CHROMOSOMAL ABNORMALITIES ASSOCIATED WITH CYCLOPIA AND SYNOPHTHALMIA* BY Rufus 0. Howard, MD, PhD

INTRODUCTION

CYCLOPIA IS THE MOST GROTESQUE DEVELOPMENTAL ABNORMALrrY IN OPHTHAL-

mology. The term is commonly used to describe either the abnormality of true cyclopia, in which a single median eye is the only ocular structure present, or synophthalmia, in which two globes are partially fused in a median position. The cause for this malformation has been obscure. Familial occurrence, occurrence in twins, and in consanguineous marriages fias been documented and would be consistent with a single gene abnormality. However, cyclopia has been produced experimentally in numerous species following exposure to various teratogenic agents, and this has been interpreted as evidence for an environmental cause of cyclopia. In recent years, several isolated case reports of cyclopia in humans have been associated with abnormal chromosomes. In this report, eight cases of human cyclopia and synophthalmia are reported with chromosome studies. Five had abnormal chromosomes; one had systemic and ocular abnormalities consistent with D trisomy (although chromosome results are not available); and two had normal chromosomes. A wide spectrum of ocular histopathologic changes were observed. In addition, the published literature on chromosomal abnormalities in cyclopia is reviewed. Most cases of human cyclopia can be attributed to a chromosomal aberration. While multiple etiology cannot be excluded, evidence will be presented to support the interpretation that even "familial" cases of cyclopia, and cyclopia attributed to environmental agents are not inconsistent with chromosomal errors in the affected individuals. *From the Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, Conn. and the Division of Ophthalmology, University of Connecticut Medical School, Farmington, Conn. TR. AM. OPHTH. Soc., vol. LXXV, 1977

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Howard CASE REPORTS

CASE 1

A black female infant was delivered by cesarean section, because of fetal distress, at 36 weeks gestation in New Haven, Conn. The infant had no spontaneous respirations at birth: the Apgar was 1 at one and five minutes. Multiple congenital abnormalities were apparent at birth (Fig. 1A), including synophthalmia in the middle of the forehead with a proboscis above the eye, low set ears, and postaxial hexadactyly of both hands and both feet. The child was pronounced dead 10 minutes following delivery. Blood was obtained for chromosome studies before death. The 23-year-old, Type A, Rh positive mother had one normal living child. POST-MORTEM EXAMINATION

This 1460 gm infant was 42.5 cm long and had a head circumference of 24 cm. A 20 x 7 mm nasal proboscis with imperforate opening was located above the median diamond shaped eye socket which measured 15 mm x 9 mm. The mouth was 29 mm wide. Several facial bones, especially those associated with the nose, were missing. Cardiac anomalies included left ventricular hypoplasia, widely-patent ductus arteriosus, widelypatent foramen ovale, dilated right atrium, and dilated proximal portion of the ascending aorta. A single umbilical artery connected with the left common iliac artery. An accessory spleen was present in the phrenococolonic ligament. The 74 gm brain was holoprosencephalic. The cerebral hemispheres were not cleaved rostrally. Posteriorly, there was partial cleavage with formation of symmetrical occipital lobes. The brain-stem and cerebellum appeared normal. No optic or olfactory nerves or tracts were seen at the base of the brain. Coronal sectioning of the brain confirmed the presence of a holosphere; the cortex and white matter were over 1 cm thick. Microscopic examination of all nonocular tissues were normal except for: degenerative cystic dilatation of thyroid follicles; accessory splenic tissue in the tail of the pancreas; immature ovarian follicles with paraovarian simple cysts. In the brain, rather distinct lamination of the cortex was present with six identifiable layers. A rostral ventricular cavity had not developed, but the aqueduct and fourth ventricle were identified. The meninx primitiva was continuous with the leptomeninges rostrally and caudad. It was not possible to identify any basal ganglion or midbrain structure on serial section. The leptomeninges over the cerebellar hemispheres were markedly congested.

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FIGURE 1

Case 1. A: This female infant with synophthalmia has 13 trisomy (47,XX, +13). B: The enucleated synophthalmic eyes are small. Only a single optic nerve is present. c: All layers of the cornea are abnormal. The superficial stroma is vascularized. D: The iridocorneal angle in the synophthalmic eye is immature. E: The lens epithelium extends posteriorly to completely line the capsule. The tunica vasculosa lentis persists. F: Retinal dysplasia, gliosis and intraretinal hemorrhage were present in the synophthalmic eye.

GROSS OCULAR EXAMINATION

The orbital contents consisted of two fused globes (Fig. IB), and measured 24 x 18 x 14 mm. The right cornea measured 4 x 2 mm, and was separated from the 3 x 2 mm left cornea by a segment of scleral tissue. The corneas were hazy and the anterior chambers and angle structures were not identified on gross examination. Only a single optic nerve was evident. After the synophthalmic globes were sectioned in a horizontal plane, a

Howard septum was observed to separate the two partially fused globes. Two separate corneas, anterior chambers, irides, and lenses were present. The lenses were partially opaque and spherical. Remnants suggestive of ciliary body were identified. The retina appeared redundant and folded, and the disc was not visualized. The sclera of the two globes was fused medially.

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MICROSCOPIC OCULAR EXAMINATION

The junction of the globes and surface epithelium was keratinized with some rete peg formation. The corneal epithelial cells had an irregular arrangement (Fig. 1C). Bowman's membrane was not identified. The corneal stroma was thick and vascularized and the lamellae were irregular. Descemet's membrane was poorly defined but intact. A peripheral area of coiled Descemet's membrane was present. The endothelium was several cell layers thick and had pigment granule inclusions. The anterior chambers were filled with eosinophilic material and erythrocytes. In both eyes the iridocorneal angles were incompletely formed and the trabecular meshwork was not well defined (Fig. 1D). The iris remained attached to Descemet's layer in peripheral areas. The iris stroma was a dense mesenchymal tissue with pigment containing cells, and the iris appeared necrotic. At the pupillary margin, the iris was folded posteriorly. In the ciliary body, the stroma and ciliary muscles were very cellular and contained a few extravasated red blood cells. The ciliary processes were of variable length, and in places, extopic retina was attached. A persistent tunica vasculosa lentis surrounded a thickened lens capsule (Fig. IE). Within the lens, there was posterior migration of epithelial cells, occasional bladder cells, and Morgagnian globules. The lens cortical fibers showed areas ofdegeneration and the nuclei were sclerotic. Hemorrhage separated the detached, dysplastic retina from the retinal pigment epithelium. There was loss of the normal retinal architecture with extensive dyplastic retina formation, gliosis, and intraretinal hemorrhage (Fig. 1F). A few ganglion cells were seen. A mass of loosely arranged cells, probably representing primary vitreous, was identified in the vitreous cavity. The retinal pigment epithelium was necrotic in areas. The choroid was highly cellular with areas of intrachoroidal hemorrhage. A single optic nerve was seen coursing through the attached orbital fat.

