Skip to main content
Download PDF

Brittle cornea syndrome: a case report and review of the literature

BMC Ophthalmology volume 18, Article number: 252 (2018) Cite this article

Abstract

Background

To report a patient who presented with bluish scleral discoloration, keratoconus, and progressive high myopia.

Case presentation

A 6-year-old Chinese female patient presented with a significant bluish discoloration of the sclera in both eyes and extreme corneal thinning with anterior corneal protrusion. General pediatric physical examination was normal for all systems and no genetic disorders known were observed.

Conclusions

We aim to highlight the importance of diagnosis and treatment of patients suffering from Brittle cornea syndrome. Timely diagnosis and early provision of protective glasses seem to be the most important step in treating BCS. To our knowledge, this is the first case of BCS being reported in the Asia area.

Peer Review reports

Background

Brittle cornea syndrome (BCS) is a rare autosomal recessive connective tissue disease that characteristically presents with corneal thinning and fragility. It’s first reported by Stein et al. [1] and propagated by Ticho et al. [2] It is generally believed that mild corneal thinning and blue sclera are associated with heterozygous mutations [3]. Because the corneal stroma is very thin, it’s very easily leads to keratoglobus, keratoconus, high myopia and irregular corneal astigmatism [4, 5]. What’s more, under the normal biomechanical stresses, corneas of BSC are unable to maintaining their shape and structural integrity and are prone to develop spontaneous rupture. Therefore, almost all the patients have lost their vision due to corneal rupture and scar [6, 7]. So, early diagnosis and treatment of BCS is very important for the patients. As far as we known, this is the first case of BCS reported in the Asia area. Unfortunately such molecular analyses were not performed in our case. However, she did not present bone fractures or deafness as in osteogenesis imperfecta. Nor did present skin or ligament hyperelastic changes as in Ehlers-Danlos syndrome, or changes in stature similar to the Marfan syndrome.

Case presentation

A 6-year-old Chinese girl presented to People’s hospital of Leshan, Department of Ophthalmology, in August 2017. The parents reported their child with a progressive loss of vision and bluish discoloration of sclera. Family history was negative for known conspicuous eye disorders, no infections or abnormalities in pregnancy or birth, and show no genetic disorders were known. General pediatric physical examination was normal for all systems. The parents and other members of the family were all native Chinese, had no abnormality of the eyes. Overall general physical examination was normal for all systems.

On ophthalmological examination showed that the cornea were obviously prominent, with a significant bluish discoloration of the sclera in both eyes (Fig. 1). The examination of anterior segment eye manifested that an obviously thin cornea with protrusion and the posterior segment was examined by Optosmap Daytona and showed no retinal anomalies or retinal detachment (Fig. 2). Pentacam HR anterior segment tomography indicated that keratoconus with steepening in both eyes which have a maximum keratometric power of 54.10 D in the right eye and a maximum keratometric power of 54.40 D in the other eye (Fig. 3). The thinnest point of cornea assessed by Pentacam,which showed that the right eye was 324 μm thickness with corneal astigmatism in topography (− 2.6D at 163 degrees) and 313 μm thickness measured in the other eye with corneal astigmatism in topography (− 2.7D at 172 degrees) (Fig. 3).

Fig. 1
figure 1

Digital photograph of the 6-year-old girl with brittle cornea syndrome,intense bluish discoloration of the sclera and keratectasia. The Scheimpflug image of cornea showed extreme corneal thinning. Central corneal thickness was 324 μm in right eye and 313 μm in the left eye

Full size image
Fig. 2
figure 2

Ultra-widefield fundus imaging of case

Full size image
Fig. 3
figure 3

Pentacam-refractive maps of the right and left eyes of Case

Full size image

The best corrected visual acuity of right eye was 80/200 and the manifest refraction was − 4.75 /− 2.25 × 180. In the left eye, the best corrected visual acuity was 60/200 with − 3.00/ -4.00 × 170. Intraocular pressure was within normal levels (10 mmHg in the both eyes) [8]. Axial length was 21.45 mm in the right eye and 21.33 mm in the left eye. All which suggested that she is a refractive myopia. Specular microscopy showed that the right eye with the density of 3,459 cells/mm2 in corneal endothelial and 3,654 cells/mm2 in the left eye. According to clinical symptoms and signs, the child was diagnosed with keratoconus, blue sclera, and refractive myopia. Therefore, a presumptive diagnosis of BCS can be made and referred her to the Contact Lens Department to improve her visual acuity.

