Chapter 18 Developmental anomalies of the lids

NORMAL DEVELOPMENT AND ANATOMY OF THE EYELIDS

CLINICAL EVALUATION OF THE EYELIDS

DEVELOPMENTAL ANOMALIES OF THE PERIORBITAL REGION

ABNORMAL ASPECT OF THE INNER CANTHUS

MAJOR MALFORMATIONS OF THE EYELIDS

ABNORMAL PALPEBRAL FISSURES

ABNORMAL POSITION OF THE EYELIDS

PTOSIS

EYEBROWS AND EYELASHES

SPARSE OR ABSENT EYEBROWS AND/OR EYELASHES

DYSMORPHOLOGY DATABASES AND GENES INVOLVED IN SYNDROMES WITH EYELID ANOMALIES

REFERENCES

Major developmental anomalies create significant medical problems.¹ They often require specific surgical or medical management. Minor anomalies are features that vary from those commonly seen in the normal population; they do not cause increased morbidity. Major anomalies are not a variation of the normal spectrum. Developmental anomalies of the eyelids can belong to both categories. They can be isolated or observed in a syndromic context.

Single developmental anomalies are divided into four categories:²

1. A deformation is caused by an abnormal external force (usually, but not always) before birth, that results in an abnormal growth or formation of a body part.

2. A disruption occurs when a normally growing region is disrupted by some process, such as anoxic necrosis. Usually, disruptions and deformations are isolated and not associated with multiple congenital anomalies.

3. A malformation is an abnormal development of a body part due to an underlying genetic, epigenetic, or environmental or stochastic factor that alters normal development.

4. A dysplasia is an alteration of an intrinsic cellular architecture that can appear, or evolve with time (by opposition to a malformation). Malformation and dysplasia are not mutually exclusive: a malformation can be underlined by a tissue dysplasia.

When several developmental anomalies are present, three situations are defined:

1. An association is a group of anomalies that occur more frequently together than expected by chance, but which do not have a unified underlying etiology. Many associations described in the literature are syndromes (such as the CHARGE “association”).

2. A sequence is a group of anomalies that stem from a single major anomaly that alters the development of other surrounding or related tissues or structures. The term “field defect” describes malformations of distinct anatomic structures located in a particular region of the body.

3. A syndrome is a well-characterized constellation of major and minor anomalies that occur together in a predictable fashion, presumably due to a unique underlying etiology that may be monogenic, chromosomal, mitochondrial, or teratogenic in origin. A syndrome is clinically defined, and several distinct etiologies may be causative (e.g. Bardet-Biedl syndrome can be caused by more than 16 different gene defects).

Normal development and anatomy of the eyelids

Embryology of the eyelids

Development of the eyelids is characterized by three main stages:

1. Initial development

2. Fusion

3. Final reopening.

Morphology and anatomy of the eyelids

The eyelids have several characteristic horizontal and vertical folds.

The most conspicuous is a well-demarcated horizontal skin crease 3–4 mm above the upper lid margin, which flattens out on depression and becomes deeply recessed when the upper lid is elevated. It divides each lid into an orbital and tarsal portion. The orbital portion lies between the margin of the orbit and the crease; the tarsal portion lies in direct relationship to the globe. A tarsal plate composed of dense connective tissue is found in both the upper and lower eyelids. The upper lid tarsal plate has a marginal length of 29 mm and is 10–12 mm wide. The lower lid tarsal plate is 4 mm wide.

The palpebral fissure is the entrance into the conjunctival sac bounded by the margins of the eyelids; it forms an asymmetrical ellipse that undergoes complex changes during infancy.⁴ After birth, the upper lid has its lowest position with the lower eyelid margin close to the pupil center. Between ages 3 and 6 months, the position of the upper lid reaches its maximum. The distance between the pupil center and the lower eyelid margin increases linearly until age 18 months.⁴ By adulthood, the upper eyelid covers the upper 1–2 mm of the cornea, the lower lid lies slightly below its inferior margin.⁵ Palpebral fissures have a slight outer-upward inclination as the outer canthus is positioned 1 or 2 mm higher than the inner canthus. The normal orientation of the eyelids varies depending on ethnic origin. Palpebral fissure length increases during normal development.⁶

The principal muscle involved in opening the upper lid and in maintaining normal lid position is the levator palpebrae superioris. Müller’s muscle and the frontalis muscle play accessory roles.

