History
Eye removed post-mortem from a female infant of 33 weeks gestation with multiple congenital anomalies and
apparent anophthalmos.
Diagnosis
Microphthalmos, with
 | corneal scarring and neovascularization |
| dysgenesis of anterior segment |
| cataract |
| retinal dysplasia |
| persistent hyperplastic primary vitreous |
Histopathology
There is parakeratosis of the corneal epithelium. Bowman's membrane is absent and there is scarring of the
anterior stroma. Blood vessels are present in the anterior and mid-stroma. Descemet's membrane has formed
but the trabecular meshwork is not recognizable. Both iris leaflets are markedly hypoplastic. The lens
occupies much of the globe and there is posterior migration of the subcapsular epithelium with formation of
bladder cells and also Morgagnian globules. There is a cyst of the pigmented ciliary epithelium on one side
with posterior displacement of the ciliary processes. At the ora serrata non-pigmented ciliary epithelium
is hyperplastic and has been drawn inwards behind the lens in a fibrovascular membrane. Between this
membrane and the folded, dysplastic retina there is hemorrhage. The retinal pigment epithelium (RPE) shows
focal reduplication. The sclera is unremarkable.
{The smaller right eye accidentally was bisected during orbital dissection. The following elements could be
recognized histologically: sclera containing cartilage, choroid, RPE, neurosensory retina, non-pigmented
ciliary epithelium and cataractous lens surrounded by fibrovascular tissue.}
Discussion
This eye was removed from a newborn infant with facial dysmorphism (incomplete left lip, low-set ears), an
anteriorly placed anus, bilateral diaphragmatic herniae, pulmonary hypoplasia, and segmental ureteric
stenosis. The karyotype was normal and a diagnosis of Fryns syndrome was made by the clinical geneticists.
Fryns syndrome is an autosomal recessive condition with a normal karyotype that is usually lethal. It is
associated with a variety of malformations, of which facial dysmorphism, diaphragmatic herniae and digital
hypoplasia are the most consistent.1 Abnormalities of the central and peripheral nervous systems, e.g.
aganglionic bowel and ureter, have suggested associated neuronal migration defects, involving neural crest
to some extent. In the first two cases reported by Fryns et al2 the eyes were reported as small
with cloudy corneas but these have not been consistent findings. Ayme et al3 collected 28 cases
from the literature and found microphthalmos in 4 and cloudy corneas in 5. These authors examined the eyes
from 3 cases microscopically: one was normal and the others displayed irregularities of Bowman's membrane,
retinal dysplasia, and cataractous changes.
In the current case the eyes had not been recognizable clinically and the status of the corneas was unknown.
As is often the case with a diagnosis of clinical anophthalmos, exploration of the orbits revealed two small
ocular remnants. The larger measured 8.1 mm in antero-posterior diameter, with a cornea of 2.1 x 1.6 mm;
the smaller was damaged during removal. The histological findings in these remnants are similar to those of
Ayme et al3 and the anterior segment dysgenesis is consistent with defective neural crest
migration. An unusual finding in this case was the presence of intra-scleral cartilage in the smaller
remnant on the right side. Intra-ocular cartilage has been described in a number of conditions:
medulloepithelioma and retinal hemangioblastoma (von Hippel-Lindau syndrome) within the tumours, trisomy 13
(within the coloboma), chromosome 18 deletion defect (within the sclera)4 and isolated microphthalmos
(within the vitreous).5
Congenital anophthalmos and microphthalmos are relatively rare developmental anomalies with prevalences of
0.3 - 0.6 per 10,000 births and 1.4 - 3.5 per 10,000 births, respectively.6 They may be unilateral or
bilateral and may occur in association with other ocular, systemic and intracranial abnormalities.7 Most
cases are sporadic in occurrence but they may be genetic in origin, as in the current case, or acquired from
a prenatal insult such as rubella infection.8,9 A small eye may be received as a surgical specimen when
an orbital surgeon removes an ocular remnant from an apparently anophthalmic socket in preparation for a
prosthesis.
The size of the eye and its histological appearance are helpful guides to gestational age in normal fetuses
and premature neonates. Figures have been published10 that allow a reasonable estimation of age from the
antero-posterior (sagittal) diameter and the dimensions of the cornea (Table 1). Since the eye is a small
organ with a very precise anatomical arrangement of its component tissues, it has proved ideal for
morphogenetic studies and the stages of prenatal human ocular development have been well documented (for
references see)11 . The major difficulty with these sources lies in the different descriptions of
gestational age and the lack of a precise definition of 'months' and 'weeks'. Table 2 provides a summary of
the most readily recognizable, and hence most useful, histological features that may assist the pathologist
in the determination of the gestational age of a fetus.
