Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition

Ocular Manifestations of Systemic Disease

28

Skeletal

Alex V. Levin

Thomas W. Wilson

Skeletal and connective tissue disorders will often have significant ocular manifestations. The connective tissue disorders are often the result of defects within tissue collagen. The abnormal collagen leads to structural weaknesses of the cornea, sclera, lens zonules, and Bruch membrane. These defects also cause systemic disorders of the skin, musculoskeletal system, heart, and vascular system. Collagen abnormalities of the cornea result in keratoconus and keratoglobus (Chapter 5: Cornea, Figures 5.18 through 5.20). Structural defects within the sclera lead to globe elongation resulting in high myopia, retinal detachment, and susceptibility to ruptured globe following minor trauma. Weakness of the Bruch membrane (the basement membrane of the retinal pigment epithelium) results in angioid streaks and subsequent vision-threatening subretinal neovascular membrane. Ectopia lentis is secondary to abnormal lens zonules. Vitreous collagen abnormality may lead to retinal detachment.

Similar defects in collagen may affect the heart valves and vascular tissues. Patients may present with an ocular problem and have a life-threatening systemic abnormality. One example would include a patient with Marfan syndrome presenting with symptoms of ectopia lentis and aortic root dilation detected before aneurysmal rupturing. A patient presenting with acute changes in vision secondary to angioid streaks and subretinal neovascular membrane may have the potential for severe uterine or gastrointestinal bleeding. Ocular abnormalities may be the key factor in the identification of a skeletal system disorder that also has other associated serious systemic abnormalities.

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Figure 28.1 Stickler Syndrome

Stickler syndrome is an autosomal dominant–inherited disorder with ocular and systemic features. The underlying abnormality is in the production of type 2A1 (12q13.11), 11A1 (1p21), or 11A2 (6p21.3) collagen. The latter form does not have ocular signs. Clinical features include high myopia, wedge-shaped cortical cataract, optically empty vitreous, perivascular lattice, and retinal detachment. Systemic findings include midfacial hypoplasia with Pierre Robin sequence, deafness, heart valve abnormalities, and progressive arthropathy. This photograph demonstrates pseudoproptosis from the axial myopia as well as the characteristic facies with midface hypoplasia and flat nasal bridge.

 

Figure 28.2 Pierre Robin Sequence

The Pierre Robin sequence is also associated with Stickler syndrome. This complex includes micrognathia, high arched or cleft palate, and relative glossoptosis. The primary defect is the failure of the fetal mandible to grow. This leaves the tongue in an elevated position, which prevents closure of the palatal shelves. Approximately one-third of patients with Pierre Robin sequence have no systemic manifestations, one third have a recognizable syndrome, and one third have other manifestations but no recognizable syndrome. The ophthalmologist must be careful when examining children with Pierre Robin sequence in the supine position, as the tongue may obstruct the airway. In this child, recurrent tongue obstruction led to the need for tracheostomy.

 

Figure 28.3 Stickler Syndrome— Cortical Wedge Cataract

Cataracts are common in patients with Stickler syndrome, but due to the peripheral location, they may not require surgery. However, more visually significant cataracts may occur including presenile nuclear sclerosis and even total white cataract. The cataract in this photograph is the classic wedge-shaped cataract and is not causing any visual loss. Due to the vitreous abnormalities in this syndrome and the high risk for retinal detachment, it is advisable not to invade the posterior capsule during surgery. Fortunately, cataract surgery is rarely needed in infancy.

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Figure 28.4 Stickler Syndrome— Vitreous Abnormalities

The vitreous of patients with Stickler syndrome becomes optically empty. The vitreous is liquefied but may contain freely mobile avascular bands or veils. These bands do not cause significant retinal traction or visual compromise. In Stickler syndrome due to mutations in the COL11A1 gene, the vitreous may be visible but synergetic with beaded fibrils. In this photograph, the vitreous can be seen in the retrolenticular space and fleck-shaped opacities are located with the lens.

