Association of infantile-onset glaucoma with collagen disorders

Christian Apsey and Brenda L. Bohnsack*

Kellogg Eye Center and Department of Ophthalmology and Vision Sciences, University of Michigan, Ann Arbor, Michigan 48105, USA

---

Abstract

 Primary infantile-onset glaucoma is a rare, potentially blinding disease that is due to malformation of the trabecular meshwork and aqueous outflow tracts (goniotrabeculodysgenesis). While goniotrabeculodysgenesis is typically an isolated finding, there are reports of primary infantile-onset glaucoma in the setting of collagen disorders, specifically Stickler syndrome and osteogenesis imperfecta.

In Stickler syndrome, defects in type II or type XI collagen are commonly associated with craniofacial anomalies, hearing loss, hypermobile joints, and vitreoretinal abnormalities. Osteogenesis imperfecta is caused by disruption in type I collagen synthesis and is characterized by frequent bone fractures. Both type I and type II collagens are major structural proteins in the trabecular meshwork of the eye and both of these collagen disorders show higher incidences of adult-onset glaucoma. Herein we review the association between primary infantile-onset glaucoma and collagen disorders, which gives insight into the development of the trabecular meshwork and the aqueous outflow tracts of the eye.

---

 

Primary infantile-onset glaucoma

Primary infantile-onset glaucoma is a potentially blinding disease that has an incidence of approximately 1 in 10,000 live births1,2. This congenital eye disease is more common in males (2:1) and can affect one or both eyes3. Light sensitivity (photophobia), tearing (epiphora), and excessive blinking (blepharospasm), which are due to corneal clouding and edema, constitute the classic triad of symptoms3,4. Primary infantile-onset glaucoma is characterized by elevated intraocular pressure (IOP) caused by abnormal development of the trabecular meshwork and aqueous outflow tracts in the eye (goniotrabeculodysgenesis)5,6. This is in contrast to glaucoma that is secondary to other congenital eye anomalies such as in Axenfeld-Rieger Syndrome, congenital cataracts, microphthalmia, Peters Anomaly, and aniridia7-11. Mutations in the CYP1B1 gene are the most commonly identified genetic cause of primary infantile onset-glaucoma, however, the molecular mechanism by which this gene regulates eye development has yet to be determined12-14.

Increased IOP has more deleterious effects on eye structure and visual function in infants and young children than in adults. The cornea and sclera are more distensible in children such that increased IOP causes globe enlargement (buphthalmos) and axial lengthening15. This correlates with increased refractive error (high myopia) and predisposes these eyes to retinal detachment and lens subluxation16-18. Further, increased IOP results in breaks in Descemet’s membrane, the less compliant basement membrane of the corneal endothelium (Haabs striae) that cause image distortion and irregular astigmatism4,19,20. In addition, prolonged elevated IOP can cause decompensation of the corneal endothelium which may necessitate corneal transplantation21. As in adult-onset glaucoma, elevated IOP in children leads to loss of the retinal nerve fiber layer, which results in the characteristic cupping of the optic nerve22. In addition to the damage to ocular structures, vision loss in children can be due to amblyopia. Persistently decreased vision in one or both eyes due to high myopia, Haabs striae, corneal edema, or optic neuropathy during the first decade of life can result in dense amblyopia23.

Unlike other forms of glaucomas, surgical management is required to control IOPs in primary infantile-onset glaucoma. The mainstay of treatment is angle surgery (goniotomy or trabeculotomy), which involves the incision of the trabecular meshwork to remove resistance of aqueous outflow from the anterior chamber into Schlemm’s canal. Both goniotomy and trabeculotomy have high success rates (70-80%) in primary infantile-onset glaucoma, especially in children diagnosed between 2 and 12 months of age24-26. Cases refractory to goniotomy or trabeculotomy, may require surgery to create alternative aqueous outflow paths (trabeculectomy or glaucoma drainage device placement) or surgery to decrease aqueous humor production (ciliary body ablation)23,27-29. Thus, primary infantile-onset glaucoma is a rare disease that requires early diagnosis and surgical intervention to optimize visual outcomes.

