8.2 Scleral Thinning (Blue Sclerae)

blood rises above 1.5 mg/100 ml; bilirubin binds strongly to the elastin fibers of the sclera.

Unilateral yellow discoloration of the sclera may appear after choroidal hemorrhage following surgery for retinal detachment; [76] the yellow staining is due to accumulation of unconjugated bilirubin derived from the breakdown of hemoglobin from the hemorrhage; bilirubin binds weakly to the elastin and to the collagen fibers of the sclera.

Although the exact biochemical defect is not known, the disorder is thought to be caused by a basic anomaly of connective tissue.

The most conspicuous physical features of a patient with Marfan’s syndrome are the musculoskeletal defects. There is a generalized overgrowth of long bones; patients are tall and have long slender fingers and toes (aracnodactylia). Prognathism, high arched palate, kyphoscoliosis, pectus excavatum, muscular hypoplasia, and hypotony also are characteristic. Cardiovascular anomalies include degeneration of the tunica

Bluish sclera, although considered normal in premature infants and in white newborns, is pathologic if it persists beyond the first month of infancy. Several inherited or congenital disorders may be associated with blue sclerae. The blue color is due to translucency of the sclera as a result of scleral thinning, allowing the uveal pigment to show through.

Other causes of blue sclerae are acquired disorders, the most common being iron-deficiency anemia [77–82]. Iron is an important cofactor in the hydroxylation of proline and lysine residues in collagen synthesis. Fibroblasts in culture do not synthesize collagen in the presence of iron-chelat- ing agents [80]. Iron deficiency in vivo may lead to impaired collagen synthesis and a thin sclera through which the choroid can be seen, making the sclerae appear blue. Blue sclerae also may be seen associated with myasthenia gravis [83].

8.2.1Scleral Thinning in Inherited or Congenital Diseases

8.2.1.1 Marfan’s Syndrome

Marfan’s syndrome, as it was described in 1896, is a congenital mesodermal dystrophy classically characterized by the triad of subluxated lenses, skeletal abnormalities, and cardiovascular disease. Marfan’s syndrome also may involve lungs, muscles, genitourinary system, skin, and nearly every structure of the eye, including the sclera [84, 85]. This autosomal-dominant condition affects both sexes equally and is seen in all races.

which may cause dissecting aneurysms.

Other ocular manifestations aside from subluxated lenses include myopia, ptosis, megalocornea, strabismus, hypoplasia of the iris dilator muscle, spherophakia, glaucoma, peripheral retinal degeneration, and blue sclerae. Since the anomalous scleral connective tissue is unable to resist elevated intraocular pressure, it allows the intraocular contents of the globe to bulge, producing a staphyloma. Cataract formation, lens dislocation, and glaucoma may necessitate ocular surgery, but surgical complications, such as vitreous loss and incarceration in the wound, iris prolapse, hyphema, persistent anterior uveitis, and corneal edema are seen more often in these patients than in the general population [86, 87].

The diagnosis is clinical; approximately 50% of patients with Marfan’s syndrome are diagnosed by the ophthalmologist, usually because of myopia not adequately corrected by lenses. The differential diagnosis is principally from homocystinuria, an inborn error of amino acid metabolism which is also characterized by subluxated lenses, myopia, strabismus, spherophakia, glaucoma, peripheral retinal degeneration, long slender extremities, kyphoscoliosis, and pectus excavatum; however, scleral connective tissue in homocystinuria is thicker and more resistant to high intraocular pressure than in Marfan’s syndrome. The diagnosis in homocystinuria is established by amino acid electrophoresis and chromatography of urine and plasma [88].

Any patient with congenital blue sclerae should be questioned and examined for skeletal

anomalies and cardiovascular disease. The immediate family also should be evaluated.

