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Original contributors: Yazdian A, Nandigam L, Jaber J, Yen MT.

Disease Entity: Cryptophthalmos

Cryptophthalmos when translated from its latin derivations means “hidden eye”. As such, cryptophthalmos presents with fused eyelids covering the globe and socket with absent palpebral fissures¹. Namely, the skin of the forehead is continuous with the skin of the cheek. There are 3 types of cryptophthalmos mentioned in literature, known as complete/typical, incomplete/atypical, and the abortive form of cryptophthalmos (also referred to as congenital symblepharon). Regardless of the type, it can be unilateral, bilateral, and isolated or syndromic. It is commonly associated with Fraser syndrome, an autosomal recessive disorder with mutations in either the FRAS1, GRIP1, or FREM2 genes.

Figure 1: A photo of a patient with the complete form of cryptophthalmos¹. Note the lack of identifiable lashes, brows, and glandular structures. Open access under terms of the Creative Commons License: http://creativecommons.org/licenses/by/4.0/. Original figures available at: https://www.omjournal.org/articleDetails.aspx?coType=1&aId=2939

Etiology

Complete Cryptophthalmos

Complete cryptophthalmos is the most extreme presentation of the condition. It presents with complete occlusion of the eye sockets and fusion of the forehead and cheek skin. There is absence of eyebrows, lashes, and gland structures. The overlying skin is fused with the cornea and there is no conjunctival sac present. Microphthalmos is very common with this subtype. The complete form is more prevalent and associated with more severe anomalies of the globe¹.

Incomplete Cryptophthalmos

With incomplete cryptophthalmos, there are rudimentary eyelids present and small conjunctival sacs placed laterally. However, the parts of the eyelids that have not developed remain fused to the abnormally developed globe. The globe is generally small, almost covered by skin, and the palpebral fissure is about one-third of the normal length.

In both complete and incomplete cryptophthalmos, an ocular cyst can be present.

Abortive Cryptophthalmos

In abortive cryptophthalmos, the upper lid is absent, and the forehead skin adheres to and covers the top 75% of the cornea. The globe can range from small to normal size with the covered cornea presenting as opaque with keratinization. It is possible for the free cornea to be clear. No punctum is visualized in the upper lid and there is no conjunctival fornix present. The lower lid is often present^1,2.

For almost all cases of cryptophthalmos, there is little to no visual potential. Treatment focuses on reconstruction of the ocular region. Prior to surgery, imaging is required and visual potential will be assessed.

Pathophysiology

There is no consensus on the pathophysiology. The neural ectodermal optic vesicle is vital to the development of the lens in the fetus, and defects in this layer prevent proper development of the cornea, lens and anterior chamber¹⁵. The overlying eyelids cannot form without ectodermal and mesodermal differentiation, suggesting the role of this key step. Since many of the synonyms associated with cryptophthalmos entail fused digits, larynx, or genitalia, it is proposed that a defect in apoptosis, or programmed cell death, plays a key role¹⁷.

Incidence

As of 2018, only 55 cases were reported in the literature. Cryptophthalmos is exceedingly rare, with an incidence of 0.043:10,000 liveborn infants and 1.1:10,000 stillbirths¹⁵.

80% of individuals diagnosed with Fraser syndrome present with cryptophthalmos, with fewer than 5,000 individuals estimated to have this condition in the United States^{1, 16}.

Diagnosis

Physical examination

The most pressing symptom is blindness, as the patient’s eye(s) are obstructed by skin and there are no eyelid(s). The cornea of the affected eye(s) fuse with the overlying skin. The vast majority of cryptophthalmos cases have bilateral blindness, although a few cases of unilateral blindness have been reported³. Typically, the disorder is also symmetric across both eyes, although asymmetry does occur in one-third of cases¹⁰.

Prenatal ultrasound can detect cryptophthalmos in utero at around 18 weeks gestation. The ultrasound will demonstrate lack of the palpebral fissure between the upper and lower eyelids and continuous skin from the fetal forehead to the cheek. Additionally, one or both eyes have malformed anterior segments. Typically one of the eyes is also abnormally smaller than the other eye. If the fetus has other symptoms such as syndactyly, enlarged echogenic lungs, oligohydramnios (decrease in amniotic fluid), they likely have Fraser syndrome, discussed below.

Differential diagnosis

Fraser syndrome is an autosomal recessive genetic abnormality with a variety of congenital defects. Cryptophthalmos is one of the four major diagnostic criteria for Fraser syndrome, along with syndactyly, genitalia abnormalities, and limb anomalies. Other minor criteria include ear and nose deformities, cleft lip and palate, hairline variations, teeth abnormalities, and renal anomalies. 84-93% of Fraser patients have cryptophthalmos¹⁴. Moreover, Fraser syndrome has also been called Cryptophthalmos syndrome in literature. Fraser syndrome can be diagnosed after birth, and death is common in utero or within the first year of life.

However, cryptophthalmos can also be isolated. The isolated condition can arise through familial vertical transmission, specifically through an autosomal recessive, or sporadic origins. It has equal incidence across genders¹³.

