Trisomy 13

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Disease Entity

Trisomy 13, also known as Patau Syndrome, is a disorder of fetal development with wide-ranging and often severe developmental manifestations. The disorder was first described by Patau, et al., in 1960[1]. Ocular malformations are commonly observed in patients with Trisomy 13.

Etiology

Trisomy 13 is an aneuploidy (lacks 46 chromosomes) in which three copies of chromosome 13—instead of the typical two—are present. Complete, mosaic, and partial forms of trisomy 13 exist. A complete trisomy occurs when a chromosomal nondisjunction happens during meiosis, a process that occurs in sex cells before fertilization. In such cases, all cells in an organism fertilized by the aneuploid sex cell will harbor an aneuploid genome. Complete trisomy 13 is the most common form of the disorder[2][3]. The vast majority of trisomy 13 cases are due to nondisjunction in the female gamete[4][5].

Mosaic trisomy 13 occurs when some cells contain euploid genomes and others contain aneuploid genomes. Phenotypes of such cases is generally less severe. Mosaicism occurs due to nondisjunction during mitosis, the process of cell division during development[6]. Only cells derived from the errant cell will harbor extra copies of the chromosome. Partial trisomy 13 occurs when cells contain two full copies plus an additional portion of chromosome 13. Phenotypes of partial trisomy 13 are also less severe than the complete form[7].

Pathophysiology

Phenotypes that arise from aneuploidy are thought to occur due to abnormal levels of gene expression involving genes of the duplicated chromosome[3][6]. The following fetal developmental processes are thought to be disrupted during eye development in trisomy 13[8]:

  • Organogenesis (third-fourth weeks): optic pit changes into the optic vesicle
    • Potential abnormality in trisomy 13: anophthalmia
  • End of fourth week: lens pit and vesicle appear, optic vesicle invaginates to form optic cup
    • Potential abnormalities in trisomy 13: aphakia, congenital cystic eye, disturbed retinal lamination
  • Sixth week: fetal fissures close; lens separates from surface and primary fibers form, retinal differentiation begins, tunica vasculosa begins
    • Potential abnormalities in trisomy 13: coloboma, microphthalmia with orbital cysts, nuclear cataract
  • Seventh-ninth weeks: secondary lens fibers form, secondary vitreous forms, neural crest cells grow into the anterior segment
    • Potential abnormalities in trisomy 13: nuclear cataract, anomalies of the retina and/or vitreous, anterior segment dysgenesis
  • Tenth-twelfth weeks: secondary lens fibers progress, development of ectodermal layers of iris and ciliary body begins
    • Potential abnormalities in trisomy 13: zonular cataract, malformations of anterior segment

Epidemiology

The prevalence of Trisomy 13 is between 1 in 5,000 and 1 in 29,000 live births and is the third most common autosomal trisomy in newborns after trisomy 21 and trisomy 18[9][10]. Estimated prevalence of trisomy 13 is 1:5,300 in Europe[11] and 1:14,000 in the United States[12]. The clearest risk factor for fetal aneuploidy is advanced maternal age, as the risk begins to increase significantly after a maternal age of 35 years for trisomies 13, 18, and 21[10].

Clinical Features

Systemic Manifestations

Complete trisomy 13 typically results in malformations of multiple organ systems and severe intellectual disability[3]. Common findings include microcephaly; cleft lip and palate; polydactyly; cutis aplasia; and cardiac, CNS, and genitourinary anomalies[6][11][13]. Trisomy 13 is the most common cause of holoprosencephaly, which causes severe abnormalities of midine facial structures[14]. Many other systemic features of trisomy 13 have been described[2][3].

Ocular Manifestations

Ocular abnormalities are present in approximately 30% of live-born neonates[11]. While the incidence of any particular ocular findings is difficult to ascertain due to the rarity of the disorder and the brief lifespan of affected individuals, anophthalmos/microphthalmos (Figure 1), congenital cataract, and iris coloboma (usually inferonasal[13], Figure 2) are common[11][13][15][16]. Other reported findings include:

