D I F F E R E N T I A L D I A G N O S I S O F R E T I N O B L A S T O M A 621

be marked. In the first part of this report, it was noted that the diagnoses in five cases of larval granulomatosis and in two cases of Coats' disease were confirmed microscopi-cally. In these seven cases, retinoblastoma was considered a strong possibility clinical-ly, and excision of the globe was recom-mended.

Annual follow-up of patients who have been apparently cured of retinoblastoma is recommended not only to diagnose the occa-sional late occurrence of tumor, but also for the purpose of genetic counseling. There were three instances in this series in which parents of children with retinoblastoma were not aware of the hereditary nature of their disease.

Retinal dysplasia is a bilateral develop-mental abnormality, present at birth. Its manifestations range in degree from retinal folds with preservation of some useful vi-sion to severely damaged blind eyes with microphthalmos, cataract and glaucoma. As-sociated skeletal and central nervous defects are common and a familial tendency has been reported.

Three cases of retinal dysplasia, including one which came to autopsy, are reported here. They illustrate much of the range of the clinical manifestations which retinal dysplasia may exhibit. These cases also il-lustrate the differential diagnosis, which has been largely clarified by Reese and

* From the Division of Ophthalmology, Univer-sity of Rochester School of Medicine and Dentis-try. This work was supported in part by funds granted by the Rochester Eye-Bank and Research Society.

SUMMARY

Five hundred children with the question-able clinical diagnosis of retinoblastoma were referred to the Tumor Clinic of the Institute of Ophthalmology, New York, for examination under anesthesia during a five-year period; 235 had retinoblastoma and the other 265 had a variety of congenital and acquired conditions which were discussed in Part I of this report. In the present article, factors relating to the diagnosis of retino-blastoma are discussed, and the several in-traocular diseases which the tumor may mimic are mentioned.

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Straatsma.1 The most important differential diagnoses are retinoblastoma, retrolental fibroplasia and persistent hyperplastic pri-mary vitreous.

CASE REPORTS

CASE 1

M. P. was a white boy of approximately two years of age. There was no family history of ocu-lar or skeletal or neurologic disease. Gestation and delivery were unremarkable. Birth weight was 3,200 gm. He was hospitalized at the age of three weeks for a period of six days with a diagnosis of pneumonia, during which time he was treated with oxygen. The mother had observed since birth that the infant did not exhibit following movements of the eyes so she believed the infant to be blind. Labo-ratory findings, including chromosome analysis, were not abnormal. A pneumoencephalogram revealed nothing abnormal. Upon physical examination at about two years of age the patient exhibited motor retardation. He was barely able to sit without assis-tance and showed no signs of walking or talking. He exhibited a mild torticollis. There was a slight dis-tortion in the shape of the skull, consisting of a

R E F E R E N C E S

1. Howard, G. M., and Ellsworth, R. M. : Differential diagnosis of retinoblastoma : A statistical sur-vey of 500 children: I. Relative frequency of the lesions which simulate retinoblastoma. Am. J. Ophth., 60:610, 1965.

2. Reese, A. B. : Tumors of the Eye. New York, Hoeber, 1963, ed. 2.

RETINAL DYSPLASIA*

ALBERT C. SNELL, M.D. Rochester, New York

622 A L B E R T C. S N E L L

Fig. 1 (Snell). Case 1. Left eye. Congenital retinal fold extending from the disc to a temporal retrolental membrane.

little flattening on the left side with the left ear dis-placed more posteriorly than the right.

The eye examination was consistent and un-changing through the two-year period of observa-tion. There was no microphthalmos and no abnor-mality of the lids, conjunctivas, corneas, irises or of the anterior chambers. The pupils reacted well to light. There was no apparent limitation of the extraocular motions but there was a gross nystag-mus tending to exhibit a slow drift to the left with a quick component toward the central position. With the pupils dilated, it was seen that both lenses were clear. There was, however, a temporal retrolental membrane in contact with one sixth of the poste-rior lens surface. The right and left eyes were symmetrical in this respect. The ophthalmoscopic examination showed that the abnormalities in the right eye were identical to those in the left (fig. 1). A short distance from the extreme peripheral mass or retrolental membrane a stalk or fold was formed, consisting of material which seemed to have the general color and texture of retina and which extended in an almost straight line posterior-ly and nasally and terminated in the disc. This stalk was slightly more broad temporally, quickly narrowed and then only gradually tapered, its pos-terior dimension being a disc diameter in size. The macular region was obscured. Retinal vessels origi-nated from the posterior margins of this fold, rath-er than from the disc.

