Accepted Manuscript

Management of Neonatal Proptosis: A Systematic Review

Benjamin P. Erickson, MD David T. Tse, MD

PII: S0039-6257(13)00269-5
DOI: 10.1016/j.survophthal.2013.11.002
Reference: SOP 6492

To appear in: Survey of Ophthalmology

Received Date: 12 August 2013

Revised Date: 4 November 2013
Accepted Date: 12 November 2013

Please cite this article as: Erickson BP, Tse DT, Management of Neonatal Proptosis: A Systematic
Review, Survey of Ophthalmology (2013), doi: 10.1016/j.survophthal.2013.11.002.

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 ACCEPTED MANUSCRIPT

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Management of Neonatal Proptosis: A Systematic Review

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Benjamin P. Erickson MD1, David T. Tse MD1
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Bascom Palmer Eye Institute, Miami, Florida, United States
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Correspondence:
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David T. Tse MD
dtse@med.miami.edu
900 NW 17th Street
Miami, FL 33136
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Abstract. Gross proptosis presenting at birth is an uncommon manifestation of a variety

of lesions that can compromise vision and result in disfigurement or even loss of life.
Notably, many disease entities have different presentations and prognoses in neonates
compared to older children. A structured mental framework is essential to an efficient
and coordinated response. We present three challenging cases of neonatal proptosis and
discuss the clinical presentation and biological behavior of the lesions that are most often
implicated.

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Key words. neonatal proptosis, fetal ultrasound, globe sparing surgery, orbital tumor

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I. Introduction

Gross proptosis at birth, a source of profound anxiety for both families and clinicians,
is an uncommon but well documented presentation for a variety of lesions that can
result in vision loss, disfigurement and even death. Despite the relative rarity, all
obstetricians, neonatologists, pediatricians, ophthalmologists and orbital surgeons
must be prepared to evaluate and manage neonatal proptosis expeditiously. An

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organized and evidence based approach is paramount.

While the differential for neonatal proptosis does overlap with that for proptosis in

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infancy and early childhood, there are also important differences in terms of relative
incidence, presentation, treatment considerations, and tumor biology.

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With advances in fetal ultrasound and magnetic resonance imaging (MRI), many
ocular and orbital conditions can be detected reliably as early as the first trimester.52
Ideally, this permits a proactive approach in which the obstetrician obtains prenatal
consultations with a pediatric ophthalmologist, orbital surgeon, and oncologist. The

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goal of this multidisciplinary team should be to implement a coordinated plan of care
at the time of delivery, thereby maximizing the chances of preserving life, normal
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anatomy and vision. Occasionally, however, prenatal visits are missed or significant
orbital lesions are not identified on fetal ultrasound, and massive proptosis at delivery
comes as a surprise and creates much consternation among medical staff.
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We present three challenging cases of gross neonatal proptosis, a review of the
literature, and a discussion of the clinical presentation and biological behavior of each
lesion. A hierarchical approach is suggested as a starting point for evaluation and
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management by obstetricians, neonatologists, pediatric ophthalmologists, and orbital

surgeons. A mnemonic is offered to ensure an orderly sequence of clinical
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examination and intervention immediately following delivery.

II. Case Presentations

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A. Case 1

A two-day-old Caucasian male was born with massive proptosis of the right eye. An
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abnormality was first observed on fetal ultrasound at 20 weeks. Maternal

hypertension did not require medical intervention. The neonate was delivered
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vaginally at 38 weeks to a 33-year-old gravida 1, para 0. APGAR scores were 8 and

9, and the birth weight was 3.13 kg. Neonatal heart rate, respiratory rate and blood
pressure were all high normal or slightly elevated.

An orbital MRI obtained on day 1 revealed a right-sided retrobulbar mass, measuring

5.6 x 4.6 x 4.4 cm and containing T2 voids consistent with vascular channels. The
irregular post-contrast enhancement pattern was considered ‘almost pathognomonic
for cavernous hemangioma' by the interpreting radiologist (Figure 1).
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On initial evaluation, his right eye was grossly proptotic with injection and foci of
subconjunctival hemorrhage (Figure 2). The ipsilateral eyelids were diffusely
stretched and retracted. The cornea was hazy and the anterior chamber shallow with
prominent iris vessels. The orbital mass resisted retropulsion and could not be
transilluminated. There was an absent direct pupillary response to light with a brisk
consensual reaction. The left eye and periocular structures were within normal limits.

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There were several firm, bluish subcutaneous nodules on the trunk, extremities and
tongue. B-scan ultrasound disclosed a highly reflective, irregular mass with low to
medium sound attenuation, occupying nearly the entire orbit. These characteristics

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were considered most consistent with teratoma, but a diagnosis of neuroblastoma was
also entertained given the presence of tachycardia and skin nodules. Abdominal
ultrasound revealed a 1.4 x 1.1 cm lesion of the right adrenal gland. Biopsy of a

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superficial lesion was consistent with metastatic neuroblastoma and this diagnosis
was subsequently confirmed with bone marrow aspiration.