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DIAGNOSIS

Synophthalmia Abnormal cornea (abnormal epithelium, Descemet's, and endothelium; absent Bowman's layer; vascularized stroma) Immature iridocorneal angle Cataract Persistent tunica vasculosa lentis and primary vitreous Retinal detachment and retinal dysplasia Choroidal hemorrhage Fused optic nerve CHROMOSOMAL EXAMINATION

Peripheral leucocytes were cultured and chromosomes were harvested and stained by a Giemsa banding technique. The modal chromosome count was 47,XX, +13 (in 12 cells). An apparently random artifactual chromosomal loss was seen in four cells: 46,XX, +13, - (9, 19, or 20). CASE2-

A female infant was stillborn in London, England at 38 weeks gestation following induced labor. Polyhydramnios was recognized at 34 weeks gestation. The 2690 gm cyclopic girl was not macerated; her crown-heel length was 50 cm; the crown-rump length was 31 cm; and the head circumference was 32 cm. A third fontanelle was present. A trunk-like probiscis protruded above a single diamond-shaped central eye opening. No gross tissue was apparent in this space. The ears were low set and the mouth was small. Mild bilateral talipes equinovarus was present. The mother was 27 years old, and she had blood Type A, Rh positive. POST-MORTEM EXAMINATION

The 63 gm brain was grossly malformed; the anterior fossae were small and fused. Prominent blood vessels covered the surface of the cerebrum. Most of the cranial cavity was occupied by a very thin walled cyst which contained clear fluid. The centrally situated cerebrum was represented by a crescent of cerebral tissue which occupied the anterior third of the cavity and was continuous with the thin cyst wall. No olfactory nerves were present, and the posteriorly placed central and single optic nerve was rudimentary (3 mm). The mid- and hind-brain appeared normal. No deep grey matter, corpus callosum or other internal cerebral tissues were seen. An anterior thalamic mass was present, but the geniculate bodies were not identified.

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The 2.5 gm thyroid was large and dark red. The lungs (right 20 gm, and left 28 gm) were deeply congested. A few petechial hemorrhages were present on the surface of the heart (15 gm), and the aortic valves were bicuspid. The kidneys (right 29 gm, and left 28 gm) showed marked lobulation and were twice the expected size. A few subcapsular hemorrhages were identified on the liver (124 gm). In the intestinal tract, a Meckel's diverticulum was present. All other organs were examined and appeared grossly normal. On microscopic examination, the third and fifth cranial nerves were identified, and possibly the optic tract. The quadrigeminal plate was abnormal with large superior and poorly demarked, poorly separated inferior collicluli. The nuclei ponti were replaced by a rudimentary grey mass with no obvious corticospinal fibers above, below, or in it. The pyramidal tract was rudimentary. There was a large grey right and small left olive. One area of squamous metaplasia was present, and a few clumps of lymphocytes were seen. Marked congestion and hemorrhage were present in the lungs. Hematopoiesis was prominent in the liver. The renal tubules were dilated. Clumps of lymphocytes and a mild increase in fibrous tissue were present in the pancreas. The umbilical cord was normal, but patchy intervillous fibrin deposits occurred in the placenta. GROSS OCULAR EXAMINATION

No gross ocular tissue was identified, and no enucleation was performed. The orbital tissues were therefore not available for microscopic examination. DIAGNOSIS

Midline clinical anophthalmia CHROMOSOMAL EXAMINATION

A chromosomal analysis was performed on an ovary taken postmortem. Giemsa banding revealed the karyotype to be 47,XX, +13. CASE 3

A synophthalmic female infant was born in Los Angeles, California to Mexican parents. The duration of the pregnancy was uncertain. The 21 year old mother had mild pre-eclampsia, which was treated with chlorothiazide during the last

511 month. At birth, 'the 2900 gm girl was 43 cm long and had a head circumference of 26 cm. A synophthalmic eye was present in a central, diamondshaped opening, with a proboscis above the orbit. On the ulnar side of the fifth digit was a rudimentary sixth finger. A previous pregnancy had resulted in spontaneous abortion in the eighth month.

Cyclopia and Synophthalmia

POST MORTEM EXAMINATION

The frontal bones were hypoplastic and there was no anterior fossa. Cystic changes were present in the right petrous ridge. The heart was dilated, with hypertrophy of the right ventricle, and with only two 1eaflets on the tricuspid valve. A probe could be passed through the foramen ovale; the ductus arteriosus was patent. A Meckel's diverticulum was present. The kidneys were hyperlobulated. The external genitalia were normal female, but there was a marked cobblestone appearance of the vaginal mucosa. The frontal lobes were fused and hypoplastic, but the cerebellum was normal. GROSS OCULAR PATHOLOGY

The specimen consisted of two eyes fused posterior to their medial equators (Fig. 2A and 2B). The overall dimensions were 23 x 22 x 8 mm with a single 4 mm optic nerve in the midline posteriorly. The ovoid optic nerve sheath was collapsed as if optic nerve tissue was absent. Each cornea measured 4 (horizontal) x 3 mm (vertical). Both anterior chambers were well formed. The right pupil was deformed by a nasal coloboma, and the left by an inferior coloboma. MICROSCOPIC OCULAR EXAMINATION

The contents of the fused globes were separated by a scleral septum. In addition to the two corneas, there were two anterior chambers, two rudimentary irides, two lenses, two disorganized retinas, and a single optic nerve. The findings in each eye were similar. Corneal epithelial cells were arranged irregularly and with variable thickness. A Bowman's layer was not identified. Blood vessels were present in the superficial third of the corneal stroma. A thin Descemet's layer was present. A single cell layer of non-uniform cells formed the endothelium. The anterior chamber was formed and contained a few erythrocytes. The iridocorneal angle was immature. A rudimentary iris had numerous dilated stromal vessels and several pigmented stromal cells. The pupillary margin was

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FIGURE 2

Case 3. A: The corneas of the synophthalmic eye are horizontally oval and separated by a band of sclera. B: the fused globes are separated by a septum.

513 Cyclopia and Synophthalmia folded in toward the ciliary processes. A well defined muscle layer and ciliary processes of variable length formed the ciliary body. The lens had a well defined capsule, and a single epithelial cell layer that extended posteriorly for almost 3600. Nuclei persisted in many lens fibers. The vitreous cavity contained some blood vessels, and hemorrhage, and a few cells that may represent residual primary vitreous cells. The retina was detached, disorganized, and had extensive areas of dysplasia. In some regions it was possible to crudely identify three cell layers, but no distinct photoreceptor layer was identified. The retinal pigment epithelium, choroid, and sclera were well defined; the sclera was highly cellular and appeared thickened. The optic nerve was distorted by a coloboma filled with dysplastic retina, choroid, blood vessels, and disorganized nerve and glial tissue. DIAGNOSIS

Synophthalmia Abnormal cornea (abnormal epithlium and endothelium; absent Bowman's layer; vascularized stroma) Immature iridocorneal angle Cataract Retinal detachment and retinal dysplasia Optic nerve coloboma Fused optic nerve CASE 4

This pregnancy was apparently normal, but spontaneous rupture of the membranes occurred at 36 weeks. After one hour of labor, the vertex delivery of a stillborn 2000 gm female synophthalmic infant occurred in London, England. Her appearance was typical for the cyclopian deformity (Fig. 3A), with a frontal proboscis over a midline synophthalmic eye. Her ears were low set and her eyes small. This child represented the third pregnancy for a 41-year-old white woman who had experienced two previous spontaneous abortions. Her blood type was 0 positive. POST-MORTEM EXAMINATION

The heart was grossly normal, but both lungs were hypoplastic. Polycystic kidneys were present on the right (12 gm) and left (195 gm) side. The left ovary lay over the lower renal pole. No skeletal defect was apparent. The 87 gm brain consisted of a cerebral holosphere. The ophthalmic tracts were absent. The placenta weighed 310 gm and was normal.

