Download The Ocular Manifestations of Jacobsen Syndrome: A Report of Four

Ophthalmic Genetics, 27:1–7, 2006
c Taylor and Francis Group, LLC
Copyright ISSN: 1381-6810 (print) / 1744-5094 (online)
DOI: 10.1080/13816810500481832
RESEARCH REPORT
The Ocular Manifestations of Jacobsen Syndrome:
A Report of Four Cases and a Review of the Literature
Garfield L. Miller and Sohel Somani
University of Toronto, Toronto, Ontario, Canada
Malgorzata J. M. Nowaczyk
Clinical Genetics Service, McMaster University, Hamilton, Ontario, Canada
Annette Feigenbaum, Ronald G. Davidson, and Teresa Costa
University of Toronto, Toronto, Ontario, and Sainte-Justine Hospital and Université de Montréal,
Montréal, Quebec, Canada
Alex V. Levin
University of Toronto and Department of Ophthalmology, Hospital for Sick Children, Toronto, Ontario,
and Sainte-Justine Hospital and Université de Montréal, Montréal, Quebec, Canada
Purpose: We report ophthalmic manifestations in four Jacobsen syndrome cases, review the literature, and suggest phenotype-genotype correlations. Methods: Chart review of Ocular Genetics
Program patients at The Hospital for Sick Children, Toronto, Canada. Results: Four del11qter
cases are presented. Hypertelorism/telecanthus, abnormally slanted palpebral fissures, abnormal retinal findings, nasolacrimal duct obstruction, anomalous extraocular muscles, amblyopia,
and microcornea were found. Conclusions: We report typical findings and novel ocular presentations. Visual prognosis is generally good. Retinal dysplasia and coloboma seem associated
with del11q23. ABCG4, NCAM, and Mfrp are candidate genes in this region that theoretically
may be disrupted.
Keywords Jacobsen syndrome; 11q terminal deletion disorder; 11q monosomy; review; eye
findings
INTRODUCTION
A terminal deletion of 11q was first associated with specific
clinical findings by Jacobsen and coworkers in 1973.1 Since
then, more than 90 cases of terminal 11q deletion,2 most of them
arising de novo, have been described as the clinical entity called
Jacobsen syndrome, also known as the 11q terminal deletion disorder (Table 1).3 The most frequent breakpoints for the terminal
deletion are located at 11q23.3 and have been attributed to the
presence of fragile site FRA11B and other breakpoint clusters in
the vicinity.4−6 A small number of patients have been reported in
whom the 11q deletion was in the more distal 11q24 band, while
still manifesting the Jacobsen phenotype. Band 11q24.1 has been
suggested to be the critical region responsible for the typical features of the syndrome.7,8 This is supported by cases in which an
11q24.2-qter deletion was not associated with features characteristic of Jacobsen syndrome.7,9 Interstitial deletions proximal
to 11q24.1, but involving 11q23, have also produced some of
the features but a different overall phenotype.3,9,10
Ocular abnormalities most commonly associated with the
11q deletion disorder include telecanthus and/or hypertelorism,
ptosis, epicanthal folds, and strabismus. Other ocular abnormalities such as unilateral or bilateral coloboma with
or without microphthalmia,11,12 nuclear cataract,12 abnormal
eyelashes/eyebrows,13,14 and iris discoloration have been variably reported.13 A review focused on the ocular findings of
Jacobsen syndrome was recently performed by Lee et al.15
Most other reports have not thoroughly reported on ophthalmic
Accepted 7 November 2005.