Discussion

Brittle cornea syndrome was first described by Stein et al. for two siblings of a consanguineous Tunisian Jewish family, characterized by red hair, blue sclera, and brittle cornea with recurrent spontaneous perforations [1]. By now, more than 60 patients involved white and black race have been reported [9]. However, there is no yellow race about BCS have been reported in Asia. As we know, this is the first case of BCS reported in the Asia area. Although BCS is a rare genetic disease, it’s extreme corneal thinning (220–450 μm) (normal range 520–560 μm) affected individuals are at high risk of corneal rupture, leading to irreversible blindness [1, 5, 10]. So, It is urgent for us to better understanding this disease and taking timely measures to manage and follow-up this disease.

The genetics of BCS

Clinically, there has no clear diagnostic criteria for BCS. Therefore, early genetic detection seem to more important for the diagnosis of BCS. Previous studies showed that BCS results from mutations in one of two genes:ZNF469 (encoding zinc finger protein 469) and PRDM5 (encoding PR domaincontaining protein 5). [11,12,13]. Mutations in the ZNF469 gene are causative for brittle cornea syndrome type1 (BCS1) and brittle cornea syndrome type2 (BCS2) is caused by mutations in the PRDM5 gene [5, 10]. As transcriptional regulators, both ZNF469 and PRDM5 are participate in pathways regulating extracellular matrix. ZNF469 is a single exon gene located at 16q24 and produes 3953 amino acid residues. Although the functional research about ZNF469 is confined, the mutations in ZNF469 gene are thought to be associated with changes in central corneal thickness. Recent researches also confirmed that ZNF469 take an important role in anterior segment development and participate in pathogenesis of common ocular disorders such as glaucoma [14,15,16]. PRDM5 is located at 4q25-q26,which consisting of 16 exon genes and encoding a 630 amino acid residues [17]. Although the mechanisms by which mutations in PRDM5 cause disease are not understood, a role in extracellular matrix physiology has been suggested by the recent characterization of a PRDM5 conditional knock-out mouse [18]. What’s more, Galli GG et al. using chromatin immunoprecipitation (ChIP) – sequencing also demonstrated that a direct role for PRDM5 in the regulation of collagen genes [19]. How both genes cause BCS is not yet understood, but most published disease-causing mutations in both PRDM5 and ZNF469 are homozygous mutations.

Diagnosis and differential diagnosis

Apart form the definitively associated with ZNF469 and PRDM5 gene mutations, there are some common clinical features in BCS patients [20]. For example, ocular features include extreme corneal thinning, blue sclera, keratoconus, keratoglobus and high myopia. Extra-ocular manifestations include deafness, joint hypermobility, skin hyperelasticity, arachnodactyly, and developmental dysplasia of the hip [5, 10]. If there is no obvious extra-ocular features, extreme corneal thinning or spontaneous ocular rupture should be highly suspected to diagnosis of BCS. Moreover, there exist some other diseases associated with brittle cornea and blue sclera like the Ehlers-Danlos syndrome, osteogenesis imperfecta, and the Marfan syndrome [2, 21, 22]. However, patients with these diseases are frequently have more pronounced generalized connective tissue manifestations. As regards this case we observed, she did not present any other systemic symptoms.

