MARILYN C. KINCAID
Table Of Contents
PHAKOMATOSES (DISSEMINATED HEREDITARY HAMARTOMAS)
|Any of a number of agents may cause malformations of the eye during embryologic
and fetal life; these include genetic abnormalities, infectious
agents, and other teratogens. Often, the specific cause of a given
malformation is unknown.1,2|
In anophthalmia, the orbit lacks an eye. Clinically, however, such an orbit may contain a small, rudimentary eye; thus, the diagnosis of true anophthalmia can be made only after serial sectioning and histologic examination of the orbital tissue.3 Cases of histologically proven true anophthalmia are extremely rare. Clinical anophthalmia refers to the absence of an eye on physical examination alone, and this condition is more common. Anophthalmia may be sporadic, or familial and associated with chromosomal abnormalities.3 The anomaly may occur in the setting of other abnormalities of the ectoderm and mesoderm, such as focal dermal hypoplasia and Waardenburg syndrome.4 There are three types of anophthalmia5:
Cases in which there is histologic evidence of neuroectodermal elements come under the heading of extreme microphthalmia.
Any eye that is smaller than normal at birth is microphthalmic. The normal eye at birth is 16 to 19 mm in diameter; a microphthalmic eye is 15 mm or less. Such an eye may range in size from just smaller than normal to clinical anophthalmia.8
As noted above, an eye may be extremely microphthalmic, simulating anophthalmia. Microphthalmia is a congenital abnormality and should not be confused with atrophia or phthisis bulbi, conditions in which the initially normal eye is shrunken after trauma or disease postnatally. Three types of microphthalmia exist:
CONGENITAL CYSTIC EYE
Another anomaly that occurs very early in embryonic development is congenital cystic eye. This occurs when the optic vesicle fails to invaginate to form the optic cup, as it normally does in the fourth gestational week. Ocular structures that originate from surface ectoderm (the lens, corneal epithelium) and from neural crest (uveal stroma, corneal stroma) are typically not present.14
CYCLOPIA AND SYNOPHTHALMIA
In cyclopia and synophthalmia, the telencephalon fails to divide into two hemispheres, and thus midline structures, including the septum pellucidum, corpus callosum, neurohypophysis, and olfactory lobes, do not develop. As would be expected, this extensive malformation is lethal, with a maximum survival of only days.15,16
Because of the failure of telencephalic division, the eyes develop as a completely or partially fused structure in the midline of the face. The other facial anomalies in turn result from the ocular structure's interference with migration. The lids are fused medially to form a diamond-shaped palpebral fissure. The proboscis is located superior to the median ocular structure and has no connection with respiratory apparatus.
True cyclopia is the complete fusion of the two eyes in a single midline pseudo-orbit. Synophthalmia, the more common variant, is characterized by partial fusion of the eyes; this is always more marked posteriorly.15–17 The degree of disorganization within the ocular structure is highly variable but tends to be greater medially. Cases that have an associated chromosomal abnormality, such as trisomy 13, tend to be more dysplastic and have more heterotopic elements present, such as cartilage.18
A possible variant of synophthalmos and cyclopia is unilateral diplophthalmos. In this condition, there is a supernumerary, partially fused second eye in the orbit. In a single case presentation, the authors postulated that an anomalous fold had formed in the retina. This fold then came in contact with the surface ectoderm, inducing formation of a second lens and subsequent formation of a fused second eye.19
Anencephaly is a lethal disorder, although it is compatible with completion of pregnancy. It is the most common lethal central nervous system disorder, occurring in 1 to 5 per 1,000 births. The cause is unknown but is postulated to be due to any of several possible teratogens acting at about the third or fourth week of pregnancy.20,21 Folate deficiency is one possible cause; vitamin supplements containing folate reduce the incidence of this condition.