Address correspondence to Alex V. Levin, M.D., MHSc, FRCSC,
Department of Ophthalmology, M158, The Hospital for Sick Children,
555 University Avenue, Toronto, Ontario M5G 1X8, Canada. E-mail:
[email protected]
1
2
G. L. MILLER ET AL.
TABLE 1
Non-ocular clinical findings characteristic of Jacobsen
syndrome
Pre- and postnatal growth retardation
Microcephaly
Trigoncephaly or other craniosynostosis
Mental retardation (mild to moderate)
Short, flat nasal bridge with anteverted nares
Short philtrum
Carp mouth
Micro/retrognathia
Low-set ears with minor external malformations
Miscellaneous minor hand anomalies
Joint contractures
Congenital heart disease
Thrombocytopenia/pancytopenia
were found with 11q deletions in the 11q23-24 region who did
not have the Jacobsen phenotype. We included patients who had
their deletions as part of a translocation only when the phenotype was consistent with Jacobsen syndrome. All of the patients
in our database with translocations involving this region had a
Jacobsen phenotype.
CASE REPORTS
findings, but have tried to make genotype-phenotype correlations. Here, we describe the ocular manifestations of four cases
of Jacobsen syndrome seen in our clinic (Table 2), review the
literature, and also look at chromosomal breakpoint correlations with ocular and oculofacial phenotypes. In our patients,
we found many of the typical findings of Jacobsen syndrome,
but also noted presentations rarely or never reported including
funduscopic changes, nasolacrimal duct obstruction, amblyopia,
and anomalous extraocular muscles.
Case 1
This boy has a karyotype of 46,XY,del(11),+der(11)t(9;11)
(p24.1;q24.2)mat. He was the first child of healthy nonconsanguineous parents. He was born at 38 weeks by cesarean
section due to breech position, decreased intrauterine movements, and poor growth. His birth weight was 2375 g. Nonocular features in infancy included hepatosplenomegaly, developmental and growth delay, atrial septal defect, pancytopenia,
recurrent ear infections, hearing deficit, lower limb hypertonia,
upper limb hypotonia, and hyperreflexia. Dysmorphic features
included widely spaced nipples, single palmar creases, anteverted nares, small mouth, and a prominent forehead (Fig. 1).
METHODS
We reviewed the records of all cases of 11q deletion with clinical features of the syndrome seen by one of the staff ophthalmologists (AVL) of the Ocular Genetics Program at The Hospital
for Sick Children, University of Toronto. This program is a multidisciplinary ocular genetics service providing referral-based
adult and pediatric care for much of the province of Ontario
(population: approximately 12 million). Our database currently
contains 14,254 patients, including those with retinoblastoma.
We found four patients for inclusion in this report. No patients
TABLE 2
Ocular findings in study patients
Case 1 Case 2 Case 3 Case 4
11q24.2 11q23.3 11q23 11q23.3
Microcornea
Exotropia
Amblyopia
Nystagmus
Ptosis
Nasolacrimal duct
obstruction
Retinal abnormality
Optic atrophy
∗
Transient finding.
+
+
+
−
−
−
−
+
−
+∗
−
+
+
+
−
+∗
−
−
−
+
−
−
+
−
−
−
+*
−
+
−
+∗
+
FIG. 1. Case 1. Note characteristic facies, left head tilt, and right
exotropia.
THE OCULAR MANIFESTATIONS OF JACOBSEN SYNDROME
3
Ocular examination at one year of age revealed a comitant exotropia of 40 prism diopters that appeared exaggerated
by the presence of gross hypertelorism. He also had downslanting palpebral fissures and bilateral microcornea (9.5 mm
OU). The remainder of the examination, including dilated retinal examination, was within normal limits. At three years, he was
astigmatic in both eyes (+0.50 + 0.75 × 60 OD, +0.50 + 0.75×
150 OS).
He developed strabismic amblyopia that improved with occlusion of the right eye. When the child was 15 months old, the
exotropia was corrected surgically with a bilateral lateral rectus
recession of 4 mm. At surgery, he was noted to have anomalous extraocular muscles: the lateral rectus tendons were thin
and tapered with narrow insertions (width 4.0 mm), although
the muscle bellies appeared normal. A subsequent MRI showed
the other extraocular muscles to be of normal size and location.