The mass was excised on day 3 to minimize corneal exposure-related morbidity and

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to decrease the risk of necrosis and infection during chemotherapy. Access was
achieved via lateral canthotomy and conjunctival peritomy (Figure 3). The mass was
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dissected free from the superior, medial and inferior rectus muscles but the optic
nerve and lateral rectus were grossly infiltrated and had to be sacrificed. The globe
itself was successfully preserved.
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Microscopic analysis revealed undifferentiated, round basophilic cells in a matrix of
vascularized connective tissue. The partially encapsulated mass was 90% necrotic
with scattered calcification and 6 mitotic figures per 10 high-powered fields.
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Immunostains was positive for neuron specific enolase (NSE) and S-100 but negative
for glial fibrillary acidic protein (GFAP), neurofilaments, leukocyte common antigen,
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chromagranin and desmin. Genetic analysis disclosed diploid DNA and intermediate
Myc-N proto-oncogene expression.
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He underwent 4 cycles of cyclophosphamide and VP-16 chemotherapy with apparent

resolution of his adrenal mass and skin lesions. During the 5th cycle, however, repeat
MRI revealed hydrocephalus secondary to multiple new brain metastases. The infant
deteriorated rapidly despite shunting and aggressive chemotherapy and died at 8
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months of age.
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B. Case 2

Routine transabdominal ultrasound at 23 weeks disclosed a large cystic mass of the

left orbit in the fetus of a 24-year-old gravida 1, para 0. Subsequent transvaginal
ultrasound revealed a 3.3 x 3.9 x 3.0 cm lesion (Figure 4). Follow-up examinations at
26, 30, 34, and 38 weeks gestation demonstrated interval fetal development without
lesion enlargement. A girl was delivered at 39 weeks via Cesarean section with
APGAR scores of 9 and 9, and birth weight of 4.0 kg.
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Ophthalmic examination on day 1 showed a profoundly proptotic left globe

enveloped by a large, transilluminating cystic lesion. No pulsations or bruit were
detected. The ipsilateral eyelids were retracted, and there was a central corneal ulcer.
The left pupil reacted sluggishly to light with a brisk relative afferent pupillary defect
(RAPD). The right eye and periocular structures were within normal limits. Orbital
ultrasound, CT, and MRI confirmed the isolated, cystic nature of the mass and
revealed a stretched and atrophic left optic nerve (Figure 5).

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Complete cyst excision was performed 6 days after birth via a transconjunctival
orbitotomy approach. A cleavage plane was identified in the cyst, which was

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dissected free from adjacent structures and removed in toto without rupture. A lateral
tarsorrhaphy was required to correct postoperative lid malposition. The globe was
preserved in order to maintain orbital volume and minimize hypoplasia of the bony

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orbit.

Gross examination of the specimen revealed a fluid-filled sac measuring 3.3 x 4.0 x
3.0 cm. Microscopic examination disclosed an encapsulated cyst lined with stratified

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squamous and cuboidal epithelium that contained proteinaceous fluid without
evidence of bone, cartilage, hair, or glandular elements. All components appeared
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histologically benign, confirming the diagnosis of a simple epithelial cyst.

The left eye retained excellent motility, but developed large angle esotropia.
Electrophysiological testing failed to elicit visual evoked potentials, suggesting the
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absence of useful sight. At 15 months of age, the patient was fitted with a painted
scleral shell and achieved an excellent cosmetic outcome (Figure 6). Fifteen years
later, she has good facial symmetry and functions well in social settings.
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C. Case 3
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Routine transabdominal ultrasound in a 30-year-old gravida 5, para 4 appeared

unremarkable at 16 weeks. Repeat testing at 34 weeks, however, revealed a
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heterogenous 3.1 x 3.0 cm mass involving the right orbit. Serial ultrasounds were
obtained at two-week intervals to document lesion growth. Planned caesarean section
was performed at 40 weeks because of concern for tumor rupture during passage
through the birth canal.
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Initial examination was notable for profound proptosis of the right globe with
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exposure keratopathy, chemosis and superotemporal erosion accompanied by focal

protrusion of the underlying mass (Figure 7). CT and MRI demonstrated a 5.0 x 3.4 x
3.8 cm partially encapsulated, heterogeneous, intraconal mass displacing the globe
and stretching the optic nerve.

On day 7, the patient underwent surgical debulking of the lesion. While every effort
was made to spare the globe, intraoperative evidence of gross tumor infiltration into
the globe necessitated a lid-sparing orbital exenteration.
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Microscopic evaluation disclosed a spindle cell tumor, and the diagnosis of congenital
infantile fibrosarcoma was made after cytogenetic analysis revealed the characteristic
t(12;15) translocation. The apical margin of the exenteration specimen was positive,
and the neonate received adjuvant chemotherapy with vincristine, actinomycin, and
cyclophosphamide.

After successful tumor eradication was confirmed, a cantilevered orbital tissue

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expander was placed to prevent the development of hemifacial deformity.
Conventional static implants or dermis fat grafts could not be entertained because of
absence of orbital tissues and blood supply. She is currently alive and well without

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evidence of recurrence or significant orbital volume disparity.

III. Discussion

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A. Background

Tumors are diagnosed prenatally in 7.2 fetuses per 100,000 live births.48,58

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Neoplasms involving the orbit are even more rare, and there is no reliable estimate of
incidence. Non-neoplastic causes of gross neonatal proptosis are also relatively
uncommon. AN
Despite the rarity of this presentation, however, it causes significant distress and
anxiety for both families and clinicians. Given recent advances in neonatal imaging,
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we believe that a proactive strategy is possible in the vast majority of cases. The
concept of ‘prenatal ophthalmic consultation’ is evolving in conjunction with these
technical improvements.43,49
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With expanded medical and surgical capabilities, there has also been a shift towards a
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globe-sparing paradigm. Several disease entities that can present as orbital lesions
are capable of rapid growth in the perinatal period. Vision loss and deformity may
therefore be minimized by prompt diagnosis and intervention. Assembly of a
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multispecialty team prior to birth facilitates decisions regarding postnatal intervention

and permits consideration of early delivery for neonates of appropriate gestational age
and maturity.
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B. Neonatal Imaging
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1. Ultrasound