514

Howard

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515

GROSS OCULAR EXAMINATION

The overall dimensions of the fused globes were 12 x 17 x 11.5 mm (Fig. 3B). A single posterior opening in the sclera between the two globes probably represented the exit of a single optic nerve. The right cornea measured 4.5 x 5.0 mm; the left 4.5 x 5.5 mm, and both were hazy. The pupil of each eye measured approximately 4 x 3 mm. The optic nerve, if present, had been cut flush with the globe. The specimen was sectioned in a horizontal plane. Two separate anterior chambers were present and grossly clear. Inferonasal colobomata of the iris were present bilaterally. Lenses were present bilaterally, but the ciliary bodies were not identified. The vitreous was clear and the retina was folded. The choroid was thickened and hemorrhagic. MICROSCOPIC OCULAR EXAMINATION

The corneal epithlium was of variable thickness and altered to suggest rete peg formation. Bowman's layer was not identified. Blood vessels were present in the superficial stroma; stromal lamellae were packed and irregular. The endothelium and Descemet's membrane were not seen. Hemorrhage filled the anterior chamber. No normal iridocorneal angle structure was identified. The iris consisted of dilated blood vessels, dense mesenchymal tissue containing fresh hemorrhage, and a single layer of vacuolated pigment epithelium. Ciliary body structures were not seen, except for a remnant of ciliary epithlium attached to the lens. The cataractous lens was surrounded by a persistent tunica vasculosa lentis. In places, iris pigment was adherent to the lens capsule. A single layer of epithelial cells extended posteriorly to completely surround the lens. There was nuclear sclerosis and vacuolation and fragmentation of the lens cortical fibers. The vitreous space contained a few red blood cells and pigment granules. The retina was detached. A remnant of retina was attached anteriorly to the ciliary epithelium; the layers were poorly differentiated and intraretinal hemorrhage was present. A circle of poorly differentiated retinal tissue was also present in the vitreous space. Retinal photoreceptor elements were not present anywhere. Gliosis was present in the ganglion cell layer. A few fine strands of eosinophilic material, erythrocytes and pigment granules were in a space external to a detached internal limiting membrane. The retinal pigment epithelium was intact, though there was some dispersion of pigment. The choroid was hemorrhagic, but the sclera was normal. The two globes were fused anteriorly by vascularized connective tissue. A band of muscle and loose connective tissue was between the globes posteriorly.

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Howard

Microscopic details of the second globe were similar, except retinal dysplasia was present in areas of detached and folded retina. Optic nerve fiber bundles were located in the orbital fat posterior to the globe. DIAGNOSIS

Synophthalmia Corneal vascularization Iris coloboma Cataract Ectopic retina Retinal dysplasia Fused optic nerve

CHROMOSOMAL EXAMINATION

Cells from the ovary were used to determine the karyotype, which was 47,XX, +D. A banding study was not performed, and it is not possible to further specify which D group chromosome is present in triplicate. CASE 5

This cyclopic embryo (Fig. 4A) was identified in a study of chormosome aberrations occurring in human spontaneous abortion specimens in Paris, France. The products of abortion were collected at home by the parents, placed into a sterile flask which contained Hanks' solution and penicillin, and carried to the laboratory. The specimen was kept at 40 C until tissue culture was performed, using chorion, amnion, and, or embryonic tissue. The chromosome determination was made directly on cultured cells, without the use of colchicine or colcemide. The cells were treated with a hypotonic solution fixed with Carnoy's solution, and stained with Giemsa's stain. The karyotype was based on the analysis of 10 to 20 different metaphase chromosomes. This embryo was collected prior to chromosome banding techniques, so the karyotype can only be designated 47, XY, +B, and it is not possible to specify if this represents trisomy 4 or trisomy 5. Following the establishment of tissue culture lines from the embryo, it was fixed in Bouin's solution and embedded in paraffin. Serial sections were made at 5 or 10 microns, and the sections were stained with hematoxylin-eosini. The age of the embryo was estimated on the basis of developmenital features and morphologic details, such as the presence of forelimbs, hanids and fingers, as described by Hamilton. Age was not estimated from a calculation involving the last menstrual period, because there is a variable, but average interval of seven weeks between death ofthe embryo and expulsioni of the products of conception associated with a chromosomal abnormality. The crown-rumnp, or

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How)ard 518 other measurement was not considered a valid criterion for age determination because the specimens of this study were often macerated or edematous. The precise correlation of estimated age with true developmental time is not known. EMBRYO 1424

This 35-day-old embryo had a single midline eye (Fig. 4B). The optic cup measured 0.31 x 0.22 mm and the lens measured 0.25 x 0.13 mm in the largest dimensions on serial section examination of fixed tissue specimens. Only a single optic cup and single lens were present. No intraocular partitions were identified, and no duplications or bilobed structures were found intraocularly or extraocularly to suggest the partial fusion of two separate cups. The cornea consisted of a single layer of epithelial cells (Fig. 4C). The lens vesicle was surrounded by a capsule and tunica vasculosa lentis, but remained attached to the cornea. The lens vesicle was filled by abnormal primary lens fibers of variable size and shape, with swollen cytoplasm, and disorganized in their arrangement (Fig. 4D). The optic cup, which had closed behind the lens vesicle, was compressed in an anteroposterior direction (Fig. 5). Pigment was absent in the cells of the posterior layer of the optic cup. The optic ventricle and optic fissure persisted. The internal layer of the optic cup was folded and disorganized. Retinal nerve fibers were not identified. Poorly differentiated cells extended posteriorly and laterally from each side of the optic cup; they had no connection with the globe or central nervous system on examination of serial sections. This would be consistent with their not representing optic stalks. No optic stalk or extraocular muscles were identified. DIAGNOSIS

True cyclopia Cataract Ocular albinism Abnormal optic cup closure Retarded retinal development Absent extraocular muscles Retarded size and structural development CASE 6

A survey was carried out at the Guy's Hospital Medical School London, England between September, 1970 and May, 1973. All infants dying in the neonatal period were carefully evaluated to determine the cause of death. An-

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FIGURE 5

Case 5. The optic cup has closed posterior to the lens.

other cyclopic infant detected in this survey was examined; however, the ocular tissues were not preserved for further study. The chromosome examination was stated to show a normal karyotype, but no autoradiographic or banding study had been undertaken. CASE 7

This male child was born after 36 weeks gestation in Boston, Massachusetts. Hydramnios was diagnosed late in the pregnancy and spontaneous labor began during the 36th week. Fetal hydrocephalus was detected by roentgenography. Consequently, vaginal delivery and labor were assisted by decompression of the head, followed by a forceps delivery. Multiple congenital abnormalities were present. There was a single, central, elliptical, synopthalmic eye. No nose or nasal cavity were identified. The ears were low set and abnormally formed, and the mouth was slit-like. The boy was declared dead 2 minutes after birth. He was the second child of a 30 year old white, Rh negative mother. The first pregnancy was unremarkable.

