Congenital Anomalies

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Congenital Anomalies

Phakomatoses (Disseminated Hereditary Hamartomas)

General Information

I. The phakomatoses are a heredofamilial group of congenital tumors having disseminated, usually benign, hamartomas in common.

The term phakomatosis (Greek: phakos = “mother spot” or “birthmark”) was introduced by van der Hoeve in 1923.

II. In each type of phakomatosis, the hamartomas tend to affect one type of tissue predominantly (e.g., blood vessels in angiomatosis retinae and neural tissue in neurofibromatosis).

A hamartoma is a congenital tumor composed of tissues normally found in the involved area (e.g., lid hemangioma), in contrast to a choristoma, which is a congenital tumor composed of tissues not normally present in the involved area (e.g., orbital epidermoid cyst).

Angiomatosis Retinae [von Hippel’s Disease (VHL)]

I. General information

A. The onset of ocular symptoms is usually in young adulthood. Retinal capillary hemangiomas (hemangioblastomas) occur in more than 50% of patients (Fig. 2.1), and central nervous system lesions occur in 72% of patients.

Fig. 2.1 Angiomatosis retinae. A, Fundus picture of peripheral retinal capillary hemangiomas in 16-year-old patient. B, Retinal capillary hemangioma of optic nerve head, shown with fluorescein in C. D, Capillary hemangioma (hemangioblastoma) replaces full thickness of retina. E, High magnification shows capillary blood-filled spaces intimately associated with characteristic pale, foamy, polygonal stromal cells. (B and C, Courtesy of Dr. GE Lang; D and E, courtesy of Dr. DH Nicholson.)

B. VHL disease is an inherited cancer syndrome (autosomal-dominant) characterized by a predisposition to development of multiple retinal angiomas, cerebellar “hemangioblastomas,” bilateral renal cysts and carcinomas, bilateral pheochromocytomas, pancreatic cysts, and epididymal cysts.

The combination of retinal and cerebellar capillary hemangiomas (and capillary hemangiomas of medulla and spinal cord) is called von Hippel–Lindau disease. The retinal component, von Hippel’s disease, was the first to be described. The responsible VHL gene resides at human chromosome 3 (band 3p25.5–p26). Genetically, the disease gene behaves as a typical tumor suppressor, as defined in Knudson’s theory of carcinogenesis.

II. Ocular findings

A. A retinal capillary hemangioma (see Chapter 14), usually supplied by large feeder vessels, may occur in the optic nerve or in any part of the retina. Retinal exudates, often in the macula even when the tumor is peripheral, result when serum leaks from the abnormal tumor blood vessels.

Unusual retinal hamartomas may be seen in the inner retina, usually adjacent to a retinal vein, and are characterized by small, moss fiber-like, relatively flat, vascular lesions with smooth or irregular margins but without enlarged afferent and efferent vessels.

B. Ultimately, organized fibroglial bands may form and neural retinal detachment may develop. Secondary closed-angle glaucoma also may be found.

III. Systemic findings

A. Retinal capillary hemangioma may occur in the cerebellum, brainstem, and spinal cord.

B. Cysts of pancreas and kidney are common.

C. Hypernephroma and pheochromocytoma (usually bilateral) occur infrequently.

IV. Histology

A. The basic lesion is a capillary hemangioma (hemangioblastoma) (see Chapter 14) composed of endothelial cells and pericytes. Between the capillaries are foamy stromal cells that appear to be of glial origin.

1. Immunohistochemical studies show that the foamy stromal cells stain positively for glial fibrillary acid protein and neuron-specific enolase.

2. The VHL gene deletion may be restricted to the stromal cells, suggesting that the stromal cells are the neoplastic component in retinal hemangiomas and induce the accompanying neovascularization.

B. Secondary complications may be found—for example, retinal exudates and hemorrhages, fixed retinal folds and organized fibroglial membranes, neural retinal detachment, iris neovascularization, peripheral anterior synechiae, and chronic closed-angle glaucoma.

Meningocutaneous Angiomatosis [Encephalotrigeminal Angiomatosis; Sturge–Weber Syndrome (SWS)]

I. General information

A. SWS (Fig. 2.2) usually consists of unilateral (rarely bilateral) meningeal calcification, facial nevus flammeus (port wine stain and phakomatosis pigmentovascularis), frequently along the distribution of the trigeminal nerve, and congenital glaucoma.

Fig. 2.2 Meningocutaneous angiomatosis. A, The fundus shows both the characteristic bright-red appearance, caused by the choroidal hemangioma, and an enlarged optic nerve cup, secondary to increased pressure. B, Left eye in same patient shows normal fundus for comparison. C, Choroid thickened posteriorly by cavernous hemangioma that blends imperceptibly into normal choroid. D, Cavernous hemangioma of choroid in same eye shows large, thin-walled, blood-filled spaces. (A and B, Courtesy of Dr. HG Scheie; C and D, courtesy of Dr. R Cordero-Moreno.)

B. The condition is congenital (heredity does not seem to be an important factor).

II. Ocular findings

A. The most common intraocular finding is a cavernous hemangioma (see Chapter 14) of the choroid on the side of the facial nevus flammeus.

Extremely rarely, the choroidal hemangioma can be bilateral even with unilateral facial nevus flammeus. Port wine stain also can occur in Klippel–Trenaunay–Weber syndrome (ipsilateral varicosities and bony hypertrophy) and cutis marmorata telangiectasia congenita.

B. A cavernous hemangioma or telangiectasis (see Chapter 14) of the lids on the side of the facial nevus flammeus is common.

C. Congenital glaucoma is associated with ipsilateral hemangioma of the facial skin in approximately 30% of patients.

When nevus flammeus and congenital oculodermal melanocytosis occur together, especially when each extensively involves the globe, a strong predisposition exists for the development of congenital glaucoma.

1. The lids, especially the upper, are usually involved.

2. The cause of the glaucoma is unclear, but in most instances it is not related to the commonly found ipsilateral choroidal hemangioma.

III. Systemic findings

A. Cavernous hemangioma or telangiectasis of the skin of the face (“birthmark” or port wine stain) is the most common visible sign.

B. Hemangioma of the meninges and brain on the side of the facial hemangioma is usually present, along with meningeal or intracranial calcification.

C. Seizures and mental retardation are common.

IV. Histology

A. The basic lesion in the skin of the face (including lids), the meninges, and the choroid is a cavernous hemangioma (see Chapter 14). In addition, telangiectasis (see Chapter 14) of the skin of the face may occur.

1. The vascular dermal lesion in the SWS differs, however, from non-SWS, “garden-variety” cavernous hemangioma in that the vascular wall in the SWS lesion lacks a multilaminar smooth muscle. The vascular abnormality in SWS would be better termed a vascular malformation or nevus telangiectaticus rather than cavernous hemangioma.

