Congenital Upper and Lower Eyelid Coloboma
Key Points
A congenital eyelid coloboma is a full-thickness defect that can be unilateral or bilateral
It may present with or without corneopalpebral adhesions and can be associated with anomalies such as Fraser syndrome, Goldenhar syndrome, or Treacher Collins syndrome
The defect involves conjunctiva, tarsal plate, orbicularis muscle, and skin and leaves the cornea exposed
The etiology is varied and multifactorial, with a genetic basis in associated syndromes and possibly craniofacial clefts and developmental factors such as abnormal neural crest cell migration, anomalous vascular development, defective migration and fusion of mesoderm, or amniotic bands
The clinical features of eyelid coloboma vary from a simple limited defect with minimal adhesions to the cornea to complete absence of the eyelid as in cryptophthalmos
Small and moderate-sized upper eyelid colobomas can usually be closed primarily or with simple reconstructive techniques
Larger defects or those associated with corneopalpebral adhesions and craniofacial clefts will require more major reconstructive procedures including grafts and flaps
The cosmetic and functional prognosis for simple colobomas is usually excellent, but when associated with facial clefts or various syndromes, multiple surgical procedures are usually necessary to achieve a fair to good outcome
Coloboma (plural, colobomas, colobomata) implies a full-thickness, curtailed structure, or a hole or a defect in a tissue,1,2 and is a term that is almost exclusively used in ophthalmology.1 First described in the iris in 1673 by Bartholin the younger, ocular colobomata can involve any layer of the eye3 and usually result from defective closure of the embryonic fissure.3 Eyelid colobomata, on the other hand, may involve the upper or the lower eyelids; can be unilateral or bilateral, symmetrical or asymmetrical; and can involve animals or humans. They may present with or without corneopalpebral adhesions (CPAs) and may be an isolated finding or be part of a larger spectrum of congenital anomalies as in the case of Fraser syndrome, Goldenhar syndrome, or Treacher Collins syndrome.4 Congenital upper eyelid coloboma, in particular, may threaten vision at a very early age and is one of the few true nontraumatic oculoplastic emergencies that require prompt management when it presents in the first few days of life with a corneal ulcer or impending perforation. The classic congenital eyelid defect includes a shortage of conjunctiva, tarsal plate, orbicularis muscle, and skin, which leaves the cornea unprotected, resulting in possible exposure keratopathy. Even after closing the defect, close monitoring of visual function is of paramount importance because of the very high risk of amblyopia.4
Each of the disorders described below is given a large number of different names in the literature. Cryptophthalmos (CO) and its syndromic counterpart, Fraser syndrome (FS), have been assigned 17 different names.5,6,7 Goldenhar syndrome (GS) has also been christened with at least 16 different names, the most famous of which are craniofacial microsomia and oculoauriculovertebral spectrum (OAVS).8,9,10 Treacher Collins syndrome (TCS) also goes by the names of mandibulofacial dysostosis or Franceschetti-Zwahlen-Klein syndrome.11,12 Craniofacial clefts have also been described under at least 10 different names the most popular name being Tessier clefts (TCs), and in the case of clefts involving the eyelids, the term oblique facial clefts is also a popular name.13,14,15 For practical purposes, we have retained the use of the terms CO, FS, GS, TCS, and TC throughout this chapter until a single orthonym is universally adopted for each of these disorders.16
Etiology and Pathogenesis
To date, the network of genetic mutations responsible for eyelid colobomas is largely unknown. Quite possibly, environmental factors or mechanical events during pregnancy may contribute to their development. FS and TCS are probably primary genetic abnormalities defined as a defect in the gene structure of an organ or part of an organ.9,12 On the other hand, GS may be a secondary disruption anomaly or an interruption of the normal development of an organ that can be attributed to mechanical or teratogenic factors or may be of multifactorial origin where several genes and/or environmental factors influence the phenotype.9,12 Facial clefting syndromes may also belong to the latter variety, although a genetic defect has been demonstrated recently.17
The exact etiopathogenetic events in FS are largely unknown; however, an insight into the genetics of FS has greatly been increased with the study of a certain family of mice mutants termed “bleb mice.” In patients with FS as well as in bleb mice, the shared defect is a profound loss of adhesions