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POST-MORTEM EXAMINATION

Pulmonary abnormalities included a hypoplastic right lung (1 x 0.6 cm); bilateral deficient pulmonary lobulation; and bilateral simple pulmonary vein. In the heart, a patent ductus arteriosus and patent interatrial foramen primum were identified. The left kidney was malpositioned with an anteriorly placed ureter. The left testis was undescended. The palate was highly arched and a dorsal cleft was on the superior surface of the tongue. A large central omphalocele contained the digestive tract from the stomach to the rectum, in addition to the liver, spleen, and pancreas. The anus was located posteriorly. The cerebral hemispheres were hypoplastic; they were fused anteriorly and absent posteriorly. A meningeal cyst replaced the posterior cerebral cortex and contained approximately 100 cc of blood stained fluid. A single hypoplastic optic nerve was present. Both olfactory nerves were absent. The Arnold-Chiari malformation was present. The spinal cord extended to the lower lumbar region. The 400 gm placenta was mature, and was grossly normal, except only two vessels were present in the umbilical cord. On microscopic examination of the central nervous system, the subarachnoid space was filled with hemorrhage and neural and glial tissue. The blood vessels appeared to be normal. In the choroid plexus, there were areas where the stroma was less dense, and other areas containing dark staining, high columnar epithelium. The cerebral hemispheres were fused and a dorsal sac probably represented both lateral and third ventricles together. A definite lamination pattern was present in the grey matter, but a six layer pattern was absent or rare. abnormal tissue representing the thalamus was present in the dorsal aspect of the cerebrum; the hippocampus was identified at the lateral margins of the cerebrum. No definite optic nerves, chiasm or optic tracts were identified. The cerebellum appeared to be normally developed, except for a dysgenetic focus near the dentate nucleus on one side, consisting of small deformed folia and many cells which seemed to represent external granular cells. In addition, the Purkinje cell layer was incomplete, which would be consistent with an immature brain. In the brainstem, the third cranial nerve was identified bilaterally and was well myelinated. The medial longitudinal fasciculus and some pontocerebellar fibers were myelinated. Fibers of the medial lemniscus was not myelinated. The locus coeruleus, motor trigeminal nucleus, facial nucleus, superior olivary nucleus and inferior olivary nucleus were identified and appeared to be normal. The red nucleus was grossly normal. The cerebral peduncles were not definitely identified. While the basis pontis was very small, the medullary pyramids were absent.

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GROSS OCULAR EXAMINATION

Two fused globes were located centrally behind a 4 x 3 cm diamond shaped opening in the skin. The two noncontiguous corneas were horizontally ovoid, and measured approximately 5 x 3 mm, bilaterally. The pupils were displaced inferiorly and measured approximately 3 x 2 mm. In the course of enucleating this specimen, the fused globed were entered posteriorly, and some collapse occurred. The globes measured approximatley 20 mm horizontally and 15 mm from cornea to optic nerve. On transillumination, the pigmentation of the eye appeared quite deficient posteriorly where there was a cystic outpouching (possibly representing a staphyloma or ectasia) of the eye on the inferior side. A long single cylindrical structure, which emerged just above the cyst, was considered to represent the optic nerve. The eye was opened in a horizontal meridian. Two corneas, two irides, two ciliary bodies, and two lenses were present (Fig. 6). The retina was distorted and partially protruded through the accidental enucleation incision. The ciliary body and pars plana appeared scanty; a fine linear structure extended from the ciliary body and pars plana posteriorly in the meridian of a coloboma. There was no choroidal lining of the posterior cystic outpouching, but folds of retina were in this space. The two globes were fused posteriorly, and a single optic nerve emerged centrally. MICROSCOPIC OCULAR EXAMINATION

The corneal epithelial cells were aligned irregularly, and the cell thickness varied. Bowman's layer was not identified. Small blood vessels were present in the superficial stroma. Descemet's layer was present, but the endothelium was formed by cells of varying size, in multiple layers, and containing pigment granules. The iridocorneal angle was immature, but Schlemm's canal was present. The iris stroma was formed by mesenchymal cells; cells of the pupillary sphincter contained pigment granules. A double layer of iris pigment epithelium cells were present. In the lens, a single layer of cells completely lined the lens capsule. Nuclei persisted in numerous posterior lens fibers. A few blood vessels on the surface of the lens represent remnants of the tunica vasculosa lentis. The ciliary muscle is highly cellular, and ciliary processes are of variable length. No cells were identified in the vitreous cavity. Three nuclear layers could be identified in the retina but ganglion cells were deficient. No photoreceptor layer was present. Some patches of retinal dysplasia were present. The retinal pigment epithelium, choroid and sclera were intact. The optic nerve was filled with nerve fibers and glial cells.

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FIGURE 6

Case 7. Synophthalmia occurred in a male infant with normal chromosomes (46,XY).

DIAGNOSIS

Synophthalmia Corneal vascularization Immature iridocorneal angle Cataract Retinal dysplasia Fused optic nerve CHROMOSOMAL EXAMINATION

The karyotype of this cyclopic boy, determined from leukocytes, was 46,XY in all seven cells studied. A chromosome determination on skin fibroblasts also showed normal chromosomes; however, no banding or autoradiographic examination was performed. CASE 8

A severely malformed girl was born at term in Los Angeles, California and expired after 15 minutes. In the middle of her forehead was a 28 x 15 x 12 mm

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FIGURE 7

Case 8. A: True cyclopia occurred in a girl with multiple congenital abnormalities consistent with trisomy D. B: A white plaque adhered to the posterior surface ofthe lens and contained cartilage.

proboscis which had no lumen. A diamond-shaped opening (Fig. 7A) in the sldn below the proboscis contained a single eye. The nasal bones were absent. Both ears were low set and positioned posteriorly. The mouth was positioned low on the face, and the neck was short. Postaxial hexadactyly was present on all four extremities. POST-MORTEM EXAMINATION

The heart was deformed by a tetralogy of Fallot. Both kidneys were hyperplastic. The cerebrum was holoprosencephalic, undivided, and hypoplastic. GROSS OCULAR EXAMINATION

Following enucleation of the eye, a 7 mm foramen was visualized that penetrated the calvarium in front of a large sella turcica. The ocular specimen was a single eye which measured 12 x 11 x 11 mm. The iris transilluminated at several areas in the horizontal meridian. The

524

Howard cornea was rounded and had a diameter of 6.5 mm. The anterior chamber was shallow, and an iris coloboma extended from the pupillary margin to the iris base. No surface indentation of the sclera suggested any fusion of two globes, and no double intraocular tissues were present. The eye was opened in a frontal plane at the equator. The tunica vasculosa persisted. A white plaque (Fig. 7B) adhered to the posterior surface of the lens below the center and was continuous with a thick strand of white tissue resembling organized primary vitreous, which extended posteriorly. The retina was organized into irregular folds. The anterior insertion of the retina appeared to be at the pars plicata. MICROSCOPIC OCULAR EXAMINATION