2. The choroidal hemangiomas in SWS show a diffuse angiomatosis and involve at least half the choroid, often affecting the episcleral and intrascleral perilimbal plexuses. SWS hemangioma shows infiltrative margins, making it difficult to differentiate tumor from normal choroid.

Hemangioma of the choroid unrelated to SWS, conversely, is usually well circumscribed, shows a sharply demarcated pushing margin, often compresses surrounding melanocytes and choroidal lamellae, and usually (in 70% of cases) occurs in the region of the posterior pole (area centralis).

B. Congenital glaucoma may be present.

C. Secondary complications, such as microcystoid degeneration of the overlying retina (see Chapter 11) and leakage of serous fluid (see Chapter 11), are common.

Neurofibromatosis (Figs. 2.3–2.5)

I. Neurofibromatosis type 1 (NF-1: von Recklinghausen’s disease or peripheral neurofibromatosis)

A. General information

1. Diagnosis of NF-1 is made if two or more of the following are found: six or more café-au-lait spots >5 mm in greatest diameter in prepubertal persons and 15 mm in postpubertal persons; two or more neurofibromas of any type or one plexiform neurofibroma; freckling in the axillary, inguinal, or other intertriginous region; optic nerve glioma; two or more Lisch nodules; a distinctive osseous lesion (e.g., sphenoid bone dysplasia); and a first-degree relative who has NF-1.

2. Multiple tumors are found that are derived from Schwann cells of peripheral and cranial nerves and glial cells of the central nervous system. A superimposed malignant change (fibrosarcoma, neurofibrosarcoma, and malignant schwannoma) may occur.

3. NF-1 is transmitted as an irregular autosomal-dominant trait (prevalence approximately one in 3000 to 4000). The responsible gene is located on chromosome 17 (band 17q11.2).

B. Ocular findings

1. Café-au-lait spots

2. Neurofibromas

a. Fibroma molluscum, the common neurofibroma, results from proliferation of the distal end of a nerve and produces a small, localized skin tumor.

b. Plexiform neurofibroma (“bag of worms”) is a diffuse proliferation in the nerve sheath and produces a thickened and tortuous nerve.

c. Elephantiasis neuromatosa is a diffuse proliferation outside the nerve sheath that produces a thickening and folding of the skin.

3. Thickening of corneal and conjunctival nerves and congenital glaucoma

If a plexiform neurofibroma of the eyelid is present (especially upper eyelid), 50% will have glaucoma. Ectropion uvea results from endothelialization of the angle in severe pediatric glaucoma.

4. Hamartomas in trabecular meshwork, uvea, neural retina, and optic nerve head: melanocytic nevi in trabecular meshwork and uvea; glial hamartomas in neural retina and optic nerve head; retinal capillary hemangiomas and combined pigment epithelial and retinal hamartomas; sectoral neural retinal pigmentation (sector retinitis pigmentosa of Bietti); optic nerve glioma (juvenile pilocytic astrocytoma); orbital plexiform neurofibroma; neurilemmoma (schwannoma); absence of greater wing of sphenoid; enlarged optic foramen; pulsating exophthalmos (pulsating exophthalmos may be associated with an orbital encephalocele).

Clinically, the multiple, small, spider-like, melanocytic iris nevi (Lisch nodules) are the most common clinical feature of adult NF-1, found in 93% of adults. Rarely, Lisch nodules may be found in NF-2. Approximately 25% of patients who have optic nerve gliomas have neurofibromatosis, almost exclusively type 1. NF-1 patients who have negative neuroimaging studies of the optic pathways may later develop optic nerve gliomas.

C. Histology

1. In the skin and orbit, a diffuse, irregular proliferation of peripheral nerve elements (predominantly Schwann cells) results in an unencapsulated neurofibroma, composed of numerous cells that contain elongated, basophilic nuclei and faintly granular cytoplasm associated with fine, wavy, “maiden-hair,” immature collagen fibers.

a. Special stains often show nerve fibers in the tumor.

b. Vascularity is quite variable from tumor to tumor and in the same tumor.

Histologically, neurofibromas are often confused with dermatofibromas, neurilemmomas, schwannomas (see Chapter 14), or leiomyomas (see Chapter 9).

2. In the eye, the lesion may be a melanocytic nevus (see Chapter 17), slight or massive involvement of the uvea (usually choroid) by a mixture of hamartomatous neural and nevus elements, or a glial hamartoma.

Rarely, a uveal melanoma may arise from the uveal nevus component.

II. Neurofibromatosis type 2 (NF-2; central neurofibromatosis, bilateral acoustic neurofibromatosis)

A. General information

1. Diagnosis of NF-2 is made if a person has either bilateral eighth-nerve tumors or a first-degree relative who has NF-2; and either a unilateral eighth-nerve tumor or two or more of the following: neurofibroma, meningioma (especially primary nerve sheath meningioma), glioma, schwannoma, ependymoma, or juvenile posterior subcapsular lenticular opacity.

a. NF-2 is transmitted as an irregular autosomal-dominant (prevalence about 1 in 40,000).

b. The responsible gene is located on chromosome 22 (band 22q12).

2. Combined pigment epithelial and retinal hamartomas may occur.

The most common ocular abnormalities found in NF-2 are lens opacities (67%—mainly plaque-like posterior subcapsular or capsular, cortical, or mixed lens opacities) and retinal hamartomas (22%).

III. Because of the neuromas, café-au-lait spots, and prominent corneal nerves that may be found, the condition of multiple endocrine neoplasia (MEN) type IIB must be differentiated from neurofibromatosis.

A. MEN, a familial disorder, is classified into three groups.

1. Type I (autosomal-dominant inheritance) consists of multiple neoplasms of the pituitary, parathyroid, pancreas islets, and less often pheochromocytoma (as a late feature) and neoplasms of the adrenal and thyroid glands.

The Zollinger–Ellison syndrome consists of gastric, duodenal, and jejunal ulcers associated with gastrin-secreting non-β islet cell tumors of the pancreas (gastrinomas). The tumors may arise in multiple sites in MEN type I.

2. Type IIA (autosomal-dominant inheritance; also called Sipple syndrome) consists of medullary thyroid carcinoma, pheochromocytoma (as an early feature), parathyroid hyperplasia, and prominent corneal nerves (less prominent than in type IIB).

3. Type IIB (Fig. 2.6; 50% autosomal-dominant and 50% sporadic inheritance; also called type III) consists of medullary thyroid carcinoma and, less often, pheochromocytoma.

In addition, marfanoid habitus, skeletal abnormalities, prominent corneal nerves (more prominent than in IIA), multiple mucosal (including conjunctival, tongue, and intestinal) neuromas, café-au-lait spots, and cutaneous neuromas or neurofibromas may occur.

B. Linkage analysis shows:

1. In MEN I, the predisposing genetic linkage is assigned to chromosome region 11q13.

2. In MEN IIA and IIB, the predisposing genetic linkage is assigned to chromosome region 10q11.2.

The mutation for MEN IIA and IIB occurs at the site of the human RET proto-oncogene at 10q11.2, the same site where a mutation also causes the autosomal-dominant Hirschsprung’s disease. An oncogenic conversion (not a loss of suppressor function) converts RET into a dominant transforming gene.