Once the strabismus and amblyopia were successfully treated,
a 30–45 degree non-ocular left head tilt, which had been intermittent pre-operatively, became more apparent and constant.
The patient still has pseudo-exotropia from the prominent hypertelorism, but remains without true strabismus. No ocular, neurologic, or skeletal cause of the anomalous head position has been
found. Follow-up visits at five and six years of age revealed no
new findings.
Case 2
This girl has a karyotype of 46,XX,del(11)(q23.3). She was
the second of three children born to healthy non-consanguineous
parents. She was born at term by cesarean section due to
cephalopelvic disproportion. Her birth weight was 4 kg. She
had developmental delay, recurrent urinary tract and lower respiratory tract infections, hearing deficit, hypotonia, and hyperreflexia. Dysmorphic features included low-set ears, anteverted
nares with wide bridge of the nose, small mouth, and a prominent
forehead (Fig. 2).
She was referred to the Ophthalmology Service after parental
concerns over her right eye, which appeared to ‘drift out’. Ocular examination at three months of age revealed absent fixation and following movements with occasional brief bursts of
nystagmus. Vestibular induced nystagmus was intact and dampened appropriately. Optokinetic nystagmus was absent with only
an occasional upward beat to a vertical stimulus. There was
a comitant right exotropia of 30 prism diopters with full extraocular movements. Her pupils measured 5 mm in diameter
bilaterally and were round with a sluggish reaction to light.
No relative afferent pupillary defect was present. Dilated funduscopic examination revealed a mild cherry red spot bilaterally. Systemic evaluation revealed no other cause. An electroretinogram (ERG), performed in accordance with ISCEV
standards,16 showed that all responses were at the lower limit of
normal.17
At 12 months, the macula appeared normal and both eyes
had normal age-appropriate fixation and following movements.
The nystagmus had also resolved. Glasses were prescribed for
FIG. 2. Case 2. Characteristic facies of Jacobsen syndrome.
bilateral astigmatism (plano+2.50 × 90 OD, plano+3.00 × 90
OS). The patient also had a right nasolacrimal duct obstruction
which was being managed conservatively. After being hospitalized for left periorbital cellulitis and left maxillary/ethmoid
sinusitis, nasolacrimal duct probing and irrigation was successfully performed at 20 months of age. Her exotropia resolved
spontaneously by two years of age.
Case 3
This girl has a karyotype of 46,XX, del(11)(q23). She was
the fourth child of healthy non-consanguineous parents. She was
born at 38 weeks after an uncomplicated pregnancy and delivery. One sibling of the proband was diagnosed with cerebral
palsy after a premature birth, while another sibling had strabismus but was otherwise normal. Non-ocular features in our
proband with Jacobsen syndrome included developmental and
growth delay, clinodactyly, toe syndactyly, thrombocytopenia,
and pyloric stenosis. Dysmorphic features included a broad nasal
bridge, anteverted nares, small mouth, dysmorphic external ears,
and a prominent forehead.
Ocular examination at two months of age revealed ageappropriate fixation in both eyes. Although vestibular induced
4
G. L. MILLER ET AL.
nystagmus was normal, there was mild manifest symmetric
horizontal nystagmus worse on side gaze. Extraocular movements were full, but there was a variable alternating exotropia
of approximately 30–40 prism diopters. She had bilateral microcornea (9.5 mm OU). The anterior chambers were shallow.
Pupils were normal with no relative afferent pupillary defect.
Both corneas and lenses were clear. Dilated funduscopic examination was unremarkable except for a granular appearance
throughout the retinal pigmented epithelium (RPE). There was a
hyperopic refractive error in both eyes (+5.00 sphere). At seven
months, her strabismus had resolved and vision responses remained normal. Follow-up at two years revealed no changes. The
granular appearance of the RPE was still present, but no other
signs of retinal dystrophy were noted. The inner canthal distance
(ICD) was 31 mm (90th percentile), the measured interpupillary distance (IPD) 52 mm (97th percentile), and the palpebral
fissure lengths 21 mm (<3rd percentile). The Mustarde index
(ICD/IPD) was 0.59, indicating telecanthus.18 When examined
at seven years of age, the mottling of the RPE was within normal
limits.
