Exophthalmos

Exophthalmos may be defined as an eye that is protruding anterior to the plane of the face to a greater extent than is typical, or in other words, bulging out of the orbit.

The terms “proptosis”, “exophthalmia”, “exorbitism” and “prominent eyes” are also used. The spelling variant “exophthalmus” can sometimes be also found.

There is no consensus measurement during the prenatal period, making objective categorization challenging; threfore the diagnosis relies heavily on the physician’s expertise (1).

In the neonatal period, the clinical diagnosis may be confirmed and quantified traditionally with an ophthalmometer, or more recently by Magnetic Resonance Imaging (MRI). On MRI the perpendicular distance between the interzygomatic line and the posterior surface of the cornea is measured in both eyes and the result is evaluated according to population distribution (2).

In the International classification of diseases 10 (ICD-10) exophthalmos has numerous codes according to the cause and age of onset (congenital vs. acquired etc.) e.g.:

H05.2 - Exophthalmic conditions

H06.2 - Dysthyroid exophthalmos

Q15.8 - Other specified congenital malformations of eye

In The Human Phenotype Ontology (HPO) database it is called proptosis and it has an identifier HP:0000520. HPO database provides a standardized vocabulary and unequivocal coding of phenotypic abnormalities encountered in human disease.

The incidence of exophthalmos in fetuses or neonates is not known, however it is considered rare.

Exophthalmos can be caused by any mechanism shifting the globe of the eye forward, such as: inflammation of the tissues within orbit (may rarely be caused in maternal Graves’ disease by maternal autoantibodies crossing the placenta), benign or malignant growth (various tumors as orbital teratoma, orbital rhabdomyosarcoma), abnormal venous return from the orbit, abnormal position of the orbit within face due to malformations (e.g. craniosynostoses), facial lesions with or without underlying genetic background, trauma to the bony structures of the orbit and a foreign body within the orbit (3-5).

Associated anomalies are determined by the main diagnosis: there may be damage to the surrounding structures in cases of tumors, facial and neurological complications in craniosynostosis syndromes, neonatal Graves’ disease (often fatal if not recognized),  etc. (6).

Exophthalmos may impair eyelid closure, which usually does not lead to severe complications before birth, as the amniotic fluid protects the cornea and conjunctiva, but postnatally desiccation and trauma can induce inflammation and result in vision loss. To protect the cornea in cases of corneal exposure, part or all the eyelids may be sewn together to narrow the eyelid opening (this relatively simple and safe procedure is called tarsorrhaphy). Extreme forward displacement of the eye may lead to entrapment of the eyelids behind the eye, damage to the optic nerve, muscles, and ligaments (7).

As exophthalmos is a symptom rather than a disease, the risk to the subsequent offspring is dependent on the diagnosis. If it is a part of a genetic syndrome, the probability of recurrence depends on the type of inheritance, e.g., in the case of a fetus with exophthalmos due to Yunis-Varon syndrome, which has autosomal recessive transmission, the recurrence risk will be 25%.

Shallow orbits are the main entity which needs differentiating from exophthalmos, but not always the distinction between these two is clear-cut.    

Presence of concomitant anomalies of the face such as: hypoplasia of the midface, underdevelopment of the supraorbital ridge, hypoplasia of the zygomatic arch may simulate proptosis but may be more accurately defined as “shallow orbits” (prominent ocular globes appearance in the presence of a reduced orbit depth).  Both findings may affect the objective measurement by ophthalmometer; therefore, their coexistence      makes the differential diagnosis even more challenging (8).

In The Human Phenotype Ontology (HPO) database “shallow orbits' ' have the identifier: HP:0000586. Synonyms of this condition according to the HPO database are: “decreased depth of eye sockets'' or “small shallow orbits” or “shallow eye sockets’ or “decreased depth of orbits”. Exophthalmos should not be confused with buphthalmos, in which there is an enlarged eyeball which can also be protruding out of the the orbit. Buphthalmos is a rare prenatal finding which can be related to congenital glaucoma and other causes such as aniridia, neurofibromatosis, Sturge/Weber syndrome.