A skilled fetal ultrasonographer can detect many abnormalities of the eye and orbit
from an early gestational age. By 11 to 12 weeks, the eyes and periocular tissues are
visible as distinct structures. Autosomal dominant cataracts have been identified in
fetuses as early as 14 weeks.53 Prenatal diagnosis of retinoblastoma, persistent
hyperplastic primary vitreous, high myopia, strabismus, microphthalmia,
anophthalmia, hypertelorism and orbital masses is possible.7,37,43,63,68
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A number of recent studies have established the anticipated ocular and orbital
dimensions in each stage of development. There is a strong linear correlation
between gestational age and orbital diameter, circumference and surface area;
therefore deviations from expected measurements may provide important diagnostic
clues.14,25,35,75

Three-dimensional ultrasound (3DUS) can now demonstrate planes of section

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unavailable with two-dimensional studies, making detection of orbital tumors and
mass lesions easier and more reliable.39,51 3DUS also permits spatial reconstruction
of the fetal face with simultaneous visualization of all features.40 This reconstructed

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view permits those unfamiliar with fetal ultrasound to recognize orbital defects such
as gross proptosis. Even with unfavorable head positioning, 3DUS can provide a
variety of diagnostic clues related to the morphology of the orbit and eyelids.83

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2. Magnetic Resonance Imaging (MRI)

Fetal MRI is developing as a useful adjunct to ultrasound. While there are currently

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no reports of MRI findings for orbital mass lesions, the anticipated lens, orbit, and
intraocular dimensions have between characterized between 17 and 39 weeks of
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gestation.58,66 Even without contrast, which is not recommended for fetal studies,
MRI has been demonstrated to offer improved soft tissue contrast in other anatomic
locations. An added benefit is that the image quality is not degraded by
oligohydramnios as with fetal ultrasound.13
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1. The obstetrician and neonatologist

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The task of initial evaluation and stabilization typically falls to the obstetrician and/or
neonatologist. We suggest structuring this assessment using the acronym SPARE, which
stands for Systemic features, Presence/Absence of a formed eye, Retrobulbar
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hemorrhage, and Exposure of the ocular surface.

Systemic features. At the time of delivery, the first priority is to ensure overall stability
of the neonate and to provide an appropriate level of support. Neuroblastoma with
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metastases to the orbit can elaborate vasoactive substances resulting in tachycardia and
rarely hemodynamic instability. Monitoring and documentation of these systemic
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parameters is particularly important when early surgical intervention is planned.3

Presence/Absence of a formed eye. The next step is to establish the presence and
condition of the involved eye. With anophthalmia, cystic protrusion may simulate gross
proptosis, but careful examination will fail to disclose recognizable ocular structures. In
microphthalmia with cyst, the cornea and iris/uveal tissue are usually present, but may be
hard to identify. A fully formed globe is generally seen in conjunction with other causes
of neonatal proptosis, though it may be compressed, distorted, or infiltrated by tumor. If a
formed globe is identified, visual potential must be presumed, and immediate steps
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should be taken to protect the ocular surface from desiccation. Coordinated imaging
assessment and surgical intervention aimed at reducing optic nerve compromise may
prove necessary.

Retrobulbar hemorrhage. It is then essential to rule out a compartment syndrome

caused by retrobulbar hemorrhage, which may result in gross proptosis and simulate a
mass lesion. Bleeding may be iatrogenic (e.g. from forceps or vacuum delivery), related

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to traumatic passage through the birth canal, or from suction generated by disimpaction
of the neonatal head from the maternal pelvis.62 Perhaps for medico-legal reasons, few
cases are documented in the literature and none report long-term visual outcomes.18 As

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in other age groups, however, this condition is potentially blinding and emergent
decompression should be undertaken when appropriate. Clinical clues include significant
proptosis absent on third trimester ultrasound, evidence of periorbital trauma, and

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conjunctival congestion or frank subconjunctival hemorrhage. An urgent ophthalmology
consultation should evaluate for signs of optic nerve compression and ischemia. These
include presence of an afferent pupillary defect, arterial pulsations, and/or impaired
retinal perfusion.

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Exposure. The next priority is to prevent corneal decompensation, which can lead to
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permanent scarring, superinfection, and even globe perforation. In many cases of gross
proptosis, the eyelids cannot close adequately, resulting in evaporative loss and ocular
surface desiccation. While in the womb, placental fluid bathes the cornea, providing
lubrication and nutrition. Following birth, however, severe conjunctival and corneal
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exposure develop rapidly, and it is therefore essential that the primary team act promptly.
We suggest coating the entire exposed ocular surface, both cornea and conjunctiva, with
bland ointment and then covering it with plastic wrap (e.g. Saran wrap). This layer does
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not have to be sterile and will not abrade the corneal epithelium. A moisture chamber is
impractical to construct and maintain, and does not achieve the broad ocular surface
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lubrication required.

2. The ophthalmologist
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After this initial assessment, responsibility for further evaluation typically falls to a
general ophthalmologist who may not have immediate access to an orbital specialist and
must be prepared to manage all aspects of care leading up to surgical intervention.
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A careful pupillary exam provides important clues regarding visual potential of the
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involved eye. Diminished light reactivity and presence of a RAPD suggest optic nerve
compression. In certain circumstances, prompt excision or debulking of the impinging
mass may partially reverse this. Optic nerve swelling caused by axoplasmic stasis
occasionally may be visualized on a dilated exam. Pallor and atrophy of the nerve are not
anticipated for at least 6 weeks; their presence at birth therefore implies a longstanding in
utero insult and a poor visual prognosis.