The entire cranial vault is missing, with only disorganized neural and vascular tissue present. The orbits are shallow, so the eyes have a characteristic proptosis. The eyes themselves usually are grossly normal. The most common histologic finding is aplasia or hypoplasia of the nerve fiber and ganglion cell layers of the retina and of the optic nerve (Fig. 2).22 Other less-common findings include angle abnormalities, uveal colobomas, retinal dysplasia, epibulbar dermoid, persistent hyaloid artery, and retinal neovascularization.23
|PHAKOMATOSES (DISSEMINATED HEREDITARY HAMARTOMAS)|
|The phakomatoses are congenital lesions, many of which are hereditary. They
are characterized by hamartias or hamartomas of different organ systems.24 The name phakoma, meaning “mother spot” or birthmark, was given by van der Hoeve
in 1923 to this group of disorders.24,25 A hamartia, which means “defect” in Greek, is an anomaly of
tissue elements that are normally found at the involved site, such as
the anomalous conjunctival vessels of the Louis-Bar syndrome. If a tumor
is present at the site of the anomaly, it is referred to as a hamartoma. (In
contrast, a choristoma refers to a tumor composed of tissue
elements not normally present at the involved site.) Generally, these
tumors are benign and tend to affect predominantly one tissue type in
a given phakomatosis.24|
ANGIOMATOSIS OF THE RETINA (VON HIPPEL DISEASE)
The characteristic retinal lesion in this disease is a capillary hemangioma (hemangioblastoma), composed of blast-like vascular endothelial cells and pericytes, along with foamy cells that contain lipid (Figs. 3 and 4).26,27 The origin of these foamy cells has been controversial.28 Recent work has shown that they are the true neoplastic component of the hemangioblastoma. Von Hippel-Lindau angiomatosis is inherited as an autosomal dominant with incomplete penetrance. The mode of inheritance and the mechanism of disease are similar to those of retinoblastoma—that is, the condition is inherited as an autosomal dominant trait, so that the patient is heterozygous for the abnormal gene. However, at the cellular level, within the tumor, the neoplastic cells undergo a second mutation and are homozygous. These homozygous cells are the tumor cells, and they express vascular endothelial growth factor.29
Large feeder vessels supply and drain the hemangioblastoma, which is typically located inferotemporally near the equator. The small vessels within the tumor leak lipid-rich fluid, which can result in retinal exudates and hemorrhages. By electron microscopy, the tumor vessels have fenestrations, making them permeable to these metabolites.30 Secondary complications include exudative retinal detachment and fibroglial bands. Also, neovascularization of the iris, peripheral anterior synechiae, and secondary angle-closure glaucoma may result.
New lesions appear in the retina as small, flat, red nodules with normal afferent and efferent vessels; these patients must be followed and treated when appropriate, because these lesions will develop into typical capillary hemangiomas.31,32 Less commonly, such lesions spontaneously regress.33
The retinal capillary hemangiomas are bilateral in 50% of patients. Lindau described a similar malformation in the cerebellum; such lesions occur in 20% of patients. Other parts of the brain, including the medulla and spinal cord, less commonly have capillary hemangiomas.34 Other systemic visceral findings include cysts of the pancreas and kidney, renal cell carcinoma, and pheochromocytoma.24
MENINGOCUTANEOUS (ENCEPHALOTRIGEMINAL) ANGIOMATOSIS—STURGE-WEBER SYNDROME
This syndrome is characterized by hemangioma of the face (nevus flammeus or port-wine stain), frequently in the distribution of the first and second divisions of the fifth cranial nerve; meningeal calcification; and congenital glaucoma, all generally on the same side. This condition is congenital but usually is not hereditary. In some families, it may be inherited as an irregular autosomal dominant trait.23
A choroidal hemangioma is often present on the same side of the face as the nevus flammeus. This hemangioma is characteristically different from hemangiomas not associated with Sturge-Weber syndrome in that it tends to be flatter, more diffuse, and more extensive, and to have indistinct margins. Moreover, these hemangiomas are more likely to consist of a mix of capillary and cavernous vessels than are sporadic hemangiomas. There can be associated retinal leakage, edema, and retinal detachment (Fig. 5).35 The vascular lesions of the face, meninges, brain, and choroid are cavernous hemangiomas. The brain and meningeal lesions may calcify and may be associated with seizures and mental retardation.23
Glaucoma is present in 30% of cases, especially if the ipsilateral lids are involved in the facial hemangioma.36 Often the glaucoma is congenital, with buphthalmos and abnormalities of the chamber angle similar to other congenital glaucomas. The glaucoma may not occur until later in life; at that time it is associated with a more normal-appearing anterior chamber angle. It has been proposed that elevated episcleral venous pressure is involved in the pathogenesis of the glaucoma, and that the draining vessels are part of an intrascleral or episcleral hemangioma.36 In cases of glaucoma of later onset, accelerated aging changes in the angle as seen in trabeculectomy specimens have been noted.37
VON RECKLINGHAUSEN NEUROFIBROMATOSIS
In recent years, it has become clear that there are two types of neurofibromatosis, both of which are inherited as autosomal dominant traits. However, they map to different chromosomes and have different characteristic findings. The gene products of the two conditions are both tumor suppressor proteins.