8.2.1.2 Osteogenesis Imperfecta

Osteogenesis imperfecta (van der Hoeve’s syndrome) is a genetically determined defect in the synthesis of extracellular matrix leading to abnormalities in connective tissue, primarily collagen, and proteoglycans. Partially described in 1896 by Spurway [89] and in 1900 by Eddowes [90], and completely described in 1918 by van der Hoeve [91], osteogenesis imperfecta is characterized by the triad of blue sclerae, brittle bones, and deafness (otosclerosis) [92]. It may be inherited as either an autosomal dominant or autosomal recessive condition; the autosomal recessive form is associated with more severe skeletal abnormalities. Osteogenesis imperfecta has an incidence of 1 in 20,000 births, affects both sexes equally, and is seen in all races [93]. The disorder is caused by anomalies at the level of the type I collagen genes which result in the failure of type I collagen fibers to mature to their normal diameters. Individual variants result from a structural or regulatory abnormality of the alpha1 or alpha2 chains of type I collagen.

Two classifications have been proposed for osteogenesis imperfecta. The oldest one classifies the disease into the congenital form, which is manifest at birth, leading to early death, and the tarda form, which is manifest early in childhood and has a relatively benign course [94, 95]. In the congenital form, musculoskeletal defects, including extremity deformities, rib fractures, and muscular hypotony, may be detectable at birth. In the tarda form, fractures may occur at 2–4 years of age, and skeletal deformities, such as scoliosis may become manifest early in life. Some patients with osteogenesis imperfecta tarda do not have gross bony abnormalities and go through life without a fracture; the disease is limited to minimal radiologic defects associated with ear manifestations and blue sclerae. Deafness occurs in 30% of these patients. Other ear abnormalities may include tinnitus and vertigo [96, 97].

Osteogenesis imperfecta also may be classified into types I, II, III, and IV, on the basis of inheritance, clinical features, and severity [93].

Blue sclerae, the most characteristic ocular manifestation in all types of osteogenesis imperfecta [93, 95], are due to increased thinness of the scleral wall allowing the visualization of the underlying uveal layer. Ocular histopathologic examination reveals a 50–75% thinning of the sclera. Osteogenesis imperfecta patients with blue sclerae have significantly lower ocular rigidity measurements than do patients without the disease [98]. The Saturn ring, a white ring in the paralimbal sclera, is a common finding; the lack of uvea behind the sclera in the paralimbal area gives a comparative whitening aspect. The corneas also are thin and vulnerable to perforation from minor trauma. Sclera and cornea can usually withstand the normal intraocular pressure, but elevated pressures will produce a staphyloma.

Ultrastructurally, the scleral and corneal fibers in eyes of patients with osteogenesis imperfecta appear immature. There have been some reports showing either a decreased number [99, 100], or a reduced diameter [101–106] of collagen fibers in both the sclera and the cornea. An ultrastructural study revealed vacuoles in the endoplasmic reticulum of scleral fibrocytes and in keratocytes, as well as deposits (possibly chondroitin sulfate) between the scleral lamellae, suggesting a disturbance of the fibroblasts [107]. In addition to abnormalities of collagen, biochemical quantitative and qualitative defects of glycosaminoglycans also have been reported [108]. Keratoconus, megalocornea, hypermetropia, posterior embryotoxon, zonular cataracts, retrobulbar neuritis, optic atrophy, and glaucoma may develop.

The diagnosis of osteogenesis imperfecta is clinical. Any patient with congenital blue sclerae should be examined for skeletal and ear abnormalities. The immediate family also should be evaluated.