CASE 2

J. N., a white boy had been followed closely since 1951 when he was first examined at 11 weeks of age. His only sibling, an older brother, and his mother and father have been examined and are known to be normal. There are no relatives with known ocular or skeletal or nervous system disease.

General physical examination at approximately 13 years of age revealed this boy to be small and slim, weighing 24.5 kg and measuring 136 cm in height. The head was small, 47 cm in greatest cir-cumference. The ears were large. The digits of the hands and feet were unusually long, as were the extremities, giving the impression of an arachno-dactylic child. At birth an extra digit was present on the left thumb (fig. 2) ; it had since been ex-cised. There was an abnormality of the right clavi-cle. There was no evidence of cardiac abnormality. Psychometric studies reported an average I.Q. Chromosome studies revealed no abnormality.

When this patient was about eight weeks of age, his mother noticed that there was a filmy appear-ance in the right eye. An eye examination was done at 11 weeks of age when he was hospitalized for observation. At that time the patient exhibited bi-lateral irregular, coarse nystagmus. The right eye was observed to be larger than the left, although measurements were not obtained. The right iris was seen to be partly atrophie and the anterior chamber was obliterated. The right cornea and lens were both entirely clear. Through the clear lens, a completely opaque membrane was seen to cover the posterior surface of the lens. It contained an occa-sional large blood vessel. The right lens remained clear for three years, eventually becoming opaque. At present the right eye is the smaller, the tactile tension is below normal, the anterior chamber is completely absent although the cornea remains clear. The lens is entirely opaque. There is no light perception.

The left eye has remained essentially unchanged during the 12-year period of observation. It still

Fig. 2 (Snell). Case 2. X-ray photograph of the left hand, showing supernumerary digit.

RETINAL D Y S P L A S I A 623

exhibits an irregular, coarse, although rather rapid nystagmus. The corneal diameter is estimated as reduced by perhaps one-half mm from average. The cornea is clear. The anterior chamber is nor-mal. The pupil reacts normally and dilates reason-ably well with mydriatic drugs. The left lens is seen to be entirely clear but the temporal one fifth of its posterior surface is in contact with a white retrolental membrane. This membrane obscures the retinal periphery in this area. The retrolental mem-brane can be clearly seen to be the anterior termi-nation of a stalk or fold whose origin also includes the temporal ora and which traverses the vitreous cavity, running posteriorly and nasalward and ter-minating precisely in the disc. The foveal area and a bit of the posterior retina and temporal retina are obscured by the stalk. The undersurface of the stalk is not visible and it cannot be determined with certainty if this is the margin of an elevated fold of retina, or an actual tubelike structure traversing the vitreous cavity. There seems to be some irregu-larity in pigmentation of the choroid near the re-gion that is obscured by the fold. Visual acuity in the left eye is 3/200 and the visual field is grossly full.

In brief, the right eye in Case 2 appears clinical-ly to exhibit typical persistent hyperplastic primary vitreous. The left eye in Case 2 shows a congenital retinal fold identical with that seen in each eye in Case 1.

CASE 3

A. R., a white boy, was first examined at three months of age. The chief complaint was that the right eye had been observed to be the smaller since birth. There was no family history of ocular or systemic disease. The pregnancy had been uncom-plicated. Delivery had been effected with forceps which left marks on the eyelids. A general physical examination revealed an apparently healthy white infant, possibly retarded in development. The only positive finding on the general physical examination was enlargement of the skull. X-ray films of the skull revealed thinning of the bones, suggesting the presence of increased intracranial pressure. Ventric-ulography was eventually performed and revealed an immense hydrocephalus with destruction of es-sentially all of the cerebrum (fig. 3) . No ocular or intracranial calcifications were demonstrated by X-ray.