Treatment

The mainly challenge for the treatment of BCS is relies on early diagnosis, which allows us to take prompt measures to prevent ocular rupture. Protective measures and disease education are most important, provided both protective spectacles and suitable education for patients, their parents, other caregivers and school staff about these and other lifestyle measures. Previous studies showed that patients at early diagnosis of BCS whom corneal perforation was averted by the use of special protective glasses [5, 20]. For BCS patients, any reduction of central corneal thickness should be actively recommended to wear the protective glasses, but whether it is necessary to continuous use is not clear [5]. At the early period of BCS, visual acuity often impaired by keratoglobus, keratoconus and high myopia [23, 24]. The use of contact lenses is optional, however the efficacy of correction of the irregular astigmatism caused by keratoglobus and keratoconus is limited. Furthermore, the progressive corneal thinning is frequently restricted the use of contact lenses. In cases of progressive BCS, epikeratoplasty (A partial thickness corneal graft) has been used in prevention of corneal rupture, which objective to increase the thickness of limbus to limbus and allow a penetrating keratoplasty subsequently [25, 26]. Additional corneoscleral grafting is the other option for extreme corneal thinning, which will not improve vision, but may reinforce the peripheral cornea [27]. What’s more, lots of researches have demonstrated that collagen crosslinking was an effective approach in treating progressive keratoconus in children and adults [28, 29]. However, because of the extreme thinning and frailty, the corneas in BCS patients were not suitable for a CXL procedure according to the original Dresden protocol [30]. Recently, Claude K et al. used a modified collagen crosslinking for corneal stabilization in a child with BCS have achieved encouraging preliminary results [31]. But only time will tell whether the collagen crosslinking can prevent the rupture of cornea or not.

Conclusions

In conclusion, with this case report and review of the literature, we aim to highlight the importance in the diagnosis and treatment of patients suffered from this syndrome. Timely diagnosis and early provision of protective glasses are seem to be the most important step in treating BCS. What’s more, therapeutic methods like contact lenses, keratoplasty and collagen crosslinking are recommended, but the efficacy of treatment is unsatisfactory and limited and with serious complications.

Abbreviations

BCS:

Brittle cornea syndrome

References

  1. Stein R, Lazar M, Adam A. Brittle cornea. A familial trait associated with blue sclera. Am J Ophthalmol. 1968;66(1):67–9.

    Article  CAS  Google Scholar 

  2. Ticho U, Ivry M, Merin S. Brittle cornea, blue sclera, and red hair syndrome (the brittle cornea syndrome). Br J Ophthalmol. 1980;64(3):175–7.

    Article  CAS  Google Scholar 

  3. Lechner J, Porter LF, Rice A, Vitart V, Armstrong DJ, Schorderet DF, Munier FL, Wright AF, Inglehearn CF, Black GC, et al. Enrichment of pathogenic alleles in the brittle cornea gene, ZNF469, in keratoconus. Hum Mol Genet. 2014;23(20):5527–35.

    Article  CAS  Google Scholar 

  4. Ramappa M, Wilson ME, Rogers RC, Trivedi RH. Brittle cornea syndrome: a case report and comparison with Ehlers Danlos syndrome. Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus. 2014;18(5):509–11.

    Article  Google Scholar 

  5. Burkitt Wright EM, Porter LF, Spencer HL, Clayton-Smith J, Au L, Munier FL, Smithson S, Suri M, Rohrbach M, Manson FD, et al. Brittle cornea syndrome: recognition, molecular diagnosis and management. Orphanet journal of rare diseases. 2013;8:68.

    Article  Google Scholar 

  6. Royce PM, Steinmann B, Vogel A, Steinhorst U, Kohlschuetter A. Brittle cornea syndrome: an heritable connective tissue disorder distinct from Ehlers-Danlos syndrome type VI and fragilitas oculi, with spontaneous perforations of the eye, blue sclerae, red hair, and normal collagen lysyl hydroxylation. Eur J Pediatr. 1990;149(7):465–9.

    Article  CAS  Google Scholar 

  7. Avgitidou G, Siebelmann S, Bachmann B, Kohlhase J, Heindl LM, Cursiefen C. Brittle cornea syndrome: case report with novel mutation in the PRDM5 gene and Review of the literature. Case reports in ophthalmological medicine. 2015;2015:637084.