The iridocorneal angle was incompletely developed; this lack of development was more marked at the location of the iris coloboma. In this region a band of connective tissue containing cartilage became continuous with remnants of the tunica vasculosa lentis and primary vitreous. The lens was spherical; cell nuclei persisted within the nuclear lens fibers. Marked retinal dysplasia was apparent. In the posterior segment of the globe, a colobomatous defect of the optic nerve sheath was covered by retinal pigment epithelium. No true optic nerve tissue was identified. DISCUSSION HISTORY

Malformed human monsters, with a single median eye, have been recognized for several thousands of years, and generally have been interpreted to represent a sign of disaster or impending adversity. Cuneiform characters on Babylonian clay tablets K3867 and K4065, now in the British Museum in London, refer to a monster who had one eye in the middle of the forehead, that is, a cyclops, which will bring calamity to the country. These tablets were found in a mound near the Tigris River, and may be almost 4000 years old.1 Since the cyclopian deformity has been recognized for centuries, it would not be surprising if stories of this anomaly were to appear in folk lore. Indeed, cyclopia occurs in mythology at least thrice. Homer described cyclopic giants who lived as shepherds in Sicily. These cannibals were ignorant of law and order, and had fear of neither gods nor men. Polyphemus, the son of Poseidon, was the most prominent of these cyclops. Odysseus blinded Polyphemus' eye with a burning stake so as to escape with his companions.

525 Cyclopia and Synophthalmia Hesiod tells of three cyclopic storm gods, Brontes, Steropes, and Arges, who were sons of Uranus and Gaea, and belonged to the family of Titans. Zeus released them from Tartarus, and out of gratitude, they furnished him with thunder and lightening. They were slain by Apollo because they forged the thunderbolt with which Zeus slew Aesclepius. In later legend, they lived at Mt. Aetna, The Lipari Islands, or Lemos, where they assisted Hephaestus at his forge. A third group of cyclopian giants had abdominal arms. These mythical prehistoric workmen and architects are said to have built the walls of Mycenae and Tiryns, and were the object ofworship. The term cyclopian masonry persists in architecture to denote the crude polygonal walls used by the early Greeks and Estruscans to surround their cities. There has been speculation as to the origin of cylopia for several centuries. Ambroise Pare in 1579 declared that monsters, including cyclops, may have many causes, including "God may punsih man's wickedness or show signs of punishment at hand."2 The superstition, fears, misunderstanding and mystery of the ancients persisted into the early history of this country. The belief that members of different species could be fertile with each other has been called hybridization. Hybridization was considered to be a real possibility by the early American immigrants. A cyclopic pig was born in the New Haven colony. A servant, George Spencer, who had one good eye, also had a blind and deformed eye which resembled that of the cyclopic pig. The good people of the New Haven colony considered this deformed pig to be due to the "unnatureall spell and abominable filthynes" of this man. Following a trial during 1641 and 1642, the cyclopic pig was killed in front of this man, and he was executed on April 8, 1642.3 CLINICAL FEATURES OF CYCLOPIA

In this survey, a total of 31 case reports of human cyclopia have been collected where chromosome examinations have also been performed (Table I). In six additional cases of cyclopia, a presumed diagnosis of chromosome aberration was made by the author on the basis of family history, and/or clinical and post-mortem gross and microscopic abnormalities. The incidence of the cyclopia-synophthalmia deformity in humans is unknown. By 1963, more than 250 published case reports had been collected.32 In one hospital, an incidence of approximately 1/40,000 births was reported.33 In another study, from a different Japanese) population, six cyclopian monsters were identified among 3,400 fetuses, but none

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Howard occurred among 63,800 live births.34 This suggests the total systemic abnormalities associated with the cyclopian deformity are generally inconsistent with fetal viability and that only a few cyclopic individuals survive pregnancy to be stillborn or die shortly following birth; although one cyclops is reported to have lived ten years.35 This abnormality appears to occur in all races: Caucasian, Negro, American Indian, and Chinese-Polynesian (in this series), as well as in the Japanese, Indian36, etc. The basis for the increased frequency in females in unknown, but has been noted in prior studies. It may reflect increased fetal wastage of affected males. The details of previous pregnancies, and of complications during the cyclopic pregnancies were very variable in the published case histories. Nonetheless, it appeared that the reported occurrence of prior abortion in seven cases, with multiple prior abortion in four; of polyhydramnios in four pregnancies; and of hypertension in two of the pregnancies, may represent a slightly increased risk of these complications in a cyclopic pregnancy. The known ages of the mothers in this series of cyclopic infants varied from 23 to 45 years, with a median age of 35 years. Most of the cyclopic pregnancies terminated early with the delivery of a child that was not only malformed, but small in size for estimated age. The cyclopian deformity is characteristically accompanied by numerous systemic malformations. The infant is small for estimated age. A microcephalic head has a proboscis over a midline diamond-shaped opening for the single or fused eyes. The ears and mouth are usually of abnormal shape and position. Postaxial hexadactyly may be observed. At postmortem examination, the forebrain is fused with a single ventricle, and a single or absent optic nerve. The olfactory bulbs and tracts are absent, and other cranial nerves may be absent. A significant cardiac abnormality is almost always present (patent foramen ovale; interventricular septal defect; patent ductus arteriosus; dilated atrium or ventricle; or abnormal cardiac valves). The lungs may be atelectatic, edematous, or small. Intestinal lesions range from a small, low positioned mouth, to a high arched palate, or malrotation, or Meckel's diverticulum, or a posteriorly located anus. The kidneys may be duplicated, or small, or polycystic, or have hydronephrosis. The data available with these case reports does not permit statistical evaluation of the incidence of specific tissue disorders, or of any possible significant differences between the abnormalities present in trisomy D and other different chromosome aberrations, or between trisomy D and the cases with "normal" chromosomes.

529 Cyclopia and Synophthalmia The ocular abnormalities are summarized in Table II. True cyclopia occurred in a male embryo and in a liveborn girl. One stillborn girl had clinical anophthalmia in an otherwise typically median cycopian deformity. One male child had a normal right eye, and synophthalmia of the left eye. This bizzare anomaly has been recognized at least one other time.37 All remaining cases represented synophthalmia. Ocular histology is described for only six cases. The orbital tissue in the case of clinical anophthalmia was not examined. In the fetus with true cyclopia, development of the eye was retarded for estimated age: the globe and lens were smaller than expected; the lens remained attached to the cornea; and the optic ventricle persisted. Ocular dysgenesis also occurred: cyclopia, the optic cup closed behind the lens; pigment was absent in the posterior layer of the optic cup (ocular albinism); and, the optic stalk and extraocular muscles were absent. The eye of the full term true cyclops was microphthalmic. No partitions or septae, or duplicated tissues were identified grossly or microscopically. The iridocorneal angle was immature. An iris coloboma was TABLE

II:

OCULAR ABNORMALMES IN CYCLOPIA (THIS STUDY)

