ORPHA: 88632; DO: 0080611;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p22.2 | Anterior segment dysgenesis 6, multiple subtypes | 617315 | Autosomal recessive | 3 | CYP1B1 | 601771 |
A number sign (#) is used with this entry because of evidence that anterior segment dysgenesis-6 (ASGD6) is caused by homozygous or compound heterozygous mutation in the CYP1B1 gene (601771) gene on chromosome 2p22.
Anterior segment dysgeneses (ASGD or ASMD) are a heterogeneous group of developmental disorders affecting the anterior segment of the eye, including the cornea, iris, lens, trabecular meshwork, and Schlemm canal. The clinical features of ASGD include iris hypoplasia, an enlarged or reduced corneal diameter, corneal vascularization and opacity, posterior embryotoxon, corectopia, polycoria, an abnormal iridocorneal angle, ectopia lentis, and anterior synechiae between the iris and posterior corneal surface (summary by Cheong et al., 2016).
Anterior segment dysgenesis is sometimes divided into subtypes including aniridia (see 106210), Axenfeld and Rieger anomalies, iridogoniodysgenesis, Peters anomaly, and posterior embryotoxon (Gould and John, 2002).
Patients with ASGD6 have been reported with the Peters anomaly subtype.
Peters anomaly consists of corneal opacity, defects in the posterior structures of the cornea, and iridocorneal and/or keratolenticular adhesions. Over 50% of patients develop glaucoma in childhood (summary by Vincent et al., 2001).
Vincent et al. (2001) reported a 6-year-old boy of Native American (Mohawk)/French Canadian background with Peters anomaly and glaucoma. The patient presented with a history of bilateral cloudy corneas and tearing since birth. Examination at 3 weeks of age showed bilateral corneal edema with central corneal opacities, superficial pannus (corneal vascularization), and iridocorneal adhesions with a well-formed anterior chamber. The child was otherwise well, with no other malformations and no significant family history. The patient had a left corneal transplant for visual rehabilitation. Microscopic examination of the left corneal button showed that the corneal epithelium was of normal thickness, although there was some edema of the basal cells. Bowman membrane was not recognizable, and the anterior stroma was hypercellular with a disordered lamellar pattern. The posterior stroma was absent centrally, and there was a basophilic granular deposit containing a small amount of extracellular melanin. Descemet membrane was not identified; however, transmission electron microscopy showed a recognizable but abnormal Bowman membrane, which contained scattered keratocytes. A small segment of Descemet was observed, but it was thin with a poorly defined banding pattern.
Edward et al. (2004) studied 11 patients from 10 Saudi Arabian families with Peters anomaly, including 3 members of 2 previously reported pedigrees (KKECG-122, Bejjani et al., 1998; KKECG-106, Bejjani et al., 2000) that were described as having primary congenital glaucoma (PCG; see GLC3A, 231300) only. All patients presented in the immediate postnatal period with unilateral (3 patients) or bilateral (8 patients) malformations. The diagnosis of Peters anomaly was made from clinical examinations under sedation or anesthesia, based on the presence of signs such as central corneal opacities, with or without central corneal thinning, that were associated with a surrounding cornea that was less hazy. Anterior iris adhesions were observed clinically or detected by anterior segment ultrasound. Anterior chamber depth was variable, depending on the position of the crystalline lens within the eye. Intraocular pressure (IOP), reported in 10 of the patients, was elevated in 5. Pathologic examination of corneal tissue obtained upon penetrating keratoplasty, performed in 7 patients, showed a spectrum of findings consistent with Peters anomaly, including absence or fragmentation of the Bowman layer, absence of large segments of the central Descemet membrane, and iris or lenticular adhesions. At the periphery of the specimens, the Descemet membrane showed thinning and loss of endothelial cells. The visual outcomes of most eyes were poor, ranging from no light perception to light perception or hand motion in most eyes.
Oliva-Bienzobas et al. (2017) reported a 2-week-old Mexican boy, born of consanguineous parents from the state of Oaxaca, who had bilateral corneal opacification noted at birth. Examination showed diffuse corneal edema and bilaterally elevated IOP, and visual acuity was light perception only. Evaluation under anesthesia revealed 360-degree peripheral vascularization of the cornea, with a central avascular bulge. Ultrasound biomicroscopy of the anterior segment showed increased corneal thickness of more than 3 mm bilaterally, with no visible Descemet membrane. The anterior chamber was shallow with an open trabecular angle bilaterally, and the iris was straightened, with stromal thinning. There was moderate excavation of the optic nerve on B-scan ultrasound. Histopathologic examination of the corneal button removed at penetrating keratoplasty revealed loss of the Bowman membrane in the central cornea, fibrosis of the stroma, absence of endothelial cells, and loss of the Descemet membrane centrally. The authors stated that the phenotype was consistent with internal corneal ulcer of von Hippel, characterized by glaucoma due to elevated IOP and by diffuse corneal opacification due to stromal edema as a consequence of the absence of both Descemet membrane and the endothelial layer.
In a Native American (Mohawk)/French Canadian male with Peters anomaly and secondary congenital glaucoma, Vincent et al. (2001) identified compound heterozygosity for mutations in the CYP1B1 gene (601771.0009-601771.0010).