Ancillary techniques for determining visual potential exist, but are not uniformly reliable.
Visual evoked potentials are cortical responses elicited by a flashing light or pattern
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visual stimulus. They provide clues as to integrity of the visual pathways, but results are
challenging to interpret when the brain is immature.12,34

Lesion characteristics can often help refine the differential diagnosis. Transillumination
helps to determine whether a mass is sold or cystic. Engorgement with crying suggests a
venous malformation or encephalocele. A bruit indicates an abnormal arterial-venous
connection. Pulsatility suggests arterial flow or encephalocele, and these usually can be

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distinguished based on pulsation frequency. Resistance to retropulsion can also provide
clues as to the density of an orbital lesion.

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A thorough examination of the body surface is essential. In Case 1, the presence of
cutaneous lesions, coupled with diaphoresis, flushing and tachycardia, suggested
metastatic neuroblastoma as an alternative diagnosis. Malignant rhabdoid tumors and

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alveolar rhabdomyosarcoma also may present with subcutaneous nodules.20,27

B-scan ultrasound, an excellent initial modality for evaluating neonatal proptosis, is

quick, doesn’t require sedation, and readily permits distinction among solid, cystic and

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vascular lesions. Color Doppler modes enable quantitative evaluation of intralesional
flow as well as detection of feeding and draining channels. This is helpful not only for
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diagnostic purposes but also for surgical planning. Ultrasound can help characterize the
relationship between the globe, anterior optic nerve and lesion. Attenuation of sound
waves, however, limits evaluation of the deeper tissues and orbital apex. MRI permits
more accurate distinction between the mass and normal orbital structures and is also
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critical to determining whether the lesion is confined to the orbit or extends to involve the
brain and adjacent sinuses. CT scans provide the best characterization of bony orbital
anatomy and may be helpful in distinguishing cystic lesions and heterotopic brain tissue
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from orbital encephalocele.

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Ancillary lab tests can occasionally provide useful diagnostic clues. High 24-hour
homovanillic acid (HMA) and vanilmandelic acid (VMA) levels or an elevated serum
norepinephrine may help to support the diagnosis of neuroblastoma.
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3. The orbital surgeon

It is important to how medically stable the neonate is prior to surgery. Particularly with
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longer procedures, the risk of blood loss and hypothermia must be weighed against the
anticipated benefits of early intervention. When vision or the integrity of the globe is
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threatened by a large or rapidly growing mass, as in our cases, surgery should be

undertaken with an appropriately prepared anesthesia staff. In other situations, as with
the correction of encephalocele, surgeons may choose to defer intervention for several
months to permit maturation.

With orbital malignancy, another important consideration is how best to coordinate

surgery and adjuvant therapy. When integrity of the globe is not acutely threatened, it
may be appropriate to attempt chemoreduction prior to surgical intervention. This
increases the likelihood of negative margins and may reduce the need for an aggressive
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and potentially disfiguring resection. As with Case 1, however, it is often preferable to

debulk or resect a large lesion in advance of chemotherapy in order to reduce the risk of
complications from necrosis and infection.

With cystic lesions, it is debatable whether aspiration should be attempted prior to a

definitive surgical resection. In most circumstances, aspiration should be viewed as a
temporizing measure. Despite the inevitable re-accumulation of fluid, aspiration may

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protect against exposure related complications. There are also some reports of functional
cures resulting from multiple aspirations in conjunction with partial cyst wall excision.1,72

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Historically, cases of gross proptosis were treated with exenteration, but this decision
should be based on medical necessity and not surgical expedience. The massive loss of
orbital volume resulting from acquired anophthalmia presents a formidable challenge, as

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sustained bone stimulation is necessary to prevent the development of hemifacial
deformity.

4. Considerations for follow up

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Management of gross proptosis does not end with lesion resection: Corneal protection
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remains an ongoing concern. In the aftermath of surgery, the eyelids are often
overstretched and hypotonic. Limited ocular motility and a poor protective Bell
phenomenon may compound this. It is therefore necessary to continue aggressive
lubrication and to maintain a low threshold for performing additional lid procedures.
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Presence of an eye or adequately sized substitute is critical to development of the mid-
face and orbits. In cases that require enucleation, volume may be replaced with an orbital
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implant or dermis fat graft if residual malignancy or infection is not suspected. Implants
may also be required in cases of microphthalmia following cyst excision, as the globe
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itself is too small to stimulate bony growth. If a mass has resulted in significant
expansion of the bony orbit, it may be possible to place a definitive implant of sufficient
volume. Otherwise it is necessary to use staged implants of increasing volume, or an
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orbital tissue expander that permits progressive volume expansion with injections of
saline.77

In Case 3, neither standard orbital implants nor dermis fat grafts are appropriate
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following exenteration as the result of lack of orbital tissues and absence of blood supply.
In such situations, a cantilevered tissue expander anchored to the lateral orbital rim best
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replaces the volume deficit in order to stimulate bone growth.

Amblyopia must also be treated aggressively if visual potential remains following a

globe-sparing procedure. Secondary motility disorders and strabismus are also common.

D. Etiology of neonatal proptosis

Differentials for proptosis at birth are often extrapolated from that pertaining to infants
and children. While overlap does exist, there are salient differences to consider in terms
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of incidence, presentation, treatment and prognosis. We discuss the causes of gross

neonatal proptosis, organized by etiology and frequency of presentation. Lesions are
categorized as malignant neoplastic, benign neoplastic, cystic, vascular or miscellaneous
(Table 1).