Neurofibromatosis 1 (NF1) is the “classic” neurofibromatosis, which occurs in about 1 in 4,000 persons. The genetic mutation occurs on the long arm of chromosome 17,38 and the gene product has been identified.39 Requisite for the diagnosis of neurofibromatosis is the café-au-lait spot; six or more such spots, larger than 1.5 cm in diameter, should be present. They are highly suggestive for neurofibromatosis, although by themselves are not diagnostic. Familial café-au-lait spots do occur but are very rare.39
Histologically, café-au-lait spots show hyperpigmentation of the basal layer of the epidermis. They appear at birth or within the first 2 years of life, although they are smaller in prepubertal individuals.
In addition to café-au-lait spots, other diagnostic criteria include Lisch nodules, freckling in the axillae or groin, dysplasia of the sphenoid bone or of long bone cortex, and a first-degree relative with NF1.
Lisch nodules of the iris are well-demarcated, pigmented, dome-shaped lesions that are readily visible on the iris surface. However, on a dark iris, they may appear hypopigmented. These nodules are present in more than 90% of older children and adults with neurofibromatosis.40 Histologically, they are composed of melanocytes with long, interwoven processes.41,42
Dysplasia or partial absence of the greater wing of the sphenoid bone can give rise to pulsating exophthalmos.43 This partial absence allows communication between the orbit and cranial cavities, sometimes with an associated encephalocele.
Tumors are a hallmark of NF1, because this is a disorder of a tumor suppressor gene. The characteristic lesions include neurofibromas and neurilemmomas, which can be seen anywhere in the central, sympathetic, or peripheral nervous systems, including the cranial nerves. Cutaneous neurofibromatoses generally appear before puberty and may become very numerous, but they do not become malignant.39 They consist of proliferations of peripheral nerve elements and can be found in the eyelids and orbit, as well as elsewhere in the body. Small pedunculated lesions on the skin are called fibroma molluscum (Fig. 6). In the periocular area they can be difficult to manage, because they can alter eyelid function. They are characteristically found on the lateral aspect of the upper lid, giving it an S shape and causing ptosis.
Plexiform neurofibroma is nearly always a congenital lesion. It consists of a proliferation within a nerve sheath, which produces a markedly thickened, tortuous nerve. On palpation, it has been described as resembling a bag of worms. Microscopically, each of the nerves is surrounded by a thick perineural sheath (Fig. 7). These can become malignant.
Other tumors, which may affect the optic nerve as well as other nerves, include juvenile pilocytic astrocytoma (glioma) and meningioma. At least 10% of patients who have optic nerve glioma have neurofibromatosis. Occasionally, the recognition of neurofibromatosis is made only after diagnosis of the glioma or meningioma.44
Hamartomas of the retina and uveal tract are frequent; they tend to be glial in the retina and choroid and melanocytic in the trabecular meshwork (Fig. 8). A case of sectoral retinitis pigmentosa has been reported in association with neurofibromatosis.45 Although prominent corneal nerves have been described as a characteristic of neurofibromatosis, it now seems likely that such cases, reported earlier in the 20th century, represented unrecognized cases of multiple endocrine neoplasia type IIb.46
Glaucoma is commonly present and can be secondary to several mechanisms. It has been estimated that glaucoma is present in 50% of eyes in which the upper lid is involved with neurofibroma. In some cases, there is a developmental anomaly of the angle; in others, there can be involvement of the angle with hamartomatous tissue; and in still others, angle occlusion is caused by a hamartomatous tumor of the anterior ciliary body.47 Glaucoma can also be secondary to peripheral anterior synechiae and iris neovascularization.