Primary infantile-onset glaucoma and collagen tissue disorders

Although primary infantile-onset glaucoma is typically an isolated finding, goniotrabeculodysgenesis has been associated with genetic defects in collagen synthesis. Collagens are the major structural proteins in the extracellular matrix and types I and II are the most abundant. Different genes encode for specific collagen chains that through a series of enzymatic modifications aggregate into groups of three to form tropocollagen. Polymers of tropocollagen form collagen fibrils and fibers. Mutations in the genes encoding for collagen chains or modifying enzymes required for fiber formation can affect numerous tissues throughout the body30-32.

Stickler Syndrome is due to mutations in the collagen type 2 alpha 1 (COL2A1, Type I Stickler Syndrome) or the collagen type 11 alpha 1 (COL11A1, Type II Stickler Syndrome) genes, which result in abnormal type II and type XI collagen fibril formation33,34. In the eye, type II collagen is in the vitreous humor, sclera, cornea, and trabecular meshwork35-37. Type XI collagen, a minor form that consists of collagen type 2 and 11 chains, is predominantly in cartilage but is also in the vitreous38,39. While Stickler Syndrome typically follows an autosomal dominant pattern, there are rare cases of autosomal recessive inheritance. People affected with Stickler Syndrome have craniofacial anomalies (Pierre Robin sequence, cleft palate, micrognathia), hearing loss, and hypermobile joints. The most common eye abnormality is non-glaucomatous axial lengthening with associated high myopia and predisposition for retinal detachments33,34. The mechanism of the posterior lengthening of the globe is not well understood, but is likely due to abnormal vitreo-retinal interactions due to type II and XI collagen abnormalities.

It is generally accepted that adults with Stickler syndrome have a higher incidence of ocular hypertension (10%) and angle abnormalities (26%), and mutations that may affect COL2A1 splicing may be more likely to cause adult-onset glaucoma40,41. Glaucoma in children is more rare as only 2 cases of infantile-onset glaucoma associated with Stickler syndrome have been reported in the literature42,43. There are also a few reported cases from the 1960s of infantile glaucoma in the setting of Pierre Robin sequence, which was prior to recognition of Stickler Syndrome as a specific entity44,45. Primary infantile-onset glaucoma in Stickler syndrome is likely underreported, however, it is unclear the prevalence of goniotrabeculodysgenesis in the setting of Stickler Syndrome.

The mechanism behind defective trabecular meshwork development and function in infants with Stickler Syndrome is unknown. In the prenatal eye, type II collagen may play a role in the formation of the anterior segment and trabecular meshwork. Transgenic mice carrying mutations in the Col2a1 gene show anterior segment alterations including abnormal trabecular meshwork, thickened lens capsule, and shallow anterior chambers46. Further, type II collagen, which interacts with hyaluronic acid to mediate aqueous outflow resistance, is decreased in the trabecular meshwork in eyes with adult-onset glaucoma37,47. Decreased or absence of type II collagen in the trabecular meshwork may also compromise function in young children. Thus, infantile-onset glaucoma in the setting of Stickler syndrome could be a result of both structural malformations and function of the trabecular meshwork. Further studies are required to discern the mechanism behind this disease.

Osteogenesis imperfecta is a group of connective tissue disorders due to defects in type I collagen, which is the predominant protein in bone. The hallmark of osteogenesis imperfecta is frequent bone fractures that lead to skeletal deformities48. Additional findings include progressive hearing loss, abnormal teeth, and cardiopulmonary problems. There are 8 types of osteogenesis imperfecta that are categorized based on severity of the disease. Types I through IV are the most common forms and are due to mutations in genes encoding the collagen type 1 alpha 1 chain (COL1A1) or collagen type 1 alpha 2 chain (COL1A2)48-50. Type I collagen is located throughout the eye including in the sclera, cornea, trabecular meshwork, lens capsule, uvea, and lamina cribosa51. The most common ocular finding in type I and III osteogenesis imperfecta is a bluish hue to the sclera. This was originally thought to be due to decreased scleral thickness, however, electron microscopy demonstrated that the blue color is a result of thinner collagen fibers and altered extracellular matrix composition52-54. On the other hand, the central corneas are significantly thinner in children and adults with osteogenesis imperfecta55. The alterations in these tissues may account for the few reports of degenerative ocular pathologies such as retinal detachment, posterior staphyloma, and keratoconus in adults with osteogenesis imperfecta56-62. In addition, there is an association between osteogenesis imperfecta and primary open angle glaucoma. One case series showed that all members of a particular family affected with osteogenesis imperfecta developed early adult-onset primary open angle glaucoma63. Recently, a second case series reported increased intraocular pressures and early onset glaucoma in 2 unrelated patients with osteogenesis imperfecta64. The pathophysiology between type I collagen defects and adult primary open angle glaucoma is not clear. It may be related to altered corneal biology, increased distensibilty of the lamina cribrosa, or alterations in trabecular meshwork.

