From the Vanderbilt Eye Institute (PJ-A, JK, RK), Vanderbilt University; and Genetics Associates, Inc. (VGD), Nashville, Tennessee.
Supported by an unrestricted departmental grant and a career development award to Rachel Kuchtey from Research to Prevent Blindness, Inc. and National Eye Institute Grant P30-EY008126 (Core Grant in Vision Research).
Dr. Dev is employed by Genetics Associates, Inc., Nashville, Tennessee, which performs diagnostic karyotyping and comparative genomic hybridization services described in this manuscript. Ms. Jaru-Ampornpan and Drs. J. Kuchtey, and R. Kuchtey have no financial or proprietary interest in the materials presented herein.
The authors thank Dr. Guangyu Gu, Genetics Associates, for performing genetic testing, Jennifer Shaw, Vanderbilt Vision Research Center, for help in making figures, and Tracy L. McGregor, MD, Department of Pediatrics, Vanderbilt University, for helpful discussion.
Address correspondence to Rachel Kuchtey, MD, PhD, The Vanderbilt Eye Institute,Vanderbilt University, 2311 Pierce Avenue, Nashville, TN 37232.
Primary congenital glaucoma1 is characterized by elevated intraocular pressure (IOP) due to the impairment of aqueous humor outflow facility in the absence of other associated ocular abnormalities. Although the anterior chamber angle appears open clinically in primary congenital glaucoma, elevated IOP is due to dysgenesis of the trabecular mesh-work and Schlemm’s canal. Early onset of elevated IOP may result in corneal edema, buphthalmos, and eventual optic nerve damage. Diagnosis is typically made within the first 3 years of life and surgery is often needed as a first-line treatment. The prevalence of primary congenital glaucoma is approximately 1 in 10,000 in Western populations.2 Although most cases are sporadic, primary congenital glaucoma can be inherited as an autosomal recessive trait.2 Studies of families with inherited primary congenital glaucoma have identified three primary congenital glaucoma loci. However, only one causative gene, cytochrome P450 1B1 (CYP1B1), on chromosome 2 has been identified. The proportion of primary congenital glaucoma cases due to mutations in CYP1B1 varies across populations from approximately 20% for Japanese, 50% for Brazilian, and 100% for Saudi Arabian populations.3
Patau syndrome, or trisomy 13, has a prevalence of approximately between 1 in 12,000 and 1 in 29,000 births and commonly presents with severe systemic defects and developmental delay.4 Life expectancy is short: approximately 86% of patients with full trisomy 13 die within the first year of life.5 Only eight cases with trisomy 13 older than 10 years of age have been reported.5 Multiple ocular findings are associated with this syndrome, including microphthalmia, coloboma of the iris and ciliary body, retinal dysplasia, persistent hyperplastic primary vitreous, cataract, cyclopia, and primary aphakia.4,6 To date, only 8 cases of congenital glaucoma associated with trisomy 13 have been reported,7,8 some of which were secondary to other ocular defects.
We report a case of a patient with trisomy 13 and primary congenital glaucoma. The patient was the second child born to healthy, non-consanguineous parents from Honduras with unremarkable family history. Her brother and two half-siblings were also normal. The pregnancy was uncomplicated per the patient’s mother and the infant was delivered vaginally at full term without any complications. Polydactyly in all extremities, bony deformity of the left foot with eversion, scalp defect, and micrognathia were noted at birth. She also had significantly delayed development and spasticity. The infant was diagnosed as having trisomy 13 at birth by karyotyping of 20 lymphocytes.
Asymmetry of globe size was first noticed at 1 year of age by the patient’s mother. Glaucoma was diagnosed at another institution and surgery was offered, but the patient was lost to follow-up.
At 8 years of age, the patient first presented to the Vanderbilt Eye Institute with prominent asymmetry of corneal size (Fig. 1A). During the initial examination under general anesthesia, her IOP was 15 mm Hg in the right eye and 22 mm Hg in the left eye, as measured by a tonometer (Tono-Pen XL; Reichert, Inc., Depew, NY). The horizontal cornea diameter was 12.5 mm in the right eye and 14.5 mm in the left eye. Axial length was 19.23 mm in the right eye and 24.67 mm in the left eye, as determined by ultrasound A-mode scan. Gonioscopic examination revealed open angles in each eye, although prominent iris processes were noted in both eyes. The rest of the anterior segment examination was otherwise unremarkable bilaterally. Dilated fundus examination revealed a healthy optic nerve with a cup-to-disk ratio of 0.3 in the right eye and a glaucomatous optic nerve in the left eye (Figs. 1B and 1C). There was significant thinning of the neuroretinal rim and the cup-to-disk ratio was estimated to be 0.8 in the left eye (Fig. 1C). No other ocular abnormalities were identified.
