Brittle Cornea Syndrome
Brittle Cornea Syndrome (BCS) is a rare autosomal recessive connective tissue disease characterized by progressive corneal thinning and blue sclera, resulting in increased susceptibility for perforation and rupture. First described by Israeli ophthalmologist, Dr. Richard Stein in 1968, who stated that the cornea broke into “crumbs” during suturing in an attempt to repair a brittle cornea following perforation.
BCS is genetically heterogeneous. There are 2 types of BCS;
- 1. Brittle Cornea Syndrome Type 1: Type 1 results from a homozygous mutation in the zinc finger protein-469 gene (ZNF469/KIAA1858) on chromosome 16q24. Genome-wide association studies have associated this locus with changes in central corneal thickness through pathways regulating extracellular matrix. Mutations in ZNF469 have also been associated with keratoconus. In these instances, keratoconus corresponds with heterozygous missense mutations of ZNF469 while BCS corresponds with homozygous frameshift or truncating mutations of ZNF469. Some dispute that ZNF469 mutations are associated with keratoconus due to lack of replicability after larger cohort analyses.
- 2. Brittle Cornea Syndrome Type 2: Type 2 results from a homozygous mutation in the PR domain-containing protein-5 gene (PRDM5/PFM2) on chromosome 4q27. PRDM5 is also implicated in corneal thickness, as well as in development of the retina.
ZNF469 is a single exon gene whose protein product is made up of three, type C2H2, zinc-finger domains near the 3′ end and is involved in sequence-specific DNA-binding motifs and protein-protein interactions. An in vivo study showed decrease in extracellular matrix genes (CLU, GPC6, PCOLCE2, THBS1) in ZNF469 mutant fibroblasts.
The gene product of PRDM5 is involved in the regulation of hematopoiesis-associated protein-coding and microRNA genes that are associated with cell fate and Wnt signaling. PRDM5 has also been implicated in regulation of fibrillar collagens (COL4A1, COL11A1), connective tissue (HAPLN1), and cell migration/adhesion (EDIL3, TGFB2).
An in vivo study of fibroblasts from cultured BCS patients demonstrated that genes (COL4A1, COL11A1, EDIL3, HAPLN1, TGFβ2) involved in the development and maintenance of the extracellular matrix were reduced. Additionally, immunofluorescence of the fibroblasts showed disruption in the organization of collagens type I/III, fibronectin, and α2β1/α5β1 integrins, all a part of the extracellular matrix.
Patients usually first present in childhood with corneal perforation or rupture, and mean age of rupture occurs around 4.3 years (range 1.5-19 years) according to reported literature. Family history is often remarkable for consanguinity.
Signs & Symptoms
Progressive corneal thinning (i.e. keratoconus, keratoglobus, irregular astigmatism) is an initial sign of the disease, which can lead to perforation or rupture. BCS patients have central corneal thickness that is less than 400 μm. Scarring of the cornea may be found in areas where perforation has occurred. Other ocular signs may include blue-colored sclera, high myopia and/or retinal detachment. Blue sclerae are characteristic of decreased scleral thickness.
Systemic signs can consist of joint hypermobility, skin hyperelasticity, hypercompliant tympanic membranes, osteopenia, hip dysplasia, arachnodactyly, contractures especially of the fifth digit, hypotonia in infancy, abnormal dentition, hernias, scoliosis or kyphoscoliosis. Patients may also have hearing loss, which can be conductive or sensorineural, however this mechanism is unclear since both types have been found in BCS patients. BCS has also been associated with red hair.
- Kyphoscoliotic Ehlers Danlos Syndrome: BCS has many intersections with other types of EDS, especially the kyphoscoliotic type. BCS was previously considered kyphoscoliotic type. Kyphoscoliotic type and BCS patients share similar signs of kyphoscoliosis, dental abnormalities, arachnodactyly, hypermobility, osteopenia, and hypotonia in infancy. Kyphoscoliotic type patients differ in their tendency for arterial rupture and early death due to cardio-pulmonary insufficiency. Additionally, ocular rupture is usually scleral rather than corneal. Kyphoscoliotic type is due to a deficiency in lysyl hydroxylase-1, which is involved in post-translational modification of collagen. This type can be diagnosed by increased urinary output of total pyridinoline content and lysyl pyridinoline (to hydroxylysyl pyridinoline), while this is normal in BCS patients. Additionally, collagen α-chains in kyphoscoliotic type show faster electrophoretic migration, while this is normal in BCS patients.