There are few cases of congenital eye anomalies in children with osteogenesis imperfecta. One child had Rieger anomaly who developed secondary glaucoma as a teenager65. The other was an infant with anterior megalophthalmos of one eye and primary infantile-onset glaucoma of the other eye. The eye with glaucoma had goniotrabeculodysgenesis and intraocular pressure control was successfully obtained with angle surgery66. Interestingly, another patient, who was not clinically affected with osteogenesis imperfecta, was reported to have heterozygous variants in the COL1A1 gene that caused primary infantile-onset glaucoma64. Type I collagen is a major component of the core of the endothelial-covered trabecular beams in the trabecular meshwork67. In animal models, decreased structural integrity of the trabecular beams results in collapse of the trabecular meshwork. Interestingly, in mice, mutation of Cyp1b1, the gene associated with primary infantile-onset glaucoma in humans, causes fragmentation and disorganization of the collagen fibers in the trabecular meshwork68. The question raised is why are there not more cases of infantile-onset glaucoma associated with type I collagen defects and osteogenesis imperfecta. While this may be due to lack of genetic testing for mutations in collagen chains in cases of infantile-onset glaucoma, this could also be due to the specific collagen chains affected, the type of mutation, and effect of other genes involved in trabecular meshwork development. Both collagen type 1 alpha 1 and collagen type 1 alpha 2 chains contribute to type I collagen fibers. However, the ratio between these two chains as well as the incorporation of additional chains into final collagen fibers varies. The development and function of trabecular meshwork may be sensitive to the specific composition of the type I collagen fibers. Further numerous COL1A1 and COL1A2 mutations have been identified and there is a wide range of phentoypes as evidenced by the differences between the types of osteogenesis imperfecta. Different mutations have various effects on collagen fibril formation such that there are differences in collagen fiber thickness, integrity, and length between patients with osteogenesis imperfecta48-50. The specific structure of the collagen fiber in these patients may more highly affect the formation of the trabecular beams. In addition, the abnormal collagen fibers in the trabecular beams may be influenced by polymorphisms in other genes that regulate trabecular meshwork development and function. Mild alteration in the function of a gene such as CYP1B1 may not be disease causing, however, in the setting of abnormal type I collagen fibers, development and function of the trabecular meshwork may be compromised. Additional studies that investigate the role of type I collagen in trabecular meshwork development and function are required to better understand the relationship between collagen mutations and primary infantile onset glaucoma.

Conclusions

Primary infantile-onset glaucoma is a congenital disease, which can lead to significant visual impairment and in some cases complete blindness. Early diagnosis and appropriate surgical treatment to obtain intraocular pressure control is critical for good visual outcomes. Primary infantile-onset glaucoma is due to goniotrabeculodysgenesis, which in rare cases can be associated with Stickler Syndrome and osteogenesis imperfecta. Type I and type II collagens are both integral to trabecular meshwork structure and function. The few cases of primary infantile-onset glaucoma associated with collagen diseases suggest that these collagens are important in trabecular meshwork development.