Fig. 2.3 Neurofibromatosis. A, A plexiform neurofibroma has enlarged the left upper lid; the neurofibroma was removed. B, The gross specimen shows a markedly expanded nerve. A thin slice of the nerve is present at the bottom left. C, In another similar case, diffuse proliferation of Schwann cells within the nerve sheath enlarges the nerve (n, thickened abnormal nerves). (A, Courtesy of Dr. WC Frayer.)

Fig. 2.4 Neurofibromatosis. A, Iris shows multiple, spider-like melanocytic nevi, characteristic of neurofibromatosis. B (light microscope; n, nevi) and C (scanning electron microscope): The iris nevi, also called Lisch nodules, are composed of collections of nevus cells. (C, Courtesy of Dr. RC Eagle, Jr.)

Fig. 2.5 Neurofibromatosis. A and B, Gross and microscopic appearance of hamartomatously, markedly thickened choroid (c). Sclera contains thickened, abnormal nerves (n). C, High magnification of diffuse choroidal hamartoma shows structures resembling tactile nerve endings and cells resembling nevus cells. (A and C, Courtesy of Dr. RC Eagle, Jr.; B, courtesy of Dr. L Calkins.)

Fig. 2.6 Multiple endocrine neoplasia type IIB. A, Thickened corneal nerves are seen to crisscross in the slit beam. B, Characteristic neurofibromatous submucosal nodules are seen along the front edge of the tongue. C, A large submucosal neurofibromatous nodule is present in the conjunctiva. D, Histologically, the conjunctival nodule consists of enlarged nerves in the conjunctival substantia propria.

Tuberous¹ Sclerosis (Bourneville’s Disease; Pringle’s Disease)

I. General information

A. Symptoms usually appear during the first three years of life and consist of the triad of mental deficiency, seizures, and adenoma sebaceum (angiofibroma).

B. The prognosis is poor (death occurs in 75% of patients by 20 years of age).

C. The disease is transmitted as an irregular autosomal-dominant (prevalence approximately one in 6000 to 10,000). Tuberous sclerosis complex (TSC)-determining loci have been mapped to chromosome 9q34 (TSC1) and 16p13.3 (TSC2).

II. Ocular findings (Fig. 2.7)

A. Adenoma sebaceum (angiofibroma) of lids

B. Glial hamartoma of retina (occurs in 53% of patients), most of which remain stable over time, but some become calcified, and rarely some may show progressive growth.

Hamartomas of the neural retina in infants have a smooth, spongy appearance with fuzzy borders, are gray-white, and may be mistaken for retinoblastoma. Older lesions often become condensed, with an irregular, white surface, resembling a mulberry. The whitened, wrinkled clinical appearance is caused by avascularity, not calcium deposition. The lesions are frequently multiple and vary in size from one-fifth to two disc diameters. New lesions may rarely develop from areas of previously normal-appearing retina.

C. Glial hamartoma of optic disc anterior to lamina cribrosa (giant drusen) may occur. Neuroectodermal hamartomas of the iris pigment epithelium and ciliary body epithelium may occur rarely. Also, RPE punched-out lesions occur.

Infrared imaging, spectral-domain optical coherence tomography, and fundus autofluorescence are helpful in identifying the lesions. The giant drusen of the optic nerve head may be mistaken for a swollen disc (i.e., pseudopapilledema). Most patients who have drusen of the optic nerve do not have tuberous sclerosis.

Fig. 2.7 Tuberous sclerosis. A, Fundus shows typical mulberry lesion involving the superior part of the optic nerve. B, Histologic section of another case shows a giant druse of the optic nerve. C, Juxtapapillary glial hamartoma contains calcospherites and replaces full thickness of retina. D, Histologic section of an early lesion shows no calcification but simply a proliferation of glial tissue (s, sclera; c, choroid; l, lesion; r, retina).

III. Systemic findings

A. Glial hamartomas in the cerebrum occur commonly and result in epilepsy in 93% of patients, in mental deficiency in 62% of patients, and in intracranial calcification in 51% of patients.

B. Adenoma sebaceum of the skin of the face occurs in 83% of patients.

C. Hamartomas of lung, heart, and kidney, which may progress to renal cell carcinoma, also may be found.

IV. Histology

A. Giant drusen of the optic disc occur anterior to the lamina cribrosa and are glial hamartomas (see Chapter 13).

B. Adenoma sebaceum are not tumors of the sebaceous gland apparatus but are angiofibromas (see Chapter 6).

C. Glial hamartomas in the cerebrum (usually in the walls of the lateral ventricles over the basal ganglia) and neural retina are composed of large, fusiform astrocytes separated by a coarse and nonfibrillated, or finer and fibrillated, matrix formed from the astrocytic cell processes.

1. The cerebral tumors are usually well vascularized, but the neural retinal tumors tend to be sparsely vascularized or nonvascularized.

2. Calcospherites may be prominent, especially in older lesions.

Retinal tumors display the same spectrum of aberrant development and morphologic characteristics as other central nervous system lesions, including the occurrence of giant cell astrocytomas that stain positive for γ-enolase but negative for glial acid fibrillary protein and neural filament protein.

Other Phakomatoses

Numerous other phakomatoses occur. Ataxia–telangiectasia (Louis–Bar syndrome), an immunodeficient disorder, consists of an autosomal-recessive inheritance pattern (gene localized to chromosome 11q22), progressive cerebellar ataxia, oculocutaneous telangiectasia, and frequent pulmonary infections; arteriovenous communication of retina and brain (Wyburn–Mason syndrome) consists of a familial pattern, mental changes, and arteriovenous communication of the midbrain and retina (see Chapter 14) associated with facial nevi. Most other phakomatoses are extremely rare or do not have salient ocular findings.

Chromosomal Aberrations

I. The normal human cell is diploid and contains 46 chromosomes: 44 autosomal chromosomes and 2 sex chromosomes (XX in a female and XY in a male).

A. Individual chromosomes may be arranged in an array according to morphologic characteristics. The resultant array of chromosomes is called a karyotype.

1. A karyotype is made by photographing a cell in metaphase and then cutting out the individual chromosomes and arranging them in pairs in chart form according to predetermined morphologic criteria (i.e., karyotype; Fig. 2.8). The paired chromosomes are designated by numbers.

Fig. 2.8 Trisomy 13. A, Karyotype shows extra chromosome in 13 group (arrow). B, Karyotype shows banding in normal 13, 14, and 15 pairs of chromosomes. (A and B, Courtesy of Drs. BS Emanuel and WJ Mellman.)

2. In genetic shorthand, 46(XX) means that 46 chromosomes occur and have a female pattern; 46(XY) means that 46 chromosomes occur and have a male pattern.