Case 4
This girl has a karyotype of 46,XX,del(11),+der(11)t(5;11)
(q35.3;q23.3)pat. She was the first child of healthy nonconsanguineous parents. Delivery was at 34 weeks after premature rupture of the membranes. Birth weight was 2 kg.
Non-ocular features included developmental and growth delay, thrombocytopenia, recurrent upper respiratory infections
and otitis media, hearing deficit, a single left palmar crease,
camptodactyly, and hypotonia. There was also a generalized
skeletal dysplasia which manifested as shortened metatarsals,
leg-length discrepancy, and decreased extension of the proximal interphalangeal finger joints. Dysmorphic features included
dysplastic and low-set external ears, small mouth, and a prominent forehead.
Ocular examination at 18 months of age revealed visual fixation that was central, steady, and maintained in the right eye.
The left eye was central and steady, but not maintained. There
was a history of mild bilateral ptosis, which had been surgically
treated elsewhere. She had a left exotropia of 40 prism diopters
with full extraocular movements. The pupils were normal with
no relative afferent pupillary defect. The anterior chambers were
unremarkable. The right optic disc was small and pale temporally with two small lacunae inferior to the disc, suggestive of
colobomas. The maculae appeared hypoplastic.
DISCUSSION
Our cohort of patients demonstrated karyotypes and features
indicative of the 11q deletion syndrome. Growth retardation
(3/4), mental retardation (4/4), craniosynostosis (4/4), abnormal facies (4/4), thrombocytopenia/pancytopenia (4/4), congenital heart malformations (1/4), and hand/foot skeletal dysplasia
(2/4) were some of the more common characteristics that were
present. Our cases also demonstrated some of the typical ocular
findings that have been mentioned in previous reports along with
some novel findings.
Two of the cases that we investigated were the result of
translocations. In addition to the deletion of chromosome 11,
Case 1 had a trisomy of 9p24.1ter and Case 4 a trisomy of
5q35.3ter. Although these cases matched the Jacobsen phenotype, there is still the possibility that some of the features may
have been caused by the trisomy. There is some overlap between
Jacobsen syndrome and trisomy 9p or 5q, but there was only one
feature found in our cases that can be best explained by the trisomic region. Atrial septal defect (Case 1) has not been strongly
associated with Jacobsen syndrome. However, its incidence is
increased with 9p duplication.19
Oculofacial
Oculofacial abnormalities, including hypertelorism, epicanthus, upward or downward slanting palpebral fissures, and ptosis, are some of the more common features seen in Jacobsen
syndrome.2,14,20,21 Hypertelorism/telecanthus was observed by
clinical inspection in 3/4 of our cases. Only one of these was confirmed using the Mustardé index measurements. In the literature,
hypertelorism has been associated with many different chromosome 11 interstitial deletions and terminal deletions.3,8,9,11,12,22
Perhaps there may be more than one gene on 11q that affects
interpupillary and intercanthal distance. Hypertelorism may be
a finding that is secondary to another gene(s) on 11q that affects
craniofacial development.
Epicanthus is reported in up to 50% of the Jacobsen syndrome
cases.20,22 This was seen in 1/4 of our cases. Abnormally slanted
palpebral fissures were observed in 3/4 of our cases. Upward
or downward slanted palpebral fissures, which are common in
various genetic syndromes, appear to be present in over half of
the Jacobsen cases.20−22
Typically reported in about 50% of the Jacobsen syndrome
cases,6,20,22 ptosis was seen in 1/4 of our patients. Our patient had bilateral ptosis, but both bilateral and unilateral
cases have been documented without association to a specific
breakpoint.7,11,13,23 It is seen with breakpoints as proximal as
11q22 and as distal as 11q25, suggesting a possible candidate
region near the end of the chromosome.