Figure 1: anophthalmia
Figure 2: iris coloboma
Figure 3: persistent fetal vasculature (PFV). Reproduced with permission from Eyerounds.org[17] under a Creative Commons license.
  • Cyclopia[14][18]
  • Aniridia[19]
  • Ciliary body coloboma[20]
  • Persistent fetal vasculature (PFV, Figure 3)[13][17]
  • Persistent tunica vasculosa lentis (PTVL)[13]
  • Congenital glaucoma/buphthalmos[19][21][22]
  • Dysgenesis of the anterior segment[18][23]
  • Cartilaginous mass of the anterior segment[13][15]
  • Corneal opacity[15]
  • Optic nerve coloboma[24]
  • Retinal dysplasia[18][20]
  • Coats disease (retinal telangectasias)[13]
  • Nasolacrimal duct obstruction[25]
  • Upslanting palpebral fissures[16]
  • Hyper- or hypotelorism[16]

Diagnosis

Trisomy 13 may be suggested or diagnosed with prenatal screening and testing using fetal ultrasound, biochemical and molecular testing of maternal blood, amniocentesis, and chorionic villus sampling[2][26]. Postnatal diagnostic genetic testing may be undertaken if features of the syndrome are suspected in an infant who was not diagnosed in the prenatal period.

Management

Given the limited life expectancy for most patients with trisomy 13, ophthalmic surgery is generally not recommended. However, for patients with better prognoses and eye conditions amenable to surgical intervention, surgery may be considered[13][25][27].

Prognosis

Many cases of trisomy 13 (49% in one study[28]) end in spontaneous abortion, and most of those born with the condition have a very limited life expectancy. 75-80% of affected infants do not survive beyond the first month, with a higher fatality rate for males[2][29][30]. However, some affected individuals live much longer. In one study, among affected individuals who lived beyond one year, five-year survival was 84%[30]. The most common causes of death are cardiopulmonary arrest (69%), complications of congenital heart disease (13%), and pneumonia (4%)[29].

Summary

Trisomy 13, or Patau Syndrome, is a severe developmental disorder that results in developmental anomalies in multiple organ systems. Ocular pathology is common and varies widely among individuals. Common findings include anophthalmos/microphthalmos, congenital cataract, and inferonasal iris coloboma, but many other findings have been reported[11][13][15][16][18][19][24][25].