B. To differentiate the chromosomes, special techniques are used, such as autoradiography or chromosomal band patterns, as shown with fluorescent quinacrine (see Fig. 2.8).

II. Chromosomes may be normal in total number (i.e., 46), but individual chromosomes may have structural alterations.

A. The genetic shorthand for structural alterations is as follows: p = short arm, q = long arm, + = increase in length, − = decrease in length, r = ring form, and t = translocation.

B. Therefore, 46,18p– means a normal number of chromosomes, but one of the pair of chromosomes 18 has a deletion (decrease in length) of its short arms.

III. Chromosomes may also be abnormal in total number, either with too many or with too few.

A. For example, trisomy 21 (Down’s syndrome, or mongolism) has an extra chromosome. It may be written 47,21+.

B. Also, too few chromosomes may occur [e.g., in 45(X), Turner’s syndrome, where only 45 chromosomes exist and one of the sex chromosomes is missing].

IV. A chromosomal abnormality has little to do with specific ocular malformations. In fact, except for the presence of cartilage in a ciliary-body coloboma in trisomy 13, no ocular malformations appear specific for any chromosomal abnormality.

Trisomy 8

See later, under Mosaicism.

Trisomy 13 (47,13+; Patau’s Syndrome)

I. General information

A. Trisomy 13 results from an extra chromosome in the 13 pair of autosomal chromosomes (i.e., one set of chromosomes exists in triplicate rather than as a pair; see Fig. 2.8). It is caused by an accidental failure of disjunction of one pair of chromosomes during meiosis (meiotic nondisjunction) and has no sex predilection.

B. The condition, present in one in 14,000 live births, is usually lethal by age six months.

C. Because the condition was described in the prekaryotype era (i.e., before 1957), many names refer to the same entity: arhinencephaly, oculocerebral syndrome, encephalo-ophthalmic dysplasia, bilateral retinal dysplasia (Reese–Blodi–Straatsma syndrome), anophthalmia, and mesodermal dysplasia (cleft palate).

D. Ocular anomalies, usually severe, occur in all cases (Fig. 2.9; see Fig. 2.15).

Fig. 2.9 Trisomy 13 (see also Fig. 2.16, synophthalmos). A, An inferior nasal iris coloboma and leukoria are present. B, A coloboma of the ciliary body is filled with mesenchymal tissue containing cartilage (c). Note the retinal dysplasia (r). In trisomy 13, cartilage is usually present in microphthalmic eyes smaller than 10 mm. (A, Courtesy of Dr. DB Shaffer; B, reported in Hoepner J, Yanoff M: Ocular anomalies in trisomy 13–15: An analysis of 13 eyes with two new findings. Am J Ophthalmol 74:729, 1972. © Elsevier 1972.)

II. Systemic findings include mental retardation; low-set and malformed ears; cleft lip or palate or both; sloping forehead; facial angiomas; cryptorchidism; narrow, hyperconvex fingernails; fingers flexed or overlapping or both; polydactyly of hands or feet or of both; posterior prominence of the heels (“rocker-bottom feet”); characteristic features of the dermal ridge pattern, including transverse palmar creases; cardiac and renal abnormalities; absence or hypoplasia of the olfactory lobes (arhinencephaly); bicornuate uterus; apneic spells; apparent deafness; minor motor seizures; and hypotonia.

III. Ocular findings, usually severe, occur in all cases (see Figs. 2.9 and 2.15).

A. Bilateral microphthalmos (<15 mm in greatest diameter) is common and may be extreme so as to mimic anophthalmos (i.e., clinical anophthalmos). In rare instances, synophthalmos (cyclops; see later) or glaucoma can occur.

B. Coloboma of the iris and ciliary body, cataract, and persistent hyperplastic primary vitreous are present in most (~80%) of eyes.

C. Retinal dysplasia is found in at least 75% of eyes. Retinal folds and microcystoid degeneration of the neural retina are also common findings.

When retinal dysplasia is unilateral and the other eye is normal, the condition is usually unassociated with trisomy 13 or other systemic anomalies.

D. Central and peripheral dysgenesis of the cornea and iris (see Chapter 8) is present in at least 60% of eyes.

IV. Histology

A. The coloboma of the iris and ciliary body often contains mesodermal connection between the sclera and the retrolental area. Cartilage is present in the mesodermal tissue in approximately 65% of eyes, most commonly when the eyes are small (i.e., <10 mm).

Ocular cartilage has also been reported in teratoid medulloepithelioma, in chromosome 18 deletion defect, in angiomatosis retinae, in synophthalmos, and in a unilateral anomalous eye in an otherwise healthy individual; however, in none of these conditions is the cartilage present in a coloboma of the ciliary body, as occurs in trisomy 13.

B. The cataract may be similar to that seen in rubella, Leigh’s disease, and Lowe’s syndrome, and it shows retention of cell nuclei in the embryonic lens nucleus. Anterior subcapsular, anterior and posterior cortical, nuclear, and posterior subcapsular cataractous changes may also be seen.

Trisomy 18 (47,18+; Edwards’ Syndrome)

I. General information

A. Trisomy 18 has an extra chromosome in the 18 pair of autosomal chromosomes.

B. The condition has an incidence of 1 in 14,000 live births and usually proves fatal at an early age. Girls are predominantly affected.

C. Ocular malformations, usually minor, occur in approximately 50% of patients.

II. Systemic findings include mental retardation; low-set, malformed, and rotated ears; micrognathia; narrow palatal arch; head with prominent occiput, relatively flattened laterally; short sternum; narrow pelvis, often with luxation of hips; fingers flexed, with the index overlapping the third or the fifth overlapping the fourth; hallux short, dorsiflexed; characteristic features of the dermal ridge pattern, including an exceptionally high number of arches; cardiac and renal malformations; Meckel’s diverticulum; heterotopic pancreatic tissue; severe debility; moderate hypertonicity.

III. Ocular findings tend to be minor and mainly involve the lids and bony orbit: narrow palpebral fissures, ptosis, epicanthus, hypoplastic supraorbital ridges, exophthalmos, hypertelorism or hypotelorism, nystagmus; and rarely nictitating membrane, corneal opacities, anisocoria, uveal and optic disc colobomas, cataract, microphthalmos, severe myopia, megalocornea, keratitis, scleral icterus, blue sclera, persistent hyaloid artery, increased or absent retinal pigmentation, and irregular retinal vascular pattern.

IV. Histology—especially related to hyperplasia, hypertrophy, and cellular abnormalities

A. Corneal epithelium, mainly in the basal layer, may show cellular hypertrophy, swelling, disintegration, bizarre chromatin patterns, and atypical mitoses. Focal or diffuse hyperplasia of the corneal endothelium may be present.

B. Posterior subcapsular cataracts, minor neural retinal changes (gliosis and hemorrhage), and optic atrophy may be seen.