    Article  Google Scholar 

  8. Berti TB, Ghanem VC, Ghanem RC, Binder PS. Moderate keratoconus with thick corneas. J Refract Surg. 2013;29(6):430–5.

    Article  Google Scholar 

  9. Abu A, Frydman M, Marek D, Pras E, Stolovitch C, Aviram-Goldring A, Rienstein S, Reznik-Wolf H, Pras E. Mapping of a gene causing brittle cornea syndrome in Tunisian jews to 16q24. Invest Ophthalmol Vis Sci. 2006;47(12):5283–7.

    Article  Google Scholar 

  10. Porter LF, Gallego-Pinazo R, Keeling CL, Kamieniorz M, Zoppi N, Colombi M, Giunta C, Bonshek R, Manson FD, Black GC. Bruch's membrane abnormalities in PRDM5-related brittle cornea syndrome. Orphanet journal of rare diseases. 2015;10:145.

    Article  Google Scholar 

  11. Swierkowska J, Gajecka M. Genetic factors influencing the reduction of central corneal thickness in disorders affecting the eye. Ophthalmic Genet. 2017:1–10.

  12. Abu A, Frydman M, Marek D, Pras E, Nir U, Reznik-Wolf H, Pras E. Deleterious mutations in the zinc-finger 469 gene cause brittle cornea syndrome. Am J Hum Genet. 2008;82(5):1217–22.

    Article  CAS  Google Scholar 

  13. Burkitt Wright EMM, Spencer HL, Daly SB, Manson FDC, Zeef LAH, Urquhart J, Zoppi N, Bonshek R, Tosounidis I, Mohan M, et al. Mutations in PRDM5 in brittle cornea syndrome identify a pathway regulating extracellular matrix development and maintenance. Am J Hum Genet. 2011;88(6):767–77.

    Article  CAS  Google Scholar 

  14. Lu Y, Dimasi DP, Hysi PG, Hewitt AW, Burdon KP, Toh T, Ruddle JB, Li YJ, Mitchell P, Healey PR, et al. Common genetic variants near the brittle cornea syndrome locus ZNF469 influence the blinding disease risk factor central corneal thickness. PLoS Genet. 2010;6(5):e1000947.

    Article  Google Scholar 

  15. Rohrbach M, Spencer HL, Porter LF, Burkitt-Wright EM, Burer C, Janecke A, Bakshi M, Sillence D, Al-Hussain H, Baumgartner M, et al. ZNF469 frequently mutated in the brittle cornea syndrome (BCS) is a single exon gene possibly regulating the expression of several extracellular matrix components. Mol Genet Metab. 2013;109(3):289–95.

    Article  CAS  Google Scholar 

  16. Ulmer M, Li J, Yaspan BL, Ozel AB, Richards JE, Moroi SE, Hawthorne F, Budenz DL, Friedman DS, Gaasterland D, et al. Genome-wide analysis of central corneal thickness in primary open-angle glaucoma cases in the NEIGHBOR and GLAUGEN consortia. Invest Ophthalmol Vis Sci. 2012;53(8):4468–74.

    Article  Google Scholar 

  17. Micheal S, Khan MI, Islam F, Akhtar F, Qamar R, Tassignon MJ, Loeys B, den Hollander AI. Identification of mutations in the PRDM5 gene in brittle cornea syndrome. Cornea. 2016;35(6):853–9.

    Article  Google Scholar 

  18. Watanabe Y, Toyota M, Kondo Y, Suzuki H, Imai T, Ohe-Toyota M, Maruyama R, Nojima M, Sasaki Y, Sekido Y, et al. PRDM5 identified as a target of epigenetic silencing in colorectal and gastric cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2007;13(16):4786–94.

    Article  CAS  Google Scholar 

  19. Galli GG, Honnens de Lichtenberg K, Carrara M, Hans W, Wuelling M, Mentz B, Multhaupt HA, Fog CK, Jensen KT, Rappsilber J, et al. Prdm5 regulates collagen gene transcription by association with RNA polymerase II in developing bone. PLoS Genet. 2012;8(5):e1002711.

