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.

Tuberous ¹ 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.