1. The retinal pigment epithelium (RPE) may show hypopigmented or hyperpigmented areas.

2. Rare, severe, optic disc colobomas may occur.

Trisomy 21 (47,21+; Down’s Syndrome; Mongolism)

I. General information

A. Trisomy 21 results from an extra chromosome in the 21 pair of autosomal chromosomes.

B. The condition is the most common autosomal trisomy, with an incidence of 1 in 700 live births (in white populations). Major ocular malformations are rare.

II. Systemic findings include severe mental retardation; flat nasal bridge; an open mouth with a furrowed, protruding tongue and small, malformed teeth; prominent malformed ears with absent lobes; a flat occiput with a short, broad neck; loose skin at the back of the neck and over the shoulders (in early infancy); short, broad hands; short, curved little fingers with dysplastic middle phalanx; specific features of the dermal ridge, including a transverse palmar crease; cardiovascular defects; Apert’s syndrome; and anomalous hematologic and biochemical traits.

III. Ocular findings include hypertelorism; oblique or arched palpebral fissures; epicanthus; ectropion; upper-eyelid eversion; speckled iris (Brushfield spots); esotropia, high myopia; rosy optic disc with excessive retinal vessels crossing its margin; generalized attenuation of fundus pigmentation regardless of iris coloration; peripapillary and patchy peripheral areas of pigment epithelial atrophy; choroidal vascular “sclerosis”; chronic blepharoconjunctivitis; keratoconus (sometimes acute hydrops; see Fig. 8.54); and lens opacities.

IV. Histology

A. Brushfield spots consist of areas of relatively normal iris stroma that are surrounded by a ring of mild iris hypoplasia. They also may show focal stromal condensation or hyperplasia.

B. A cataract may have abnormal anterior lens capsular excrescences similar to that seen in Lowe’s and Miller’s syndromes.

The aforementioned three trisomies are all autosomal chromosomal trisomies. An example of a sex chromosomal trisomy is Klinefelter’s syndrome (47,XXY—a rare case of Klinefelter’s syndrome associated with incontinentia pigmenti has been reported); the ocular pathologic process in this condition is not striking. In XYY syndrome (47,XYY), patients have normal height, psychological and social problems, gonadal atrophy, luxated lenses, and iris and choroid colobomas.

Triploidy

I. General information

A. Triploidy, which is common in spontaneous abortions but rare in live births, refers to that specific defect in which an individual’s cells have 69 chromosomes (three of each autosome and three of each sex chromosome) instead of the normal component of 46 chromosomes.

B. Triploid mosaic individuals may survive to adult life. Survivors have some cell lines with 46 chromosomes and other cell lines with 69 chromosomes.

II. Systemic findings include triangular face; low-set ears; absent nose or nose with single nostril; cleft lip; cleft palate; single transverse palmar crease; talipes equinovarus; syndactyly; meningomyeloceles; cardiac abnormalities; genitourinary abnormalities; and adrenal hyperplasia.

III. Ocular findings include telecanthus; hypotelorism or hypertelorism; blepharophimosis; blepharoptosis; proptosis; microphthalmos; ectopic pupil; anophthalmos (unilateral); microcornea; and iris and cornea colobomas (normal eyes have been reported).

IV. Histologic ocular findings include microcornea; iris and choroid colobomas; persistent hyaloid vasculature; retinal dysplasia; and optic atrophy.

Chromosome 4 Deletion Defect

The chromosome 4 deletion defect (4p–) results from a partial deletion of the short arm of chromosome 14 (46,4p–). Also known as the Wolf–Hirschhorn syndrome (or Wolf’s syndrome), it consists of profound mental retardation, antimongoloid slant, epicanthal folds, hypertelorism, ptosis, strabismus, nystagmus, cataract, and iris colobomas.

Chromosome 5 Deletion Defect (46,5p–; Cri du Chat Syndrome)

I. General information

A. It results from a deletion of part of the short arm of chromosome 5 (46,5p–). Only one of the chromosome 5 pair is affected.

B. Many newborn infants with the defect have an abnormal cry that sounds like a cat, hence the name cri du chat syndrome. The abnormal cry usually disappears as the child grows older.

Chromosome 4 deletion defect differs from cri du chat syndrome in not having the distinctive cry.

C. Affected patients usually live a normal life span.

II. Systemic findings include severe mental retardation; low-set ears; microcephaly; micrognathia; moon-shaped face; short neck; transverse palmar creases; scoliosis and kyphosis; curved fifth fingers; limitation of flexion or extension of fingers; and abnormalities of the cardiovascular system and kidneys.

III. Ocular findings include hypertelorism; epicanthus; mongoloid or antimongoloid eyelid fissures; exotropia; optic atrophy; tortuous retinal artery and veins; and pupils supersensitive to 2.5% methacholine.

IV. Significant histologic ocular findings have not been reported.

Chromosome 11 Deletion Defect

Deletion of chromosome 11p (aniridia–genitourinary–mental retardation syndrome—AGR triad) shows aniridia as its main ocular finding.

A. The chromosome band 11p13 has been associated with aniridia and Wilms’ tumor.

B. Deletion of chromosome 11q results in trigonocephaly, broad nasal bridge and upturned nose, abnormal pinnae, carp mouth, and micrognathia; and numerous ocular abnormalities.

Chromosome 13 Deletion Defect

See Chapter 18.

Chromosome 17 Deletion (17p11.2; Smith–Magenis Syndrome)

I. General information: The Smith–Magenis syndrome is a multiple-anomaly, mental retardation syndrome associated with deletions of a contiguous region of chromosome 17p11.2.

II. Systemic findings include dysmorphic facial features (brachycephaly, prominent forehead, synophrys, epicanthal folds, broad nasal bridge, ear anomalies, and prognathism), brachydactyly, self-injurious behaviors, autoamplexation (self-hugging) stereotypy, speech delay, sleep disturbances, mental and developmental retardation, and peripheral neuropathy.

III. Ocular findings include ptosis, telecanthus, strabismus, myopia, microcornea, iris abnormalities (Brushfield spots and colobomas), bilateral cataract, optic nerve hypoplasia, and retinal detachment.

IV. Significant histologic ocular findings have not been reported.

Chromosome 18 Deletion Defect (46,18p–; 46,18q–; or 46,18r; Partial 18 Monosomy (Fig. 2.10)

I. General information

A. Chromosome 18 deletion defect results from a straight deletion of part of the short arm of chromosome 18 (46,18p–), part of the long arm (46,18q–), or parts or all of the long and short arms, resulting in a ring form (46,18r). Only one of the chromosome 18 pair is affected.

B. Affected patients usually live a normal life span.

II. Systemic findings include low-set ears, nasal abnormalities, external genital abnormalities, hepatosplenomegaly, cardiovascular abnormalities, and holoprosencephaly.