Figure 1. A Patient with Trisomy 13 at 11 Years of Age, 3 Years After Successful Treatment of Primary Congenital Glaucoma by Trabeculotomy in the Left Eye. Buphthalmos and Megalocornea in the Left Eye, Similar to Initial Presentation, and Corneal Scar in the Left Eye Resulting from Corneal Ulcer Are Apparent in Photograph of Patient’s Eyes (A). Fundus Photographs Showing Normal Optic Disc in the Right Eye (B) and Glaucomatous Optic Disc in the Left Eye (C).
The patient underwent uneventful trabeculotomy in her left eye. During the 3-year postoperative period, her IOP and optic nerves remained stable without the use of antiglaucoma medications. She developed a corneal ulcer in her left eye during the follow-up period, which was treated successfully with topical antibiotics. A corneal scar developed as a sequela of the infection (Fig. 1A).
Due to such long survival for a patient with trisomy 13, karyotyping was repeated at 11 years of age (Fig. 2). Consistent with the results at birth, karyotyping of 20 lymphocytes showed full trisomy 13 (47, XX, +13). Further chromosomal analysis was performed by comparative genomic hybridization using a high-density pericentromeric microarray covering all chromosomes.9 Array-based comparative genomic hybridization can detect low-level mosaicism (> 20%) and microscopic chromosomal abnormalities that may not be detectable by conventional karyotyping.9,10 Comparative genomic hybridization confirmed full trisomy 13 and showed no evidence of other chromosomal rearrangements or mosaicism (Fig. 3A). High-density coverage of the long arm of chromosome 13 did not reveal any intrachromosomal insertions or deletions, including within 13q14, previously identified as a locus associated with Rieger syndrome11 (Fig. 3B).
Figure 2. Karyotyping of Patient’s Lymphocytes Demonstrating Extra Full Copy of Chromosome 13, with No Other Chromosomal Anomalies Apparent.
Figure 3. Microarray-Based Comparative Genomic Hybridization9 Comparing Patient to Control Dna from Lymphocytes. Overlapping Pink and Blue Lines Indicate Patient and Control Are the Same. The Deflection at Chromosome 13 Indicates a Single Copy Gain for the Patient (A). The Single-Copy Gain Extends over the Entire Long Arm of Chromosome 13, Suggesting the Patient Had Complete Trisomy 13 (B).
We also screened the CYP1B1 gene for mutations using established primers and protocols.12,13 No previously reported or novel CYP1B1 disease-causing mutations were found, although the patient is heterozygous for two common polymorphisms, 3947 C → G (R48G; exon 2) and 4160 G → T (A119S; exon 2) (GenBank Accession Number U56438).
Long-lived patients with trisomy 13 are rare because Patau syndrome occurs approximately between 1 in 12,000 and 1 in 29,000 births and most die by 1 year of age.4,5 Although it is possible that some mosaic forms may account for longer survival, 4 of the 8 patients described in the literature by Fogu et al.5 were reported to be homogeneous and full trisomy 13. Other studies suggested that long survival in Patau syndrome is not completely related to cytogenetic mosaicism but is rather strongly correlated with the severity of clinical manifestations.8,14 Patients with major neural and cardiac defects were rarely seen in long-term survivors. Our patient had relatively mild clinical manifestations of Patau syndrome without any of these features, likely explaining her long survival. Our cytogenetic and array-based comparative genomic hybridization studies showed that the patient described here has full trisomy 13, suggesting that her long survival is not attributed to trisomic mosaicism, although this remains a possibility because peripheral blood was the only tissue investigated.
Intra-chromosomal deletions of chromosome 13 have been reported in two cases of Rieger syndrome,15 an inherited anterior segment dysgenesis associated with glaucoma for approximately 50% of patients. A locus for Rieger syndrome has been mapped to chromosome 13q14 in a family with autosomal dominant Rieger syndrome with 9 of 11 affected individuals having glaucoma.11 No evidence of structural insertions or deletions within 13q14 was found in our array-based comparative genomic hybridization (Fig. 3B), although small alterations not detectable with this array are not ruled out. The patient did not exhibit disease-causing mutations in the known primary congenital glaucoma gene, CYP1B1.