Case

True cyclopia Synophthalmia Clinical Anophthalmia Microphthalmia Cornea abnormal epithelium absent Bowman's layer vascularized stroma abnormal Descemet's abnormal endothelium Iridocorneal angle immature Iris coloboma Cataract Persistent tunica vasculosa lentis Absent ciliary body Persistent primary vitreous Retina ectopic immature dysplasia gliosis Choroidal hemorrhage Scleral ectasia Optic nerve coloboma abnormal fibers single absent Intraocular cartilage

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Howvard present, and the iris transilluminated irregularly in the horizontal meridian. A band of intraocular cartilage was present and attached to remnants of the tunica vasculosa lentis and primary vitreous. Retinal dysplasia, a coloboma of the optic nerve and absent optic nerve fibers completed the abnormal ocular findings. All cases of synophthalmia were associated with small globe size. The medial fusion of two globes always occurred posterior to the ciliary body. Generally, the two globes were fused into one structure posteriorly, with a single optic nerve emerging from the center posteriorly. The two corneas were small, horizontally oval, possibly opaque, and separated by a band of sclera. Each layer ofthe cornea may be abnormal, and the stroma may be vascularized. The iridocorneal angle is immature, but a Sclemm's canal is usually present. The iris may transilluminate irregularly or an iris coloboma may be present. The lens is spherical and cataractous. Immaturity is indicated by persistence of the tunica vasculosa lentis, and of the hyaloid system, and of the primary vitreous. The retina is detached and organized into folds. Microscopically, retinal dysplasia and retinal immaturity are found. The ganglion cell layer is poorly developed and retinal nerve fibers are not normally developed. A coloboma may distort the optic nerve. Optic nerve fibers may be scarce or absent. Intraocular cartilage is an anomalous finding, that is considered to be a characteristic for trisomy D38 or trisomy 18. Intraocular cartilage was present in one cyclops that was considered clinically to represent trisomy D (Case 8), although a chromosomne determination was not performed. ETIOLOGY

Arhinencephaly, as initially described by Kundrat in 1882,39 included variable malformations of the face, aplasia of the olfactory bulbs and tracts, and impaired midline separation of the developing forebrain. Subsequently, a detailed classification of such defects has been proposed by Yakolev,40 and DeMyer and Zemen.4143 In common usage, arhinencephaly designates facial dysgenesis, possibly involving the mouth, nose, eyes and ears, combined with defects in evagination of the optic and olfactory structures and impaired midline cleavage of the forebrain. The forebrain may be completely fused with a single ventricle (alobar holoprosencephaly), partially separated into hemispheres, or completely separated into hemispheres. The olfactory bulbs and tracts are usually missing and the optic nerves and eyes may be hypoplastic. True cyclopia or synophthalmia, associated with a single chambered prosencephalon, represents the most extreme degree of malformations in this group of in-

Cyclopia and Synophthalmia

53q1

dividuals. According to this classification, ethmocephaly and cebocephaly represent less severe forms of this malformation. The concurrence of cyclopia and cebocephaly,"'45 or cyclopia and arhinencephaly," or ethmocephaly and cebocephaly47 in the same sibship indicates the common etiology and close relationship of this group of malformations and supports the above classification. ENVIRONMENTAL THEORY

Scientific inquiry into the orgin of developmental abnormalities probably began in 1822 by E. Geoffrey de St. Hilaire.48 Born produced a cyclops by splitting an amphibian egg in a saggital plane in 1897.49 In the years 1907-09, the cyclopic deformity was produced experimentally in a teleost by Stockard,50 using a solution of magnesium chloride. In the ensuing years, it has been possible to produce cyclopia experimentally in numerous species using different environmental agents (Table III). 51 Because of this success in producing cyclopia experimentally, numerous writers, including Ida Mann,52 have been concluded that cyclopia results from exogenous factors. The multitude of environmental agents that have resulted in experimental cyclopia might appear to be acting by multiple different mechanisms. However, several hundred different evnironmental agents (physical, chemical, and biological) have been catalogued which alters chromosomes, both numerically and structurally.53 Most of the specific agents that have been employed to produce cyclopia also have been shown in different studies to produce gross chromosome aberrations. ChromoTABLE III: CYCLOPIA PRODUCED BY ENVIRONMENTAL FACTORS Species Teratogenic Agent

Physical

Cold, heat Centrigugation UV light X-ray

Chemical

Manipulative

Hyperbaric pressure Lithium, Magnesium Hypoxia NaCN, ethyl alcohol Phenol Colchicin Nicotine High vitamin A Antibiotics Operation Hair constriction

Fundulus heteroclitus Axolotl, rana pipiens Fundulus Chick, mouse Triton

Amblystoma, xenopus Fundulus

Triton Triton Rana

Fundulus Chick Amblystoma, triton, fundulus

Rat, mouse

Triton

Howard some changes have been produced by physical agents such as x-ray, UV light, gravitational forces, and temperature changes. Numerous chemicals alter chromosomes, including vitamins, alkaloids, antibiotics, alkylating agents, pesticides, CNS drugs, mitotic poisons, photodynamic drugs, nucleic acid related compounds, in addition to common substances like ethyl alcohol and metal ions. Several viruses cause structural and numerical chromosome changes. It is interesting that the possibility of a maternal viremia has been mentioned at least three times in cyclopic pregnancies. 54-56 It is, of course, quite possible that environmental agents do represent an entirely separate mode of induction of cyclopia. It is also possible that environmental agents act specifically by first altering chromosomes, and the altered chromosome is the direct causative factor. This line of reasoning could be investigated experimentally by determining the chromosomes in induced cyclops and in normal controls. Apparently such a study has not been performed yet. 532

SINGLE GENE THEORY

Others have favored a genetic basis for human cyclopia even though the cyclopic deformity does not permit survival and reproduction. Francois has suggested cyclopia is caused by a lethal recessive gene.57 This interpretation is supported by the concurrence of cyclopia in human twins; M-62 the occurrence of familial cyclopia;6O- cyclopia and arhinencephaly in sibs from normal parents who were first cousins;'" the typical hereditary malformations that accompany cyclopia; and hereditary cyclopia in guinea pigs.65 Familial cases of cyclopia are not inconsistant with a chromosome error. If the mother or father, who are clinically normal, should be the carrier of a balanced chromosome translocation, then they could produce abnormal children with an unbalanced chromosome constitution. An abnormal chromosome in an abnormal child could then occur in several children of "normal" parents; or, in numerous children in different generations, and thus mimic autosomal recessive, or dominant inheritance, with "incomplete penetrance." In this study, one normal mother, who had a balanced chromosome translocation error, had a cyclopic child with trisomy D (case 14). In another family, four cyclopic individuals and eleven abortions occurred over four generations in a family where there was a balanced chromosome translocation, probably between chromosome 3 and a C group chromosome (Cases 27, 33, 34, and 35). A parent with a balanced translocation chromosome error has the possibility of producing a normal child; or a child with a balanced translocation error that

Cyclopia and Synophthalmia S331 will be clinically normal; or a child with partial trisomy; or a child with partial monosomy. The two children with unbalanced chromosome errors are usually deformed and abnormal, based on experience with other families that have been studied carefully, where balanced translocation errors have been identified in several family members. In such families, recurring abortions are common. It is therefore most likely that the four cyclopic children in this one family all had abnormal chromosomes. In one child (Case 27) the chromosomes were determined, and, in fact, an error was demonstrated.