Krasner et al.24 proposed BARX2 (MIM #604823) as a potential candidate gene for craniofacial abnormalities in Jacobsen
syndrome, as it is located in 11q25. This gene is believed to be
involved in craniofacial development and has also been shown
to have high expression in pockets around the developing eye.
BARX2 is not, however, disrupted in Jacobsen cases with interstitial deletions proximal to 11q25 although the craniofacial abnormalities associated with Jacobsen syndrome are still
present.9,10 In addition, terminal deletions distal to 11q24.1 show
abnormalities significantly different from the classical Jacobsen
phenotype.3,7,9 These distal deletions have not been associated
with trigonocephaly, flat nasal bridge, anteverted nares, low-set
ears, or hypertelorism.
THE OCULAR MANIFESTATIONS OF JACOBSEN SYNDROME
Strabismus, Amblyopia, and Nystagmus
Strabismus, reported in up to 67% of literature cases,6,20,22
was noted in all of our cases. Each of our patients had exotropia. Only Case 1 required intervention. This child also developed strabismic amblyopia, which was treated successfully
with occlusion therapy. Upon reviewing the literature, only five
other cases of amblyopia with Jacobsen syndrome have been
found.6,15 However, given the high incidence of strabismus, this
would certainly be likely to occur as a secondary phenomenon. In
other reports,2,3,13,25 strabismus has been seen in terminal deletions with breakpoints in regions ranging from q23 to q25, but we
are not aware of any candidate genes in this region which might
offer a pathophysiology. It is also possible that the strabismus is
secondary to the craniofacial developmental abnormalities.
We noted nystagmus in 2/4 of our cases. Both cases (2 and
3) showed a breakpoint at 11q23 and their nystagmus resolved
spontaneously. To our knowledge, nystagmus has been reported
only once previously, with a terminal deletion at 11q24.2
To our knowledge, the incidental finding of anomalous extraocular muscles, as seen in Case 1, has not been previously
reported in the literature. However, the preponderance of exotropia in our patients and the lateral rectus anomalies seen at
surgery in the absence of other muscle abnormalities on MRI
scanning raises the possibility that the lateral recti are uniquely
abnormal in Jacobsen syndrome.
Anterior Segment
Anterior segment abnormalities have not typically been associated with Jacobsen syndrome. Rare cases of cataract and
glaucoma have been described,2,20,26,27 although neither was
seen in any of our cases. The breakpoint regions in these rare
cases were similar to those in our patients and in others from the
literature that did not show glaucoma or cataracts, suggesting
a coincidental occurrence. We did observe mild microcornea in
two patients, with one of them (Case 3) also having clinically
insignificant shallow anterior chambers. Lee and colleagues reported astigmatism to be a common refractive error in their case
series.15 Two of our cases demonstrated astigmatism.
Retinal Abnormalities
Retinal changes, including coloboma and retinal dysplasia,
are some of the less commonly reported abnormalities in patients with Jacobsen syndrome. In our cases, abnormal retinal
findings were found when the deletion involved 11q23 (Cases 24). Case 1, with a terminal deletion breakpoint at 11q24.2, had no
retinal findings. Funduscopic abnormalities observed included
transient cherry red spots with spontaneously improving visual
function (Case 2), nonspecific granular appearance of the RPE
(Case 3), coloboma (Case 4), and macular hypoplasia (Case 4).
The resolution of the cherry red spot and the macular underdevelopment suggest a delay in retinal development with an
overall favorable prognosis. We are unsure about an explanation
5
for the transient cherry red spot seen in Case 2. There is no
reason to believe that this child had ganglion cell deposition or
problems with arterial perfusion. Perhaps the observed findings
represent an unusual abnormality in retinal development that
later resolved.
