Brittle Cornea Syndrome: The One-in-Million Cause of Extreme Corneal Fragility

Mohammad Zeyad Mohammad Ayoub

Brittle cornea syndrome (BCS) is a rare autosomal recessive connective tissue disorder. It is characterised by progressive corneal thinning, corneal ectasia, blue sclera, and marked ocular fragility. These features lead to a significantly increased risk of spontaneous or traumatic corneal perforation (1–3). The condition was first described by Stein et al. in 1968 during an attempted surgical repair of a corneal perforation. During suturing, the cornea was observed to fragment easily, highlighting its extreme fragility (1). The syndrome was later further characterised by Ticho et al., who reported the association of brittle cornea with blue sclera and red hair (2). In contrast to other connective tissue disorders with ocular involvement, BCS primarily affects the cornea rather than the sclera. This distinction is clinically important, as it has implications for diagnosis, management, and prognosis (3).

Epidemiology

Brittle cornea syndrome (BCS) is an exceptionally rare disorder, with an estimated prevalence of fewer than one case per million people (3). To date, only around 60–70 cases have been reported in the literature. Early reports mainly described affected individuals from families of Tunisian Jewish origin. However, later studies have identified cases in European, African, and Asian populations, indicating that the condition has a wider geographic distribution than was initially recognised (3–5). Despite this broader distribution, BCS is thought to be significantly underdiagnosed. This is largely due to its clinical overlap with other ectatic corneal disorders and the fact that systemic features may be mild or absent. As a result, many patients are only diagnosed after presenting with corneal rupture, by which time the visual prognosis is often poor (3,6).

Genetics and Molecular Basis

Brittle cornea syndrome (BCS) is a genetically heterogeneous disorder caused by pathogenic variants in one of two genes: ZNF469 or PRDM5 (7–9). Mutations in ZNF469 result in Brittle Cornea Syndrome type 1, while mutations in PRDM5 cause Brittle Cornea Syndrome type 2 (3,7).

The ZNF469 gene is located on chromosome 16q24 and encodes a large zinc finger protein involved in regulating extracellular matrix components (7,10). Studies have shown a strong association between ZNF469 variants and central corneal thickness, which is a highly heritable trait (11,12). Severe BCS is usually caused by homozygous truncating or frameshift mutations in ZNF469. In contrast, heterozygous missense variants are linked to milder features, such as corneal thinning, blue sclera, and myopia (7,13). Although ZNF469 variants have been reported in keratoconus, this association remains uncertain due to inconsistent results across studies (14–16).

The PRDM5 gene is located on chromosome 4q25–q27 and encodes a transcriptional regulator that is important for extracellular matrix development and maintenance (8,9). Functional studies show that PRDM5 controls the expression of several collagen genes and other extracellular matrix components, including those in the transforming growth factor beta pathway (9,17). Cells from patients with PRDM5 mutations demonstrate abnormal collagen organisation, which helps explain the severe corneal thinning seen in BCS (8,9).

Pathophysiology

The main pathological feature of brittle cornea syndrome (BCS) is abnormal regulation of the extracellular matrix, which leads to impaired development and maintenance of the corneal stroma (3). As a result, the cornea becomes markedly thin and mechanically weak. In patients with BCS, central corneal thickness usually ranges from 220 to 450 μm, compared with a normal thickness of around 520 to 560 μm. In severe cases, thickness may be less than 300 μm (4,6). This extreme thinning means that the cornea cannot withstand normal intraocular pressure or everyday biomechanical stress. Consequently, patients are at high risk of progressive corneal ectasia, keratoglobus, and spontaneous corneal rupture. Reduced corneal hysteresis further contributes to the loss of structural stability in BCS (3).

Clinical Features

The clinical features of brittle cornea syndrome (BCS) are mainly ocular and are often present from early childhood. Patients typically show diffuse corneal thinning from limbus to limbus, with central corneal thickness consistently below 400 μm (3,6). Blue sclera is a common finding, although it is not present in all patients and may become less noticeable with age (3). Early-onset keratoconus or keratoglobus frequently develops and leads to high myopia and irregular astigmatism (3,4). Unlike keratoconus, stromal striae are usually absent in BCS, reflecting important differences in corneal biomechanical properties (3).

Corneal rupture is the most serious complication of BCS and may occur after minor trauma or even spontaneously. The average reported age at rupture is approximately 4.3 years, with cases reported between 1.5 and 19 years of age (3). More than half of affected individuals develop permanent severe visual loss or blindness following rupture (3,18). Retinal detachment and secondary glaucoma have also been reported, most often in association with extreme myopia rather than as direct features of the condition (3,6).

Extra-ocular features are variable and usually mild, but they can support the diagnosis. These include joint hypermobility, especially in the small joints, developmental dysplasia of the hip, arachnodactyly, scoliosis, pes planus, and mild skin hyperelasticity or abnormal scarring (3,6). Hearing involvement is relatively common and may be conductive, sensorineural, or mixed, often related to hypercompliant tympanic membranes (3). Hypotonia in infancy and mild contractures of the fingers, particularly the fifth digit, have also been described. Importantly, unlike severe forms of Ehlers–Danlos syndrome, arterial rupture and reduced life expectancy have not been reported in patients with BCS (3,6).

Diagnosis

There are currently no formal diagnostic criteria for brittle cornea syndrome (BCS). Diagnosis is mainly based on recognising the typical clinical features, with support from genetic testing (3). Strong suspicion should be raised in any patient, particularly a child, who presents with extreme corneal thinning below 400 μm, blue sclera, or corneal rupture following minimal trauma (4,6). Corneal pachymetry and tomography are essential investigations, as they allow accurate assessment of the severity and pattern of corneal thinning. Genetic testing for mutations in ZNF469 and PRDM5 is recommended to confirm the diagnosis, distinguish BCS from other connective tissue disorders, and support genetic counselling (3,9). Examination of family members is also important, as heterozygous carriers may show mild corneal thinning or myopia (8).