CHROMOSOMAL ABNORMALlTY THEORY

The results ofchromosomal study are available for 31 case reports of human cyclopia. In six additional cases of cyclopia, a presumptive diagnosis of chromosomal error was made on the basis of family history, and clinical and post-mortem gross and microscopic abnormalities, although chromosomal studies were either not successful, or were not attempted. Abnormal chromosomes were present in 24/31 cyclops, or, 30/37, if the presumptive cases of cyclopia are included. A high frequency of chromosomal error associated with cyclopia has been demonstrated in those case reports available for review. Seventeen cyclops had trisomy for a D group chromosome; two had 18p-; one each had B trisomy; 18 trisomy; 18r; 46/45,-G; and 46/47, +mar; and seven were reported to be normal. The D group of chromosomes includes chromosomes 13, 14, and 15. In the seventeen cyclopic individuals with D Trisomy, a more definitive banding technique or autoradiographic examination was performed in only five instances: the additional D group chromosome was always number 13. Presumably, the other cases of D trisomy are also 13 trisomy. Trisomy 15 has been identified in several human abortuses, but none have had cyclopia or survived. While most of the karyotypes of cyclopic individuals have been abnormal, several reports of normal findings have been published, including results from experienced, well established laboratories. The obvious interpretation is that cyclopia may occur both with normal or with abnormal chromosomes. It is also possible, however, that mosaicism was not detected because cytologic examination was limited to too few cells or body tissues. Alternatively, a submicroscopic chromosomal error could have been present and not identified because a more sensitive, discriminating banding technique was not employed. A banding examination

Howard was not performed on any of the seven "normal" cases, and two different cyclopic tissues were examined in only one "normal" case. It has been suggested15 that cyclopia arising from a D trisomy error is clinically different grom cyclopia which results from other chromosomal errors, or from normal chromosomes. According to this hypothesis, cyclopia with D trisomy always has accompanying systemic abnormalities, white the second type of cyclopia has only ocular and cerebral defects. The report of a D trisomy cyclops with only abnormal eyes and forebrain12 would seem to refute this classification. Cure, Boue, and Boue66 have shown that cultured fibroblasts from humans with chromosomal aberrations replicate at a slower rate than those from individuals with a normal chromosome complement. Thus a chromosomal aberration is consistent with growth retardation as well as with structural dysgenesis affecting multiple tissues; both features are characteristic of cyclopia. In less severe cases of arhinencephaly and facial maldevelopment than cyclopia, chromosomal aberrations have also been observed. Arhinencephaly and cebocephaly have been associated with D trisomy,67-73 18p-,74-79 and 18 trisomy.80 These reports would support the hypothesis of a chromosomal error as the cause of arhinencephaly and cyclopia. There are, however, several reports of arhinencephaly with normal chromosomes. 41,8144 In none of the normal cases has a chromosome banding examination been performed. The association of multiple different chromosomal aberrations with cyclopia is different from the usual understanding of a chromosomal syndrome. In Down's syndrome, for example, the relatively constant clinical features are associated with one basic chromosomal error. Alternative explanations are possible. Cyclopia may be the common end result of several different unrelated processes. Or, cyclopia may result from the disturbance of some organizer substance, and this critical substance may be influenced by numerous factors. According to the present understanding of chromosomal disorders, an individual with a trisomic anomaly would code for the cellular production of excessive enzymes, proteins, control genes and organizers, corresponding to the genes present in the extra chromosome. Similarly, a deficiency of an entire chromosome or segment of chromosome would produce lower than normal levels of cellular enzymes, proteins, control genes and organizers. Presumably the alteration of critical levels of these gene products during the vital early days of embryogenesis is the insult that results in the cyclopian deformity. Thus a chromosomal theory of cyclopia relates the cause to an imbalance of multiple genes. IZ34

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535

MULTIFACTORIAL THEORY

In theory, cyclopia might result from the interaction of a genetic susceptibility with one or more different environmental factors. The occurrence of arhinencephaly4' 85 and cyclopiam in children of diabetic mothers might possibly support such a hypothesis, since diabetes is a multifactorial disease, but this really seems unlikely. SUMMARY

At the present time, essentially all known facts concerning cyclopia are consistent with some chromosomal disease, including clinical features of the pregnancy (fetal wastage, prematurity, intrauterine growth retardation, maternal age factor, complications of pregnancy), the generalized developmental abnormalities, specific ocular dysgenesis, by the high incidence of chromosomal abnormality already demonstrated, and the possibility of error in those cases of cyclopia with normal chromosomes. Even if chromosomal aberrations represent only one group of several different etiologic factors leading to cyclopia, at the present time chromosomal errors would seem to be the most common cause of cyclopia now recognized. Further studies will establish or disprove a chromosomal error in those instances which are now considered to be the result of an environmental factor alone or those with apparent familial patterns of inheritance. This apparent diverse origin of cyclopia can be clarified iffuture cyclopic specimens are carefully investigated. The evaluation should include a carefully investigated. The evaluation should include a careful gross and microscopic examination of all organs, including the eye, and chromosome banding studies of at least two different cyclopic tissues. Then the presence or absence of multiple causative factors can be better evaluated. ACKNOWLEDGMENT

Cyclopia is a very rare anomaly, and, in a lifetime, one individual will never have the opportunity to examine many such affected individuals. This report could not possibly have been prepared without the most gracious and generous sharing of cyclopic specimens by the following people: Professor William H. Spencer, Pacific Medical Center, San Francisco. Doctor G. A. Machin, University of Calgary, Calgary, Alberta, Canada. Doctor R. A. Petersen, Children's Hospital Medical Center, Boston.

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Professor Paul Polani, Guy's Hospital Medical School, London. Professor D. M. Albert, Mass., Eye and Ear Infirmary, Boston. Professor Boue, International Children's Center, Chateau de Longchamps, Bois de Boulogne, Paris. REFERENCES 1. Warkany J: Congenital Malformations. Chicago, Yearbook Medical Publications, Inc. 1971, pp 7-10. 2. Pare, Ambroise: De Chirurgie, 1579. Cited by Warkany, p 12. 3. Hoadley CJ (ed.): Records of the Colony and Plantation of New Haven, from 1638 to 1649, Hartford, Case, Tiffany and Co. 1957, pp 62-63. 4. Fujimoto A, Ebbin AJ, Towner JW, et al: Case report: trisomy 13 in two infants with