Other tumors associated with NF1 include pheochromocytoma, juvenile chronic myeloid leukemia, and less frequently rhabdomyosarcoma.39
Neurofibromatosis 2 (NF2) is much less common, occurring in about 1 in 50,000 patients.38 The affected gene has been assigned to the long arm of chromosome 22, and the gene product has been named merlin or schwannomin. It also appears to act as a tumor suppressor.48 It is characterized by the presence of vestibular schwannomas. To make the diagnosis, these tumors must be bilateral. Alternatively, a family history of NF2 along with a unilateral eighth nerve tumor, or another tumor such as neurofibroma, meningioma, glioma, or schwannoma elsewhere, or juvenile subcapsular or cortical cataract must be present.
Schwannomas, or neurilemmomas, are proliferations of the Schwann cells that normally surround peripheral nerves. Histologically, two patterns can be evident—Antoni A, consisting of densely packed, swirling cells with indistinct cytoplasmic membranes, and Antoni B, which have a more mucoid appearance (Fig. 9). The eighth nerve tumors tend to cause deafness, so management of the cataracts becomes important to help preserve function. However, visual loss can also be caused by optic nerve and intracranial meningiomas.49 Retinal hamartomas occur in up to 22% of patients with NF2.39 In contrast, the occurrence of Lisch nodules and café-au-lait spots is unusual and not helpful in diagnosing NF2.48
TUBEROUS SCLEROSIS DISEASE (BOURNEVILLE DISEASE)
Tuberous sclerosis is so named because of the potato-like (tuberous) calcified tumors of the cerebrum, which tend to form along the ventricles. The classic triad consists of mental retardation, seizures, and “adenoma sebaceum.” The disease is transmitted as an autosomal dominant with low penetrance. Most cases are new mutations. These children die in childhood; 75% are dead by age 20.50
The characteristic reddish skin lesions, misnamed adenoma sebaceum, are present along the malar area and chin. They are not tumors of the sebaceous glands, but instead are angiofibromas, focal proliferations of fibrocytes and blood vessels. They are particularly well seen under ultraviolet light. Another characteristic skin lesion, also best seen with ultraviolet light, is the ash leaf spot.51 This hypopigmented flat skin lesion is different from vitiligo, in which melanocytes are absent. In the ash leaf spot, so called because of its shape, melanocytes are present but have decreased tyrosinase activity.50 Similar-appearing lesions of the iris and retina have been described, but no histopathology is available.52
The brain lesions are glial hamartomas, which often calcify; they cause mental retardation in about 60% of patients and grand mal seizures in more than 90%. The electroencephalogram is abnormal in 87% of patients.50
Astrocytic hamartomas can present anywhere in the retina but are most common at the optic nerve (giant drusen). They initially appear as gray, ill-defined, flat, smooth lesions overlying the retinal vessels. Years later, they become more condensed with irregular borders. They are then white with a wrinkled surface and have been called mulberry-like.53,54 Transitional forms have also been documented. Histologically, they consist of astrocytes with long processes, proteinaceous exudate, and vascular elements; they also may calcify (Figs. 10 and 11).55,56 This calcification can lead to diagnostic confusion with retinoblastoma. Thus, fine-needle biopsy may be indicated in some cases.57
ATAXIA-TELANGIECTASIA (LOUIS-BAR SYNDROME)
Ataxia-telangiectasia consists of telangiectasias (hamartias) of the conjunctiva and skin along with a progressive cerebellar ataxia, often with mental retardation. The conjunctival telangiectasias manifest in early childhood and are present in 100% of cases. Nystagmus and other abnormal eye movements also are present in all patients.58 The disease is transmitted as an autosomal recessive trait.59 Recently, the gene was localized to the long arm of chromosome 11.60
There is an associated deficiency of both cellular and humoral immunity, along with degeneration of the thymus. These patients therefore often develop sinus and respiratory tract infections, and these are the usual causes of death. These patients are generally much more sensitive to ionizing radiation and are also more susceptible to cancer, particularly leukemias and lymphomas, than the general population. Carriers, who are heterozygous for the gene, have a sensitivity to cancer and to ionizing radiation intermediate between the general population and homozygous individuals.60
ARTERIOVENOUS COMMUNICATION OF RETINA AND BRAIN (WYBURN-MASON SYNDROME)
The Wyburn-Mason syndrome is a rare syndrome that tends to become symptomatic in adolescence or young adulthood. It consists of generally unilateral arteriovenous communications in the retina (Fig. 12) and ipsilateral midbrain.61,62
The intracranial malformation may hemorrhage, but retinal hemorrhage is unusual.63 Venous occlusion and neovascular glaucoma have also been reported.64 Bleeding from similar lesions of the gums and nose can also occur, and there can be associated facial hemangiomas.23,65 All these malformations are high-velocity, high-pressure shunts that contain no intervening capillaries.65
As would be expected from a congenital stationary retinal vascular anomaly, there is no leakage on fluorescein angiography in most cases.66 However, rarely there is secondary leakage because of vascular decompensation from the continued high pressure. Vision may be good or poor, depending on the location and extent of the malformation.65 Secondary strabismus and diplopia may be present.