 

Figure 28.5 Stickler Syndrome— Perivascular Lattice

The retina of Stickler syndrome is atrophic and is typical of high myopia. The refractive error is typically 8 to 12 diopters and nonprogressive. Ametropic amblyopia can occur if not detected at an early age. Perivascular lattice degeneration, shown here, in the peripheral retina and breaks within the retina are common. Children should be monitored on a regular basis with a peripheral retinal examination because of the high risk of retinal detachment. Stickler syndrome is the most common systemic disorder associated with giant retinal tears in children.

 

Figure 28.6 Marfan Syndrome—Arachnodactyly

Marfan syndrome is a systemic abnormality secondary to mutations in the fibrillin-1 gene at 15q21. Systemic findings are predominantly cardiovascular and musculoskeletal, although other organ systems such as the pleura, skin, and dura may also be involved. Skeletal abnormalities include long arms when compared to the overall height (Marfanoid habitus), arachnodactyly (long, thin fingers and toes,left image), dolichostenomelia (long, thin arms and legs), scoliosis, pectus excavatum (depressed sternum), and pectus carinatum (prominent sternum). The positive thumb sign of Marfan syndrome (Steinberg sign) is when the long thumb can be folded under the fingers and protrudes beyond the ulnar border of the hand (right image). Normal individuals may be able to do this as well.

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Figure 28.7 Marfan Syndrome—Wrist Sign

The positive wrist sign occurs when the patient is able to overlap the thumb and fifth digit wrapped around the opposite wrist. This nonspecific sign may also be seen in normal individuals. Marfan patients also have increased joint flexibility, high arched palate with crowded teeth, and increased incidence of inguinal and umbilical hernias. Cardiac abnormalities can be life-threatening and include dilation and rupture of the aorta and mitral valve prolapse. Cardiac evaluation is an essential part of the ophthalmologist's preoperative workup for all patients with ectopia lentis of unknown cause.

 

Figure 28.8 Marfan Syndrome— Ectopia Lentis

Ectopia lentis occurs in the majority of patients with Marfan syndrome but may be absent. Classically, the lenses are displaced superiorly and laterally but may move in any direction or even stay central with phacodonesis. Lenticular myopia and astigmatism can lead to significant refractive amblyopia in younger patients. Due to the fibrillin abnormality, the zonules are stretched rather than broken as in homocystinuria (Chapter 20: Metabolic, Figure 20.3). As a result, complete dislocation of the lens into the anterior chamber or vitreous is less common. The most amblyogenic period is when the lens edge is within 3 mm of the central visual axis. Where possible, surgery may be avoided by refracting the patient through his or her aphakic visual axis. The risk of postoperative retinal detachment may be as high as 20%.

 

Figure 28.9 Weill-Marchesani Syndrome

Weill-Marchesani syndrome is a disorder that is inherited as an autosomal dominant (mutations in the fibrillin-1 gene, FBN1, at 15q21.1, which also is responsible for Marfan syndrome [Figs. 28.6, 28.7 and 28.8]) or autosomal recessive (mutations in the ADAMTS10 gene at 19p13.3-13.2) disease. The clinical features include short stature, short spadelike hands, brachydactyly, and a depressed nasal bridge. In this photograph, the affected mother's fingers (left side) are smaller than those of her 10 year old daughter(right side). Ophthalmic manifestations include microspherophakia (Chapter 7: Lens Chapter, Fig. 7.20). These globular lenses may dislocate into the anterior chamber. This can lead to angle closure or pupillary block glaucoma. The anterior chamber progressively shallows as the anterior–posterior diameter of the lens increases. Early surgery and avoidance of pilocarpine is advised.