- Marfan syndrome: Marfan syndrome and BCS patients share similar signs of blue sclerae and ocular fragility. Marfan syndrome patients differ in their tendency for aortic dissection, tall stature, and ectopia lentis.
- Osteogenesis imperfecta: Osteogenesis imperfecta and BCS patients share similar signs of blue sclerae, thin corneas, conductive hearing loss, abnormal dentition, and skin hyperelasticity. Osteogenesis imperfecta patients differ by having recurrent fractures.
Diagnosis is made based on the presence of the signs and symptoms described. If there is personal or family history of ocular rupture or BCS, genetic testing is implicated. Genetic testing for carriers may inform those with risk for keratoconus and aid genetic counseling. Genetic panels for BCS available in the United States are listed here.
Changes in corneal thickness would be measured by optical coherence tomography, topography, or pachymetry, hearing loss would be assessed by audiometry, and musculoskeletal changes would be evaluated by x-ray or ultrasound.
The main treatment for Brittle Cornea Syndrome (BCS) patients is early diagnosis and taking measures to prevent corneal perforation. Protective eyewear (such as polycarbonate glasses and/or eye shield), and disease education to parents and school staff is very valuable in decreasing risk of perforation and thereby decreasing the inevitable risk of loosing vision from trauma. Surgical management of corneal perforation is challenging given high risk of wound leakage. Dr. Ken Nischal, Director of Pediatric Ophthalmology at the University of Pittsburgh, recommends an overlay epikeratoplasty graft for additional ocular protection. An overlay graft may also permit future penetrating keratoplasty, which is often indicated for BCS patients in instances of severe scarring or thinning of the cornea. Dr. Nischal recommends performing a paracentesis prior in order to lower the intraocular pressure, to allow the tissues to appose one another during suturing, although often a tube shunt is required. Additionally, he recommends making a smaller incision than intended due to the incisions' tendency to expand. Finally, he advises prophylactic use of glaucoma medications for BCS patients to prevent development of glaucoma and also to reduce risk for spontaneous rupture.
In a penetrating keratoplasty performed on a BCS patient with corneal scarring by Dr. Luis Izquierdo and colleagues, an intraoperative corneal rupture occurred after attempt to rotate a 10-0 nylon knot. They subsequently patched this area with a scleral patch graft, though this was described as difficult due to the tissue thickness difference between the donor and recipient as well as the delicacy of the recipient tissue. Ultimately, the graft was successful and vision improved. They recommend longer suture bites into the recipient cornea for better security between the two tissues and to reduce risk of cheese-wiring. They also recommend patching scleral or corneal allografts onto weak areas. Though they did not use 11-0 nylon, they mentioned that this size could be better than 10-0 for these cases. More recently, single-stage central lamellar keratoplasty has been described in the literature with peripheral "intra-lamellar tucking" for increasing peripheral corneo-scleral strength and for better visual outcomes in keratoglobus patients.
Corneal collagen cross-linking has been tried in an attempt to slow or reverse thinning of the cornea associated with BCS, however some disagree if this would be appropriate given the nature of BCS. In one patient diagnosed with BCS, epi-on crosslinking did not result in corneal perforation. In a different keratoconic patient with ZNF469 mutations, both epi-on and epi-off crosslinking resulted in subsequent spontaneous corneal perforation.
Enucleation is the last, and unfortunately, most frequently considered option when the rupture is beyond repair. Associated signs such as retinal detachment and myopia can be treated as usual, as well as other systemic effects such as hearing loss and musculoskeletal problems.
Unless precautions are taken (e.g. protective eyewear) to prevent even minor ocular trauma or impacts, blindness following perforation or rupture is inevitable and is the outcome in more than half of published cases. However, perforation or rupture can also occur spontaneously.
Overall, BCS has better prognosis than its close relative, kyphoscoliotic type, as life expectancy appears to be normal and the extra ocular manifestations of BCS are non-life threatening. Many families with BCS have been investigated for non-accidental trauma, some resulting in children being taken from their parents' care, emphasizing the significance of bringing attention to BCS.
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