References

1. Lim SH, Tran-Viet KN, Yanovitch TL, et al. CYP1B1, MYOC, and LTBP2 mutations in primary congenital glaucoma patients in the United States. Am J Ophthalmol. 2013;155:508-517.
2. Gencik A. Epidemiology and genetics of primary congenital glaucoma in Slovakia. Description of a form of primary congenital glaucoma in gypsies with autosomal-recessive inheritance and complete penetrance. Dev Ophthalmol. 1989;16:76-115.
3. Ho CL, Walton DS. Primary congenital glaucoma: 2004 update. J Pediatr Ophthalmol Strabismus. 2004;41:271-288.
4. Walton DS. Primary congenital open angle glaucoma: a study of the anterior segment abnormalities. Trans Am Ophthalmol Soc. 1979;77:746-768.
5. Cascella R, Strafella C, Germani C, et al. The genetics and the genomics of primary congenital glaucoma. Biomed Res Int. 2015;2015:321291.
6. Sarfarazi M, Stoilov I. Molecular genetics of primary congenital glaucoma. Eye (Lond). 2000;14(pt 3B):422-428.
7. Ito YA, Walter MA. Genomics and anterior segment dysgenesis: a review. Clin Experiment Ophthalmol. 2014;42:13-24.
8. Reis LM, Tyler RC, Volkmann Kloss BA, et al. PITX2 and FOXC1 spectrum of mutations in ocular syndromes. Eur J Hum Genet. 2012;20:1224-1233.
9. Mihelec M, St. Heaps L, Flaherty M, et al. Chromosomal rearrangements and novel genes in disorders of eye development, cataract, and glaucoma. Twin Res Hum Genet. 2008;11:412-421.
10. Traboulsi EI, Maumenee IH. Peters anomaly and associated congenital malformations. Arch Ophthalmol. 1992;110:1739-1742.
11. Lee HJ, Colby KA. A review of the clinical and genetic aspects of aniridia. Semin Ophthalmol. 2013;28:306-312.
12. Khan AO. Genetics of primary glaucoma. Curr Opin Ophthalmol. 2011;22.
13. Li N, Zhou Y, Du L, Wei M, Chen X. Overview of Cytochrome P450 1B1 gene mutations in patients with primary congenital glaucoma. Exp Eye Res. 2011;93:572-579.
14. Stoilov I, Akarsu AN, Sarfarazi M. Identification of three different truncating mutations in cytochrome P4501B1 (CYP1B1) as the principal cause of primary congenital glaucoma (Buphthalmos) in families linked to the GLC3A locus on chromosome 2p21. Hum Mol Genet. 1997;6:641-647.
15. Cronemberger S, Calixto N, Avellar Milhomens TG, et al. Effect of intraocular pressure control on central corneal thickness, horizontal corneal diameter, and axial length in primary congenital glaucoma. J AAPOS. 2014;18:433-436.
16. Jonas JB, Holbach L, Panda-Jones S. Histologic differences between primary high myopia and secondary high myopia due to congenital glaucoma. Acta Ophthalmol. 2016;94:147-153.
17. Cooling RJ, Rice NS, Mcleod D. Retinal detachment in congenital glaucoma. Br J Ophthalmol. 1980;64:417-421.
18. Azar G, Dureau P, Barjol A, Edelson C, Berges O, Caputo G. Ectopia lentis associated with primary congenital glaucoma. Eur J Ophthalmol. 2913;23:597-600.
19. Spierer O, Cavuoto KM, Suwannaraj S, Chang TC. Anterior segment optical coherence tomography imaging of Haab striae. J Pediatr Ophthalmol Strabismus. 2015;15:e55-58.
20. Patil B, Tandon R, Sharma N, et al. Corneal changes in childhood glaucoma. Ophthalmology. 2015;122:87-92.
21. Toker E, Seitz B, Langenbucher A, Dietrich T, Naumann GO. Penetrating keratoplasty for endothelial decompensation in eyes with buphthalmos. Cornea. 2003;22:198-204.
22. Richardson KT, Shaffer RN. Optic-nerve cupping in congenital glaucoma. Am J Ophthalmol. 1966;62:507-509.
23. Terraciano AJ, Sidoti PA. Management of refractory glaucoma in childhood. Curr Opin Ophthalmol. 2002;13:97-102.
24. Yassin SA, Al-Tamimi ER. Surgical outcomes in children with primary congenital glaucoma: a 20-year experience. Eur J Ophthalmol. 2016;Mar 20 {Epub ahead of print].