of the epidermis to the underlying basement membrane that results in abnormal epidermal blistering in the mouse embryo and hypothetically in FS/CO.18 In normal mouse and human embryos, a group of closely related proteins called the FRAS/FREM protein family are universally present in all basement membranes throughout the body. They contribute to embryonic epithelial-mesenchymal integrity and tight adhesions during embryogenesis.19,20,21,22 When this intricate process of epithelial-mesenchymal protein trafficking is interrupted by a genetic knockout, either experimentally (Fras1−/− mice) or in humans with a genetic defect on chromosome 4q21 or 13q13.1 (which encode FRAS1 or FREM2, respectively),23 the most common resulting phenotype is composed of renal anomalies, abnormal fusion of the digits as well as the eyelids, in addition to subcutaneous hemorrhagic blisters in mice. Mutations in either of these two autosomal recessive genes were demonstrated in 50% of patients with FS. However, other genes have also been implicated recently.23,24,25,26
of the epidermis to the underlying basement membrane that results in abnormal epidermal blistering in the mouse embryo and hypothetically in FS/CO.18 In normal mouse and human embryos, a group of closely related proteins called the FRAS/FREM protein family are universally present in all basement membranes throughout the body. They contribute to embryonic epithelial-mesenchymal integrity and tight adhesions during embryogenesis.19,20,21,22 When this intricate process of epithelial-mesenchymal protein trafficking is interrupted by a genetic knockout, either experimentally (Fras1−/− mice) or in humans with a genetic defect on chromosome 4q21 or 13q13.1 (which encode FRAS1 or FREM2, respectively),23 the most common resulting phenotype is composed of renal anomalies, abnormal fusion of the digits as well as the eyelids, in addition to subcutaneous hemorrhagic blisters in mice. Mutations in either of these two autosomal recessive genes were demonstrated in 50% of patients with FS. However, other genes have also been implicated recently.23,24,25,26
GS is an enigmatic heterogeneous disease the exact etiology of which is still not clear. The disease is usually sporadic, although familial instances have been demonstrated suggesting sometimes an autosomal dominant or autosomal recessive inheritance.27 Various chromosomal abnormalities have been found in GS such as trisomy 7, 9 or trisomy 22 mosaicisms, deletions at chromosome 18q or 22q, and unbalanced translocations between chromosomes 5 and 8.27,28,29,30,31 The most commonly accepted theory is that GS develops as a result of an interaction between environmental factors and some unknown submicroscopic genetic factors.9 Disturbances in the migration, proliferation, or differentiation of the cranial neural crest cells have been proposed as a possible mechanism for GS.32 A long list of possible teratogenic environmental factors includes smoking, cocaine use during pregnancy, diabetic embryopathy, primidone, retinoic acid or thalidomide use during pregnancy, and an unknown toxin during the Gulf war.9,32,33 All these genetic-environmental factors ultimately converge toward a final common vascular perturbation event that dictates the phenotype.9
The question that remains is how and why colobomata develop in the context of GS. Smith et al34 hypothesized that this may reflect a minor abnormality with entrapment of epidermal cells along the fusion lines of the medial and lateral protuberances of the frontonasal process late enough and insufficient enough to adversely affect the development of the cornea and conjunctiva, yet representing a weak point leading to an abnormal focal defect during the process of eyelid separation.34,35
TCS is a rare congenital disorder of craniofacial morphogenesis.36 Mutations in the TCOF1 gene (autosomal dominant [AD], chromosome 5q32), the POLR1C gene (autosomal recessive, chromosome 6p21), or the POLR1D gene (AD, on chromosome 13q12) may all cause TCS. More than 80% of cases are due to defects in the TCOF1 gene where more than 120 different mutations have been described.12 All of these genes interrupt ribosomal biogenesis, and since ribosomes produce proteins, the synthesis of proteins encoded by these genes is interrupted. The proteins produced from the TCOF1, POLR1C, and POLR1D genes are involved in early craniofacial morphogenesis of both bones and overlying cartilage and connective tissue.36
