneal Endothelial (ICE) syndrome is rare disorder characterized by three different subtypes: Chandler syndrome, Cogan-Reese syndrome, and progressive iris atrophy. It most commonly affects middle-aged adults, showing a slight trend towards females and commonly presents unilaterally. The disorder involves corneal abnormalities with clinical presentation relation to its three subtypes. Chandler syndrome shows corneal edema with few iris abnormalities. Cogan-Reese syndrome shows iris abnormalities along with endothelial cell dystrophy. Progressive iris atrophy shows holes in the iris.[20]
Molecular and Developmental mechanisms
No cause for ICE syndrome has been discovered, and etiology is still debated. However, it has been proposed that the cause of ICE syndrome is viral in nature, with HSV playing a role in the disorder causing proliferation of corneal endothelial cell dystrophy.[20]
Inheritance
Unknown[20]
Iridogoniodysgenesis syndrome
Iridogoniodysgenesis is a rare autosomal dominant disease associated with malformations of the iris stroma and trabecular meshwork, leading to iris hypoplasia and glaucoma.[21][22][23][23]
Molecular and Developmental mechanisms
The Iridogoniodysgenesis locus is mapped to 6p25, and is thought to be associated with a malfunction in the migration or induction of neural crest cells involved in the formation of the anterior segment.[22] Mutations in the RIEG gene at locus 4q25 have also been found to be associated with Iridogoniodysgenesis syndrome.[23]
Inheritance
Autosomal dominant
Congenital Iris Ectropion Syndrome
Congenital iris ectropion (CIE) is a rare neural crest disorder that commonly presents with developmental glaucoma. It is characterized by posterior iris epithelium presenting on the anterior side of the stroma.[24] The condition is autosomal recessive and most commonly presents in males.[25]
Molecular and Developmental mechanisms
Congenital iris ectropion has been linked to mutation of the PAX-6 gene found on chromosome 11.[26] CIE is characterized by neural crest abnormalities and has been shown to be associated with neurofibromatosis, primary facial hemihypertrophy, Rieger anomaly and Prader-Willi syndrome.[24]
Inheritance
Autosomal recessive
Posterior Keratoconus
Posterior keratoconus is developmental abnormality characterized by outward curvature of the posterior cornea (ectasia).[27] It is thought to be caused by delayed separation of the lens from the ectodermal layers forming the cornea.[28][29] Associations of posterior keratoconus with anterior iridal adhesions, and pigment deposition on the posterior corneal surface have been described in the literature. Overlying stromal opacifications can affect vision depending on severity and location.[27]
Molecular and Developmental mechanisms
No specific genetic mechanisms, including chromosomal abnormalities, have been discovered.[27][28]
Inheritance
Unknown
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 Ito YA, Walter MA. Genomics and anterior segment dysgenesis: a review. Clin Experiment Ophthalmol. 2014;42(1):13-24.doi:10.1111/ceo.12152
- ↑ Rennie CA, Chowdhury S, Khan J, et al. The prevalence and associated features of posterior embryotoxon in the general ophthalmic clinic. Eye. 2005;19(4):396-399. doi:10.1038/sj.eye.6701508
- ↑ 3.0 3.1 3.2 3.3 Reis LM, Semina E V. Genetics of anterior segment dysgenesis disorders. Curr Opin Ophthalmol. 2011;22(5):314-324. doi:10.1097/ICU.0b013e328349412b
- ↑ Phillips JC, del Bono EA, Haines JL, et al. A second locus for Rieger syndrome maps to chromosome 13q14. Am J Hum Genet. 1996;59(3):613-619. http://www.ncbi.nlm.nih.gov/pubmed/8751862. Accessed June 8, 2019.
- ↑ 5.0 5.1 Idrees F, Vaideanu D, Fraser SG, Sowden JC, Khaw PT. A Review of Anterior Segment Dysgeneses. Surv Ophthalmol. 2006;51(3):213-231. doi:10.1016/j.survophthal.2006.02.006
- ↑ Hanson IM, Fletcher JM, Jordan T, et al. Mutations at the PAX6 locus are found in heterogeneous anterior segment malformations including Peters’ anomaly. Nat Genet. 1994;6(2):168-173. doi:10.1038/ng0294-168
- ↑ Bhandari R, Ferri S, Whittaker B, Liu M, Lazzaro DR. Peters Anomaly: Review of the Literature. Cornea. 2011;30(8):939-944. doi:10.1097/ICO.0b013e31820156a9
- ↑ Lesnik Oberstein SA, Ruivenkamp C AL, Hennekam RC. Peters Plus Syndrome. University of Washington, Seattle; 1993. http://www.ncbi.nlm.nih.gov/pubmed/20301637. Accessed June 9, 2019.