Additional Resources

References

  1. Patau K, Smith DW, Therman E, Inhorn SL, Wagner HP. Multiple congenital anomaly caused by an extra autosome. Lancet. 1960;1(7128):790-793. doi:10.1016/s0140-6736(60)90676-0
  2. 2.0 2.1 2.2 2.3 Trisomy 13. GARD (Genetic and Rare Diseases Information Center). Published April 25, 2016. Accessed December 8, 2020. https://rarediseases.info.nih.gov/diseases/7341/trisomy-13#ref_2976
  3. 3.0 3.1 3.2 3.3 Trisomy 13 Syndrome. NORD (National Organization for Rare Disorders). Published 2007. Accessed December 8, 2020. https://rarediseases.org/rare-diseases/trisomy-13-syndrome/
  4. Bugge M, Collins A, Hertz JM, et al. Non-disjunction of chromosome 13. Hum Mol Genet. 2007;16(16):2004-2010. doi:10.1093/hmg/ddm148
  5. Hall HE, Chan ER, Collins A, et al. The origin of trisomy 13. Am J Med Genet A. 2007;143A(19):2242-2248. doi:10.1002/ajmg.a.31913
  6. 6.0 6.1 6.2 Korf BR, Irons MB. Cell Division and Chromosomes. In: Human Genetics and Genomics. Vol 4th ed. Wiley-Blackwell; 2012.
  7. Douglas C, Smith SA, Rohena L. Novel case of paternal paracentric inversion causing partial trisomy 13 and review of the literature. Am J Med Genet A. 2017;173(6):1673-1680. doi:10.1002/ajmg.a.38192
  8. Koole FD, Velzeboer CM, van der Harten JJ. Ocular abnormalities in Patau syndrome (chromosome 13 trisomy syndrome). Ophthalmic Paediatr Genet. 1990;11(1):15-21. doi:10.3109/13816819009012944
  9. Parker SE, Mai CT, Canfield MA, et al. Updated National Birth Prevalence estimates for selected birth defects in the United States, 2004-2006. Birth Defects Res Part A Clin Mol Teratol. 2010;88(12):1008-1016. doi:10.1002/bdra.20735
  10. 10.0 10.1 Savva GM, Walker K, Morris JK. The maternal age-specific live birth prevalence of trisomies 13 and 18 compared to trisomy 21 (Down syndrome). Prenat Diagn. 2010;30(1):57-64. doi:10.1002/pd.2403
  11. 11.0 11.1 11.2 11.3 11.4 Springett A, Wellesley D, Greenlees R, et al. Congenital anomalies associated with trisomy 18 or trisomy 13: A registry-based study in 16 European countries, 2000-2011. Am J Med Genet A. 2015;167A(12):3062-3069. doi:10.1002/ajmg.a.37355
  12. Rasmussen SA, Wong L-YC, Yang Q, May KM, Friedman JM. Population-based analyses of mortality in trisomy 13 and trisomy 18. Pediatrics. 2003;111(4 Pt 1):777-784. doi:10.1542/peds.111.4.777
  13. 13.0 13.1 13.2 13.3 13.4 13.5 13.6 13.7 13.8 Lueder GT. Clinical ocular abnormalities in infants with trisomy 13. Am J Ophthalmol. 2006;141(6):1057-1060. doi:10.1016/j.ajo.2005.12.048
  14. 14.0 14.1 Kruszka P, Muenke M. Syndromes associated with holoprosencephaly. Am J Med Genet C Semin Med Genet. 2018;178(2):229-237. doi:10.1002/ajmg.c.31620
  15. 15.0 15.1 15.2 15.3 Cogan DG, Kuwabara T. Ocular Pathology of the 13-15 Trisomy Syndrome. Arch Ophthalmol. 1964;72:246-253. doi:10.1001/archopht.1964.00970020246021
  16. 16.0 16.1 16.2 16.3 Petry P, Polli JB, Mattos VF, et al. Clinical features and prognosis of a sample of patients with trisomy 13 (Patau syndrome) from Brazil. Am J Med Genet A. 2013;161A(6):1278-1283. doi:10.1002/ajmg.a.35863
  17. 17.0 17.1 Vislisel JM. Persistent fetal vasculature (PFV). EyeRounds. Published May 26, 2014. Accessed December 9, 2020. https://webeye.ophth.uiowa.edu/eyeforum/atlas/pages/PFV/index.htm
  18. 18.0 18.1 18.2 18.3 Chan A, Lakshminrusimha S, Heffner R, Gonzalez-Fernandez F. Histogenesis of retinal dysplasia in trisomy 13. Diagn Pathol. 2007;2:48. doi:10.1186/1746-1596-2-48
  19. 19.0 19.1 19.2 Bunting R, Leitch J. Buphthalmos in trisomy 13. Eye (Lond). 2005;19(4):487-488. doi:10.1038/sj.eye.6701454
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  22. Keith CG. The ocular manifestations of trisomy 13-15. Trans Ophthalmol Soc U K. 1966;86:435-454.
  23. Hoepner J, Yanoff M. Ocular anomalies in trisomy 13-15: an analysis of 13 eyes with two new findings. Am J Ophthalmol. 1972;74(4):729-737. doi:10.1016/0002-9394(72)90836-7
  24. 24.0 24.1 Magni R, Pierro L, Brancato R. Microphthalmos with colobomatous orbital cyst in trisomy 13. Ophthalmic Paediatr Genet. 1991;12(1):39-42. doi:10.3109/13816819109023083
  25. 25.0 25.1 25.2 Jain SF, Saoirse Y, Conahan B, Suh D. Ocular Findings in Trisomy 13: Nasolacrimal Duct Stenosis Case Series. OJOph. 2019;09(04):161-164. doi:10.4236/ojoph.2019.94017
  26. Copel JA, Kohari K, Merriam AA. Prenatal testing. In: García-Velasco JA, Seli E, eds. Human Reproductive Genetics. Academic Press; 2020:201-221. doi:10.1016/B978-0-12-816561-4.00012-0
  27. Kanigowska K, Grałek M, Seroczyńska M. [Clinical ocular manifestation of Patau’s syndrom (trisomy 13)--own observations]. Klin Oczna. 2011;113(7-9):263-265.
  28. Morris JK, Savva GM. The risk of fetal loss following a prenatal diagnosis of trisomy 13 or trisomy 18. Am J Med Genet A. 2008;146A(7):827-832. doi:10.1002/ajmg.a.32220
  29. 29.0 29.1 Baty BJ, Jorde LB, Blackburn BL, Carey JC. Natural history of trisomy 18 and trisomy 13: II. Psychomotor development. Am J Med Genet. 1994;49(2):189-194. doi:10.1002/ajmg.1320490205
  30. 30.0 30.1 Meyer RE, Liu G, Gilboa SM, et al. Survival of children with trisomy 13 and trisomy 18: A multi-state population-based study. Am J Med Genet A. 2016;170A(4):825-837. doi:10.1002/ajmg.a.37495