The eye examination, including examination

Fig. 3 (Snell). Case 3. Ventriculogram showing ex-tensive hydrocephalus. (A) Facedown. (B) Faceup.

Fig. 4 (Snell). Case 3. Right eye, low-power view.

under anesthesia, revealed the right eye to be definitely the smaller, the left eye appearing to be of normal size. The right cornea was clear. The right anterior chamber was shallow temporally. There were multiple fine adhesions of the pupillary margin to the lens ; the pupil dilated imperfectly. The lens was clear. There was a defect in transil-lumination through the lower temporal quadrant. Ophthalmoscopic examination of the right eye re-vealed the presence of a mass in the temporal and inferior aspect of the vitreous cavity. The mass ap-peared to extend posteriorly and tapered into an ill-defined, stalk-shaped figure reaching the posterior pole in the region of the disc. The disc was not identified with certainty but the position of the disc appeared to coincide with the posterior termination of the temporal mass and stalk. The visible nasal fundus appeared to be not abnormal and exhibited a normal vascular pattern.

The left eye appeared normal, externally. The pupil dilated well. The iris and lens were not re-markable. The left disc, vessels and fundus ap-peared normal, with the exception of a mass in the upper nasal quadrant elevated a little into the vitre-ous cavity and associated with a limited serous de-tachment. The retinal vessels exhibited a normal pattern in the region of the retinal elevation, with-out evidence of neovascularization. The mass itself exhibited minimal irregular diffuse pigmentation, the pigmentation being exaggerated at the margins of the lesion.

Because of the presence of bilateral retinal masses, and because the right eye was regarded as having no potentially useful vision, the right eye was enucleated following the diagnosis of possible retinoblastoma, in spite of the obvious right mi-crophthalmos.

The child's subsequent clinical course was that of a complete decerebrate. He was accordingly in-stitutionalized. He survived for five years, finally dying from immense hydrocephalus. Chromosome studies were not obtained. General autopsy revealed the presence of an extremely enlarged skull and of an almost total hydrocephaly. No other gross or mi-croscopic abnormalities were observed in any other organs.

624 A L B E R T

Fig. S (Snell). Case 3. Right eye, essentially normal filtration angle.

Gross examination of the right eye after fixa-tion revealed it to measure 17 mm in all dimen-sions. A thick, stalklike mass of tissue was seen to extend from the temporal half of the posterior lens surface to the region of the optic disc, roughly di-viding the vitreous cavity into a smaller temporal portion and a larger nasal portion. The temporal portion of the vitreous body was replaced with pro-teinaceous, dark-colored hemorrhagic material. The nasal part of the vitreous cavity appeared to con-tain essentially normal vitreous.

Microscopic examination (fig. 4) confirmed the gross findings. The angle of the anterior chamber appeared to be normal with, at most, a slight ten-dency for the longitudinal fibers of the ciliary mus-cle to insert into the trabecular fibers (fig. 5) . There was adhesion of the margin of the pupil to the anterior lens surface, with some thinning of the pupillary margin and flattening of the sphincter muscle. The lens was distorted by a posterior and temporal bulge adjacent to abnormal vitreous con-taining a network of fibrillar material with flat-tened connective tissue cells and blood vessels (figs. 6 and 7).

This fibrillar material was, in turn, found to be attached to grossly abnormal retinal tissue charac-terized principally by the presence of numerous large rosettes and cysts whose walls consisted of external limiting membrane and external and inter-nal nuclear layers (fig. 8) . In many areas these ap-parent cysts of retinal tissue seemed to communi-cate with the subretinal space and were regarded as dysplastic infoldings and plications of the retina.