1. Malignant neoplastic

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a. Neuroblastoma

Neuroblastomas are primitive neuroendocrine tumors arising from the adrenal glands or

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sympathetic chain. Secondary orbital involvement occurs in 10 to 40% of patients and
gross proptosis may be the presenting feature.52 Infrequently, the orbit itself may be the
primary site.86 Most neuroblastomas diagnosed prenatally or at birth carry a favorable

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prognosis, even in the presence of metastatic spread. Indeed, nearly 60% of neonates
have metastases at the time of diagnosis.45 Skin lesions known as ‘blueberry muffin
spots’ suggest a disseminated presentation.2 If treated expeditiously, neonatal
neuroblastoma has a greater than 90% long-term survival.2 Nevertheless, clinical

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behavior is highly variable; a subset of tumors are highly aggressive and may prove
resistant to therapy.2
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Typically, fetal neuroblastoma is discovered on third trimester ultrasound, but tumors
have been detected as early as gestational week 19.2,45 On postnatal ultrasound, tumor is
heterogeneously echogenic and may contain anechoic foci representing hemorrhage or
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necrosis.45 Intralesional calcification is common, appearing on 80 to 90% of CT scans.45
Often there is bony destruction, particularly of the lateral wall.52 Screening CT of the
chest, abdomen, and pelvis as well as bone marrow aspiration are standard for all newly
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diagnosed cases.45 Neuroblastoma is typically hypo- to isointense on T1- weighted

images and hyperintense on T2-weighted images. The compact nature and high nuclear-
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to-cytoplasm ratio of neuroblastoma cells limits the motion of protons, markedly

increasing signal on diffusion-weighted images.79 Primary tumors and metastases may
also be evaluated with scintigraphy, making use of the catecholamine analog
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metaiodobenzylguanidine (MIBG) labeled with iodine-123.

The catecholamine metabolites HMA and VMA are elevated in more than 80% of
neonatal neuroblastoma and may cause maternal hypertension.45,82 Levels can be
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quantified with a 24-hour maternal urine sample or with fetal urine obtained via
amniocentesis.82 VMA is considered the more primitive metabolite, and a VMA-to-HVA
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ratio is sometimes used to predict tumor differentiation.82

Neuroblasts, undifferentiated, malignant sympathetic cells, are small, round and contain
scant cytoplasm. Tumors may be histologically graded based on the presence of necrosis,
mitosis, and karyorrhexis.45 Cytogenetic studies also provide important clues as to likely
tumor behavior. Deletion of chromosome 1p or gain of 17q may be linked to aggressive
behavior, while hyperdiploid DNA and increased levels of CD44 are thought to be
protective.45 Unlike in children, however, neonates with amplification of the Myc-N
proto-oncogene on chromosome 2p do not appear to have a worse prognosis.6,26
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Cycles of multi-agent chemotherapy are typically delivered. Radiotherapy is reserved for

life- or organ-threatening tumor not responding to chemotherapy or surgery.

b. Fibrosarcoma

Congenital infantile fibrosarcoma (CIFS) is a mesenchymal tumor that typically affects

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the extremities, but orbital involvement may result in gross neonatal proptosis.31,76 Forty
percent of cases are diagnosed in utero or at birth.75,83 Overall, it is the most common
soft-tissue sarcoma in neonates and infants, and is relatively indolent compared to other

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spindle cell tumors in this age group.20,31,70 Prognosis for CIFS is much more favorable
than for fibrosarcoma manifesting in children and adults; the 5-year survival rate is
84%.17

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Careful monitoring is imperative when tumors suspicious for CIFS are detected on
prenatal ultrasound, as fetal exsanguination has been reported from intrauterine
rupture.16,73 On postnatal imaging, tumors are often poorly circumscribed with a

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tendency to infiltrate surrounding tissues and encase neurovascular structures. There may
be bowing, cortical thickening of adjacent bone, and osseous destruction.73
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Biopsy with cytogenetic analysis may be required to distinguish these tumors from
benign hemangiomas and other spindle cell malignancies.20 The t(12;15) translocation
linking the ETV6 gene on chromosome 12p13 and the NTRK3 gene on 15q25 is unique
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to CIFS.31,76

Surgery may be curative, though adjuvant or post-resection chemotherapy with

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vincristine and actinomycin may permit less aggressive excisions.20,74 Local rates of
recurrence range from 30% to 50%, but this does not appear to negatively impact
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prognosis.31,74

c. Rhabdomyosarcoma
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Though a relatively common childhood malignancy, rhabdomyosarcoma (RMS) of the

orbit is exceedingly rare at birth.33 Accounting for all sites of origin, the Intergroup
Rhabdomyosarcoma Study (IRS) found that only 0.4% of cases present in neonates.44
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Unfortunately, prognosis tends to be worse in neonates than older children, and multiple
metastases may already be present at the time of delivery.29,32,33 The IRS group reported
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a 3-year overall survival of only 49% among those with RMS presenting at birth.44

Biopsy with histology, immunostaining and molecular studies is essential to establishing

a diagnosis. Further workup should include a chest CT, bone scan and marrow aspirate.
The embryonal subtype predominates in the newborn period, but orbital involvement
with alveolar RMS occurs.29 The alveolar subtype, characterized by the t(2;13)(q35;q14)
and t(1;13)(p36;q14) translocations, has a worse outcome. It is associated with the early
development of brain metastases, and disseminated skin nodules are present in more than
50% of affected neonates.20,29,65
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Immaturity of the neonatal organs makes dosing chemotherapy extremely challenging.

