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Corneal thinning and extreme fragility are characteristic of BCS2. Ruptures of the cornea may occur with minimal trauma and repair is often unsatisfactory due to the lack of healthy tissue. Keratoconus, acute hydrops, keratoglobus, and high myopia are frequently present as well. Some patients have sclerocornea that obscures the normal limbal landmarks. The sclera is also thin and the underlying uveal tissue imparts a bluish discoloration to the globe which is especially evident in the area overlying the ciliary body creating what some call a blue halo.
Skin laxity with easy bruisability, pectus excavatum, scoliosis, congenital hip dislocation, a high arched palate, mitral valve prolapse and recurrent shoulder dislocations are often present. Hearing impairment with mixed sensorineural/conductive defects is common.
This autosomal recessive disorder results from homozygous mutations in PRDM5 (4q27). Heterozygous carriers may have blue sclerae, small joint hypermobility, and mild thinning of the central cornea.
Treatment for specific defects such as joint dislocations and mitral valve malfunction may be helpful.
Blue sclerae, especially at infancy, is the most visible ocular sign in osteogenesis imperfecta but it is not always present. It is also often present in normal infants. In some patients, it is present early but disappears later in life. Some patients have significantly lower ocular rigidity, corneal diameters, and decreased globe length. Interestingly, the intensity of the blue color in the sclerae does not seem to be correlated with scleral rigidity.
A defect in type I collagen leading to brittle bones and frequent fractures is the systemic hallmark of this group of disorders. Clinical and genetic heterogeneity is evident. The nosology is as yet not fully established and will likely require more molecular information. Type I is considered the mildest of the several forms that have been reported. Relatively minor trauma during childhood and adolescence can lead to fractures while adults have less risk. Fractures generally heal rapidly without deformities and with good callous formation in patients with milder disease. However, those with more serious disease often end up with deformities and bowed bones.
Short stature, hearing loss, easy bruising, and dentinogenesis imperfecta are often seen as well.
Type II is more severe and fractures often occur in utero. Fractures may involve long bones, skull bones and vertebrae. At birth the rib case appears abnormally small and the underdeveloped pulmonary system may lead to severe respiratory problems and even death in some newborns.
A number of conditions are associated with fragile bones and the classification of these in the early literature is confusing. More confusion arises from classification schemes based solely on clinical degrees of severity.
The designation ‘osteogenesis imperfecta’ is most accurately applied to disorders caused by construction defects in type I collagen fibers which are responsible in 90% of affected individuals. The defect may occur in either the pro-alpha 1 or pro-alpha 2 chains which together form type I collagen. The responsible genes are COL1A1 (17q21.31) and COL1A2 (7q22.1). Clinical types I (166200), IIA (166210), III (259420), and IV (166220) map to these two loci. The inheritance pattern is autosomal dominant.
Mutations in the CRTAP gene (610854; 3p22) cause an autosomal recessive OI-like phenotype classified as type IIB and VII while type VIII is an autosomal recessive OI-like disorder secondary to mutations in LEPRE1 (610915; 1p34). However, these disorders, while clinically sharing some features of true OI, are better designated as separate conditions based on their unique molecular etiologies.
Avoidance of trauma is paramount. Periodic intravenous administration of pamidronate can increase bone density and reduce the risk of fractures. Oral bisphosphonates do not seem to be beneficial. Prompt reduction of fractures is important to the prevention of deformities. A multidisciplinary team is important for the treatment and rehabilitation of patients.
The globe is thin and fragile and ruptures easily. This results from scleral fragility which is in contrast to type VIB EDS (229200) in which the cornea seems to be more fragile. Retinal detachment is always a risk but no quantitative assessment can be made since early case reports did not always provide good classification of EDS types. Other ocular abnormalities such as keratoconus and structural changes in the cornea are less common but frequent changes in classification and lack of genotyping in early cases make definitive clinical correlations difficult.
The primary clinical manifestations of this form (VIA) of Ehlers-Danlos syndrome are extraocular. The skin is soft, thin, easily extensible, and bruises easily. The joints are highly flexible with a tendency to dislocate. Arterial ruptures are not uncommon, often with severe consequences. Scoliosis begins almost at birth and often progresses to severe kyphoscoliosis. Patients are floppy (hypotonic). Intellect is normal and there are generally no developmental delays. Thirty per cent of infants have a club foot at birth.
This an autosomal recessive disorder caused by molecular defects in the PLOD1 gene (1p36.3-p36.2). The gene product is an enzyme, lysyl hydroxylase 1, important for the normal crosslinking of collagen. Mutations in PLOD1 may result in hydroxylase dysfunction with abnormal hydroxylation of lysine, weakened crosslinks, and fragile tissue.
Joint dislocations, ocular trauma and vascular ruptures require prompt attention. Longevity is not impacted by this syndrome.
This seems to be a subtype of the Ehlers-Danlos syndrome in which the ocular features are prominent. The cornea is thin and can perforate following relatively minor trauma. It is often misshapen as well resulting in keratoglobus and keratoconus. The external appearance can suggest buphthalmos but intraocular pressure is normal. The sclerae are bluish suggesting that the connective tissue defect is more widespread among eye tissues. The lens is not hypermobile, however. This disorder differs from Ehlers-Danlos type VIA (225400) (sometimes called the ocular-scoliotic form) in which there is a defect in lysyl hydroxylase although the ocular phenotype has some similarities.
The skin is hyperelastic as in other forms of Ehlers-Danlos and the joints are hypermobile and are susceptible to dislocation. Some but not all cases reported from the Middle East have red hair and it has been suggested this may be part of the syndrome, at least in that part of the world.
A mutation in the ZNF469 gene (16q24), encoding a zinc finger protein, is responsible for at least some cases of autosomal recessive brittle cornea syndrome. This confirms its identity as a unique type of connective tissue disease apart from other forms of Ehlers-Danlos in which ocular disease is present (such as type VIA in which the mutation is in the PLOD1 gene).
Treatment beyond corneal repair is limited.