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Congenital Corneal Opacification in De Barsy Syndrome
Anthony J. Aldave, MD;
Ralph C. Eagle, Jr, MD;
Barbara W. Streeten, MD;
Joyce Qi, MD;
Irving M. Raber, MD
Arch Ophthalmol. 2001;119:285-288.
ABSTRACT
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A newborn male was noted to have bilateral congenital corneal opacification.
Findings from examination disclosed a variety of dysmorphic features, including
cutis laxa, progeroid aspect, short stature, multiple hyperextensible subluxated
joints, muscular hypotonia, and hyperreflexia. Bilateral penetrating keratoplasties
were performed; histopathologic examination revealed diffuse epithelial thickening,
loss of the Bowman layer, and stromal attenuation with anterior stromal scarring.
Special stains showed no deposition of abnormal material in the corneas. Electron
microscopy demonstrated absence of Bowman layer differentiation with a paucity
of collagen fibers, as well as extensive small elastic fibers in the anterior
stroma. The diagnosis of De Barsy syndrome was made, a rare progeroid syndrome
associated with characteristic ocular, facial, skeletal, dermatologic, and
neurologic abnormalities. De Barsy syndrome should be included in the differential
diagnosis of congenital corneal opacification; its distinctive clinical features
enable the clinician to easily differentiate it from other causes of congenitally
cloudy corneas.
INTRODUCTION
Congenital corneal opacification is associated with a variety of ocular
and systemic disorders. We report a case of bilateral corneal opacification
associated with De Barsy syndrome, a rare systemic syndrome associated with
distinctive clinical features. To our knowledge, this is the first report
of De Barsy syndrome in an English-language ophthalmic journal and the first
description of light and electron microscopic corneal findings in this syndrome.
REPORT OF A CASE
A newborn male born to a 32-year-old, healthy, nulliparous woman was
noted to have bilateral corneal opacification. The infant was the product
of a 42-week gestation, complicated only by diet-controlled gestational diabetes.
The mother, who received good prenatal care, was rubella immune at the beginning
of her pregnancy and had negative findings for syphilis and hepatitis on serologic
examination. There was neither a history of tobacco, alcohol, or other drug
use during pregnancy nor a family history of congenital ocular abnormalities.
Shortly after birth, the patient developed respiratory distress and
required transfer to the neonatal intensive care unit. The newborn, weighing
2721 g and measuring 44 cm long, was noted to have a variety of dysmorphic
features: short stature with a small chest and pectus excavatum; skeletal
dysplasia with short legs; multiple joint dislocations, especially involving
the hands; marked redundancy of the skin typical of cutis laxa; frontal bossing;
midfacial hypoplasia; and thin transparent skin with prominent superficial
veins (Figure 1). During the patient's
9-day hospital stay, the consulting ophthalmologist documented bilateral cloudy
corneas and made a presumptive diagnosis of congenital hereditary endothelial
dystrophy.
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Figure 1. External photograph of patient
demonstrating frontal bossing and aged, progeroid facies.
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The patient was referred to a geneticist, who made a definitive diagnosis
of cutis laxa. At age 5 weeks, the patient was referred to one of us (I.M.R.)
for evaluation and possible surgical management of the corneal clouding.
On examination, height and weight were essentially unchanged from birth,
well below the fifth percentile for age. No strabismus or nystagmus was present.
Portable slitlamp examination revealed bilateral diffuse, focally prominent
corneal stromal haze, most prominent in the anterior stroma (Figure 2). The anterior chambers were of normal depth, the horizontal
corneal diameter was approximately 9 mm in each eye, and tactile tensions
were within normal limits. No obvious lenticular opacifications were noted.
Only a red reflex was discernible through the corneal haze. The patient underwent
penetrating keratoplasties in the right eye at age 4 months and in the left
eye at age 12 months.
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Figure 2. External photograph of the right
eye detailing diffuse, focally dense corneal opacification, obscuring iris
details. The globe and cornea are normal in size.
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The corneal button from the right eye was bisected and half fixed in
10% neutral buffered formaldehyde for routine microscopy and the other half
fixed in 2.5% glutaraldehyde and processed for transmission electron microscopy.
Immunostaining for elastin (Elastin Products Inc, Owensville, Mo) was applied
to some sections for electron microscopy. The left corneal button was processed
for light microscopy. Light microscopic examination of both corneal specimens
demonstrated diffuse epithelial thickening, absence of the Bowman layer, and
attenuation of the stroma, most marked centrally (Figure 3A) with hypercellular scarring of the anterior superficial
stroma. A variety of special histochemical stains, including Verhoeff van
Giesen stain for elastic fibers, showed no abnormal deposits in the corneal
stroma except for some mucopolysaccharide in the superficial stroma. The posterior
stroma was compact. Although delicate, the Descemet membrane was intact, and
the endothelium was well preserved and quite cellular.
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Figure 3. A, Photomicrograph of corneal
button demonstrating thickened epithelium, absence of the Bowman layer, and
stromal attenuation (hematoxylin-eosin, original magnification x100).
B, Photomicrograph of corneal button demonstrating loss of the Bowman layer
and replacement with spindle-shaped cells in an amphophilic granular matrix
(hematoxylin-eosin, original magnification x400).
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Electron microscopy demonstrated loss of the normal architecture of
the Bowman layer, with replacement of the normal random pattern and regular
spacing of collagen fibers by a paucity of longitudinal and oblique collagen
fibers (Figure 4). In contrast to
the absence of elastic fibers in the normal cornea, the anterior stroma contained
many small bundles of 10- to 12-nm elastic system microfibrils (Figure 4, upper inset) associated with foci of nonstaining amorphous
material immunopositive for elastin (Figure
4, lower inset). Although the 2 basic components of elastic fibers
were present (microfibrils and elastin), no mature elastic fibers consisting
almost entirely of elastin were seen (Figure
5). The Descemet membrane had reduced evidence of the normal 100-nm
fetal banding pattern that usually extends throughout the Descemet membrane
in corneas of patients who are this age. The endothelium appeared normal.