Histologically, these lesions consist of large vessels with fibromuscular coats. Typically, no differentiation between artery and vein is possible. The vessels may occupy the entire thickness of the retina and may be adherent to Bruch's membrane. The retina in the area supplied by these vessels may show cystic degeneration.66–68
|The normal human complement of chromosomes is 46, with 22 pairs of autosomes
and two sex chromosomes, two X chromosomes in females and an X and
a Y in males. Each pair of autosomes is recognizable by its size, the
location of its centromere, and its banding characteristics.69|
There are innumerable possibilities for error in the transmission of the genetic message from generation to generation; many of these are compatible with maturation to term and some with postnatal survival. Such errors may be as small as the alteration of a single base pair of the DNA, or as extensive as the duplication of one or more whole chromosomes. Many of these involve ocular abnormalities, although no ocular malformation appears specific for a given chromosomal abnormality.69,70
Trisomy 13 results from an extra chromosome 13—that is, 47, 13+ . It occurs as a failure of the chromosomes to separate during meiosis, called nondisjunction. Like other trisomies, it is associated with increased maternal age. The frequency is estimated to be about 1 in 14,000 live births, with an equal sex incidence. The affected infants generally do not survive beyond 6 months.
Abnormalities of many organ systems have been reported. Central nervous system abnormalities include mental retardation and absence or hypoplasia of the olfactory lobes with fusion of the frontal lobes (holoprosencephaly). There is apparent deafness; apneic spells and minor motor seizures may also occur. The infant is hypotonic. Skeletal changes include low-set, malformed ears; cleft lip or palate, or both; flexed and overlapping fingers or toes, or both; narrow, hyperconvex fingernails; polydactyly; and posterior prominence of the heels, called rocker-bottom feet. The dermatoglyphics are characteristic, and there may be transverse palmar creases. Urogenital abnormalities include cryptorchidism in males and bicornuate uterus in females, and renal malformations. Other affected systems include the pulmonary, hepatic, and cardiovascular systems.71
The ocular abnormalities are extensive. Generally there is microphthalmia, and this can be extreme. In the past, anophthalmia has been described as a feature of this syndrome, but this very likely represents extreme microphthalmia (i.e., clinical anophthalmia).72 About 80% of eyes associated with this trisomy have colobomas of the iris and ciliary body, as well as cataract and persistent hyperplastic primary vitreous.73–77 Histologically, there is mesenchymal tissue between the sclera and the retrolental area in the coloboma, and cartilage is present here in 65% of these eyes, especially in those eyes that are very microphthalmic (Fig. 13). This association of cartilage within a ciliary body coloboma appears to be unique to eyes from infants with trisomy 13.74–77 (Cartilage may appear elsewhere in the eye in such conditions as teratoid medulloepithelioma, angiomatosis retinae, synophthalmia, chromosome 18 deletion defect, and in one anomalous eye of a normal person.78)
The cataract may show retention of lens nuclei within the embryonic lens nucleus, as in Lowe disease and rubella syndrome. Subcapsular and cortical cataracts may also be found. Other findings include bilateral retinal dysplasia and typical and reticular microcystoid retinal degeneration. The angle structures may be immature. About 60% of eyes show mesenchymal dysgenesis, such as Rieger syndrome and Peters anomaly. Buphthalmos from congenital glaucoma has been reported in some cases.79 One such case also included a vortex vein immediately adjacent to the optic disc.80
Trisomy 18 (47, 18+ ) is similar to trisomy 13 in incidence, about 1 in 14,000 live births, and 90% die in the first year of life.81,82 However, the ocular manifestations are much less severe. A few patients survive into their 20s but show profound neurologic deficits.83