    Article  CAS  Google Scholar 

  20. Zlotogora J, BenEzra D, Cohen T, Cohen E. Syndrome of brittle cornea, blue sclera, and joint hyperextensibility. Am J Med Genet. 1990;36(3):269–72.

    Article  CAS  Google Scholar 

  21. Biglan AW, Brown SI, Johnson BL. Keratoglobus and blue sclera. Am J Ophthalmol. 1977;83(2):225–33.

    Article  CAS  Google Scholar 

  22. Beighton P. Serious ophthalmological complications in the Ehlers-Danlos syndrome. Br J Ophthalmol. 1970;54(4):263–8.

    Article  CAS  Google Scholar 

  23. Greenfield G, Stein R, Romano A, Goodman RM. Blue sclerae and keratoconus: key features of a distinct heritable disorder of connective tissue. Clin Genet. 1973;4(1):8–16.

    Article  CAS  Google Scholar 

  24. Arkin W. Blue Scleras with Keratoglobus. Am J Ophthalmol. 1964;58:678–82.

    Article  CAS  Google Scholar 

  25. Kanellopoulos AJ, Pe LH. An alternative surgical procedure for the management of keratoglobus. Cornea. 2005;24(8):1024–6.

    Article  Google Scholar 

  26. Vajpayee RB, Bhartiya P, Sharma N. Central lamellar keratoplasty with peripheral intralamellar tuck: a new surgical technique for keratoglobus. Cornea. 2002;21(7):657–60.

    Article  Google Scholar 

  27. Al-Hussain H, Zeisberger SM, Huber PR, Giunta C, Steinmann B. Brittle cornea syndrome and its delineation from the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VI): report on 23 patients and review of the literature. Am J Med Genet A. 2004;124A(1):28–34.

    Article  Google Scholar 

  28. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003;135(5):620–7.

    Article  CAS  Google Scholar 

  29. Caporossi A, Mazzotta C, Baiocchi S, Caporossi T, Denaro R, Balestrazzi A. Riboflavin-UVA-induced corneal collagen cross-linking in pediatric patients. Cornea. 2012;31(3):227–31.

    Article  Google Scholar 

  30. Caporossi A, Mazzotta C, Baiocchi S, Caporossi T. Long-term results of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in Italy: the Siena eye cross study. Am J Ophthalmol. 2010;149(4):585–93.

    Article  CAS  Google Scholar 

  31. Kaufmann C, Schubiger G, Thiel MA. Corneal cross-linking for brittle cornea syndrome. Cornea. 2015;34(10):1326–8.

    Article  Google Scholar 

Download references

Acknowledgements

We thank Dr. Yingping Deng for his professional guidance.

Funding

There is no sponsorship or funding arrangements relating to our research.

Availability of data and materials

The datasets used and analysed during the current study available from the corresponding author on reasonable request.

Author information

Authors and Affiliations

  1. Department of Ophthalmology, The people’s hospital of Leshan, Leshan City, People’s Republic of China

    Qi Wan, Jing Tang, Yu Han & Qibin Xiao

  2. Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China

    Yingping Deng

Authors
  1. Qi Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jing Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yu Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qibin Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yingping Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YPD designed the study. YH, JT and QBX review of the literature. QW wrote the paper. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Qi Wan.

Ethics declarations

Ethics approval and consent to participate

The ethics committee of leshan hospital approved the study.

Consent for publication

Parental consent for publication was obtained for this report.

Competing interests

All authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wan, Q., Tang, J., Han, Y. et al. Brittle cornea syndrome: a case report and review of the literature. BMC Ophthalmol 18, 252 (2018). https://doi.org/10.1186/s12886-018-0903-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12886-018-0903-2

Keywords

  • Brittle cornea syndrome
  • Blue sclera
  • Case report
  • Literature review
  • Keratoconus

BMC Ophthalmology

ISSN: 1471-2415

Contact us