Myelosuppression and toxicity are common and there is a narrow therapeutic window.20
The current European protocol recommends treating children less than 1 month of age
with vincristine and actinomycin D only.20 Those receiving actinomycin D, however,
should be carefully monitored for hepatotoxicity, as they are at a higher risk compared to
older children.20 Supplemental radiotherapy may be required, but is delayed when

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possible because of the deleterious impact on development. To date, there is no record in
the literature of long-term survivors of orbital rhabdomyosarcoma presenting at birth.29

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d. Malignant rhabdoid tumor

Malignant rhabdoid tumors (MRT) are a group of neoplasms histologically similar to but

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biologically distinct from rhabdomyosarcoma.27 Orbital involvement may result in gross
proptosis and has been detected on prenatal ultrasound.38 Tumor is sometimes confined
to a single locus, but a disseminated soft tissue presentation with subcutaneous nodules is
more common.27 Mutations of the tumor suppressor gene hSNF5/INI on chromosome

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22q11.2 have been implicated in pathogenesis.20

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Microscopically, rhabdoid rumors are characterized by sheets of medium-large round or
oval cells admixed with fibrovascular septae.38 They contain abundant eosinophilic
cytoplasm with multiple inclusions and prominent nucleoli.27,38 Large areas of necrosis
are often present and multiple mitoses and apoptotic figures may be seen.27,38 Unlike
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rhabdomyosarcoma, however, cross-striations are not characteristic.27 Immunostaining is
generally positive for vimentin with variable reactivity to cytokeratin and epithelial
membrane antigen (EMA).
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The respective roles of surgery and systemic chemotherapy remain in debate.

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Recurrence-free survival may occur with excision of congenital MRT confined to the
orbit.73,81 One neonate was exenterated with tumor free margins only to die with liver
and brain metastasis.38 The prognosis for disseminated disease is poor regardless of
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management, though a multidrug regiment containing doxorubicin and vincristine is

currently the treatment of choice.20,27,81 Adjunctive Gamma Knife radiosurgery may be
used for unresectable tumors.81
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e. Miscellaneous
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Hemangiopericytomas are mesenchymal tumors derived from the vascular pericytes of

Zimmerman.74 Rarely, they may involve the orbit and produce proptosis in neonates.55
The congenital/infantile form usually presents in those younger than 2 months of age and
has an excellent prognosis.67 Doppler ultrasound demonstrates intralesional flow, and
intense post-contrast enhancement is typical on CT and MRI.55 Extreme caution must be
exercised during biopsy of these vascular tumors. There is potential for life threatening
bleeding that responds only to ligation of the external carotid artery.55,67 Neoadjuvant
chemotherapy is generally effective in rendering larger tumors surgically resectable.
Maturation to capillary hemangioma may occur after incomplete excision.67
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Mesenchymal chondrosarcoma is another rare causes of neonatal proptois.78

2. Benign Neoplastic

a. Teratoma

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Teratomas, encapsulated choristomas with cystic and solid components, arise from
pluripotent embryonic stem cells and contain contributions from all three germ cell
layers. Seventy to 80% of tumors arise in the sacrococcygeal region, but the head and

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neck are also commonly involved.80 Teratomas are among the most commonly reported
causes of gross neonatal proptosis.60,71 For unknown reasons, orbital teratomas occur
with twice the frequency in females.4,42 There are only three cases of malignant

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transformation from an orbital teratoma.23,48

Imaging typically discloses a heterogeneous mass with foci of calcification and areas of
fat density/intensity.24,41 Rapid growth is common and expansion of the bony orbital may

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result in significant deformity.24,48 As Case 1 illustrates, however, no clinical or imaging
findings are pathognomonic for teratoma. The ipsilateral globe is usually completely
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formed but may rarely be small and shrunken.59 Teratomas may also extend into
paranasal sinuses or through the superior orbital fissure to involve the cavernous sinus.41

Common ectoderm-derived components include epithelium-lined cysts, hair follicles,

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sweat glands, and neural elements. Even formed teeth may be found.64 The mesoderm
contributes muscle, bone, cartilage, and fat, while the endoderm produces cysts lined by
gastrointestinal and respiratory-type epithelium. It is these cystic spaces lined by
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glandular epithelium that are responsible for the rapid growth potential of teratomas.24
Exceptionaly, whole or partial fetuses develop within the orbit.50
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Complete surgical excision is critical because presence of residual tumor typically leads
to recurrence.42 With large tumors, some authors advocate aspirating fluid from the
larger cystic spaces to facilitate resection.71 Roughly one third of reported cases have
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been treated with globe sparing surgery, but preservation of useful vision is unfortunately
extremely rare as prolonged stretching of the optic nerve usually renders it non-
functional.42
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b. Congenital myofibroma
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Congenital myofibroma, a rare, locally invasive tumor of myofibroblasts, typically arises

in the head and neck, although visceral organs may also be involved and may be either
solitary or multifocal.84 In contrast to solitary lesions, which have an excellent prognosis,
multifocal myofibroma involving the viscera is associated with a 75% mortality.54

There is a propensity for orbital involvement.54 In cases with gross proptosis,

compressive optic neuropathy may be severe.84 Congenital myofibroma is characterized
by rapid growth in the perinatal period and may destroy bone, as well as invade adjacent
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sinuses.