Figure 2: Complete cryptophthalmos OS and incomplete cryptophthalmos OD⁸ Open access under terms of the Creative Commons License: http://creativecommons.org/licenses/by/4.0/. Original figures available at: https://bmcophthalmol.biomedcentral.com/articles/10.1186/s12886-019-1170-6

Management

Medical therapy

The primary cryptophthalmos treatment is surgical correction to separate the fused eyelids and make the eyelids functional. However, in cases where surgery is contraindicated, unfeasible, or unsuccessful, prosthetic eyelids may be a considerable treatment option. Designed to mimic the appearance of normal eyelids, prosthetic eyelids allow for the protection of the eye and improvement of cosmetic appearance for the patient.

Another option for medical therapy is ocular surface management. Cryptophthalmos has the potential to cause significant damage to the ocular surface from its exposure and inadequate protection. Ophthalmic lubricants and artificial tears may be an appropriate prescription to help circumvent the dryness and ocular discomfort.

Surgery

Cryptophthalmos often presents with not only undifferentiated lids, but also architectural elements are absent such as tarsal plates, orbicularis muscle, meibomian glands, and more. Consequently, this makes surgical construction of normal lids very difficult. The type of surgical intervention depends on the classification of cryptophthalmos based on severity: complete, partial (incomplete), and abortive⁶. Furthermore, surgery is dependent on whether the presentation is unilateral or bilateral. For example, if the condition is unilateral, no visual potential is evident, and exposure is controlled, surgery could be postponed to allow for the relaxation of tissues as the infant matures⁷.

Complete Cryptophthalmos

In patients with complete cryptophthalmos, oculoplastic reconstructive surgery is utilized in a stepwise fashion as one of the only modalities currently known for treatment⁸. The goal of such procedures in complete cryptophthalmos is purely cosmetic, and if possible, improvements in visual function. However, since normal development of the cornea is not possible, and fornix reconstruction for the placement of a prosthetic shell is challenging, prognosis for visual improvements have been proven quite rare¹². Consequently, many have deferred these surgeries as a result of the complications and difficulties associated with creating both a fornix and eyelids.

If surgical intervention becomes necessary, it is crucial to adopt a step-by-step approach. The primary objective initially is to create a conjunctival sac. This involves dividing the skin covering the ocular remnants and inserting a conformer covered with a mucous membrane (MM) graft. Subsequent to this stage, approximately one year later, eyelid reconstruction may be performed, entailing the reinforcement of the posterior lamella and, if required, additional socket MM grafting. In instances where MM grafting proves ineffective, an alternative option for socket reconstruction involves using the preputial skin in uncircumcised children¹¹.

Incomplete Cryptophthalmos

Incomplete cryptophthalmos also has poor visual potential, however, this could be misconstrued due to the less severe appearance compared to other forms of cryptophthalmos⁴. This is often due to the coloboma appearing smaller from the concealment of the skin fold, hidden diseased cornea, and painless eye¹². As a result, most surgical interventions are cosmetic to improve the appearance of the child’s eye. Rushing into surgery, however, should be avoided due to the keratinized cornea and complication possibilities such as possible recurrence of adhesions following fornix reconstruction. Primary objectives for surgical options include creating a functional conjunctival sac, reconstructing the eyelid, and potentially restoring the fornix.

Often the first step in surgical management is to create a conjunctival sac, which is useful for maintaining eye health. This involves dividing the skin covering the ocular remnants, following conformer placement, which is covered with a mucous membrane graft. Reconstructing the eyelid involves eyelid sharing or switch procedures in order to achieve functional and cosmetic improvements. Eyelid sharing consists of utilizing adjacent eyelid to aid in addressing defects of the affected eyelid, and eyelid switch procedure involves transposing normal tissue from the inferior fornix to the narrower superior fornix allowing for widening of the upper eyelid and improving its function⁹.

Furthermore, fornix reconstruction may be necessary in incomplete cryptophthalmos. The timing is widely debated in literature, as some prefer to delay until flap separation and some surgeons perform fornix reconstruction concomitantly with eyelid reconstruction. The type of graft, such as amniotic or mucous membrane, for fornix reconstruction, is widely debated too. While some have reported positive outcomes with amniotic membrane grafting, others caution against its use due to potential issues like drying out and contraction. Regardless of the graft type used, there is a risk of recurrence of corneopalpebral adhesion in its original location.

Abortive cryptophthalmos

Abortive cryptophthalmos poses a significant risk to vision due to upper eyelid coloboma and restricted ocular mobility, potentially leading to exposure keratopathy and visual impairment⁵. In severe cases without visual potential, a major goal for surgical rehabilitation methods of abortive cryptophthalmos often involves reconstruction of the upper eyelid and superior fornix. Some cases have reported that a one-stage reconstruction of upper eyelid and superior fornix with scleral and amniotic grafts have posed reasonably appropriate results⁵.

References

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Subramaniam, Nirmala et al. “Prepucial skin graft for forniceal and socket reconstruction in complete cryptophthalmos with congenital cystic eye.” Ophthalmic plastic and reconstructive surgery vol. 24,3 (2008): 227-9. doi:10.1097/IOP.0b013e31816e34c8
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