Exophthalmos and many other ocular lesions can be detected prenatally, which permits the obstetrician and other members of the perinatal multidisciplinary team to provide the neonate and her/his family with appropriate counseling and treatment, minimizing the risk of adverse outcome and enabling reproductive decisions. It is not rare however, that proptosis or other significant orbital lesions are not identified on fetal ultrasound, and severe exophthalmos at delivery comes as a surprise, creating much distress among the family and medical staff (9).

As with the risk of recurrence, the prognosis of exophthalmos is highly dependent on the underlying diagnosis.

In the first place, an attempt should be made to establish the most probable etiological diagnosis. For this, expert ultrasound, fetal MRI, and genetic studies should be used (targeted testing in cases in which the fetal phenotype is sufficiently specific, or non-targeted applying chromosomal microarray, or new generation sequencing studies such as exome sequencing, or whole genome sequencing in unspecific cases), ideally in a multidisciplinary center.                                  

If severe exophthalmos secondary to orbital tumor is detected before birth, atraumatic cesarean delivery may be considered, and a multidisciplinary team can be made available     to perform surgery to optimize outcome (10,11).

Burns NS, Iyer RS, Robinson AJ, Chapman T.; Diagnostic imaging of fetal and pediatric orbital abnormalities. AJR Am J Roentgenol. 2013 Dec;201(6):W797-808

2.       Association of anthropometric markers with globe position: A population-based MRI study; Schmidt Patrick, Kempin Robert, Langner Soenke, Beule Achim Georg; PLoS ONE 14(2):e0211817; February 2019

3.       Harada A, Miyashita S, Nagai R, Makino S, Murotsuki J.; Prenatal sonographic findings and prognosis of craniosynostosis diagnosed during the fetal and neonatal periods. Congenit Anom (Kyoto). 2019 Jul;59(4):132-141

4.       Joseph AK, Guerin JB, Eckel LJ, Dalvin LA, Keating GF, Liebo GB, Benson JC, Brinjikji W, Laack NN, Silvera VM. Imaging Findings of Pediatric Orbital Masses and Tumor Mimics.Radiographics. 2022 May-Jun;42(3):880-897

5.       Samuels SL, Namoc SM, Bauer AJ.; Neonatal Thyrotoxicosis.; Clin Perinatol. 2018 Mar;45(1):31-40

6.       Leung E, Diaz-Barbosa M, Alabiad C, Hodapp E, Tse D, Murray TG, Castaner JC, Martin D, Berrocal AM. Prenatal ultrasonographic detection of ophthalmic diseases. J Pediatr Ophthalmol Strabismus. 2012 May 22;49

7.       Greene AK, Burrows PE, Smith L, Mulliken JB.; Periorbital lymphatic malformation: clinical course and management in 42 patients.; Plast Reconstr Surg. 2005 Jan;115(1):22-30.

8.       Sargar KM, Singh AK, Kao SC.; Imaging of Skeletal Disorders Caused by Fibroblast Growth Factor Receptor Gene Mutations.; Radiographics. 2017 Oct;37(6):1813-1830] [

9.       [Diagnostic imaging of fetal and pediatric orbital abnormalities.; Burns NS, Iyer RS, Robinson AJ, Chapman T.; AJR Am J Roentgenol. 2013 Dec;201(6):W797-808]

10.      Surgical resection of antenatally diagnosed orbital teratoma resulting in preservation of the globe, Aziz, Tania, Mayer, Christopher, Lynch, Tara, Rijhsinghani, Asha, Journal of Pediatric Surgery Case Reports; 60;2020; 101565;  DO  - 10.1016/j.epsc.2020.101565

11.      Erickson BP, Tse DT.; Management of neonatal proptosis: a systematic review.  Surv Ophthalmol. 2014 Jul-Aug;59(4):378-92.]

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