MRI findings are varied, but myofibroma typically demonstrates low to intermediate
signal on T1-weighted and high signal on T2-weighted images. Peripheral post-contrast
enhancement may occur.5 Given the implications for prognosis, it is vital to evaluate for
the presence of multifocal disease with a full physical exam as well as imaging studies of
the chest, abdomen, and pelvis.54

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Microscopic examination discloses foci of myofibroblastic spindle cells in a staghorn
pattern that resembles hemangiopericytoma.5 Two distinct populations are seen; plump

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spindle cells and small round blue cells.54 Apoptosis and rare mitotic figures may be
present.5,54,84 Immunostaining is generally positive for vimentin and smooth muscle actin
(SMA).54

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Fortunately, recurrence is rare following an adequate surgical resection. Tumors are
generally encapsulated and easily dissect free of adjacent structures.84 Spontaneously
resolution may occur in other parts of the body, but prompt surgical resection is

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recommended when critical structures are involved.54

c. Miscellaneous AN
Lipoblastoma, a rare benign tumor that arises from embryonic white fat, is a rare cause of
neonatal proptois.69
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3. Cystic Lesions
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a. Microphthalmia with cyst

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Microphthalmia with cyst is a subtype of coloboma and the most common congenital eye
malformation, with an incidence of 1.8 per 10,000 live births.9,15 Microphthalmia with
cyst and other colobomata develop as a result of failure of the fetal fissure to close
between the 5th and 7th gestational weeks.15 Approximately one quarter of cases are
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bilateral.9 Sixty-seven percent of bilateral and 29% of unilateral cases are accompanied
by other congenital malformations, including congenital heart defects, central nervous
system abnormalities, cleft lip and/or palate, pulmonary hypoplasia, and renal agenesis.9
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Visual potential of the microphthalmic globe is typically poor.

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The microphthalmic eye may be difficult to visualize. In some cases, a large cyst may
displace the malformed globe so posteriorly that it is invisible to external inspection.15
Accordingly, definitive differentiation between microphthalmia with cyst and congenital
cystic eye may require histology. Microscopically, the cyst is composed of two layers; an
inner layer with primitive neuroretinal tissue and an outer connective tissue layer
continuous with the sclera of the microphthalmic globe.71 Aspiration may be a
temporizing measure for large and symptomatic cysts, but total excision is recommended
because the mass will recur.15
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b. Congenital cystic eye

Congenital cystic eye (anophthalmia with cyst) is a benign lesion resulting from partial or
complete failure of the primary optic vesicle to invaginate. This prevents
neuroectodermal elements from developing into formed ocular structures.10,71 It is
usually unilateral and is occasionally seen in conjunction with contralateral
microphthalmos with cyst.30 When bilateral, it is often associated with other congenital

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abnormalities, including cleft lip and/or palate, basal encephalocele, agenesis of the
corpus callosum, microcephaly, and tetralogy of Fallot.10 Ultrasound reveals a large
cystic cavity without any discernable ocular structures. Glial components within the cyst

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may produce fluid, resulting in progressive enlargement.10

Histologically, the cystic eye consists of dense fibrovascular connective tissue resembling

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sclera admixed with smooth muscle.10 It may be lined with immature retinal tissue,
which stains positively for S-100 and GFAP.10,30 Melanin containing cells resembling
primitive retinal pigment epithelium are occasionally visualized. An astrocytic structure
akin to the optic nerve may extend from the posterior aspect of the cyst.71

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c. Encephalocele
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Anterior encephaloceles occur in 1 of 35,000 live births.46 For unclear reasons, there is a
significantly higher incidence in South-East Asia. The frontoethmoid subtype is most
common and isolated orbital encephaloceles account for only 8% of cases.47 While
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present at birth, growth is generally slow, and profound proptosis is unusual. The orbital
mass may be pulsatile, enlarge with coughing, or reduce under direct pressure, but these
features are not consistently present.8,61 Rarely, encephaloceles are associated with
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neurofibromatosis 1 and sphenoid hypoplasia.46 Additional developmental defects may

include hypertelorism, cleft lip and/or palate, spina bifida, agenesis of the corpus
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callosum, and microphthalmos or optic nerve defects.8

Computerized tomography is the study of choice as it permits the easiest characterization

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of bony defects and aids in operative planning. Surgery is rarely indicated in neonates
without CSF leakage. Earlier intervention generally leads to better cosmetic and
functional outcomes, but most specialists advocate delaying surgery until 8 to 10 months
of age, when infants are more developed and better able to tolerate blood loss and
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hypothermia.47 Surgery for orbital encephaloceles generally entails dural repair followed
by reconstruction of the sphenoid wing using autologous rib or methylmethacrylate
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implants.46

d. Ectopic brain tissue

Choristomatous rests of brain tissue within the orbit may result in neonatal proptosis,
with or without a fully formed eye.28 These benign lesions are usually slow growing and
rarely cause profound deformity or exposure. Leading theories of etiology include
herniation through a bony defect with subsequent closure, resulting in orbital
sequestration, and presence of embryonic rests within the orbit capable of developing into
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a variety of neural tissues.8 With CSF producing lesions, a demonstrable connection to

the brain must be carefully ruled out with preoperative imaging.57 Surgical excision is
occasionally indicated for compressive sequelae and cosmesis.

e. Other cysts

Simple conjunctival cysts have been detected by prenatal ultrasound as early as 23 weeks

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and may cause profound neonatal proptosis with stretching of the optic nerve and
exposure-related phenomena.72,85 Imaging reveals a discrete cyst with no evidence of
ocular, nerve sheath, or intracranial connections. When diagnosis is uncertain, aspiration

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of cyst fluid can be used to rule out a nerve sheath meningocele; beta-2 transferrin is a
marker found exclusively in the cerebrospinal fluid.72 Microscopic examination discloses
a simple cyst lined by a non-keratinized, stratified squamous to cuboidal epithelium,