- ↑ Chouiter L, Nadifi S. Analysis of CYP1B1 Gene Mutations in Patients with Primary Congenital Glaucoma. J Pediatr Genet. 2017;06(04):205-214. doi:10.1055/s-0037-1602695
- ↑ Lim S-H, Tran-Viet K-N, Yanovitch TL, et al. CYP1B1, MYOC, and LTBP2 mutations in primary congenital glaucoma patients in the United States. Am J Ophthalmol. 2013;155(3):508-517.e5. doi:10.1016/j.ajo.2012.09.012
- ↑ Faiq M, Sharma R, Dada R, Mohanty K, Saluja D, Dada T. Genetic, Biochemical and Clinical Insights into Primary Congenital Glaucoma. Dada T, Sherwood M, Singh K, Shaarawy T, eds. J Curr Glaucoma Pract with DVD. 2013;7(2):66-84. doi:10.5005/jp-journals-10008-1140
- ↑ Nischal KK. Genetics of Congenital Corneal Opacification—Impact on Diagnosis and Treatment. Cornea. 2015;34:S24-S34. doi:10.1097/ICO.0000000000000552
- ↑ 13.0 13.1 Aldave AJ, Han J, Frausto RF. Genetics of the corneal endothelial dystrophies: an evidence-based review. Clin Genet. 2013;84(2):109-119. doi:10.1111/cge.12191
- ↑ Ahn YJ, Choi S Il, Yum HR, Shin SY, Park SH. Clinical Features in Children with Posterior Polymorphous Corneal Dystrophy. Optom Vis Sci. 2017;94(4):476-481. doi:10.1097/OPX.0000000000001039
- ↑ 15.0 15.1 Cibis G, Gulani AC. Posterior Polymorphous Corneal Dystrophy. StatPearls Publishing; 2019. http://www.ncbi.nlm.nih.gov/pubmed/28613630. Accessed June 5, 2019.
- ↑ Klintworth GK. Corneal dystrophies. Orphanet J Rare Dis. 2009;4(1):7. doi:10.1186/1750-1172-4-7
- ↑ 17.0 17.1 Ma AS, Grigg JR, Prokudin I, Flaherty M, Bennetts B, Jamieson RV. New mutations in GJA8 expand the phenotype to include total sclerocornea. Clin Genet. 2018;93(1):155-159. doi:10.1111/cge.13045
- ↑ 18.0 18.1 Mackey DA, Buttery RG, Wise GM, Denton MJ. Description of X-linked megalocornea with identification of the gene locus. Arch Ophthalmol (Chicago, Ill 1960). 1991;109(6):829-833. http://www.ncbi.nlm.nih.gov/pubmed/2043071. Accessed June 8, 2019.
- ↑ Webb TR, Matarin M, Gardner JC, et al. X-linked megalocornea caused by mutations in CHRDL1 identifies an essential role for ventroptin in anterior segment development. Am J Hum Genet. 2012;90(2):247-259. doi:10.1016/j.ajhg.2011.12.019
- ↑ 20.0 20.1 20.2 Sacchetti M, Mantelli F, Marenco M, Macchi I, Ambrosio O, Rama P. Diagnosis and Management of Iridocorneal Endothelial Syndrome. Biomed Res Int. 2015;2015:763093. doi:10.1155/2015/763093
- ↑ Knezević T, Novak-Laus K, Skunca J, Mandić Z. Iridogoniodysgenesis syndrome: a case report. Acta Clin Croat. 2008;47(3):161-164. http://www.ncbi.nlm.nih.gov/pubmed/19175065. Accessed June 10, 2019.
- ↑ 22.0 22.1 Mears AJ, Mirzayans F, Gould DB, Pearce WG, Walter MA. Autosomal dominant iridogoniodysgenesis anomaly maps to 6p25. Am J Hum Genet. 1996;59(6):1321. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1914875/. Accessed June 10, 2019.
- ↑ 23.0 23.1 23.2 Pearce WG, Mielke BC, Kulak SC, Walter MA. Histopathology and molecular basis of iridogoniodysgenesis syndrome. Ophthalmic Genet. 1999;20(2):83-88. http://www.ncbi.nlm.nih.gov/pubmed/10420192. Accessed June 10, 2019.
- ↑ 24.0 24.1 Grieshaber MC, Orgul S, Bruder E, Hadziselimovic F, Flammer J. Congenital Iris Ectropion and Glaucoma Associated With Intestinal Neuronal Dysplasia: A Manifestation of a Neural Crest Syndrome. Arch Ophthalmol. 2006;124(10):1495. doi:10.1001/archopht.124.10.1495
- ↑ Nischal KK. Developmental Anomalies of the Anterior Segment and Globe. In: Pediatric Ophthalmology and Strabismus. New York, NY: Springer New York; 2003:369-390. doi:10.1007/978-0-387-21753-6_24
- ↑ Kim WJ, Kim JH, Cho NC. Newly identified paired box 6 mutation of variant familial aniridia: Congenital iris ectropion with foveal hypoplasia. Indian J Ophthalmol. 2017;65(1):55-56. doi:10.4103/0301-4738.202305
- ↑ 27.0 27.1 27.2 Silas MR, Hilkert SM, Reidy JJ, Farooq A V. Posterior keratoconus. Br J Ophthalmol. 2018;102(7):863-867. doi:10.1136/bjophthalmol-2017-311097
- ↑ 28.0 28.1 Streeten BW, Karpik AG, Spitzer KH. Posterior Keratoconus Associated With Systemic Abnormalities. Arch Ophthalmol. 1983;101(4):616-622. doi:10.1001/archopht.1983.01040010616019
- ↑ Krachmer JH, Rodrigues MM. Posterior Keratoconus. Arch Ophthalmol. 1978;96(10):1867-1873. doi:10.1001/archopht.1978.03910060371016