The levator palpebrae superioris arises as a short tendon blended with the origin of the superior rectus from the undersurface of the lesser wing of the sphenoid bone. The levator palpebrae superioris is innervated by branches from the superior division of the oculomotor nerve.

Müller’s muscle is a thin band of smooth muscle fibers 10 mm in width that arise on the inferior surface of the levator palpebrae superioris. It courses anteriorly, between the levator aponeurosis and the conjunctiva of the upper eyelid to insert into the superior margin of the tarsus. Branches of the sympathetic nerve innervate Müller’s muscle. The eyelid is indirectly elevated by attachment of the frontalis muscle into the superior orbital portions of the orbicularis oculi muscle. The frontalis muscle is innervated by the temporal branch of the facial nerve.

Clinical evaluation of the eyelids

Dysmorphology is the study of abnormal development. Guidelines were proposed by an international group for most dysmorphologic terms.⁷^–¹⁰

The clinical assessment of craniofacial features, including eyelid malformations, is based on the overall subjective qualitative clinical evaluation and on objective quantitative measurements. Qualitative anomalies are easy to define as present or absent. The frequency of a feature in the general population defined as a “variant” (present in more than 1% of people) must be distinguished from an “anomaly.” A number of anomalies useful in dysmorphology are quantitative. An objective definition of an abnormal phenotype requires knowledge of the normal variation of the trait (usually defined as ±2 SD (standard deviation) for any measurement) in a population. Some anomalies are subjective (e.g. “a coarse face”).

Morphologic measurements can be easily performed with a transparent ruler. The measurements are compared to a normal database.⁵

Clinical landmarks

Many lid anomalies are correlated with an abnormal orbital structure. Hypertelorism and hypotelorism, for instance, influence the appearance of the eyelids. The normal distance between the orbits varies during embryogenesis and after birth in accordance with craniofacial development.

The embryonic separation of the globes (the angle between the optic nerves at the chiasm of the fetus) progresses from a 180° angle between the ocular axes in the first weeks of development to 70° at birth, 68° in adulthood ^11,¹² (Fig. 18.2A). The interorbital distance (the shortest distance between the inner walls of the orbits) increases with age¹³ (Fig. 18.2B). The most accurate interorbital measurements are obtained from X-rays (Waters half-axial projection, or posteroanterior cephalograms) or computed tomograms.¹⁴

Fig. 18.2 Evolution of the ocular axis and the inner interorbital wall during development of a human face. (A) Ocular axis from 180° for an 8-week-old embryo to 68° for a newborn (adapted from Zimmermann et al.⁸). (B) Evolution of the bony orbit: a face from a newborn compared to an adult.

Clinical evaluation of the interocular distances is based on the measurement of the following lid-based landmarks:¹⁵^–¹⁹

• Interpupillary distance

• Inner intercanthal distance

• Outer intercanthal distances

• Horizontal palpebral length.

An approximate “rule of thumb” is that the inner intercanthal distance should be equivalent to the palpebral length (Fig. 18.3).

Fig. 18.3 Normal interocular distances. “The rule of the thumb” in a 5-year-old child: inner intercanthal distance is equivalent to palpebral length (AB = BC = CD).

There are tables presenting the change in interocular distances according to age. The clinical method for assessing interocular distance is based on a biometric study that includes measurements of the inner intercanthal distance, the outer intercanthal distance, and the interpupillary distance in Caucasians from birth to 14 years. The normal intercanthal distance is 20 ± 2 mm (1 SD) at birth, increasing to 26 ± 1.5 mm by 2 years of age. The normal interpupillary distance is 39 ± 3 mm at birth, increasing to 48 ± 2 mm by 2 years of age.⁴

Ethnic variations of orbital features are important; comparison of newborns from England and Africa showed that the Caucasian and the African newborns had the same inner canthal distance, whereas the outer canthal distance and palpebral fissure length were significantly smaller in Caucasian newborns than in African newborns.²⁰

Normal growth curves for many physical parameters have been compiled by Hall et al.²¹

Eyelid developmental anomalies

Developmental anomalies of the eyelids include variable eyelid malformations. Systematic clinical eyelid evaluation is

based on:

1. Distances between the eyelids

2. General morphology of the eyelids

3. Palpebral fissures and slanting

4. Position of the eyelid, and

5. Evaluation of the eyebrows and eyelashes.

Developmental anomalies of the periorbital region

Abnormal distances between the eyelids and orbits

Conditions with abnormal distances between the eyelid landmarks are defined in Table 18.1 and schematically presented in Fig. 18.4.