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Figure 28.10 Pseudoxanthoma Elasticum

Pseudoxanthoma elasticum is caused by an abnormal production, calcification, and degeneration of the elastin component of connective tissue. Systemic findings include peripheral vascular, skin, and ocular abnormalities. The disorder may be inherited as autosomal recessive or autosomal dominant, both involving the ABCC6 gene at 16p13.1. This photograph shows weblike folds of the neck and the hypermobility of joints. The skin may have orange-yellowish lesions located in the axillae, popliteal, neck, and groin that form plaques referred to as peau d'orange. Vascular manifestations include a significant risk of gastrointestinal and uterine hemorrhage, cardiovascular disease, peripheral vascular disease, and cerebrovascular disease.

 

Figure 28.11 Pseudoxanthoma Elasticum—Angioid Streaks

Angioid streaks are caused by breaks in the Bruch membrane due to calcification and fragility of elastin fibers. The streaks radiate from the optic nerve. Subsequent formation of subretinal neovascular membranes may lead to hemorrhage and scarring of the macula. The retina may also have a peau d'orange (skin of an orange) appearance secondary to irregular yellowish-orange colored lesions with overlying mottling of the retinal pigmented epithelium. The differential diagnoses of angioid streaks in childhood include pseudoxanthoma elasticum, Ehlers-Danlos syndrome (Fig. 28.12), sickle cell retinopathy, and lacquer cracks of high myopia.

 

Figure 28.12 Ehlers-Danlos Syndrome

Ehlers-Danlos syndrome is an inherited connective tissue disorder with systemic and ocular manifestations. Ehlers-Danlos has at least 10 different clinical subtypes. All types of Ehlers-Danlos have in common hypermobility of the joints (left image). Systemic manifestations also include hyperelasticity and fragility of the skin leading to easy bruising. Patients may develop blue sclera, keratoconus, ectopia lentis, and myopia. In type VI (ocular type), the genetic defect in the enzyme lysyl hydroxylase has been located on chromosome 1p36. In this subtype, the collagen of the cornea is particularly fragile; even minor trauma can lead to a ruptured globe.

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Figure 28.13 Osteogenesis Imperfecta

Osteogenesis imperfecta is an autosomal dominant abnormality of bone strength leading to multiple fractures. The patients will commonly have blue sclera, as shown here. The primary disorder in all subtypes of this disorder is an abnormality in type I collagen (COL1A1 or COL1A2). There are at least four subtypes: Type I—mildest form, some fractures, no bone deformity, may have hearing loss; type II—most severe form, multiple fractures and bone deformity, may be lethal; and types II and III—intermediate severity. One must differentiate the milder forms from nonaccidental trauma (Chapter 12: Child Abuse).

 

Figure 28.14 Kniest Syndrome

Kniest syndrome (metatrophic dwarfism) is a rare abnormality in bone production and growth due to mutations in a gene encoding for the α1 component of collagen II (COL2A1). It is inherited as an autosomal dominant disorder. Patients have midfacial hypoplasia and hypertelorism with or without cleft palate. Hearing loss and arthropathy are common. Ocular findings are similar to Stickler syndrome and include vitreoretinal degeneration and retinal detachment. However, patients with Kniest syndrome may also have congenital glaucoma. Epiphyseal ossification is delayed in the hips, hands, and knees, leading to limited mobility and joint deformities.

 

Figure 28.15 Osteopetrosis

Osteopetrosis is an autosomal recessive bone abnormality characterized by a progressive increase in bone density and thickness. The bone marrow rapidly becomes occupied by the production and lack of reabsorption of normal bone tissue. The increasing thickness of bone within the optic foramen leads to slowly progressive visual loss from optic nerve compression. The axial view of the orbital computed tomography scan (right image) demonstrates the narrowing with the optic foramen and overall thickness and density of the cranium. Proptosis may occur when the orbit becomes increasingly occupied by bone. Retinal dystrophy has been reported in a small number of patients. Thrombocytopenia and anemia occur secondary to the limited capacity of the bone marrow to produce blood cells. This patient has a left sensory exotropia due to optic atrophy, which is worse on that side; proptosis; and severe blepharitis, perhaps due to an altered immune response seen in this disorder.