25. Zagora SL, Funnell CL, Martin FJ, et al. Primary congenital glaucoma outcomes: lessons from 23 years of follow-up. Am J Ophthalmol. 2015;159:788-796.
26. Bowman RJ, Dickerson M, Mwende J, Khaw PT. Outcomes of goniotomy for primary congenital glaucoma in East Africa. Ophthalmology. 2011;118:236-240.
27. Yu Chan JY, Choy BN, Ng AL, Shum JW. Review on the management of primary congenital glaucoma. J Curr Glaucoma Pract. 2015;9:92-99.
28. Chen TC, Chen PP, Francis BA, et al. Pediatric glaucoma surgery: a report by the American Academy of Ophthalmology. Ophthalmology. 2014;121:2107-2115.
29. Papadopoulos M, Edmunds B, Fenerty C, Khaw PT. Childhood glaucoma surgery in the 21st century. Eye (Lond). 2014;28:931-943.
30. Grant ME, Prockop DJ. The biosynthesis of collagen. N Engl J Med. 1972;286:194-199.
31. Hulmes DJ. The collagen superfamily--diverse structures and assemblies. Essays Biochem. 1992;27:49-67.
32. Sherman VR, Yang W, Meyers MA. The materials science of collagen. J Mech Behav Biomed Mater. 2015;52:22-50.
33. Hoornaert KP, Vereecke I, Dewinter C, et al. Stickler syndrome caused by COL2A1 mutations: genotype-phenotype correlation in a series of 100 patients. Eur J Hum Genet. 2010;18:872-880.
34. Richards AJ, McNinch A, Martin H, et al. Stickler syndrome and the vitreous phenotype: Mutations in COL2A1 and COL11A1. Hum Mutat. 2010;31:E1461-E1471.
35. Bishop PN. Structural macromolecules and supramolecular organisation of the vitreous gel. Prog Retin Eye Res. 2000;19:323-344.
36. van Deemter M, Kuijer R, Harm Pas H, Jacoba van der Worp R, Hooymans JM, Los LI. Trypsin-mediated enzymatic degradation of type II collagen in the human vitreous. Mol Vis. 2013;19:1591-1599.
37. Bhattacharya SK, Rockwood EJ, Smith SD, et al. Proteomics reveal Cochlin deposits associated with glaucomatous trabecular meshwork. J Biol Chem. 2005;280:6080-6084.
38. Tiku ML, Madhan B. Preserving the longevity of long-lived type II collagen and its implication for cartilage therapeutics. Ageing Res Rev. 2016;28:62-71.
39. Ponsioen TL, van Luyn MJ, van der Worp RJ, van Meurs JC, Hooymans JM, Los LI. Collagen distribution in the human vitreoretinal interface. Invest Ophthal Vis Sci. 2008;49:4089-4095.
40. Zechi-Ceide RM, Jesus Oliveira NA, Guion-Almeida ML, Antunes LF, Richieri-Costa A, Passos-Bueno MR. Clinical evalution and COL2A1 gene analysis in 21 Brazilian families with Stickler syndrome: identiifcation of novel mutations, further genotype/phenotype correlation, and its implications for the diagnosis. Eur J Hum Genet. 2008;51:183-196.
41. Spallone A. Stickler's syndrome: a study of 12 families. Br J Ophthalmol. 1987;71:504-509.
42. Shenoy BH, Mandal AK. Stickler syndrome associated with congenital glaucoma. Lancet. 2013;381:422.
43. Ziakas NG, Ramsay AS, Lynch SA, Clarke MP. Stickler's syndrome associated with congenital glaucoma. Ophthalmic Genet. 1998;19:55-58.
44. Saraux H, Dhermy P. Le glaucome du syndrome de P. Robin. Arch Ophthalmol. 1968;28:793-800.
45. Ortlepp J, Brandt HP. Hydrophthalmos with Pierre-Robin syndrome. Klin Monbl Augenheilkd 1966;148:469.
46. Ihanamaki T, Metsaranta M, Rintala M, Vuorio E, Sandberg-Lall M. Ocular abnormalities in transgenic mice harboring mutations in the type II collagen gene. Eur J Ophthalmol. 1996;6:427-435.
47. Marchant JK. Type II and XII collagen-hyaluronan interaction and distribution in the trabecular meshwork. Invest Ophthal Vis Sci. 2004;45:4422.
48. Van Dijk FS, Byers PH, Dalgleish R, et al. EMQN Best practice guidelines for the laboratory diagnosis of osteogenesis imperfecta. Eur J Hum Genet. 2012;20:11-19.