These babies tend to be born either prematurely or postmaturely, and there can be polyhydramnios. A number of central nervous system malformations have been reported. Other systemic abnormalities include cardiac, renal, and intestinal malformations. Skeletal anomalies include micrognathia, syndactyly, skeletal muscle hypoplasia, flexion contractures, malformed ears, and microstomia. Characteristically, the fifth finger overlaps the fourth or the second overlaps the third, or both.81
A number of ocular and adnexal abnormalities have been reported, although these are mostly minor. Lid abnormalities include ptosis, narrow palpebral fissures, epicanthal folds, blepharophimosis, abnormally long or sparse lashes, and abnormally thick lids. The orbits may be shallow and contain hypoplastic orbital ridges. Both hypertelorism and hypotelorism have been noted. Abnormalities of gaze, including strabismus and nystagmus, may occur.81
The ocular malformations are nonspecific for this trisomy. The most frequently reported findings include cataract, anomalies of the ciliary processes, and retinal folds.81,84–86 Both hyperplasia and hypoplasia of elements of the cornea and uveal tract have been reported.81 Angle immaturity, persistent hyperplastic primary vitreous, retinal dysplasia, optic nerve hypoplasia,86 coloboma, Bergmeister papilla,82 and nictitating membrane87 are other abnormalities that may be present.
TRISOMY 21 (DOWN SYNDROME)
Trisomy 21 is the most common trisomy, present in 1 in 700 live births. Many of these children survive well into adulthood. As with other trisomies, advanced maternal age is associated with an increased incidence.88 The eye findings tend to be minor.
Systemic malformations include mental retardation, which is variable but often severe. Skeletal abnormalities include short stature, muscular hypotonia, dental hypoplasia, short broad hands with short curved fifth fingers, and diastasis of the rectus abdominis muscle. The ears are low-set. The dermatoglyphic patterns are characteristic and include a single palmar (simian) crease. Cardiac and genitourinary malformations are common. These patients also have abnormalities of the hematologic system and are unusually prone to leukemia. The facial features are characteristic and include a broad, flat bridge of the nose, epicanthal folds, and protruding tongue.89,90
The ocular findings, in addition to the epicanthal folds, include myopia, hypertelorism, cataracts, hypopigmented areas of the iris (Brushfield spots), strabismus, nystagmus, and keratoconus.89,90 Retinal findings include increased numbers of vessels crossing the optic disc margin,91,92 relative hypopigmentation, and patchy retinal pigment epithelial atrophy.92 Recently, mesenchymal dysgenesis with glaucoma has been described in a case of Down syndrome.93 All of these findings are nonspecific, and indeed may occur in otherwise normal individuals.
Histologically, Brushfield spots are areas of iris stroma that are normal or that have minimal collagenous thickening, surrounded by hypoplastic iris (Fig. 14).94 The cataracts seen in Down syndrome may have abnormal anterior lenticular capsular excrescences, similar to those of Lowe syndrome or Miller syndrome.94,95
OTHER CHROMOSOMAL ABNORMALITIES
Other autosomal trisomies are extremely rare. Trisomies of the sex chromosomes include Klinefelter syndrome (47, XXY), in which there are minimal ocular abnormalities, and XYY syndrome (47, XYY), in which there are antisocial tendencies, gonadal atrophy, lens luxation, and colobomas.96
The only monosomy compatible with survival is Turner syndrome, a monosomy of the X chromosome (45, XO). Partial deletions and other abnormalities of the X chromosome can also result in this phenotype. Patients with Turner syndrome are phenotypic females who lack secondary sexual development. Ocular abnormalities seen with this syndrome include cataract, blue sclerae, ptosis, strabismus, and prominent epicanthal folds. A case of Coats disease in Turner syndrome has been reported.97 The incidence of colorblindness is increased, similar to that of normal males.