The retinal pigment epithelium exhibited a local-ized proliferative reaction (fig. 9 ) . At the posterior pole near the temporal aspect of the disc, the reti-nal pigment epithelium and Bruch's membrane were found to be disrupted and a mild amount of sometimes heavy subretinal and chorioretinal scar-ring was seen, in which small nests of pigment epi-thelium were included (fig. 10). The nasal retina exhibited almost no ganglion cells, a very attenuat-ed nuclear layer and an imperfectly developed rod

C. S N E L L

Fig. 6 (Snell). Case 3. Right eye, retrolental tissue and abnormal retina.

and cone layer. At the disc the nasal retina ex-hibited a remarkable overfolding (fig. 11) so that it seemed to originate at the temporal margin of the disc.

The left eye, which was removed at autopsy, showed on histologie examination a normal cornea, iris, anterior chamber, chamber angle and lens. The retinal ganglion cell layer appeared to be largely atrophie but the inner and outer nuclear layers and layers of rods and cones appeared essentially intact. The optic nerve showed marked atrophy. In the nasal area, at the equatorial region and anterior to it, there were two areas of rather heavy chorio-retinal scarring. Posterior to this a heavy fibrous band, including a few blood vessels, extended into the vitreous (fig. 12). This band tapered out both anteriorly and posteriorly to a delicate fibrillar structure which eventually was lost in normal vitre-ous. Alterations of the retinal pattern in this area suggested a tendency toward the dysplastic figures of the right eye but the derangements were minimal.

Table 1 summarizes the clinical data.

Fig. 7 (Snell) . Case 3. Right eye, retrolental fibrovascular tissue.

RETINAL DYSPLASIA 625

Fig. 8 (Snell) Case 3. Right eye, rosettes and tubes typical of retinal dysplasia.

DISCUSSION

The three cases presented here illustrate a considerable range of clinical manifesta-tions, and the question arises as to whether or not these three cases do indeed represent instances of the same basic disorder, vary-ing only in amount or in degree. Congenital retinal folds, such as those seen in Case 1 and in the left eye of Case 2, are usually re-garded as instances of a dysplastic disorder of congenital nature. Retinal folds are clas-sified as a dysplasia by Mann,2 Duke-Elder,3 and by Hogan and Zimmerman,4

One of the reasons for this classification is the fact that retinal rosettes are a histologie feature of congenital retinal folds and are similar to the rosettes seen in typical severe instances of retinal dysplasia. These rosettes are distinguished from the rosettes of reti-noblastoma by their larger size and more numerous cells, by their frequently oval shape, and by the fact that they are often identifiable as sections of tubular structures.

Case 2 of this report exhibited a typical

congenital retinal fold in one eye and, in the other eye, the clinical appearance of persis-tent hyperplastic primary vitreous. It has been pointed out by Reese and Straatsma1

that persistence of the primary vitreous is a feature frequently associated with retinal dysplasia. The anterior termination of con-genital retinal folds is characterized by a

Fig. 9 (Snell). Case 3. Right eye, hyperplastic pigment epithelium.

626 ALBERT C. S N E L L

Fig. 10 (Snell). Case 3. Right eye, chorioretinal scarring with hyperplastic pigment epithelium.

Fig. 12 (Snell). Case 3. Left eye, single peripheral chorioretinal scar with fibrous intravitreal band.

Fig. 11 (Snell). Case 3. Right eye, plication of partly dysplastic retina at the disc.

limited temporal retrolental membrane re-sembling that seen in persistent hyperplastic primary vitreous.

In Case 3 of this report the right eye ex-hibited a dysplastic aberration of about half

of the retina and abnormality of the remain-ing retina in that ganglion cells were absent. Yet the opposite eye of the same patient ex-hibited minimal changes which probably could not be classified as retinal dysplasia were it not for the changes in the right eye, although it did exhibit loss of ganglion cells and optic atrophy.

It is suggested, therefore, that retinal dys-plasia may present itself in a surprisingly wide range of severity or of degree, from congenital retinal folds to highly disorgan-ized microphthalmic eyes. This spectrum is further unified by the frequently associated skeletal and neurologic manifestations.

