Download Ophthalmic manifestations of tetrasomy 18p

Ophthalmic manifestations of tetrasomy 18p
W. Abraham White, MD,a,b Martha P. Schatz, MD,a,b Courtney Sebold,c Daniel E. Hale, MD,b,c
and Jannine Cody, PhDb,c,d
PURPOSE
To characterize ophthalmic findings in patients with tetrasomy 18p, a rare chromosomal
anomaly that has been previously associated with strabismus.
METHODS
RESULTS
All subjects underwent a complete eye examination to screen for ocular pathology.
A total of 25 subjects (13 female) were examined after they were diagnosed with tetrasomy
18p. The average age of subjects was 8.2 years (range, 13 months to 22 years). Of the 25
subjects, 18 (72% of examined subjects, 42% of the cohort) showed evidence of strabismus;
16 had esotropia (8 uncategorized, 5 infantile, and 3 accommodative), 1 had esophoria, and
1 was diagnosed with intermittent exotropia.
The coincidence of esotropia with tetrasomy 18p indicates the need to routinely screen
these patients for strabismus at the time of diagnosis. ( J AAPOS 2011;15:268-271)
CONCLUSIONS
T
etrasomy 18p is a rare chromosomal anomaly that
is thought to occur in approximately 1 in 140,000
live births.1 The first description of the associated
syndrome was published by Froland and colleagues2 in
1963. The cytogenetic sine qua non of this condition is
the presence of a supernumerary isochromosome (a chromosome with 2 identical arms) of 18p and consequently
a total of 4 copies of the short arm of chromosome 18
(Figure 1). Because the short arm of chromosome 18 harbors approximately 60 known genes, the genesis of the associated tetrasomy 18p syndrome is complex. Individuals
with this condition are usually ascertained through a routine chromosome analysis as a part of an evaluation for developmental delay.
Most of the current literature on tetrasomy 18p consists
of isolated case reports and small case series. The manifestations of the syndrome are well defined in infants, and cardinal features include developmental delay, microcephaly,
muscle tone abnormalities, low-set ears, high arched
palate, and various genitourinary anomalies.3 In contrast
with Edwards syndrome (trisomy 18), patients with tetrasomy 18p generally do not have major congenital cardiopul-
Author affiliations: aDepartment of Ophthalmology, University of Texas Health Science
Center, San Antonio, Texas; bCHRISTUS Santa Rosa Children’s Hospital, San Antonio,
Texas; cDepartment of Pediatrics, University of Texas Health Science Center, San Antonio,
Texas; and dThe Chromosome 18 Registry & Research Society, San Antonio
Research Conducted at the University of Texas Health Science Center at San Antonio
and CHRISTUS Santa Rosa Children’s Hospital, San Antonio, Texas.
Presented as a poster at the 36th Annual Meeting of the American Association for
Pediatric Ophthalmology and Strabismus, Orlando, Florida, April 14-18, 2010.
Submitted September 28, 2010.
Revision accepted February 20, 2011.
Published online June 13, 2011.
Reprint requests: W. Abraham White, MD, UTHSCSA Dept of Ophthalmology, 7703
Floyd Curl Drive, MC 6230, San Antonio, TX 78229-3900 (email: whitew3@uthscsa.
edu).
Copyright Ó 2011 by the American Association for Pediatric Ophthalmology and
Strabismus.
1091-8531/$36.00
doi:10.1016/j.jaapos.2011.02.011
268
monary defects that require intervention, and long-term
survival seems to be the rule. A variety of ophthalmic findings have also been reported, including epicanthal folds,
short palpebral fissures, strabismus, and hypertelorism.3-11
This is the first comprehensive description of ophthalmic
findings in a large series of patients with tetrasomy 18p.
Subjects and Methods
The ophthalmologic evaluation was performed as a component of
a comprehensive evaluation of individuals with tetrasomy 18p
through the Chromosome 18 Clinical Research Center at the
University of Texas Health Science Center at San Antonio; the results of the comprehensive study have been previously published.12 This protocol was overseen by the Institutional Review
Board of the University of Texas Health Science Center, San Antonio. Informed consent from subjects or their legal guardians
was obtained.
Inclusion in the study required that the subjects have been diagnosed with tetrasomy 18p by standard cytogenetic analysis,
which detects changes in chromosome number and in gross
chromosome morphology. Fluorescence in situ hybridization
was performed for all cases to confirm the clinical diagnosis.
To define the abnormal chromosome content at the molecular
level, the DNA from all subjects was analyzed with the use of
microarray comparative genomic hybridization. Eye examinations included, where possible, a focused history, assessment
of best-corrected visual acuity and ocular motility, dilated fundus examination, and cycloplegic refraction, depending on the
subject’s abilities. Magnetic resonance imaging of the brain
was performed as a component of the comprehensive systemic
evaluation.
Results
Of the 43 subjects recruited as part of the comprehensive
protocol, a total of 25 subjects (13 females; 52%) were evaluated by the ophthalmology service; not all patients in the
comprehensive protocol were evaluated by the
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Volume 15 Number 3 / June 2011
ophthalmology service as the result of logistical and scheduling issues. The results are summarized in Table 1 (see
also e-Supplement 1, available at jaapos.org). (Subject
numbers in the table and text correspond to the subject
numbers from the comprehensive tetrasomy 18p manuscript.)12 The average subject age was 8.2 years (range, 13
months to 22 years). Two subjects (8 and 32) were diagnosed with variants of tetrasomy 18p. Subject 8 was confirmed to be mosaic for tetrasomy 18p, as originally
identified in the karyotype from blood. Subject 32 was diagnosed with a variant isochromosome 18p, which included a duplication of a small part of the proximal long
arm from the centromere to 18,536,308 million bases
(Mb) (18q11.2). This created a region that was trisomic
in addition to the entire short arms that were present in
four copies. These patients were excluded from our statistical analysis, although the authors have included their clinical information because it reflects the genotypic and
phenotypic variability that is observed with the tetrasomy
18p spectrum of chromosomal anomalies.