III. Ocular findings include hypertelorism; epicanthus; ptosis; strabismus; nystagmus; myopia; glaucoma; microphthalmos; microcornea; corneal opacities; posterior keratoconus; Brushfield spots; cataract; uveal colobomas, including microphthalmos with cyst; retinal abnormalities; optic atrophy; and “cyclops.”

IV. Histology

A. Microphthalmos with cyst (see Chapter 14) and uveal colobomas are discussed elsewhere (see Chapter 9).

B. Intrascleral cartilage and intrachoroidal smooth muscle may be present anterior to and associated with a coloboma of the choroid.

C. Other findings include hypoplasia of the iris, immature anterior-chamber angle, persistent tunica vasculosa lentis, cataract, retinal dysplasia, and neural retinal nonattachment.

Fig. 2.10 Chromosome 18 deletion defect. A, Abnormal facies showing nose with single opening. B, Karyotype of child shown in A (46,XX,18r). C, Macroscopic appearance of right eye with its connected cyst (both eyes showed microphthalmos with cyst). D, The retina is nonattached and dysplastic. A large cyst is connected to the eye. E, Smooth muscle found in the choroid near the optic nerve is bright red when stained with trichrome. (From Yanoff M, Rorke LB, Niederer BS: Ocular and cerebral abnormalities in chromosome 18 deletion defect. American Journal of Ophthalmology 70:391. © Elsevier 1970.)

Chromosome 47 Deletion Defect

I. Turner’s syndrome (gonadal dysgenesis; Bonnevie–Ullrich syndrome; ovarian agenesis; and ovarian dysgenesis)

A. Turner’s syndrome is usually caused by only one sex chromosome being present, the X chromosome (45,X), or is due to a mosaic (45,X;46,XY).

B. Some cases, however, are caused by an X long-arm isochromosome [46,X(Xqi)], X deletion defect of the short arm [46,X(Xp-)], or X deletion (partial or complete) of all arms, resulting in a ring chromosome [46,X(Xr)].

C. Ocular findings include epicanthus, blepharoptosis, myopia, strabismus, and nystagmus.

Noonan’s syndrome (Bonnevie–Ullrich or Ullrich’s syndrome; XX Turner phenotype or “female Turner”; and XY Turner phenotype or “male Turner”) probably is an inherited condition in which the person (either male or female) phenotypically resembles Turner’s syndrome but has a normal karyotype (46,XY or XX).

In Noonan’s syndrome, ocular anomalies are even more frequent than in Turner’s syndrome and include antimongoloid slant of the palpebral fissures, hypertelorism, epicanthus, blepharoptosis, exophthalmos, keratoconus, high myopia, and posterior embryotoxon.

Mosaicism

I. General information

A. Chromosomal mosaicism refers to the presence of two or more populations of karyotypically distinct chromosomes in cells from a single individual.

Individuals with mixtures of cells derived from different zygotes are usually called chimeras (e.g., in a true hermaphrodite 46,XX; 46,XY), and the term mosaic is reserved for individuals who have cell mixtures arising from a single zygote.

B. Mosaicism may occur in most of the previously described chromosomal abnormalities.

II. Tetraploid–diploid mosaicism (92/46; Fig. 2.11)

A. In tetraploid–diploid mosaicism, two karyotypically distinct populations of cells exist: a large-size cell with increased DNA content containing 92 chromosomes (tetraploid) and a normal-size cell with a normal complement of 46 chromosomes (diploid). The condition is incompatible with longevity.

B. Systemic findings include micrognathia, horizontal palmar creases, deformities of the fingers and toes, cardiovascular abnormalities, microcephalus, and forebrain maturation arrest.

C. Ocular anomalies include microphthalmos, corneal opacities, and leukokoria.

D. Histologically, the eyes may show iris neovascularization, anterior peripheral synechiae, luxated and cataractous lens, nonattachment of the neural retina, and massive hyperplasia of the pigment epithelium.

Fig. 2.11 Tetraploid–diploid mosaicism (92/46). A, Child with 92/46 had peculiar facies. Proptosis of left eye is secondary to orbital cellulitis and endophthalmitis. B, Gross appearance of opened, mildly microphthalmic right eye (on right) and markedly microphthalmic left eye (on left). C and D, Microscopic appearance of right (C) and left (D) eyes. The right eye shows peripheral anterior synechiae, ectropion uveae, cataract adherent to posterior cornea, and detached gliotic neural retina containing calcium. The left eye shows phthisis bulbi as a result of the endophthalmitis.

III. Most cases of trisomy 8 (47,8+) are mosaics. The main ocular findings are strabismus and dense, geographic, stromal corneal opacities.

Infectious Embryopathy

Congenital Rubella Syndrome (Gregg’s Syndrome)

I. Congenital rubella syndrome consists of cataracts, cardiovascular defects, mental retardation, and deafness. The syndrome results from maternal rubella infection during pregnancy (50% of fetuses are affected if mother contracts rubella during first four weeks of pregnancy; 20% are affected if contracted during first trimester).

The name rubella is derived from Latin, meaning “little red.”

II. Systemic findings include low birth weight; deafness; congenital heart defects (especially patent ductus arteriosus); central nervous system abnormalities; thrombocytopenic purpura; diabetes mellitus; osteomyelitis; dental abnormalities; pneumonitis; hepatomegaly; and genitourinary anomalies.

III. Ocular findings include cataract, congenital glaucoma, iris abnormalities, and a secondary pigmentary retinopathy (Figs 2.12 and 2.13).

Rubella retinopathy is the most characteristic finding. Approximately 30% of patients with congenital rubella have cataracts and 9% have glaucoma. When rubella cataract is present, congenital glaucoma is present in 9% of cases; when congenital glaucoma is present, cataract is present in 33% of cases. Congenital rubella cataract and glaucoma therefore occur together at the frequency expected of coincidental events occurring independently. Subneural retinal neovascularization has been reported in patients between the ages of 10 and 18 years who have congenital rubella. Persistence of the rubella virus has been implicated in the delayed onset of Fuchs’ heterochromic iridocyclitis.

Fig. 2.12 Rubella. A, A dense nuclear cataract surrounded by a mild cortical cataract is seen in the red reflex. B, Cortical and nuclear cataract present. Note Lange’s fold, which is an artifact of fixation, at the ora serrata on the left (c, cornea; i, iris; cb, ciliary body; l, lens; cd, cataractous degeneration). C, The dense nuclear cataract shows lens cell nuclei (n) retained in the embryonic nucleus (ac, artifactitious clefts in lens nucleus). (A, Courtesy of Dr. DB Schaffer; B and C, from Yanoff M, Schaffer DB, Scheie HG: Rubella ocular syndrome: Clinical significance of viral and pathologic studies. Trans Am Acad Ophthalmol Otolaryngol 72:896. © Elsevier 1968.)

