Cryptophthalmos, Unilateral Or Bilateral, Isolated

A number sign (#) is used with this entry because of evidence that unilateral or bilateral isolated cryptophthalmos (CRYPTOP) is caused by homozygous or compound heterozygous mutation in the FREM2 gene (608945) on chromosome 13q13.

Mutation in the FREM2 gene can also cause a syndromic form of cryptophthalmos, Fraser syndrome-2 (FRASRS2; 617666).

Description

Cryptophthalmos is a condition of eyelid malformation with an underlying malformed eye. Complete, incomplete, and symblepharon varieties exist. The skin in complete cryptophthalmos extends uninterrupted from the forehead to the cheek. In the incomplete form, there is medial eyelid fusion, but coincident intact lateral structures. The symblepharon variety presents with fusion of the upper eyelid skin to the superior aspect of the globe. The complete variety is the most common form (summary by Egier et al., 2005).

Clinical Features

Thomas et al. (1986) reviewed syndromic and isolated cryptophthalmos. The principal syndromic form is Fraser syndrome (219000), a recessive. They found reports of 27 cases of nonsyndromic cryptophthalmos.

Traboulsi et al. (1990) and Saal et al. (1992) described mother and daughter with identical abnormalities limited to the eye. They had bilateral fusion of the upper and lower lids with a midline dimple where the cornea adhered to the upper lid. Small globes were palpable and the proband daughter, an infant, reacted to bright light. Ultrasonography and CT scan of the orbits showed microphthalmia and a lens that was adherent to the cornea. Bilateral enucleation for glaucoma had been necessary in the mother. The dominant inheritance distinguished the condition from the Fraser syndrome. Saal et al. (1992) concluded that the same condition was present in the patients reported by Coover (1910, 1910, 1915) and Magruder (1921).

Egier et al. (2005) described a female child with complete bilateral isolated cryptophthalmos and associated ocular anomalies similar to those described in the patients reported by Coover (1915) and Saal et al. (1992). The child had fusion of the eyelids to the globes with a characteristic central dimpling of the skin overlying the eyes. Ultrasound biomicroscopy showed a posterior corneal surface and abnormal iris, ciliary body, and anterior chamber, consistent with Peters anomaly. The parents were unaffected and nonconsanguineous.

Yu et al. (2018) reported a 3-year-old Chinese girl (family 1) with isolated unilateral cryptophthalmos, whose right eye was completely covered by intact skin without eyelid, eyelashes, or eyebrows, whereas the left eye was normal. MRI and ocular CT scan showed a unilateral gourd-shaped cyst with markedly enlarged cornea and anterior chamber depth, but no clear internal structures. Exploratory surgery at age 4 revealed a gourd-shaped cyst, but no iris tissue, anatomic eyelid structure, or conjunctival sac structure. The patient had no other anomalies.

Zhang et al. (2019) studied 3 unrelated Chinese children with bilateral complete cryptophthalmos. Gross examination of the periorbital area showed continuous intact skin covering the upper half of the face, without the normal development of eyelids, eyelashes, or eyebrows. Ocular B-scan ultrasound revealed bilateral gourd-shaped cysts without clear internal structures, and MRI showed normal brain morphology, extraocular muscles in a narrow orbital fat gap, and optic nerve enlargement in the expanded orbits. Upon exploratory surgery at age 4 months (patient 1), no anatomic eyelid structure was identified. A transparent anterior cyst was detected beneath the subcutaneous tissue, and a lens-like transparent spherical body was observed in the posterior cyst. However, the iris and suspensory ligament of the lens were absent, and vascular and pigment tissues in the posterior cyst were not obviously identifiable as retinal or choroid tissues. There were no other anomalies on examination or ultrasonography of the heart, brain, and urogenital system, and all 3 patients achieved normal developmental milestones with no cognitive impairment.

Inheritance

Of 27 cases of nonsyndromic cryptophthalmos found in a literature review by Thomas et al. (1986), 16 were sporadic and 11 were familial. Thomas et al. (1986) stated that the familial cases were distributed in 3 families, all with vertical transmission and thus consistent with dominant inheritance (Coover (1910, 1915); Goldberg, 1912; Magruder, 1921). Goldberg (1912) reported 5 cases in 4 generations of a family; it is possible that the entity should be labeled ankyloblepharon (presumably different from filiform ankyloblepharon, 106250). Magruder (1921) reported affected mother and daughter. Egier et al. (2005) stated that Magruder (1921) reported the same mother and daughter as Coover (1915) after the birth of a son with the same anomaly.

Kulkarni et al. (1995) reported 2 brothers with nonsyndromic complete cryptophthalmos, unilateral in 1 and bilateral in the other. Their unaffected parents were consanguineous, suggesting autosomal recessive inheritance.

Egier et al. (2005) stated that their patient with bilateral complete isolated cryptophthalmos and associated ocular anomalies and the patients in the families of Coover (1915) and Saal et al. (1992) had the same autosomal dominant condition.

Molecular Genetics

In a 3-year-old Chinese girl (patient 1) with isolated unilateral cryptophthalmos and her unaffected parents, Yu et al. (2018) performed trio whole-exome sequencing and identified homozygosity for a missense mutation in the FREM2 gene (R2167W; 608945.0004) that segregated with disease and was not found in an in-house database of 8,000 Chinese control exomes.

By whole-exome sequencing in 3 unrelated Chinese children with isolated bilateral complete cryptophthalmos, Zhang et al. (2019) identified mutations in the FREM2 gene: all 3 had the previously reported R2167W mutation, in compound heterozygosity with 3 different nonsense mutations: R736X (608945.0006), W1770X (608945.0007), and R1355X (608945.0008), respectively. Their unaffected parents were each heterozygous for 1 of the variants. No mutations were detected in other ocular morphogenesis- or Fraser syndrome-associated genes.