Ocular Manifestations of Autosomal Dominant Systemic Conditions
Steven E. Rubin
Leonard B. Nelson
This chapter reviews those autosomal dominant conditions that have associated eye findings. Familiarity with these ocular manifestations places the ophthalmologist in a unique position of helping to provide a systemic diagnosis in affected patients.
AUTOSOMAL DOMINANT INHERITANCE
Heritable conditions that follow mendelian genetics are either autosomal dominant, autosomal recessive, X-linked dominant, or X-linked recessive. Characteristics of the nonautosomal dominant modes of inheritance are reviewed elsewhere.
An autosomal dominant trait must exhibit certain characteristics. There must be vertical transmission (i.e., the trait appears in consecutive generations). A heterozygote exhibits the trait in some way. A parent of either gender with the trait passes it on to 50% of his or her children independent of the gender of the children. (The gender incidence of this trait would then be equal.) Children of unaffected parents are affected only by mutation.
Penetrance and expressivity are two parameters that have bearing on autosomal dominantly inherited disease. Penetrance is the ability of a genotype to be phenotypically detected. If a subject is known to have an autosomal dominant genotype and yet has no detectable phenotype, then that gene is impenetrant. Penetrance is binary; an autosomal dominant gene is either penetrant or impenetrant. Expressivity refers to the degree of variability that a penetrant autosomal dominant trait can have. For example, some affected individuals with neurofibromatosis may have few cutaneous neurofibromas, while others are severely disfigured.
Autosomal dominant diseases can also have seemingly unrelated manifestations in different organ systems and tissues, although only one gene is present. This is called pleiotropy.
MULTISYSTEM DISEASE
MARFAN SYNDROME
A description of what we now call Marfan syndrome was probably first made by Williams, an ophthalmologist, in 1895, who did not include ectopia lentis as a manifestation. Ironically, it was a pediatrician who first published that association in 1914. Marfan’s description of a 5½-year-old child with long, thin extremities, published in 1896, was more widely seen than Williams’ the year before, and hence this syndrome now bears his name.
Marfan syndrome is an autosomal dominant condition with complete penetrance and a high degree of expressivity. It has an incidence of 1:66,000 with a gender ratio of unity.1 Advanced paternal age is associated with the sporadic cases.2
The long arm of chromosome 15 has been identified as harboring the genetic defect for this disorder,3 which results from a point mutation in one of the fibrillin genes.4 Fibrillin is an important component of connective tissue microfibrils that form the framework for elastin deposition and are found in lens zonules, the aorta, and other connective tissue structures. The abnormal fibrillin leads to structural weakness resulting in ectopia lentis, aortic dissection, and other disorders and has been shown to cause syndactyly in mice.5 Recent work has suggested the possible role of matrix metalloproteinases (proteolytic enzymes) as well.6
Marfan syndrome’s nonocular systemic manifestations are found in the skeletal and cardiovascular systems.
Cardiovascular abnormalities are the more significant systemic manifestations. In more than 95% of the cases in which a cause of death can be established, a cardiovascular problem is at fault.7 Dilatation of the aortic root (with or without aortic regurgitation), mitral valve prolapse, and mitral regurgitation are all seen. When aortic root dilatation is demonstrated, therapy with a β-blocker has been suggested to reduce cardiac contractility in an attempt to halt progression of the aortic root dilatation and prevent aortic dissection.8 More definitive work with β-blockers is still needed.
Abnormalities of the skeletal system include scoliosis, arachnodactyly, anterior chest deformities, increased arm span to total height ratio, joint laxity, and a high arched palate. Scoliosis is the most disabling skeletal abnormality. Attempts have been made in female adolescent patients to alleviate this problem with estrogen therapy. These hormones can suppress the adolescent growth spurt that greatly aggravates the scoliosis.
Ocular Manifestations
Of the many ocular abnormalities, by far the most common is ectopia lentis, occurring in 50% to 80% of affected individuals (Fig. 1). It is usually bilateral, symmetric, and nonprogressive. It may be subtle and detectable only by observing phacodonesis or iridodonesis, sometimes visible by gonioscopy. Lens dislocation is usually superotemporal. There can also be posterior displacement, leaving a gap between lens and iris pigment epithelium. When zonules can be seen, a reduced number is usually not observed.