Table 18.1 Conditions with abnormal spacing of the orbits and eyelids

Condition	Definition	Comments
Hypertelorism	Increased distance of the inner and outer intercanthal distances	1. Not only the increased inner intercanthal distance (a common mistake) 2. Exclude erroneous hypertelorism (misleading adjacent structures) in cases of: Flat nasal bridge Epicanthic folds Exotropia Widely spaced eyebrows Narrow palpebral fissures Isolated dystopia canthorum
Hypotelorism	Reduced distance between the medial walls of the orbits with reduced inner and outer intercanthal distances	Exclude illusory hypotelorism in cases of: Esotropia Closely spaced eyebrows
Telecanthus	Increased distance between the inner canthi	Often mistaken as hypertelorism
	Primary telecanthus: increased distance between the inner canthi (normally spaced outer canthi and normal interpupillary measurement)
	Secondary telecanthus: increased inner canthi distance (associated with ocular hypertelorism)
Dystopia canthorum	Similar to secondary telecanthus (telecanthus) together with lateral displacement of the lacrimal puncta	Clinical tip: an imaginary vertical line passing through the lacrimal punctum cuts the cornea

Fig. 18.4 The spectrum of abnormal distances between the eyes from cyclopia to hypertelorism.

Appreciation of the interocular distance is biased by the shape of the nasal bridge between the glabella and the inferior boundary of the nasal bone on a vertical axis, and between the inner canthi on a horizontal axis. Excessive interocular distance can be falsely suggested by a flat nasal bridge; prominent nasal bridges can give a false appearance of hypotelorism.

Hypertelorism

Hypertelorism corresponds to an interpupillary distance of more than 2 SD above the mean. It results from excessive distance between the medial wall or bony orbits. Hypertelorism occurs in more than 550 disorders (Figs 18.5 and 18.6) and is often subjectively appreciated and confused with telecanthus. Three pathogenic mechanisms have been suggested:¹³

1. The early ossification of the lesser wings of the sphenoid, fixing the orbits in fetal position

2. The failure of development of the nasal capsule, allowing the primitive brain vesicle to protrude into the space normally occupied by the capsule, resulting in morphokinetic arrest in the position of the eyes as in frontal encephalocele (see Chapter 56)²²

3. A disturbance in the development of the skull base as in craniosynostosis syndromes (i.e. Crouzon’s or Apert’s syndromes) or in midfacial malformations such as frontonasal dysplasia.

Fig. 18.5 Hypertelorism in Optiz’ syndrome (esophageal abnormalities, hypospadias, and other midline defects).

(Image courtesy of Clinique Ophthalmologique des Hôpitaux Universitaires de Strasbourg.)

Fig. 18.6 Hypertelorism in Coffin-Lowry syndrome (a mental retardation syndrome).

The widow’s peak (frontal hairline with bilateral arcs to a low point in the midline of the forehead) is a consequence of ocular hypertelorism: the two fields of hair suppression are further apart than usual with the fields failing to overlap sufficiently high on the forehead. Widow’s peak is common in disorders with major hypertelorism, such as Opitz G/BBG syndrome (OMIM#145410).

Telecanthus and dystopia canthorum

Telecanthus is defined as a distance between the inner canthi more than 2 SD above the mean for age, sex, and ethnicity. It is common and often associated with hypertelorism. Dystopia canthorum is a specific feature of Waardenburg’s syndrome (WS) type 1 ²³ (Fig. 18.7), where telecanthus results from abnormal outward displacement of the inner canthi relative to the ocular globe. This condition is an autosomal dominant syndrome with variable expressivity, characterized by:

1. Dystopia canthorum with a broad nasal root

2. Poliosis and a white forelock

3. Heterochromia irides, and

4. Sensorineural hearing loss.²⁴

Fig. 18.7 Telecanthus and dystopia canthorum. A teenager with Waardenburg’s syndrome. Note that an imaginary vertical line at the level of the puncta cuts the cornea.

WS type 2 differs from WS type 1 by the absence of dystopia canthorum. Type 3 is the homozygous state of type 1 with limb anomalies; type 4, a genetically heterogeneous, autosomal dominant or autosomal recessive disorder, is associated with Hirschsprung’s disease.²⁵

Hypotelorism

Hypotelorism is an interpupillary distance more than 2 SD below the mean. Hypotelorism occurs in more than 60 syndromes (Fig. 18.8). It can result from premature closure of the metopic sutures resulting in vertical frontal ridge, up-slanted palpebral fissures and hypotelorism.²⁶

Fig. 18.8 Hypotelorism in a child with holoprosencephaly.