The variations in the degree of severity of this disorder, the irregular association with defects in other organs and systems and its inconstant familial occurrence might mean that retinal dysplasia represents a re-

TABLE 1

SUMMARY OF CLINICAL DATA

Case Ocular Skeletal C-N-S

R E : LE:

R E : LE:

Retinal fold Retinal fold

R E : Persistent hyperplastic Primary vitreous

L E : Retinal fold

Retinal dysplasia Retinovitreal band

Normal

Underdevelopment Supernumerary Digit Abnormal clavicle

Normal

Mental and motor retardation

Microcephaly

Hydrocephaly

RETINAL DYSPLASIA 627

sponse to more than one etiologic agent. A genetic basis as one possible etiology of

retinal dysplasia has suggested itself be-cause of the bilaterally, because of the asso-ciated systemic defects and because of a positive family history in a few instances.1

The role of a genetic influence in retinal dysplasia has recently been demonstrated by several reports of a chromosomal abnormal-ity of the 13-15 trisomy type associated with this ocular disorder.5-8 The 13-15 trisomy syndrome is associated with extensive de-formities frequently incompatible with life.8

The reported ocular defects are likewise se-vere and various, retinal dysplasia being a prominent feature accompanied by such findings as microphthalmos, underdeveloped iris, abnormal filtration angle, intraocular cartilage,6 pigment epithilium proliferation, as well as deformities of the lids and orbits.5'8

The reported cases of 13-15 trisomy syn-drome, characterized as they are by the chromosomal abnormality, by the severe systemic and ocular defects and, perhaps, by the presence of intraocular cartilage,5 seem to form a group of characteristic cases pos-sibly distinct from a group without known chromosomal abnormalities and with less severe ocular and systemic involvement. On the other hand, Smith et al8 reported an in-stance of 13-15 trisomy with what appears to be relatively mild ocular involvement con-sisting of iris colobomas and a left retrolen-

tal membrane with retention of the ability to perceive light.

In the cases reported here chromosomal karyotypes were found to be normal in the two less affected cases, but chromosomal studies were not carried out in the more se-verely affected individual who failed to sur-vive.

Undoubtedly, genetically determined fac-tors are the basis for many instances of ret-inal dysplasia. The possibility that environ-mental factors determine some instances of retinal dysplasia, particularly those that are less severe and are unassociated with gener-alized defects, cannot yet be ruled out.

S U M M A R Y

Three cases of retinal dysplasia are re-ported, one of which came to autopsy, the right eye showing histologically the typical findings and the left showing minimal non-specific involvement.

These cases exhibit a crudely graded range of findings which, along side of other re-ported cases, suggests that retinal dysplasia may present itself in mild, moderate, or se-vere form. This range is characterized at one extreme by simple congenital retinal folds in otherwise normal individuals, and at the other extreme by severely disorgan-ized microphthalmic eyes in individuals with chromosomal abnormalities whose multiple systemic defects are incompatible with life.

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REFERENCES

1. Reese, A. B., and Straatsma, B. R. : Retinal dysplasia. Am. J. Ophth., 45:199, 1958. 2. Mann, I.: Developmental Abnormalities of the Eye. Philadelphia, Lippincott, 1957, ed. 2, pp. 188-

211. 3. Duke-Elder, S. : System of Ophthalmology. London, Kimpton, 1964, v. 3, pt. 2, pp. 634-639. 4. Hogan, M. J., and Zimmerman, L. E. (ed.): Ophthalmic Pathology: An Atlas and Textbook.

Philadelphia, Saunders, 1962, pp. 479-480. 5. Miller, M., Robbins, J., Fishman, R., Medenis, R., and Rosenthal, I. : A chromosomal anomaly as-

sociated with multiple ocular defects. Am. J. Ophth., 55 :901, 1963. 6. Cogan, D. G., and Kuwabara, T. : Ocular pathology of the 13-15 Trisomy syndrome. Arch. Ophth.,

72:246, 1964. 7. Makley, T. A. : Retinal dysplasia. Surv. Ophth., 9 :130, 1964. 8. Smith, D. W., Patau, K., Therman, E., Ishorn, S. L. and DiMars, R. I. : The Di trisomy syndrome.

T. Pediat, 62:326, 1963.