The majority of subjects (18/23; 78.2%) demonstrated
some evidence of strabismus (Figure 2). Esotropia was
most common (16/23; 69.5%). The precise classification
of esotropia could not be determined in 8 of the 16 subjects
(50%) on the basis of examination and history; 5 (31.3%)
demonstrated infantile esotropia, and 3 (19%) accommodative esotropia. Nine of the 23 subjects had esodeviations
.15D; 1 subject demonstrated an esophoria, and 1 subject
was found to have an intermittent exotropia (Figure 3).
Dissociated vertical deviation was observed in 4 of the 23
subjects (17.4%). Seven subjects had undergone previous
strabismus surgery.
Only 2 subjects (9%) were diagnosed with amblyopia.
Subject 41 had a history of unilateral nasolacrimal duct obstruction that failed to resolve with 2 attempts of probing
and irrigation. Subject 42 showed 2 clock hours of superotemporal iris sphincter atrophy in both eyes. Torticollis of
nonocular origin was diagnosed in 1 subject. Only 4 subjects (17%) were found to have a normal eye examination
for their age. Of note, there were no abnormalities of the
lens or retina observed in any subject.
Refractive errors were common, with 1 subjects (4%)
displaying high hyperopia (.15.00 D) in at least one eye
and 2 (9%) subjects presenting with high myopia
(. 5.00D). Many of the subjects in the study had lower
degrees of hyperopia in at least 1 eye.
Magnetic resonance imaging of the brain was performed
on 8 of the 25 subjects (32%). The remaining patients were
either not sufficiently sedated for the examination according to the approved chloral hydrate protocol or the family
declined the examination. Four subjects (8, 26, 30, and 38)
demonstrated no abnormality. Subject 3 showed mild dilation of the left lateral ventricle. Subject 42 showed a possible delay in myelination of white matter within the forceps
major (posterior white matter tracts connecting the occipital lobes via the splenium of the corpus callosum). Subject
44 showed the presence of a cerebrospinal fluid shunt but
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FIG 1. Ideogram illustrating the appearance of tetrasomy 18p on a karyotype. The short (p) and long (q) arms are labeled.
Table 1. Subject data
Pathology
Number of subjects, n (%)
Strabismus
Uncategorized ET
Infantile ET
Accomodative ET
Esophoria
Intermittent XT
DVD
Amblyopia
NLDO
Iris atrophy
High hyperopia (. 15.00)
Moderate hyperopia (10.25 to 15.00)
High myopia (. 5.00)
Moderate myopia ( 0.25 to 5.00)
Astigmatism $ 11.00 D
Normal eye examination
18 (78)
8 (50)
5 (31)
3 (19)
1 (5.5)
1 (5.5)
4 (22)
2 (9)
1 (4)
1 (4)
1 (4)
16 (70)
2 (9)
4 (17)
10 (43)
4 (17)
DVD, dissociated vertical deviation; ET, esotropia; NLDO, nasolacrimal
duct obstruction; XT, exotropia.
otherwise had a structurally normal brain. Subject 2 was
noted to have a small corpus callosum and a relative
increase in extra-axial fluid spaces, which is suggestive of
atrophy or hypoplasia.
Discussion
Most of the subjects in the present study demonstrated
some form of clinically significant ophthalmic pathology.
In light of this and the generally good long-term prognosis
for survival, the authors recommend that all patients with
tetrasomy 18p undergo a screening examination by an ophthalmologist skilled in the diagnosis and management of
strabismus at the time of diagnosis. Because of the developmental disabilities frequently encountered in this population, optimizing visual function is important to ensure
that these patients achieve their full social and developmental potential. Although amblyopia was relatively uncommon in this series, it remains a potential comorbidity
for this cohort, given the frequency of strabismus.
Other chromosomal anomalies, such as Down syndrome
and chromosome 22q11.2 deletion (DiGeorge/velocardiofacial spectrum disorders), are also known to carry a risk of
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Volume 15 Number 3 / June 2011
FIG 2. 10-year-old with tetrasomy 18p: note esotropia, low set ears, and flat nasal bridge in the frontal (A) and side (B) views.
Literature Search
MEDLINE was searched via OVID (1963 to the present)
using the following terms: tetrasomy, 18p, and isochromosome
18p. Additional papers of interest were identified through
examination of the references retrieved from this search.
The Online Mendelian Inheritance in Man (OMIM) was
also searched: there is currently no OMIM number for
this condition.
Acknowledgments
We acknowledge the administrative assistance of Annice Hill in the conduct of the study.
References
FIG 3. Motility disorders in tetrasomy 18p. ET, esotropia; XT,
exotropia.
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DiGeorge/velocardiofacial spectrum disorders), but the
proportion of patients with esotropia appears to be much
higher with tetrasomy 18p, ranging from 46% (19/41) to
83% (19/23) based on our results.13,14 There are likely
genes on 18p whose products are dosage sensitive. This
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amount of gene product, thereby changing the
stoichiometry of a molecular interaction or the dynamics
of a rate limiting step.15 This could result in structural or
functional neurological anomalies at a cellular level that interfere with the development of stereopsis, accommodation, and fusional mechanisms. Further investigation is
necessary to more fully elucidate the correlation between
tetrasomy 18p and esotropic strabismus.
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First Person
“My new patient questionnaire includes a section asking where the child
attends day care, pre-K, and/or school. The very next question asks “Grade
in school,” to which one parent wrote "C+" !
—Steven E. Rubin, MD
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