Other reports of retinal findings in Jacobsen syndrome also
consistently show an association with deletion of 11q23, suggesting a possible region for candidate genes. Cases where
11q23 is intact due to more distal terminal deletions9,28 or to
more proximal interstitial deletions10 have not been associated
with any fundus abnormalities. Ono and colleagues have shown
retinal findings with interstitial deletions ending at 23.1 and
23.2. Our cases and an individual who presented funduscopically like familial exudative vitreoretinopathy, described by Uto
and colleagues,22 have shown terminal deletions beginning at
23.3. The fact that these interstitial and terminal deletions do
not overlap may indicate that more than one gene in the vicinity
could lead to the retinal abnormalities.
The recently cloned human ATP-binding cassette gene,
ABCG4 (MIM 607784), has been mapped to 11q23.3.29 Although the specific function of this presumed transporter is not
fully known, homologues in Drosophila melanogaster are believed to transport retinal pigment precursors or metabolites.30
Oldfield and colleagues have demonstrated that expression is
confined to the brain and neural retina.31 Perhaps this gene may
also play a role in the developmental delay seen in Jacobsen
syndrome.
A candidate gene found at 11q23.3 that may also contribute
to retinal development is Mfrp (MIM 606227). This frizzledrelated protein is expressed mainly in the lower brain, RPE, and
ciliary epithelium of the eye.33 It is believed to facilitate the
binding and signaling of Wnt, which is also expressed in the
RPE.33 Wnt is important to processes such as cell polarity, cell
adhesion, and cell proliferation during embryogenesis.
Pivnick and colleagues suggested that NCAM (MIM
#116930) may also be an important retinal candidate gene.14
It maps to 11q23.1 and plays an important role in neural cell
adhesion, particularly during the embryonic period. In chick
embryos, expression has been found in the neural retina, but
not in the pigmented retinal epithelium.34 Recently, however,
Syrrou and Fryns reported a normal ophthalmic examination
in a case with interstitial deletion 11q22.3–11q23.2, the same
region containing the NCAM gene.7,35
We believe that the lacunae seen inferior to the right optic disc
in Case 4 represent colobomas. Other literature cases involving terminal deletions beginning at 11q22-23 have been associated with unilateral or bilateral coloboms.6,11,12,20,32,36 However, most reported cases of 11q23 deletion do not present with
coloboma. Of our three cases of 11q23ter deletion, coloboma
was seen in only one (Case 4). Other reports of coloboma have
deletions that do not share any common region. For example,
one reported case of coloboma had interstitial deletion 11q21.123.1,14 while another had deletion 11q23.3-ter.14
6
G. L. MILLER ET AL.
CONCLUSIONS
It was not possible to make strong correlations between
breakpoints and phenotypes with our cases. In fact, this has been
the problem for many scientists studying this syndrome. Because
presentations often vary even when breakpoints are in the same
sub-bands, it is believed that deletions occur at slightly different
locations disrupting different genes.5,14,35 This suggests a high
concentration of genes in areas such as 11q23.3.
We have reported a variety of ocular abnormalities, both
novel and previously recognized, in Jacobsen syndrome. Patients
with this syndrome should have complete ocular examinations.
Should strabismus be present, it may be prudent to observe for
some time as spontaneous resolution does occur. If surgery is
indicated, one should be aware of the possibility of anomalous
muscle anatomy. Visual prognosis may be affected by such findings as retinal abnormalities, coloboma, or amblyopia. Continued follow-up is indicated. The overall ocular prognosis in these
patients, however, is good. Further genotype-phenotype correlation studies may be helpful in identifying candidate genes for
ocular disorders, particularly in the 11q23 region.
ACKNOWLEDGMENTS
The authors would like to acknowledge the invaluable contributions of our Research Assistant, Enza Perruzza. Presented
in part at The American Society of Human Genetics 1995 and
the International Society of Genetic Eye Disease 1995.
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