The pathogenesis of the rare craniofacial clefts is not yet fully understood and several theories have been proposed. Classical teaching dictates that TCs are multifactorial in origin and etiologically heterogeneous, with both environmental and genetic factors involved.37,38 Existing theories include abnormal neural crest cell migration, anomalous vascular development (embryonic hematoma), defective migration and fusion of mesoderm, or a mechanical disruptive event due to amniotic bands or otherwise.15,39 Although the cellular/genetic basis for TC remains unclear, recent studies have confirmed that a defect or mutation in the SPECC1L gene is contributory to the pathogenesis of TC.39 SPECC1L encodes a novel cytoskeletal cross-linking protein, which is required for the integration of frontonasal and maxillary elements and convergence of mandibular prominences.40 This important gene discovery raises the possibility that other genes might also contribute to TC.39 Therefore it is entirely plausible to hypothesize that the ultimate pathogenetic event may have to do with a failure of cranial neural crest cell migration, with resultant failure of proliferation or fusion of maxillary and lateral nasal prominences.34
Clinical Presentation
Classification of Colobomas
The genetic makeup of several syndromic and isolated eyelid colobomata outlined above suggests that in the future a categorization of eyelid colobomas may be based on the genetic or molecular signatures of each particular anomaly. But until the unique genetic bases of these misleadingly similar phenotypes are completely understood, the authors adopt a simple classification scheme solely for the present discussion, which is modified and updated from a previous classification schema that was previously suggested.4
Upper eyelid
Isolated coloboma
Coloboma associated with corneopalpebral adhesions (CPA) (for example, cryptophthalmos [CO])
Complete: No discernible eyelid differentiation and the eyes are completely covered with skin
Incomplete: A skin fold devoid of tarsus covers the medial aspect of the palpebral aperture associated with significant corneopalpebral adhesions
Abortive type/congenital symblepharon variant (CSV) or partial CO: True coloboma of variable sizes with a diverse range of CPA. The lower fornix and lateral upper eyelids are usually spared
Simple coloboma: Upper eyelid coloboma in isolation, not associated with CPA
Coloboma associated with Tessier clefts (TC) 9,10,11
Syndromic variants
Fraser syndrome (FS)
Goldenhar syndrome (GS)/oculoauriculovertebral spectrum (OAVS)
Rare syndromes: Manitoba oculotrichoanal syndrome, nasopalpebral lipoma-coloboma syndrome
Lower eyelid
Isolated coloboma
Coloboma associated with Treacher Collins syndrome (TCS)
Coloboma associated with Tessier clefts 3,4,5.
Rare conditions: Proboscis lateralis
The clinical features of isolated or syndromic CO vary from a simple coloboma with minimal adhesions to the cornea to a truly “hidden” eye or complete CO. François41 subclassified cases with CO into complete CO, incomplete CO, and CSV, all of which may coexist in both eyes of the same patient or in siblings.42 Although it is believed that the clinical spectrum of CO represents a continuum, probably resulting from the same genetic defect that may not uniformly lend itself to a rigid clinical classification schema,43 for the current discussion, Francois’ subclassification is adopted.
In patients with complete CO (Figure 29.1), the forehead skin extends over the globe and onto the cheek without any discernible differentiation of eyelids.44,45 The ocular structures in complete CO are usually atrophic and grossly disorganized, but the eye may be normal in size or even enlarged, may occasionally present as a cyst,44,45,46,47 and may rarely express a reaction to light.44 The extraocular muscles may be of normal size for age or may be ill-defined with limited ocular motility, which can be seen and felt with palpation.41,47 The globe may be central or may be displaced horizontally or vertically. The eyebrows are seldom normally developed,36 and more commonly the entire eyebrow, its medial two-thirds, or its lateral one-third is absent.44,47,48 A tongue of hair, which is not yet quite distinct at birth, may be seen extending from the scalp hair into the lateral one-third of the eyebrow.47,48 In complete CO, the conjunctiva is also wholly absent and the skin is completely adherent to the anterior surface of the sclera and cornea by fibrous tissue. The condition may be unilateral or bilateral.47 Histopathologically, the eyelids are replaced by undifferentiated fibrous tissue, with a total absence of the tarsus, meibomian glands, cilia, and lacrimal glands,41,46,47 but the orbicularis oculi and the levator muscles are usually preserved, and the extraocular muscles may be present or absent.41 The conjunctiva is usually absent in histologic sections, and the cornea is usually replaced with “intertwining collagen bundles” with no epithelial or endothelial lining.41,47 Although the anterior segment might be malformed, the choroid, retina, and optic nerves appear to be normally formed.47