49. Thomas IH, DiMeglio LA. Advances in the classification and treatment of osteogenesis imperfecta. Curr Osteoporos Rep. 2016;14:1-9.
50. Van Dijk FS, Sillence DO. Osteogenesis imperfecta: Clinical diagnosis, nomenclature, and severity assessment. Am J Med Genet Part A. 2014;164A:1470-1481.
51. Chau FY, Wallace DJ, Vajaranant T, et al. Osteogenesis imperfecta and the Eye. In: Shapiro JR, Byers PH, Glorieux FH, Sponseller PD (eds), Osteogenesis imperfecta: A translational approach to brittle bone disease. Cambridge, MA: Academic Press; 2013:289-303.
52. Blumcke S, Niedorf HR, Thiel HJ, Langness U. Histochemical and fine structural studies on the cornea with osteogenesis imperfecta congenita. Virchows Arch B Cell Pathol. 1972;11:124-132.
53. Eichholtz W, D. M. Electron microscopy findings on the cornea and sclera in osteogenesis imperfecta. Klin Monbl Augenheilkd. 1972;161:646-653.
54. Mietz H, Kasner L, Green WR. Histopathologic and electron-microscopic features of corneal and scleral collagen fibers in osteogenesis imperfecta type III. Graefes Arch Clin Exp Ophthalmol. 1997;235:405-410.
55. Evereklioglu C, Madenci E, Bayazit YA, Kutluhan Y, Balat A, Bekir NA. Central corneal thickness is lower in osteogenesis imperfecta and negatively correlates with the presence of blue sclera. Ophthalm Physiol Opt. 2002;22:511-515.
56. Beckh U, Schonherr U, Naumann GO. Autosomal dominant keratoconus as the chief ocular symptom in Lobstein osteogenesis imperfecta tarda. Klin Monbl Augenheilkd. 1995;268-272.
57. Madigan WP, Wertz D, Cockerham GC, Thach AB. Retinal detachment in osteogenesis imperfecta. J Pediatr Ophthalmol Strabismus. 1994;13:268-269.
58. Pirouzian A, O'Halloran H, Scher C, Jockin Y, Yaghmai R. Traumatic and spontaneous scleral rupture and uveal prolapse in osteogenesis imperfecta. J Pediatr Ophthalmol Strabismus. 2007;44:315-317.
59. Rosbach J, Vossmerbaeumer U, Renieri G, Pfeiffer N, Thieme H. Osteogenesis imperfecta and glaucoma: A case report. Ophthalmologe. 2012;109:469-482.
60. Scott A, Kashani S, Towler HMA. Progressive myopia due to posterior staphyloma in type I osteogenesis imperfecta. Int Ophthalmol. 2005;26:167-169.
61. Smolinska K, Olbromska W. Case of Ekman-Lobstein-van der Hoeve syndrome with bilateral glaucoma and right-sided thrombosis of the central retinal vein. Pol Tyg Lek. 1977;32:843-844.
62. Superti-Furga A, Pistone F, Romano C, Steinmann B. Clinical variability of osteogenesis imperfecta linked to COL1A2 and associated with a structural defect in the type I collagen molecule. J Med Genet. 1989;26:358-362.
63. Wallace DJ, Chau FY, Santiago-Turla C, et al. Osteogenesis imperfecta and primary open angle glaucoma: Genotypic analysis of a new phenotypic association. Mol Vis. 2014;20:1174-1181.
64. Mauri L, Uebe S, Sticht H, et al. Expanding the clinical spectrum of COL1A1 mutations in different forms of glaucoma. Orphan J Rare Dis. 2016;11:108.
65. Nwosu BU, Raygada M, Tsilou ET, Rennert OM, Stratakis CA. Rieger's anomaly and other ocular abnormaltiies in association with osteogenesis imperfecta and a Col1A1 mutation. Ophthalmic genetics. 2005;26:135-138.
66. Bohnsack BL. Infantile-onset glaucoma and anterior megalophthalmos in osteogenesis imperfecta. J AAPOS 2016;20:170-172.
67. Dua HS, Faraj LA, Branch MJ, et al. The collagen matrix of the human trabecular meshwork is an extension of the novel pre-Descemet's layer (Dua's layer). Br J Ophthalmol. 2014;98:691-697.
68. Teixeira LBC, Zhao Y, Dubielzig RR, Sorenson CM, Sheibani N. Ultrastructural abnormalities of the trabecular meshwork extracellular matrix in Cyp1b1-deficient mice. Vet Pathol. 2015;52:397-403.