 Fig. 1. Ectopia lentis in a child with Marfan’s syndrome. (Courtesy of Irene H. Maumenee, MD) |
Patients with Marfan syndrome may have poor vision. This often results from delayed and inadequate correction of the extremes of refractive error9 (especially moderate to high myopia). These and other factors, which compromise visual input, may be responsible for the increased incidence of strabismus seen in patients with Marfan syndrome.10
In Marfan syndrome, an increased axial length may also be seen. A slightly higher than normal axial length is common in patients with Marfan syndrome who have no ectopia lentis or retinal detachment. However, the axial length is higher in those patients with ectopia lentis and is even higher in those patients with retinal detachment.11 Other retinal associations include lattice degeneration and atrophic holes.
Abnormalities may also be seen in the uveal tract. Choroidal thinning has been described in myopic eyes. The iris morphology is often striking. There can be a complete absence or marked reduction in the number of furrows or crypts, giving the anterior iris surface a smooth, velvety appearance (Fig. 2). Hypopigmentation of the iris pigment epithelium has been described12,13 which probably corresponds to the transillumination of the iris base that is seen in 10% of cases.
 Fig. 2. Velvety-smooth iris in a patient with Marfan’s syndrome. |
The cornea can also be affected. Patients with Marfan syndrome can have flatter than average keratometric readings.11,14 Megalocornea15 may also be present. In eyes with ectopia lentis (with or without retinal detachment), keratometric readings may show steepening in the meridian of the lens dislocation.
Other, nonspecific findings have been described in the few ocular histologic studies that have been performed in Marfan syndrome. Separation of individual zonular fibers into their composite filaments9 and angle anomalies (such as pectinate ligaments) have been reported.12,13,16 Common to several pathologic studies is the large size of the globe corresponding to the larger axial lengths measured clinically.
THE PHACOMATOSES
The phacomatoses are a group of heredofamilial conditions that all have as a hallmark various hamartomas. The term comes from the Greek term for birthmark (“mother spot”). Hereditary hamartomatosis has been suggested as a better name for these diseases.17 We only consider the autosomal dominant disorders in this chapter (neurofibromatosis, tuberous sclerosis, and angiomatosis retinae). Despite the lack of hard evidence for autosomal dominant transmission, encephalotrigeminal angiomatosis (Sturge-Weber syndrome) is also discussed for completeness.
Neurofibromatosis
Manifestations of this condition had been observed for ages before being described by Robert William Smith in 1849.18 The more classic description was given by the German pathologist, Friedrich Daniel von Recklinghausen, who accurately described the diverse findings as a single entity in 188219; it is often referred to as von Recklinghausen’s disease. Probably because of the complex effects on these patients’ personality as a result of the sometimes severe disfigurement, neurofibromatosis maintains a high profile in the lay press20,21,22,23,24 and literature (e.g., The Elephant Man, a 1979 Broadway production written by Bernard Pomerance, and a 1980 British motion picture, although the correct diagnosis for the patient portrayed in those works was probably Proteus syndrome25).
Neurofibromatosis is a proven autosomal dominant condition with variable penetrance and a high degree of expressivity. It is estimated to occur once per 3,300 live births.26 Children of affected mothers are more severely affected than children of affected fathers; no clear mechanism is known for this maternal effect.
Recent work has allowed the division of this disorder into two major autosomal dominant conditions. Neurofibromatosis 1 (a defect on chromosome 17)27 now refers to the much more common, classic syndrome with the wide-ranging systemic and ocular manifestations described below. Neurofibromatosis 2 results from an abnormality on chromosome 22.28,29 This less common variant denotes the syndrome of bilateral acoustic neuromas that may also include neurofibromas and café-au-lait spots.
Although clinical findings are primarily neurocutaneous in nature, any organ system can be involved. The diagnosis requires six or more café-au-lait spots, each larger than 1.5 cm in diameter (Fig. 3). Axillary freckling is also highly suggestive of the diagnosis.30,31(pp508–509) Areas of hypopigmentation or hyperpigmentation can also be seen.
 Fig. 3. A 13-year-old patient with neurofibromatosis. Note the large café-au-lait spot at the base of the neck. |
The cutaneous tumors, which are common and can be extremely disfiguring, take one of three forms. A fibroma molluscum is usually referred to as the common neurofibroma. This hamartoma is the proliferation of peripheral nerve elements at the distal end of a cutaneous nerve. A plexiform neurofibroma (Fig. 4) has the appearance of a “bag of worms” and represents a diffuse proliferation of tissue within the nerve sheath. The most marked cutaneous change results from diffuse proliferation outside the sheath, elephantiasis neuromatosa. When a hamartoma develops in a restricted space, a compromise in that nerve’s function can occur.