 FIGURE 29.1 Clinical spectrum of complete cryptophthalmos. A, Bilateral cryptophthalmos. The lateral two-thirds of the eyebrows is absent and an abnormal tongue of hair is seen extending from the scalp hairline to the brows. B, Unilateral cryptophthalmos. A tuft of eyelashes can be seen at the presumed junction between the undeveloped upper and lower eyelids. C, Unilateral cryptophthalmos. No rudimentary lashes can be seen but a tongue of hair extending from the hairline to the brow can be observed. (A, Courtesy of Dr. Alan McNab.) |
In incomplete CO (Figure 29.2), patients have an ill-defined upper eyelid or an incomplete skin fold devoid of tarsus covering almost the entire cornea.4 This fold is fused to the underlying keratinized cornea along the entire length and width of the fold and may or may not extend downward to
fuse with the lower eyelid. This abnormal fold does not cover the entire eye, hence the partial or incomplete designation in François’ clinical observations. These patients usually have a deceptively insignificant upper eyelid coloboma because the colobomatous part of the eyelid is partly replaced by the oversized skin fold.4 There may be a rudimentary presence of the lateral eyelid structures and conjunctival fornix, which is almost a constant feature in incomplete CO and in CSV even in its most severe forms.41,48 A small lip of normal rudimentary upper eyelid may be present nasally, together with a functioning upper punctum and canaliculus.4 The inferior fornix may or may not be spared depending on the inferior extent of the abnormal skin fold. Patients with incomplete CO may have microphthalmic eyes or eyes that are of normal size echographically. Incomplete CO is the rarest of the three subtypes and is usually unilateral.49
fuse with the lower eyelid. This abnormal fold does not cover the entire eye, hence the partial or incomplete designation in François’ clinical observations. These patients usually have a deceptively insignificant upper eyelid coloboma because the colobomatous part of the eyelid is partly replaced by the oversized skin fold.4 There may be a rudimentary presence of the lateral eyelid structures and conjunctival fornix, which is almost a constant feature in incomplete CO and in CSV even in its most severe forms.41,48 A small lip of normal rudimentary upper eyelid may be present nasally, together with a functioning upper punctum and canaliculus.4 The inferior fornix may or may not be spared depending on the inferior extent of the abnormal skin fold. Patients with incomplete CO may have microphthalmic eyes or eyes that are of normal size echographically. Incomplete CO is the rarest of the three subtypes and is usually unilateral.49
 FIGURE 29.2 Incomplete cryptophthalmos. A, The patient has a deceptively insignificant upper eyelid coloboma because the colobomatous part of the eyelid is largely replaced by the oversized skin fold. The lateral eyelid structures are normal, and the medial lip of the upper eyelid including the lacrimal system is also preserved. The concealed part of the cornea is mostly keratinized, and the prognosis for functional reconstruction/visual development is dismal. B, The lateral eyelid structures are also preserved but the lacrimal system is absent because the abnormal skin fold in this patient also involves the medial part of the upper eyelid. |
In patients with CSV (Figure 29.3), which is also referred to as abortive CO or partial CO, the upper eyelid skin is deficient and its remnants are visibly adherent to the globe, hence the decades old designation “congenital symblepharon.” The lower eyelid is usually spared, and corneal involvement depends on the extent and severity of CPAs.48 Subramanian et al subclassified CSV into mild, moderate, and severe grades based on the extent of the coloboma and the severity of corneal adhesions,48 and the defect may indeed range from a minor notch in the eyelid margin associated with minimal CPA overlying the coloboma or even adhesions confined to the limbus to patients in whom there is a near-total eyelid colobomatous defect with extensive involvement of the cornea. The term CSV is a relic of late-nineteenth-century medicine50 and possibly should be abandoned as it may erroneously imply that in the other two varieties (complete and incomplete CO), the cornea is spared or is at least less affected than in CSV. However, CPA is a universal finding in all three types of CO, without which the diagnosis should be called into question. The extent of CPA is less in CSV than in complete or incomplete CO where the conjunctival sac may be absent.41,47 It should be remembered that prior to eyelid fusion, the corneal epithelium is fused with the surface ectoderm,51 and only after eyelid fusion do they separate and the cornea takes its normal developmental course. Consequently, by definition, a patient with CO will not have a normal cornea at least in the area of the cornea corresponding to the CPA.4
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