Differential Diagnosis

Brittle cornea syndrome (BCS) shares clinical features with several connective tissue disorders, and careful differentiation is therefore required. The kyphoscoliotic type of Ehlers–Danlos syndrome is an important differential diagnosis. It is characterised mainly by scleral rather than corneal fragility, along with severe kyphoscoliosis, hypotonia, and a high risk of arterial rupture due to lysyl hydroxylase deficiency (3,18). Osteogenesis imperfecta may also present with blue sclera, thin corneas, and hearing loss, but it is distinguished by recurrent fractures and marked skeletal fragility (3). Marfan syndrome can share features such as blue sclera and ocular fragility; however, it is typically associated with tall stature, ectopia lentis, and aortic disease, which are not characteristic features of BCS (6).

Management

The main goal in managing brittle cornea syndrome (BCS) is early diagnosis and prevention of corneal rupture (3,6). Preventive measures include wearing polycarbonate protective glasses, especially during childhood, and providing education to patients, families, caregivers, and school staff about lifestyle changes and avoiding high-risk activities (3,6). Regular eye examinations, including serial refraction and corneal imaging, are important to optimise visual correction and prevent amblyopia in children. Contact lenses may be used carefully to correct irregular astigmatism, although progressive corneal thinning often limits their safety and effectiveness (3).

Surgical treatment in BCS is extremely challenging due to the fragility of the cornea. Repairing corneal perforations is often complicated by cheese-wiring of sutures and tissue breakdown (18). Penetrating keratoplasty is technically difficult, usually requires large grafts, and is performed mainly to maintain corneal structure rather than improve vision (18,19). In cases of severe thinning, sclero-corneal grafts may be needed. Epikeratoplasty has been used to strengthen the cornea and increase thickness, potentially delaying rupture and allowing later definitive surgery (19). Onlay corneal grafts have also been used in selected non-perforated eyes to reduce extreme myopia, although long-term visual outcomes are often limited (3). In cases where rupture cannot be repaired, enucleation may be necessary.

Corneal collagen cross-linking has been suggested as a way to stabilise corneal thinning in BCS. Standard protocols are usually not suitable because of the risk of endothelial damage in very thin corneas. However, modified epithelium-on techniques with lower ultraviolet exposure have shown promising results in isolated cases, although their long-term effectiveness in preventing rupture remains unclear (20).

Prognosis

The visual prognosis in brittle cornea syndrome (BCS) is generally poor, especially after corneal rupture, which often leads to permanent vision loss. More than half of reported patients experience blindness in at least one eye (3,18). In contrast, the overall systemic prognosis is relatively good, with normal life expectancy and no confirmed risk of arterial or internal organ rupture. Early diagnosis and strict preventive measures remain the most effective way to protect vision in affected individuals (3).

References

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  2. Ticho U, Ivry M, Merin S. Brittle cornea, blue sclera, and red hair syndrome. Br J Ophthalmol. 1980;64(3):175–177.
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  4. Wan Q, Tang J, Han Y, Xiao Q, Deng Y. Brittle cornea syndrome: a case report and review of the literature. BMC Ophthalmol. 2018;18:252.
  5. Mandlik K, Betdur RA, Rashmita R, Narayana S. Brittle cornea syndrome: A tale of three brothers. Indian J Ophthalmol. 2022;70(7):2594–2597.
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  7. Abu A, Frydman M, Marek D, et al. Deleterious mutations in the zinc-finger 469 gene cause brittle cornea syndrome. Am J Hum Genet. 2008;82(5):1217–1222.
  8. Burkitt Wright EMM, Spencer HL, Daly SB, 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):767–777.
  9. Galli GG, Honnens de Lichtenberg K, Carrara M, et al. PRDM5 regulates collagen gene transcription by association with RNA polymerase II. PLoS Genet. 2012;8(5):e1002711.
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  11. Lu Y, Dimasi DP, Hysi PG, et al. Common genetic variants near ZNF469 influence central corneal thickness. PLoS Genet. 2010;6(5):e1000947.
  12. Lu Y, Vitart V, Burdon KP, et al. Genome-wide association analyses identify loci associated with central corneal thickness. Nat Genet. 2013;45(2):155–163.
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  14. Karolak JA, Gambin T, Rydzanicz M, et al. Evidence against ZNF469 being causative for keratoconus. Acta Ophthalmol. 2016;94(3):289–294.
  15. Lucas SE, Zhou T, Blackburn NB, et al. Rare ZNF469 variants are not enriched in keratoconus. Invest Ophthalmol Vis Sci. 2017;58(14):6248.
  16. Yildiz E, Bardak H, Gunay M, et al. Novel ZNF469 variants in advanced keratoconus. Curr Eye Res. 2017;42(10):1396–1400.
  17. Kaufmann C, Schubiger G, Thiel MA. Corneal cross-linking for brittle cornea syndrome. Cornea. 2015;34(10):1326–1328.
  18. Izquierdo L, Mannis MJ, Marsh PB, et al. Bilateral spontaneous corneal rupture in brittle cornea syndrome. Cornea. 1999;18(5):621–626.
  19. Stuart A. Genetic disorders of the cornea: preventing surgical surprises. EyeNet Magazine. 2020;24(5):45–46.
  20. Al-Hussain H, Zeisberger SM, Huber PR, et al. Brittle cornea syndrome and delineation from kyphoscoliotic EDS. Am J Med Genet A. 2003;124A(1):28–34.

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