It is possible for the entire chromosome complement to be duplicated, giving rise to a triploidy (69 chromosomes, with either XXX or XXY). Affected infants may be live-born and survive up to 2 months. Ocular findings in this syndrome include microphthalmia, dislocated spherical lens, coloboma, and retinal dysplasia.98,99 Duplications may involve only a single chromosome, as previously discussed, or only a portion of a chromosome, as in the “cat eye” syndrome, a partial trisomy of chromosome 22.100–101
A number of mosaic syndromes exist. These are syndromes in which at least two cell lines that are karyotypically distinct are present in the individual. There can be mosaics of whole chromosomes (e.g., a mosaic Down syndrome, such as 46/47, 21+ , in which the abnormalities are milder than in the complete syndrome; or mosaic trisomy 9, which allows survival to term),102 of deletions, or even of the entire chromosomal content (such as the reported cases of tetraploid/diploid mosaic).103,104
Chromosomal deletion syndromes involve loss of a portion of a given chromosome, and thus loss of that genetic material. Only one chromosome of a pair is affected. Several of these syndromes are known to cause ocular malformations.69 One such syndrome is the deletion of part of the short arm of chromosome 5 (46, 5p-). This is the cri du chat syndrome, named because the infant's cry resembles the mewing of a cat. Epicanthal folds, hypertelorism, exotropia, optic atrophy, tortuous retinal arteries and veins, and pupils that are supersensitive to 2.5% methacholine are associated ocular findings.105–107
Deletion of a portion of the short arm of chromosome 11 (46, 11p-) is associated with some cases of Miller syndrome,111 which consists of aniridia, abnormalities of the urogenital system, mental retardation, and Wilms tumor. The iris in aniridia is hypoplastic rather than entirely absent. The sphincter and dilator may be missing or poorly developed.112,113 Poor vision may result from macular and optic nerve hypoplasia. There may also be cataract and secondary corneal opacification with vascularization. The cataract is similar to that of Down syndrome, with capsular excrescences. Glaucoma results from immaturity of the angle or anomalous development (Fig. 15).112
Deletion of part of the long arm of chromosome 18 (46, 18q-) results in a number of nonspecific ocular and systemic findings, including corneal opacities, posterior keratoconus, Brushfield spots, colobomas of the uvea including microphthalmos with cyst, retinal dysplasia, and optic atrophy. Cyclopia may also result.114
|Often a congenital abnormality has no obvious cause, and an unknown infection
or toxic agent is invoked. With some malformations, the timing
of the agent is more easily determined than its nature. However, certain
infectious agents do result in a readily recognized syndrome, and these
may be further confirmed by antibody titers. Of these, toxoplasmosis, cytomegalic
inclusion disease, syphilis, and rubella are the most
important. The first three of these are discussed elsewhere in these
The rubella virus can pass through the placenta and infect the fetus, thereby causing abnormal development. If this takes place during the first 4 weeks, a time when the woman is often unaware of the pregnancy, there is a 50% likelihood of the fetus being affected. Overall, 20% of fetuses are affected by maternal infection during the first trimester.115
Affected infants frequently have a low birth weight and can have malformations of the central nervous system, heart, and genitourinary system. Some level of deafness is present in 66% of patients.116 Other abnormalities include juvenile diabetes mellitus,117 thrombocytopenic purpura, osteomyelitis, and dental abnormalities.
In most series, cataract is the most common ocular finding.116 Histologically, there is persistence of the lens nuclei within the embryonic nucleus, a characteristic but not pathognomonic finding.118 There is also anterior and posterior cortical degeneration. The rubella virus can survive in the lens up to 3 years. Cataract surgery can release the virus into the eye, causing an endophthalmitis, so cataract surgery should probably be done in a single procedure.119
The iris can be leathery and dilates poorly in response to mydriatics. Histologically, the iris has a poorly developed dilator muscle, with necrosis of the iris and ciliary body epithelium and chronic nongranulomatous inflammation of the stroma (Fig. 16).118 This inflammatory reaction sometimes becomes clinically manifest after cataract extraction, which can lead to cyclitic membrane formation and retinal detachment.119
Probably the most characteristic finding is the “salt-and-pepper” fundus, present in up to 60% of cases.116 Histologically, the retinal pigment epithelium is intact throughout but shows focal areas of hyperpigmentation and hypopigmentation (Fig. 17).118,120 Some older patients have developed subfoveal neovascularization.121,122
Glaucoma is also associated with the rubella syndrome, and histologically the angles appear immature, as in other types of congenital glaucoma.118 Glaucoma has also been reported in later childhood and adulthood.123 In a recent clinical series, glaucoma was significantly associated with microphthalmia.116