Trisomy 13
The ocular histopathology of trisomy 13 is distinctive and almost always bilateral. Microphthalmos is
universal and the two eyes may be affected to a different degree. It may be mild or sufficiently severe to
appear as an anophthalmos. Additional histopathological features include:
| Coloboma | usually of iris and ciliary body; caused by failure of normal closure of embryonic fissure at 6 weeks of gestation, hence infero-nasal |
| Persistent hyperplastic primary vitreous | persistence & proliferation of the hyaloid vascular system, esp. the posterior tunica vasculosa lentis; retrolental fibrovascular membrane, elongation of ciliary processes & hemorrhage |
| Cartilage | within mesenchyme within coloboma |
| Retinal dysplasia | disorderly cellular proliferation, absence of cellular stratification and rosette formation |
| Cataract | |
| Anterior chamber angle anomalies | rudimentary trabecular meshwork iris hypoplasia |
| Synophthalmia12 | variable failure to develop two separate eyes; fusion more posteriorly |
| Cyclopia13 | single median globe; variable duplication of ocular structures |
TABLE 1
Growth of the Human Eye
(Modified from Scammon & Armstrong, 1925)
| | Corneal Diameter* (mm) |
| | A-P Diameter (mm) | Horizontal | Vertical |
Crown-Heel
Length (cm) | Gestational
Age (weeks) | Range | Mean | Range | Mean | Range | Mean |
| 5-10 | 12 | 4.0-6.0 | 4.7 | 2.5-2.9 | 2.7 | 2.2-2.8 | 2.5 |
| 10-15 | 16 | 5.0-6.8 | 5.9 | 2.8-3.7 | 3.1 | 2.5-3.6 | 2.9 |
| 15-20 | 20 | 6.9-8.0 | 7.5 | 3.6-4.4 | 3.9 | 3.6-4.2 | 3.8 |
| 20-25 | 24 | 7.5-11.6 | 9.1 | 4.1-5.9 | 4.9 | 3.8-5.2 | 4.6 |
| 25-30 | 28 | 10.9-12.0 | 11.3 | 5.5-6.4 | 6.0 | 5.3-5.8 | 5.5 |
| 30-35 | 32 | 11.6-13.4 | 12.7 | 6.0-6.8 | 6.6 | 5.7-6.2 | 6.0 |
| 35-40 | 36 | 12.0-15.0 | 13.8 | 6.3-8.5 | 7.2 | 6.0-7.9 | 6.9 |
| 40-45 | 40 | 13.9-16.4 | 15.4 | 6.8-10.4 | 8.3 | 6.5-8.8 | 7.7 |
| 45-50 | Newborn | 15.0-18.0 | 16.8 | 8.7-9.7 | 9.2 | 8.0-9.1 | 8.5 |
| 50-55 | Newborn | 17-0-18.3 | 17.9 | 10.0-10.9 | 10.4 | 9.1-10.4 | 9.5 |
* Measured across base of cornea (white-to-white) with calipers and Vernier scale
|
TABLE 2
Chronological Appearance of the Principal Ocular Structures
| Age | Component |
| 6 weeks | Lens has separated from ectoderm
Lens cavity is a slit
Tunica vasculosa lentis begins to appear |
| 12 weeks | Tunica vasculosa lentis present
Descemet's membrane recognisable
Bruch's membrane begins to appear
Inner & outer plexiform layers begin to differentiate (posteriorly) |
| 16 weeks | Descemet's membrane completed
Bowman's membrane begins to appear
Schlemm's canal appears
Retinal vessels appear in the nerve fibre layer posteriorly |
| 20 weeks | Bowman's membrane clearly recognisable
Choroidal chromatophores clearly seen
Bruch's membrane complete
Schlemm's canal well formed
Iris sphincter muscle formed |
| 24 weeks | Ora serrata clearly defined
Ganglion cell layers increase in macula |
| 28 weeks | Photoreceptor outer segments differentiate
Pars plana appears
Pupillary membrane regresses
Myelination of optic nerve begins |
| 32 weeks | Trabecular meshwork established
Hyaloid system begins to regress |
| 36 weeks or over | Retinal vessels (esp. nasal) extend to periphery
Myelination of optic nerve reaches lamina cribrosa |
|
References
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- Fryns JP, Moerman F, Goddeeris P, Bossuyt C, Van den Berghe H. A new lethal syndrome with cloudy
corneae, diaphragmatic defects and distal limb deformities. Hum Genet 1979;50:65-70.
- Ayme S, et al. Fryns syndrome:report on 8 new cases. Clin Genet 1988;35:191-201.
- Yanoff M, Rorke LB, Niederer BS. Ocular and cerebral abnormalities in chromosome 18 deletion defect.
Amer J Ophthalmol 1970;70:391-402.
- Yanoff M, Font RL. Intraocular cartilage in a microphthalmic eye of an otherwise healthy girl. Arch
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- Scammon RE, Armstrong EL. On the growth of the human eyeball and optic nerve. J Comparative Neurology
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- O'Rahilly R. The prenatal development of the human eye. Exp Eye Res 1975;21:93-112.
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histopathologic, radiographic and organogenetic analysis. Doc Ophthalmol 1977;44:311-378.
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