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lacking dermal appendages.72,85 Ideal management consists of complete excision, but
when this is not safe or practical, partial cyst excision with fluid drainage can yield
favorable results.1,72

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Deep orbital dermoid cysts generally manifest in adolescence or adulthood, but may
rarely result in neonatal proptosis. As with the more common superficial form, deep
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endophytic dermoids arise from epidermal cells entrapped during embryonic
development.11,19

Other rare cysts implicated in neonatal proptosis include congenital glial cysts of the
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optic nerve and glioependymal cysts arising intracranially and extending secondarily into
the orbit.36,37,56 These consist of glial/connective tissue lined by a single layer of ciliated
cuboidal or columnar epithelium and stain positively for GFAP and S-100.56
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4. Vascular lesions
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Thrombosed orbital varices rarely cause profound neonatal proptosis. In the absence of
complete thrombosis, varices often increase dramatically in size with straining and
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crying. CT and ultrasound may disclose phleboliths while Doppler studies are useful for
characterizing flow. Surgery is indicted for optic nerve compression or severe
exposure.21
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Cavernous carotid aneurysm or other arterial lesions may also cause neonatal proptosis in
unusual circumstances.22 On MRI, T2 flow voids may be seen contiguous to the internal
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carotid artery, and post-contrast enhancement is strong. Doppler ultrasound reveals

pulsatile arterial flow. When indicated, treatment entails coiling.

IV. Conclusions

Addressing neonatal proptosis may challenging and frightening for families and
clinicians alike. A prompt, orderly and evidence-based approach, however, optimizes
outcomes. Advances in fetal imaging have improved the likelihood of prenatal diagnosis,
allowing for early assembly of multidisciplinary teams equipped to implement the best
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strategy for preservation of life, normal appearance and vision. While the differential for
proptosis in neonates overlaps with those for infants and children, there are important
differences with respect to incidence, biological behavior, and prognosis.

V. Methods for Literature Search

Case reports were identified via Medline using the search strings and keywords ‘neonatal

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proptosis,’ ‘neonatal orbit mass,’ and ‘fetal orbit mass.’ We included reports only if they
contributed new information about the characteristics, diagnosis or treatment of the
relevant disease processes. Each reference was reviewed for possible publications missed

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in the initial search.

VI. Disclosures

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The authors report no proprietary or commercial interest in any product mentioned or
concept discussed in this article.

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Legends
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Figure 1. Sagittal (A) and coronal (B) T1-weighted MRI, demonstrating a right
retrobulbar mass causing profound proptosis in a 1-day-old neonate. The mass occupies
nearly the entire right orbit and deforms the ipsilateral globe. Note the irregular post-
contrast enhancement pattern originally thought to be consistent with cavernous
hemangioma.

Figure 2. Clinical appearance of the same neonate on the second day of life, with gross
right-sided proptosis, severe exposure and retracted eyelids (A,B). Light reflex was
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absent in the right eye, and a brisk APD was observed. Vascularized oral (C, closed
arrow) and subcutaneous nodules (D) were identified during a comprehensive
examination of the cutaneous and mucosal surfaces.

Figure 3. (A) Intraoperative appearance on day 3 demonstrating the relationship

between the orbital mass and proptotic eye. Meticulous dissection permitted globe-
sparing surgery with tumor-free margins. (B) Postoperative appearance at 1 month

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demonstrating significant improvement in eyelid position. (C) Hematoxylin and eosin
stain demonstrating basophilic cells in a vascularized connective tissue matrix with areas
of extensive necrosis (10x magnification). (D) Homer-Wright rosettes (20x

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magnification). This histopathologic appearance is consistent with metastatic
neuroblastoma.

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Figure 4. (A) Prenatal ultrasound at 23 weeks of gestation demonstrating a large left
orbital cyst surrounding the globe and optic nerve (open arrow) and measuring 3.3 x 3.9 x
3.0 cm. This mass remained stable in size on subsequent fetal imaging studies. (B) One-
day-old neonate with extreme left sided proptosis, corneal opacification, and marked

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prolapse of a transilluminating orbital cyst.

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Figure 5. Coronal (A) and axial (B) T1-weighted MRI scans demonstrating a large left
orbital cyst without dural connections. Significant globe displacement and attenuation of
the ipsilateral optic nerve (open arrow) is visible on the axial image. (C) Intraoperative
image demonstrating a cleavage plane within the orbital cyst. Its identification permitted
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full surgical excision without rupture. Histopathology demonstrated a simple epithelial
cyst lined by stratified squamous and cuboidal epithelium. (D) Direct visualization of the
severely attenuated left optic nerve (closed arrow).
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Figure 6. The globe was successfully preserved, but the patient subsequently developed
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a large angle sensory exotropia. She pictured here at the 15-month postoperative visit
after fitting of a cosmetic scleral shell (A). At age 15, she demonstrates symmetric
craniofacial development with absence of forehead flattening, brow depression or cheek
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hypoplasia (B).

Figure 7. (A) Profound proptosis of the right globe in a 7-day-old neonate with corneal
epithelial defect, chemosis and superotemporal conjunctival erosion. Focal protrusion of
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the underlying mass is readily apparent, suggesting aggressive clinical behavior. (B)
Respected specimen demonstrating gross infiltration of the eye. Globe sparing surgery
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could not safely be performed. (C) Retraction of the stretched eyelids reveals the
exenterated orbit. The apex was positive for residual infantile fibrosarcoma, prompting
the initiation of chemotherapy. (D) Appearance of the child 4 years following
chemotherapy. She is wearing a prosthesis over an inflated orbital tissue expander. Note
the absence of forehead flattening, brow depression or cheek hypoplasia.
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