cyclops. J Med Genet 10:294, 1973 5. Machin GA: Chromosome abnormality and perinatal death. Lancet 1:549, 1974. 6. Howard RO, Boue J, Deluchat C, et al: The eyes of embryos with chromosome abnormalities. Am J Ophthalmol 78:167, 1974. 7. Arakaki DT, Waxman SH: Trisomy D in a cyclops. J Pediatr 74:620, 1969. 8. Toews HA, Jones HW: Cyclopia in association with D trisomy and gonadal agenesis. Am J Obstet Gynecol 102:53, 1968. 9. Cat I, Filho LF, Marinoni LP, et al: Sinoftalmia associada a sindrome de Pierre Robin. Pediatria (Napoli) 34:187, 1969. 10. Manshot WA: Die kongenitale primare Aphakie in genetischer Sicht. Klin Monatsbl Augenheilkd 154:1, 1969. 11. Carr DH, Law EM, Elkins JG: Chromosome studies in selected spontaneous abortions. IV. Unusual cytogenetic disorders. Teratology 5:49, 1971 12. Halbrecht I, Kletzky 0, Komlos L, et al: Trisomy D in a cyclops. Obstet Gynecol 37: 391, 1971. 13. Batts JA, Jr, Punnett HH, Valdes-Dupena M, et al: A case of cyclopia. Am J Obstet Gynecol 112:657, 1972. 14. Golob E, Schaller A, Kunze-Muhl E: Zyclopie mit D-trisomie. Wien Klin Wochenschr 84:272, 1972. 15. Taysi K, Tinaztepe K: Trisomy D and the cyclops malformation. Ami Dis Child 124: 710, 1972. 16. Bugnon C, Gainet F, Royer J, et al: A propos d'un cas de cyclopie avec trisomy 13-15. Ann Ocul (Paris) 1181, 1972. 17. Fernandez IP, Ortiz LC, Onzono Al: de Feto ciclope con trisomia D. Rev Esp Obstet Ginecol 31 653, 1972. 18. Philippe N, Requin C, Combe R, et al: Un cas de cyclopie avec trisomy D. Pediatrie 27:757, 1972. 19. LangAP, Schlager FM, Gardner HA: Trisomy l8andcyclopia. Teratology 14:195, 1976. 20. Cohen MM, Storm DF, Capraro VJ: A ring chromosome (No. 18) in a cyclops. Clin Genet 3:249, 1972. 21. Nitowski HM, Sindhvananda N, Konigsberg UR, et al: Partial 18 monosomy in the cyclops malformation. Pediatrics 37:260, 1966. 22. Faint S, Lewis FJW: Presumptive deletion of the short arm of chromosome 18 in a cyclops. Human Chromosome Newsletter 14:5, 1964. 23. Cohen MM: Chromosomal mosaicism associated with a case of cyclopia. J Pediatr 69: 793, 1966. 24. Pfitzer P: Extra minute chromosome in cyclops. Lancet 2:102, 1967. 25. Harnden DG, Jacobs PA, Buckton KE: Personal communication. Cited in Sohval, AR. Recent progress in human chromosome analysis and its relation to the sex chromatin. Am i Med 31:397, 1961.

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26. Juberg RC: Personal communication, 1965. Cited in Cohen MM. J Pediatr 69:793, 1966. 27. Lejeune J: Personal communication, 1965. Cited by Cohen MM. J Pediatr 69:793, 1966. 28. Lieber E, Hsu LYF, Gertner M, et al: Cytogenetic studies in holoprosencephaly (Abstr.). Program and Abstracts, p 126. The American Pediatrics Society and the Society for Pediatric Research, 1970. 29. Cohen MM, Gorlin RJ: Genetic considerations in a sibship of cyclopia and clefts. Birth Defects 2:113,1969. 30. Pfitzer P, Muntefering H: Cyclopism as a hereditary malformation. Nature 217:1071, 1968. 31. Ventura T, Giannoni E, Corbacelli A, et al: Osservazioni su due casi di ciclopia con ulteriori reperti attribuibili a una sindrome da trisomia 13-15. G Ital Pat 182:45, 1971. 32. Sedano HO, Gorlin RJ: The oral manifestations of cyclopia. Oral Surg 16:823, 1963. 33. Barber A, Muelling RJ: Cyclopia with complete separation ofthe neural and mesodermal elements of the eye. Arch Ophthalmol 43:989, 1950. 34. Nishimura H, Takano K, Tanimura T, et al: High incidence of several malformations in early human embryos as compared with infants. Biol Neonate 10:93, 1966. 35. von Hippel E: Die Missbildungen und angeborened Fehler des Auges. GraefeSaemisch Handb Augenheilk 2:93, 1900. 36. Vare AM: Cyclopia Am J Ophthalmol 75:880, 1973. 37. Meeker LH, Aebli R: Cyclopean eye and lateral proboscis with normal one half face. Arch Ophthalmol 38:159, 1947. 38. Cogan DG, Kuwabara T: Ocular pathology of the 13-15 trisomy syndrome. Arch Ophthalmol 72:246, 1964. 39. Kundrat H: Arhinencephalie als Typische Art von Missbildung Graz, Leuschner and Lubensky, 1882. Cited by Yakolev. 40. Yakolev PI: Pathoarchitectonic studies of cerebral malformations. III. Arhinencephalies (Holotelencephalies). J Neuropathol Exp Neurol 18:22, 1959. 41. DeMyer W, Zeman W: Alobar holoprosencephaly (arhinencephaly) with median cleft lip and palate: clinical, electroenecephalographic and nosologic considerations. Confin Neurol 23:1, 1963. 42. DeMyer W, Zeman W, Palmer CG: Familial alobar holoprosencephaly (arhinencephaly) with median cleft lip and palate. Neurology 13:913, 1963. 43. DeMyer W, Zeman W, Palmer CG: The face predicts the brain: diagnostic significance of median facial anomalies for holoprosencephaly (arhinencephaly). Pediatrics 34:256, 1964. 44. Klopstock A: Familiares Vorkommen von Cyclopie und Arhinencephalie. Monatschr Geburtsch Gynak 56:59, 1921. 45. Grebe H: Zur atiologie der Arhinencephalie. Z Kinderheilkd 85:19, 1961. 46. Dominok W, Kirchmair H: Familiare Haugung von fehbildungen der arhinencephailie Gruppe Z Kinderheilkd 85:19, 1961. 47. Welter ES: Consecutive hydrocephalies. 2 Sibs with ethmocephaly and cebocephaly. Ill Med J 133:177, 1968. 48. Adelmann HB: The problem of cyclopia. Q Rev Biol 11:161, 284, 1936. 49. Born A: Arch Entwickl Mech Org 4:349; 517, 1897. Cited by Duke-Elder, S. System of Ophthalmology, St. Louis, C. V. Mosby III, 1963, p 449. 50. Stockard C: Arch Entwickl Mech Org 23:249, 1907. Cited in Rogers KT: Dev Biol 8: 129, 1963. 51. Rogers KT: Experimental production of perfect cyclopia in the chick by means of LiCL, with a survey of the literature on cyclopia produced experimentally by various means. Dev Biol 8:129, 1963. 52. Mann I: Developmental Abnormalities of the Eye, 2nd Ed. London, British Medical Association, 1957, pp 55-58. 53. Shaw MW: Human chromosome damage by chemical agents. Ann Rev Med 21:409, 1970.

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Chromosomal abnormalities associated with cyclopia and synophthalmia.

CHROMOSOMAL ABNORMALITIES ASSOCIATED WITH CYCLOPIA AND SYNOPHTHALMIA* BY Rufus 0. Howard, MD, PhD INTRODUCTION CYCLOPIA IS THE MOST GROTESQUE DEVELO...
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