In 11 patients with Peters anomaly from 10 consanguineous Saudi Arabian families, Edward et al. (2004) analyzed 5 ASGD-associated genes, and identified homozygosity for mutations in the CYP1B1 gene in 6 patients from 5 families. Five of those patients, including a brother (PE-10) and sister (PE-11) from a previously reported PCG pedigree (KKECG-122; Bejjani et al., 1998), were homozygous for the G61E variant (601771.0003) that had been previously reported in PCG patients. The remaining patient (PE-09), who was homozygous for a 10-bp deletion in CYP1B1 (601771.0020), belonged to another previously reported PCG pedigree (KKECG-106; Bejjani et al., 2000), and he had a sister with PCG who was also homozygous for the deletion. Noting that homozygosity for CYP1B1 mutations had been detected in individuals within families who were clinically unaffected, had classic PCG, or had Peters anomaly, Edward et al. (2004) suggested the existence of modifiers of the ocular phenotype that could either mitigate or worsen the deleterious effects of CYP1B1 mutations.
In a 2-week-old Mexican boy with an ASGD phenotype of internal corneal ulcer of von Hippel, Oliva-Bienzobas et al. (2017) identified homozygosity for a 1-bp deletion in the CYP1B1 gene (601771.0021). The deletion was present in heterozygosity in his consanguineous parents, and was not found in public variant databases.
Thanikachalam et al. (2020) performed exome sequencing in 24 families from south Florida with various types of anterior segment dysgenesis, and identified homozygosity for a 1-bp deletion in the CYP1B1 gene (601771.0011) in a 13-year-old Hispanic boy (14-II:1) with bilateral Peters anomaly. The authors noted that the same mutation had previously been identified in patients with primary congenital glaucoma by Belmouden et al. (2002).
Bejjani, B. A., Lewis, R. A., Tomey, K. F., Anderson, K. L., Dueker, D. K., Jabak, M., Astle, W. F., Otterud, B., Leppert, M., Lupski, J. R. Mutations in CYP1B1, the gene for cytochrome P4501B1, are the predominant cause of primary congenital glaucoma in Saudi Arabia. Am. J. Hum. Genet. 62: 325-333, 1998. [PubMed: 9463332] [Full Text: https://doi.org/10.1086/301725]
Bejjani, B. A., Stockton, D. W., Lewis, R. A., Tomey, K. F., Dueker, D. K., Jabak, M., Astle, W. F., Lupski, J. R. Multiple CYP1B1 mutations and incomplete penetrance in an inbred population segregating primary congenital glaucoma suggest frequent de novo events and a dominant modifier locus. Hum. Molec. Genet. 9: 367-374, 2000. Note: Erratum: Hum. Molec. Genet. 9: 1141 only, 2000. [PubMed: 10655546] [Full Text: https://doi.org/10.1093/hmg/9.3.367]
Belmouden, A., Melki, R., Hamdani, M., Zaghloul, K., Amraoui, A., Nadifi, S., Akhayat, O., Garchon, H.-J. A novel frameshift founder mutation in the cytochrome P450 1B1 (CYP1B1) gene is associated with primary congenital glaucoma in Morocco. Clin. Genet. 62: 334-339, 2002. [PubMed: 12372064] [Full Text: https://doi.org/10.1034/j.1399-0004.2002.620415.x]
Cheong, S.-S., Hentschel, L., Davidson, A. E., Gerrelli, D., Davie, R., Rizzo, R., Pontikos, N., Plagnol, V., Moore, A. T., Sowden, J. C., Michaelides, M., Snead, M., Tuft, S. J., Hardcastle, A. J. Mutations in CPAMD8 cause a unique form of autosomal-recessive anterior segment dysgenesis. Am. J. Hum. Genet. 99: 1338-1352, 2016. [PubMed: 27839872] [Full Text: https://doi.org/10.1016/j.ajhg.2016.09.022]
Edward, D., Al Rajhi, A., Lewis, R. A., Curry, S., Wang, Z., Bejjani, B. Molecular basis of Peters anomaly in Saudi Arabia. Ophthal. Genet. 25: 257-270, 2004. [PubMed: 15621878] [Full Text: https://doi.org/10.1080/13816810490902648]
Gould, D. B., John, S. W. M. Anterior segment dysgenesis and the development glaucomas are complex traits. Hum. Molec. Genet. 11: 1185-1193, 2002. [PubMed: 12015278] [Full Text: https://doi.org/10.1093/hmg/11.10.1185]
Oliva-Bienzobas, V., Navas, A., Astiazaran, M. C., Chacon-Camacho, O. F., Bermudez-Magner, J. A., Takane, M., Graue-Hernandez, E., Zenteno, J. C. CYP1B1 cytopathy: uncommon phenotype of a homozygous CYP1B1 deletion as internal corneal ulcer of Von Hippel. Cornea 36: 1256-1259, 2017. [PubMed: 28644236] [Full Text: https://doi.org/10.1097/ICO.0000000000001263]
Thanikachalam, S., Hodapp, E., Chang, T. C., Swols, D. M., Cengiz, F. B., Guo, S., Zafeer, M. F., Seyhan, S., Bademci, G., Scott, W. K., Grajewski, A., Tekin, M. Spectrum of genetic variants associated with anterior segment dysgenesis in south Florida. Genes (Basel) 11: 350, 2020. [PubMed: 32224865] [Full Text: https://doi.org/10.3390/genes11040350]
Vincent, A., Billingsley, G., Priston, M., Williams-Lyn, D., Sutherland, J., Glaser, T., Oliver, E., Walter, M. A., Heathcote, G., Levin, A., Heon, E. Phenotypic heterogeneity of CYP1B1: mutations in a patient with Peters' anomaly. J. Med. Genet. 38: 324-326, 2001. [PubMed: 11403040] [Full Text: https://doi.org/10.1136/jmg.38.5.324]