(Courtesy of Pr Sylvie Odent.)

Hypotelorism can also result from insufficient development of the brain hemispheres, as in holoprosencephaly. Holoprosencephaly is a rare brain anomaly, frequently associated with facial anomalies (see Chapter 56).^27,²⁸ It results from an early abnormal formation of the telencephalic vesicles: they remain partially or totally fused. Holoprosencephaly usually leads to underdevelopment of middle facial structures. Severity of midfacial anomalies usually correlates with the severity of the underlying brain malformation,^29,³⁰ forming a spectrum that goes from:

• A single median orbit with fused eye globes (cyclopia with or without synophthalmia), to

• Nasal and premaxillary agenesis, to

• A single central maxillary incisor with hypotelorism (see Table 18.1).

Holoprosencephaly may be due to environmental/maternal factors (such as maternal diabetes), chromosomal abnormalities (trisomy 13, 18q deletion), or single gene defects ³¹ (Table 18.2).

Table 18.2 Gene identification in syndromes with developmental eyelid anomalies cited in this chapter (updated August 2011)

Abnormal aspect of the inner canthus

Epicanthus palpebralis

Epicanthus palpebralis (or epicanthal fold) is a vertical cutaneous fold arising from the nasal root and directed toward the internal part of the upper lids (Fig. 18.9). It can be subdivided into the areas where they occur such as preseptal, pretarsal, or orbital. The fold may cover the inner canthus. It is normal in fetuses of all ethnic origins and common in young children with a flat nasal bridge. Epicanthus palpebralis is a normal feature in many populations, mostly Asians. It is common in syndromes where the nasal bridge is flat, such as trisomy 21. Epicanthus often vanishes with age.

Fig. 18.9 Epicanthus. (A) Superciliaris; (B) palpebralis (most frequent); (C) tarsalis (“Asian epicanthus”); (D) inversus (blepharophimosis–ptosis– epicanthus inversus syndrome). (E) Epicanthus in the straight-ahead position. This child can be seen to have a broad base to his nose and mild epicanthus. In the straight-ahead position his eyes appear straight. (F) On looking right the adducting eye appears to be convergent, giving rise to a pseudosquint.

Epicanthus inversus

Epicanthus inversus is a fold of skin starting at the medial aspect of the lower lid and arching upward to cover the medial canthus (see blepharophimosis; Chapter 19). It is the hallmark of the blepharophimosis–ptosis–epicanthus inversus syndrome (BPES).

Major malformations of the eyelids

Ablepharon

Ablepharon is the absence of lids. It occurs in several settings:

1. Neu-Laxova syndrome – with intrauterine growth retardation, syndactyly, swollen “collodion” skin, microcephaly, and severe developmental brain defects.³²

2. Autosomal dominant ablepharon-macrostomia syndrome – absent or rudimentary eyelids,³³ a hypoplastic nose, ambiguous genitalia, absent zygoma, and macrostomia with possible familial recurrence³⁴ (Fig. 18.10).

3. Say-Barber syndrome ³⁵ – hypertrichosis of the back, macrostomia, microblepharon, ectropion, and sometimes ablepharon. It could be allelic to ablepharon-macrostomia syndrome.

Fig. 18.10 Bilateral ablepharon. Ablepharon-macrostomia syndrome.

(Image courtesy of Dr A. A. Cruz.)

Cryptophthalmos (see Chapter 17)

Cryptophthalmos is rare: there is failure of development of the eyelid folds with continuity of the skin from the forehead to the cheek.^36,³⁷ In complete cryptophthalmos, the epithelium that is normally differentiated into cornea and conjunctiva becomes part of the skin that passes continuously from the forehead to the cheek. The eyebrow is usually absent and the globes are microphthalmic. In the incomplete form, a rudimentary lid and conjunctival sac is present. Abortive cryptophthalmos presents with a normal lower lid and an absent or abnormal upper lid, the forehead skin passing directly to and fusing with the superior cornea (Fig. 18.11).

Fig. 18.11 Cryptophthalmos. Unilateral partial abortive cryptophthalmos (symblepharon): the upper lid is fused to the eye.

Cryptophthalmos may be an isolated finding or present as part of Fraser’s syndrome.³⁶ Fraser’s syndrome is a rare autosomal recessive syndrome with cryptophthalmos, hypoplasia of the genitalia, laryngeal stenosis, and renal hypoplasia or agenesis.