Ocular abnormalities are common in patients with trisomy 13,4,6 but only 8 cases with congenital glaucoma have been reported in the literature7,8 and only 4 of these cases did not appear to be secondary to other ocular defects. The case presented here had no other clinically apparent ocular anomalies and thus appears to be a case of primary congenital glaucoma. Of the 8 reported cases of trisomy 13 with long-term (> 10 years) survival,5 all but one noted the presence of microphthalmia and coloboma and none were reported to have glaucoma. The case of trisomy 13 we have described is the first reported case of primary congenital glaucoma in a long-term survival trisomy 13 case. Despite multiple anomalies and severe developmental delay in patients with trisomy 13, long-term survival is possible, and thus maintaining vision needs to be kept in mind.
- deLuise VP, Anderson DR. Primary infantile glaucoma (congenital glaucoma). Surv Ophthalmol. 1983;28:1–19. doi:10.1016/0039-6257(83)90174-1 [CrossRef]
- Sarfarazi M, Stoilov I, Schenkman JB. Genetics and biochemistry of primary congenital glaucoma. Ophthalmol Clin North Am. 2003;16:543–554, vi. doi:10.1016/S0896-1549(03)00062-2 [CrossRef]
- Chakrabarti S, Kaur K, Kaur I, et al. Globally, CYP1B1 mutations in primary congenital glaucoma are strongly structured by geographic and haplotype backgrounds. Invest Ophthalmol Vis Sci. 2006;47:43–47. doi:10.1167/iovs.05-0912 [CrossRef]
- Keith CG. The ocular manifestations of trisomy 13–15. Trans Ophthalmol Soc U K. 1966;86:435–454.
- Fogu G, Maserati E, Cambosu F, et al. Patau syndrome with long survival in a case of unusual mosaic trisomy 13. Eur J Med Genet. 2008;51:303–314. doi:10.1016/j.ejmg.2008.03.004 [CrossRef]
- Hoepner J, Yanoff M. Ocular anomalies in trisomy 13–15: an analysis of 13 eyes with two new findings. Am J Ophthalmol. 1972;74:729–737.
- Bunting R, Leitch J. Buphthalmos in trisomy 13. Eye (Lond). 2005;19:487–488.
- Hsu HF, Hou JW. Variable expressivity in Patau syndrome is not all related to trisomy 13 mosaicism. Am J Med Genet A. 2007;143A:1739–1748. doi:10.1002/ajmg.a.31835 [CrossRef]
- Ballif BC, Hornor SA, Sulpizio SG, et al. Development of a high-density pericentromeric region BAC clone set for the detection and characterization of small supernumerary marker chromosomes by array CGH. Genet Med. 2007;9:150–162. doi:10.1097/GIM.0b013e3180312087 [CrossRef]
- Ballif BC, Rorem EA, Sundin K, et al. Detection of low-level mosaicism by array CGH in routine diagnostic specimens. Am J Med Genet A. 2006;140:2757–2767.
- Phillips JC, del Bono EA, Haines JL, et al. A second locus for Rieger syndrome maps to chromosome 13q14. Am J Hum Genet. 1996;59:613–619.
- Melki R, Colomb E, Lefort N, Brézin AP, Garchon HJ. CYP1B1 mutations in French patients with early-onset primary open-angle glaucoma. J Med Genet. 2004;41:647–651. doi:10.1136/jmg.2004.020024 [CrossRef]
- Panicker SG, Reddy AB, Mandal AK, et al. Identification of novel mutations causing familial primary congenital glaucoma in Indian pedigrees. Invest Ophthalmol Vis Sci. 2002;43:1358–1366.
- Iliopoulos D, Sekerli E, Vassiliou G, et al. Patau syndrome with a long survival (146 months): a clinical report and review of literature. Am J Med Genet A. 2006;140:92–93.
- Stathacopoulos RA, Bateman JB, Sparkes RS, Hepler RS. The Rieger syndrome and a chromosome 13 deletion. J Pediatr Ophthalmol Strabismus. 1987;24:198–203.