Fig. 2.13 Rubella. A, Fundus picture shows mottled “salt-and-pepper” appearance with both fine and coarse pigmentation. B and C, From same eye. Retinal pigment epithelium (RPE) shows areas of hyperpigmentation (B) (h, hypertrophied RPE) and hypopigmentation (C) (a, atrophy). The alternating areas of hyperpigmentation and hypopigmentation cause the salt-and-pepper appearance of the fundus (nr, neural retina; c, choroid). (Modified from Yanoff M: In Tasman W, ed: Retinal Diseases in Children. New York, Harper & Row, 1971:223–232. © Lippincott Williams & Wilkins.)

IV. The rubella virus can pass through the placenta, infect the fetus, and cause abnormal embryogenesis.

The rubella virus can survive in the lens for at least three years after birth. Surgery on rubella cataracts may release the virus into the interior of the eye and cause endophthalmitis.

V. Histology

A. Retention of lens cell nuclei in the embryonic lens nucleus is characteristic (but not pathognomonic, because it also is seen in trisomy 13, Leigh’s disease, and Lowe’s syndrome), and posterior cortical lens degeneration and dysplastic lens changes may be seen.

B. The iris shows a poorly developed dilator muscle and necrotic epithelium along with a chronic, nongranulomatous inflammatory reaction.

The combination of the dilator muscle abnormality and chronic inflammation often causes the iris to dilate poorly and to appear leathery.

C. The ciliary body shows pigment epithelium necrosis, macrophagic pigment phagocytosis, and a chronic nongranulomatous inflammatory reaction.

D. Atrophy and hypertrophy, frequently in alternating areas of RPE, are seen in most, if not all, cases, resulting in the clinically observed “salt-and-pepper” fundus of rubella retinopathy.

E. Other findings, such as Peters’ anomaly and Axenfeld’s anomaly, may occasionally be seen.

F. After cataract or iris surgery, complications caused by virus infection may cause a chronic nongranulomatous inflammatory reaction around lens remnants and secondary disruption of intraocular tissues with fibroblastic overgrowth, resulting in cyclitic membrane and neural retinal detachment.

Drug Embryopathy

Fetal Alcohol Syndrome (FAS) (Fig. 2.14)

I. FAS is a specific, recognizable pattern of malformations caused by alcohol’s teratogenic effect secondary to maternal alcohol ingestion during pregnancy. The leading cause of mental retardation in the United States, FAS involves various neural crest-derived structures.

II. Systemic findings include developmental delay and retardation; midface hypoplasia (flattened nasal bridge and thin upper lip); smooth or long philtrum; and central nervous system manifestations, including microcephaly, hyperactivity, and seizures.

III. Ocular findings include narrow palpebral fissures, epicanthal folds, ptosis; blepharophimosis; strabismus; severe myopia; microcornea; Peters’ anomaly (see Fig. 2.14); iris dysplasia; glaucoma; hypoplasia of the optic nerve head; and microphthalmia.

IV. Histology depends on the structures involved.

Fig. 2.14 Fetal alcohol syndrome. Child who was born with the fetal alcohol syndrome was seen because of cloudy corneas (A and B). Corneal grafts were performed. Light (C) and electron microscopy (D) of the anterior cornea show irregular epithelium and absence of Bowman’s membrane. The epithelial cells project processes from their bases directly into anterior stroma. Light (E) and electron microscopy (F) of the posterior cornea show irregularity of stromal lamellae and absence of Descemet’s membrane (Peters’ anomaly). (From Sassani JW: Presented at the Eastern Ophthalmic Pathology Society meeting, 1991.)

Thalidomide

I. Thalidomide ingestion during the first trimester of pregnancy may result in a condition known as phocomelia, the condition of having the limbs extremely shortened so that the feet or hands arise close to the trunk.

II. Ocular findings include ocular motility problems (e.g., Möbius’ and Duane’s syndromes), uveal colobomas, microphthalmos, and anophthalmos.

III. Histologically, hypoplasia of the iris and colobomas of the uvea and optic nerve may be seen.

Lysergic Acid Diethylamide (LSD) (Fig. 2.15)

I. LSD ingestion during the first trimester of pregnancy may result in multiple central nervous system and ocular abnormalities.

II. Central nervous system abnormalities: arhinencephaly; fusion of the frontal lobes; Arnold–Chiari malformation with hydrocephalus; and absence of the normal convolutional pattern in cerebral hemispheres and of foliar markings in the cerebellum.

III. Ocular findings include cataract and microphthalmia.

IV. Histologically, the lens may show anterior and posterior cortical degeneration and posterior migration of lens epithelial nuclei, and the neural retina may contain posterior retinal neovascularization and juvenile retinoschisis.

Fig. 2.15 LSD embryopathy. Mother took LSD (and other drugs) during entire pregnancy. A, Microphthalmic right eye shows cataract, nonattachment of retina, and retinoschsis. B, Posterior retina shows neovascular vessels growing out of the retina onto the retinal inner surface (baby 7 lb, 8 oz. at birth without oxygen administration).

Other Congenital Anomalies

Cyclopia and Synophthalmos

I. Cyclopia and synophthalmos (Fig. 2.16) are conditions in which anterior brain and midline mesodermal structures develop anomalously (holoprosencephaly—also called arhinencephaly and holotelencephaly).

A. The conditions are incompatible with life.

B. The prevalence is approximately one in 13,000 to 20,000 live births.

Chromosomes may be normal or abnormal, usually trisomy 13, rarely 13q– and 18p– karyotypes. Embryologically, the gene, ET, acts as a transcription factor and causes the retina in the frog, Xenopus laevis, to emerge early as a single retinal field. A transcription factor is a DNA-binding protein that controls gene activity. A nearby piece of the embryo, the precordial mesoderm, suppresses retinal formation in the median region, resulting in the resolution of the single retinal field into two retinal primordia. The lack or deficiency of the splitting induction, as has been shown also with the PAX6 gene in chick embryos, may result in either cyclops or synophthalmos in humans.

Fig. 2.16 Synophthalmos. A, The patient was born with clinical cyclops. When the proboscis is lifted, a single pseudo-orbit is seen clinically. Note the fairly well-formed eyelids under the proboscis. B, Karyotype from the same patient shows an extra chromosome (three instead of two) in the 13 group (trisomy 13). C, Histologic section shows that the condition is not true cyclops (a single eye) but, rather, the more commonly seen synophthalmos (partial fusion of the two eyes) (re, rudimentary eyelid; c, cartilage; l, lens; dr, dysplastic retina).

II. The prosencephalon fails to cleave, a large dorsal cyst develops, and midline structures such as the corpus callosum, septum pellucidum, olfactory lobes, and neurohypophysis are lacking.

III. The orbital region is grossly deformed from failure of the frontonasal bony processes to develop; the maxillary processes then fuse, resulting in an absent nasal cavity and a single central cavity or pseudo-orbit. The nose is usually present as a rudimentary proboscis above the pseudo-orbit.