8.2.1.3 Pseudoxanthoma Elasticum

Pseudoxanthoma elasticum is an autosomal recessive disorder characterized by skin elasticity; small yellow papules and plaques eventually form redundant folds typically located on the neck, antecubital and popliteal fossae, abdomen, perineum, thighs, axillas, and groin areas [108]. Angioid streaks of the retina, gastrointestinal

bleeding and cardiovascular abnormalities also develop [109–111]. Thin blue sclerae may appear in pseudoxanthoma elasticum patients and in their relatives [81]. Pseudoxanthoma elasticum usually begins by age 30, although it may appear at a younger or older age, and is more common in women than in men (2:1). Although the exact biochemical defect is not known, the disorder is thought to be caused by abnormal formation of the elastic fibers of connective tissue [112]. Angioid streaks of the retina, occurring in 85% of the patients, consist of cracks in an abnormal Bruch’s membrane which may interfere with visual acuity if they involve the macular area [108, 109, 113, 114]. Angioid streaks may not be visible on fundus examination, but they can be clearly seen on fluorescein angiography.

The diagnosis of pseudoxanthoma elasticum is based on clinical findings. Any patient with congenital blue sclerae should be examined for skin and retinal abnormalities. The immediate family also should be evaluated.

8.2.1.4 Ehlers–Danlos Syndrome

Ehlers–Danlos syndrome is a multisystem genetic disorder characterized by hyperelasticity and fragility of the skin; bleeding, atrophic scars, and even hemangiomatous pseudotumors often occur after minor trauma around joints or pressure points [115]. Other findings include hyperextensibility of the joints, particularly those of the fingers, toes, and knees, blood vessel fragility, with varicose veins or aneurysms and arterial ruptures, and ocular abnormalities, such as marked epicanthal folds, angioid streaks, strabismus, keratoconus, keratoglobus, microcorneas, subluxated lenses, retinal detachment, severe myopia, or blue sclerae [116–124]. Ehlers–Danlos is usually an autosomal-dominant condition, although it may be recessive in some families.

At least nine types of Ehlers–Danlos syndrome have been described depending on inheritance, clinical features, severity, ultrastructural abnormalities, and biochemical defects. In type VI or ocular-scoliotic form of Ehlers–Danlos, ocular features are prominent; it is also characterized by severe scoliosis and joint and skin disturbances. Within the ocular features, thin

blue sclerae may lead to spontaneous perforation of the sclera [125]. Surgery should be avoided, if possible, because of the high incidence of complications secondary to fragility of tissues [126, 127]. The ocular-scoliotic form of Ehlers–Danlos syndrome has been associated with a primary deficiency of the enzyme lysyl hydroxylase [94, 128, 129]. Lysyl hydroxylase converts lysine to hydroxylysine; aldehydes which cross-link spontaneously are formed. A deficiency in lysyl hydroxylase results in a lack of collagen cross-linking and, subsequently, in a weakened connective tissue; however, normal enzyme levels have been described, suggesting that the ocular form of Ehlers–Danlos syndrome has some degree of genetic heterogeneity [130].

The diagnosis of Ehlers–Danlos syndrome is based on clinical findings. Any patient with congenital blue sclerae should be examined for skin and joint abnormalities, marked epicanthal folds, and retinal findings. The immediate family should also be evaluated.

8.2.1.5 Keratoconus

Blue sclerae or scleral thinning may occur in association with keratoconus [124]. Keratoconus or ectatic corneal dystrophy is a disorder characterized by corneal thinning of the central cornea; conical ectasia or protrusion may occur leading to a painless, progressive loss of vision due to a progressive irregular myopic astigmatism. Heredity plays a significant role in at least some keratoconus patients [131–135], although the majority of cases show no definitive inheritance pattern. In the early form, distortion of keratometric mires or retinoscopic reflex occurs. In the advanced form, Vogt’s striae or a Fleisher ring may be seen. Vogt’s striae are fine vertical folds in the deep stroma and Descemet’s membrane that parallel the steep axis of the cone. A Fleisher ring is a yellow brownish corneal epithelial pigment ring localized around the base of the cone; the color is due to deposition of ferritin in the subepithelium. Breaks in Bowman’s layer, enlarged corneal nerves, increased intensity of the corneal endothelial reflex, and fine subepithelial fibrillary lines also may occur.