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Figure 4. Electron micrograph demonstrating
loose superficial stroma with bands of elastic fibers composed primarily of
microfibrils (arrow), focally positive for gold-labeled elastin amongst infrequent
30-nm collagen fibers (upper inset). Deeper elastic fiber clump (arrowhead)
has multiple gold-labeled elastin cores (lower inset). E indicates epithelium
(original magnification x20 714; insets, x67 770).
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Figure 5. Electron micrograph demonstrating
multiple small- and medium-sized elastic fibers (arrow) between the cell layers,
with gold-labeling of scanty and poorly organized elastin cores (inset of
arrowed fiber) (original magnification x32 400; inset, x54 000).
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Postoperatively, serial examinations under anesthesia demonstrated clear
grafts, normal intraocular pressures, and healthy fundi. Unfortunately, the
patient died at age 13 months, several weeks after receiving the graft in
the left eye, of respiratory failure. An autopsy was not performed.
COMMENT
In 1968, De Barsy et al1 reported the
case of a 22-month-old girl who had an "old-looking facies," congenital generalized
cutis laxa, mental retardation, hypotonia, hyperreflexia, growth retardation,
and corneal opacification associated with degeneration of the Bowman layer.
Although 18 additional cases of children with the syndrome that now bears
his name have appeared in the medical literature, we found no reports in an
English-language ophthalmic journal.2-11
De Barsy syndrome, likely inherited in an autosomal recessive manner,6 has not been associated with a specific chromosomal
anomaly. The life expectancy is unknown, as all patients described in the
literature were infants or children when the diagnosis was made. To our best
knowledge, the oldest living patient described in the literature was 24 years
old.6
Skin biopsy specimens from patients with De Barsy syndrome demonstrate
sparse short or fragmented, irregular elastic fibers1-2,5, 7
and reduced elastin expression in skin cell cultures.5
The results of the histochemical elastic stains on the corneas in the present
report were likely negative because of the small amount of elastin in these
immature fibers. To our knowledge, this is the first light and electron microscopic
examination of the corneal findings in this syndrome. Many of the clinical
features in the syndrome may be related in part to a disorder of elastogenesis,
such as the cutis laxa, some skeletal features, and even the presence of aberrant
elastic fibers in the cloudy corneas. However, features such as muscle hypotonia,
cataracts, mental retardation, and neurologic deficits are not readily explained
by abnormalities of the elastic system. Investigators disagree as to whether
abnormalities of collagen play a role in the phenotypic features of this disorder.3, 7, 9 Further exploration
of the corneal elastogenesis and associated changes in the present case is
in progress.
The differential diagnosis of congenital corneal opacification includes
a variety of ocular and systemic disorders. De Barsy syndrome is an unusual
cause of congenital corneal opacification that is associated with characteristic
ocular, facial, skeletal, dermatologic, and neurologic abnormalities (Table 1). Classified as one of the "progeroid"
syndromes, De Barsy syndrome has distinctive clinical features that enable
the clinician to differentiate it from the other causes of congenital corneal
opacification and progeroid syndromes. Cockayne syndrome, the other progeroid
syndrome associated with ocular abnormalities, is characterized by dwarfism,
mental retardation, a thick cranial vault, deafness, cataracts, corneal clouding,
and retinal degeneration with optic atrophy.12-13
While corneal opacification is common to both syndromes, our patient did not
manifest the other clinical features associated with Cockayne syndrome. In
addition, he demonstrated nearly all of the features most commonly associated
with De Barsy syndrome such as cutis laxa (not associated with Cockayne syndrome);
frontal bossing and a progeroid aspect; muscular hypotonia and hyperreflexia;
hyperextensible joints (characteristically stiff in patients with Cockayne
syndrome); growth retardation; and the presence of the characteristic features
at birth (as opposed to after the first year of life in patients with Cockayne
syndrome).5
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Clinical Manifestation of De Barsy Syndrome
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In this case, the diagnosis of De Barsy syndrome was based primarily
on the unique constellation of clinical features that clearly distinguish
it from the other progeroid syndromes. These characteristic clinical manifestations
also enable the clinician to easily differentiate it from the other systemic
disorders associated with neonatal corneal opacification.
AUTHOR INFORMATION
Accepted for publication June 23, 2000.
This study was supported in part by the Neal T. and Sarah L. Simmonds
Foundation for Ophthalmic Pathology, Philadelphia; Wills Eye Hospital (Dr
Eagle); National Institutes of Health, Bethesda, Md, grant EY01602; and a
grant from Research to Prevent Blindness Inc, New York, NY (Drs Streeten and
Qi).
Presented in part at the annual meeting of the Contact Lens Association
of Ophthalmologists, Las Vegas, Nev, January 24, 2000.
Corresponding author and reprints: Irving M. Raber, MD, Cornea Service,
Wills Eye Hospital, 900 Walnut St, Philadelphia, PA 19107 (e-mail: Raber101{at}aol.com).
From the Cornea Service (Drs Aldave and Raber) and the Department of
Pathology (Dr Eagle), Wills Eye Hospital, Thomas Jefferson University, Philadelphia,
Pa, and the Departments of Ophthalmology and Pathology (Drs Streeten and Qi),
State University of New York, Upstate Medical University at Syracuse. Dr Aldave
is now with the Francis I. Proctor Foundation and the Department of Ophthalmology,
University of California, San Francisco.
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SECTION EDITOR: W. RICHARD GREEN, MD
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