 Fig. 4. Plexiform neurofibroma in right upper lid of a patient with neurofibromatosis. (Courtesy of David B. Schaffer, MD) |
Neurofibromas may occur anywhere in the central nervous system. They can produce a neurologic deficit corresponding to the affected nerve. Although these neurofibromas are generally benign, malignant change has occurred.32(p1) Meningiomas can also be seen with a higher incidence than the general population, especially involving the orbital portion of the optic nerve.33 When they occur in this location, they are more aggressive than their benign counterparts found in other locations.
Pheochromocytoma has been noted more frequently in patients with neurofibromatosis than in the general population, although it may be difficult to distinguish the clinical features of neurofibromatosis from multiple endocrine neoplasia (MEN) type IIb, in which pheochromocytomas also occur along with neuromas, café-au-lait spots, and prominent corneal nerves.34(p31–32) Other tumors, such as rhabdomyosarcoma and liposarcoma, have rarely been reported with this disorder which may represent an unrelated association.32(p1)
Skeletal deformities, unrelated to the neural tumors, may also occur. Scapular elevation, asymmetries or absences of long bones, misshapen sphenoid or absence of its greater wing, scoliosis, spina bifida, rib fusion, and many others have all been described (Fig. 5).26,31(pp508–509),32(p1)
 Fig. 5. Scoliosis and café-au-lait spots in a patient with neurofibromatosis. (Courtesy of David B. Schaffer, MD) |
Individuals affected with neurofibromatosis 2 often have bilateral acoustic neuromas, which are Schwann cell tumors arising from the vestibular nerves, producing hearing loss or unsteadiness of gait in the second or third decade of life.28 Café-au-lait spots, cutaneous neurofibromas, and plexiform neurofibromas may also be seen in these patients and may even predate the acoustic nerve symptoms.
OCULAR MANIFESTATIONS.
Ocular involvement in neurofibromatosis involves the cornea, uvea, trabecular meshwork, optic nerve, and retina. Corneal nerves can be thickened; the nerves in the conjunctiva may be thickened as well. Along with an increased incidence of pheochromocytoma, corneal nerve hypertrophy is also seen in multiple endocrine neoplasia. The significance of this commonality is as yet unknown.
Hamartomas of the iris (melanocytic nevi) can be seen and are called Lisch nodules (Fig. 6). They are variable in size and have a smooth, domeshaped configuration.35 One series35 found these nodules in 92% of their affected population above the age of 6 years; this may mean that their absence prior to that age does not rule out their later occurrence. Hamartomas may also be seen in the trabecular meshwork.34(p30) In a more recent series, the incidence of Lisch nodules was 100% of patients with neurofibromatosis beyond the second decade of life.36
 Fig. 6. Lisch nodules of the iris in a patient with neurofibromatosis. |
Congenital glaucoma may occur in neurofibromatosis. If the upper lid is affected by a neurofibroma, then the eye on that side has a 50% chance of having glaucoma.34(p30)
The retina and optic nerve head may also be involved with hamartomas; in contradistinction to the uveal hamartomas, which are usually melanocytic nevi, the retinal and optic nerve head hamartomas are generally of glial elements.
Posterior to the papilla, the optic nerve may be involved by a glioma, which is different from the acquired gliomas of adulthood. The optic nerve glioma of neurofibromatosis is a true hamartoma, more accurately described34(p30) as a juvenile pilocytic astrocytoma. They are generally benign, but malignant degeneration has been known to occur following radiotherapy.37 Gliomata of the anterior visual pathway (nerve and chiasm) may occur in 15% of patients with neurofibromatosis using computed tomography (CT) scan criteria.38 In all patients with optic nerve gliomata, the incidence of neurofibromatosis is 25%. The glioma may produce proptosis and visual loss.39
The hamartomas may also be found in the nonocular neural elements of the orbit, most commonly as plexiform neurofibroma or neurilemmoma, possibly causing proptosis. Also, absence of the greater wing of the sphenoid may occur, resulting in pulsatile exophthalmos.
Ocular involvement in neurofibromatosis 2 is much less frequent and extensive than in type 1. Approximately half of affected patients have cortical or posterior subcapsular opacities.40 Lisch nodules, which can be diagnostic of neurofibromatosis 1 when multiple, are rarely seen in neurofibromatosis 2.36
TUBEROUS SCLEROSIS
This disorder is occasionally referred to as Bourneville’s disease, after Desiré Maglorie Bourneville, the French physician who, in 1880, described the triad of seizures, mental retardation, and cutaneous changes.41 The multiple “potatolike” tumors found in the brain gave rise to the term tuberous sclerosis, as named by Bourneville.
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