IV. If only one eye is present (i.e., complete and total fusion of the two eyes) in the pseudo-orbit, the condition is called cyclopia. A much more common situation is synophthalmos, wherein two eyes are present in differing degrees of fusion, but never complete fusion.

Even rarer is a supernumerary eye, called diplophthalmos.

V. Histology

A. In cyclopia, the one eye may be relatively normal, completely anomalous, or display all degrees of abnormality in between.

B. In synophthalmos, the partially fused two eyes may be relatively normal, totally anomalous, or display all degrees of abnormality in between.

Anencephaly

I. Anencephaly is the most serious congenital malformation occurring spontaneously in humans that is compatible with completion of pregnancy.

A. The condition is characterized by absence of the cranial vault.

B. The cerebral hemispheres are missing completely or reduced to small masses attached to the base of the skull.

C. The condition appears to be caused by a defect in the development of the affected tissues at the 5th to 10th week of gestation, probably close to the 5th week.

II. Macroscopically, the eyes are normal.

A. Histologically, the main finding is hypoplasia (or atrophy) of the retinal ganglion cell and nerve fiber layers and of the optic nerve.

B. Uncommonly, uveal colobomas, retinal dysplasia, corneal dermoids, anterior-chamber angle anomalies, and vascular proliferative retinal changes may be seen.

Anophthalmos (Fig. 2.17)

I. The differentiation between anophthalmos (complete absence of the eye) and extreme microphthalmos (a rudimentary small eye) can be made only by the examination of serial histologic sections of the orbit. The differentiation cannot be made clinically.

The term clinical anophthalmos is applied to the condition in which no eye can be found clinically.

II. Three types of anophthalmos are recognized:

A. Primary anophthalmos: caused by suppression of the optic anlage during the mosaic differentiation of the optic plate after formation of the rudiment of the forebrain (occurs before the 2-mm stage of embryonic development).

B. Secondary anophthalmos: caused by the complete suppression or grossly anomalous development of the entire anterior portion of the neural tube.

C. Consecutive or degenerative anophthalmos: caused by atrophy or degeneration of the optic vesicle after it has been formed initially.

Consecutive anophthalmos has been reported in the focal dermal hypoplasia syndrome (Goltz’s syndrome, congenital cutis hypoplasia).

III. Histologically, serial sections of the orbit fail to show any ocular tissue.

Fig. 2.17 Anophthalmos. Infant died from postoperative complications after repair of choanal atresia; other multiple systemic congenital anomalies were found. Apparent anophthalmos was present bilaterally. Serial sections of the orbital contents showed small nests of pigmented cells in each orbit (A and B, right orbit; C and D, left orbit) as only evidence of eyes. (From Sassani JW, Yanoff M: Anophthalmos in an infant with multiple congenital anomalies. Am J Ophthalmol 83:43. © Elsevier 1977.)

Microphthalmos

I. Microphthalmos (see Figs. 2.9–2.11) is a congenital condition in which the affected eye is smaller than normal at birth (<15 mm in greatest diameter; normal eye at birth varies between 16 and 19 mm).

Microphthalmos should be differentiated from atrophia bulbi, an acquired condition wherein the eye is of normal size at birth but shrinks secondary to ocular disease. Rarely, the microphthalmos disproportionately affects the posterior ocular segment, called posterior microphthalmos.

II. Three types of microphthalmos are recognized:

A. Pure microphthalmos alone (nanophthalmos or simple microphthalmos), wherein the eye is smaller than normal in size but has no other gross abnormalities except for a high lens/eye volume.

1. Such eyes are usually hypermetropic and may have macular hypoplasia.

2. Nanophthalmic eyes may have thickened sclera and a tendency toward postoperative or spontaneous uveal effusion, secondary neural retinal, and choroidal detachments, and they are susceptible to acute and chronic closed-angle glaucoma.

A fraying or unraveling of the collagen fibril into its constituent 2- to 3-nm subunits may occur and may be related to an abnormality of glycosaminoglycan metabolism.

B. Microphthalmos with cyst (see Fig. 2.10 and Chapter 9 and 14).

C. Microphthalmos associated with other systemic anomalies (e.g., in trisomy 13 and congenital rubella). This type of microphthalmos is discussed in the appropriate sections.

III. Histologically, the eye ranges from essentially normal in nanophthalmos to rudimentary in clinical anophthalmos, and all degrees of abnormality in between.

Walker–Warburg Syndrome

I. Walker–Warburg syndrome (Fig. 2.18) is a lethal, autosomal-recessive, oculocerebral disorder. The diagnosis is based on at least four abnormalities: type II lissencephaly, cerebellar malformation, retinal malformation, and congenital muscular dystrophy.

Type II lissencephaly (lissencephaly variant) consists of a smooth cerebral surface [agyria, polymicrogyria, and pachygyria (broad gyri)] and microscopic evidence of incomplete neuronal migration. Type I lissencephaly (classic lissencephaly) also consists of a smooth cerebral surface but excludes polymicrogyria. The most frequent cause of classical lissencephaly is deletions of the lissencephaly critical region in chromosome 17p13.3.

Fig. 2.18 Walker–Warburg syndrome. A 3890-g child at birth died at age 5 days. Autopsy showed type II lissencephaly (“smooth” brain), hydrocephalus, and occipital meningocele. Gross and microscopic examination of the right (A and B) and left (C and D) eyes showed bilateral Peters’ anomaly, cataract, total neural retinal detachment, neural retinal dysplasia, and colobomatous malformation of the optic nerve. In addition, the right eye showed peripheral anterior synechiae, anterior displacement of the ciliary processes, and persistent hyperplastic primary vitreous. (From Yanoff M: Presented at the meeting of the Verhoeff Society, 1989.)

II. Previous names for Walker–Warburg syndrome include Warburg’s syndrome, Walker’s lissencephaly, Chemke’s syndrome, cerebro-ocular–muscular syndrome, cerebro-ocular dysplasia muscular dystrophy, and cerebro-ocular dysgenesis.

III. Ocular findings include microphthalmia, microcornea, Peters’ anomaly, anterior-chamber malformations, coloboma, cataracts, persistent hyperplastic primary vitreous, retinal detachment, retinal disorganization, and retinal dysplasia.

Oculocerebrorenal Syndrome of Miller

I. Miller’s syndrome consists of Wilms’ tumor, congenital nonfamilial aniridia (Fig. 2.19),² and genitourinary anomalies.

A. Mental and growth retardation, microcephaly, and deformities of the pinna may be present.

B. Aniridia and Wilms’ tumor have been found in deletion of the short arm of chromosome 11 and are associated with the chromosome band 11p13.

Aniridia is caused by point mutations or deletions affecting the PAX6 gene, located on chromosome 11p13. A rapid polymerase chain reaction-based DNA test can be performed to rule out chromosome 11p13 deletion and its high risk of Wilms’ tumor in patients who have sporadic aniridia. A case of two monozygous twins has been reported in which both had bilateral aniridia and cataracts, but only one had Wilms’ tumor.