Hospital for Sick Children's, The: Atlas of Pediatric Ophthalmology & Strabismus, 1st Edition

Ocular Manifestations of Systemic Disease



Alex V. Levin

Thomas W. Wilson

David Rootman

Elise Héon

Dermatologic diseases will often have an associated ophthalmic manifestation because of the common embryologic origin of the ocular structures and the skin. The skin and ocular surface are both of ectodermal origin. The skin covering the eyelids, the lashes, all eyelid glands, the lacrimal gland, the conjunctival epithelium, and the corneal epithelium are all derived from surface ectoderm. The lens of the eye is also a surface ectoderm derivative. Dermatologic disease involving the periorbital skin area can cause secondary abnormalities of the ocular surface. Skin diseases affecting the mucous membranes such as Stevens-Johnson syndrome will often have ocular manifestations as conjunctiva is a mucous membrane. The ectodermal dysplasias are a group of rare genetic diseases with a wide clinical spectrum involving skin, eyes, teeth, hair, nails, and sweat glands. Ocular manifestations may include corneal surface disease, conjunctival disorders, lid abnormalities, or cataract.

Skin pigment is derived from melanosomes, which originate as neural crest cells. Likewise, the melanocytes of the uveal tract are also neural crest descendants. Melanosomes are also found in the retinal pigment epithelium, a neuroectodermal derivative, where pigmentation is required for normal development of the overlying retina. Oculocutaneous albinism refers to those disorders in which deficiency of melanin or melanosomes manifests in both skin and eye. Ocular albinism refers to an isolated ocular hypopigmentation disorder.

Dermatologic treatments can also cause ocular side effects. Steroid creams can cause an increase in intraocular pressure and lead to glaucoma cataracts. Systemic tetracycline used to treat acne can cause pseudotumor cerebri. The retinoids are natural and synthetic compounds that produce similar effects to vitamin A and can also cause pseudotumor cerebri.

There are numerous other examples of combined dermatologic and cutaneous manifestations, many of which are covered elsewhere, such as the phakomatoses (Chapter 23), rheumatologic disorders such as lupus (Chapter 27), and skeletal disorders such as pseudoxanthoma elasticum (Chapter 28). This chapter will focus on disorders that are primarily dermatologic and that have associated involvement of the oculofacial regions.



Figure 15.1 Ectrodactyly–Ectodermal Dysplasia (EEC Syndrome)

The predominant features of this autosomal dominant syndrome are ectrodactyly (shown here), ectodermal dysplasia, and cleft lip/palate. When associated with urinary tract abnormalities, the syndrome is named EEC-UT. Other manifestations include oral and facial abnormalities, dry eye, and hypohidrosis. Patients have absence of eyelashes, thin hair and eyebrows, and decreased skin pigmentation. Meibomian glands are decreased or absent, leading to corneal vascularization and scarring. The lacrimal punctum may be small or absent. Aggressive tear replacement therapy is necessary to maintain normal ocular surface and reduce photophobia. Retinal detachment may also occur. One variant is the rare autosomal recessive association of ectodermal dysplasia and macular dystrophy: Ectrodactyly–ectodermal dysplasia–macular dystrophy (EEM) syndrome.


Figure 15.2 Incontinentia Pigmenti (Bloch-Sulzberger Disease)

Incontinentia pigmenti is an X-linked dominant disorder that is almost always lethal in males. It is caused by mutations in the NEMO gene at Xq28 with another locus postulated for the disorder at Xp11. The cutaneous lesions, which are distributed along the lines of Blaschko, evolve from an early bullous phase with erythematous papulosquamous lesions (left image) to a hyperkeratotic verrucous stage, followed by swirling and patchy hyperpigmentation (right image) with or without hypopigmentation, atrophy, and scarring in its later stages. Neurologic features include seizures and mental retardation. (The authors are grateful for the contributions of Dr. Christopher Cessna to this legend.)


Figure 15.3 Incontinentia Pigmenti (Bloch-Sulzberger Disease)

Ocular manifestations are often asymmetric and include peripheral retinal avascularity similar to that seen in retinopathy of prematurity (Chapter 8: Retina and Vitreous, Figs. 8.6, 8.7, 8.8, 8.9, 8.10, 8.11, 8.12, 8.13, 8.14, 8.15, 8.16, 8.17, 8.18, 8.19, 8.20, 8.21, 8.22and 8.23) with retinal ischemia inducing neovascularization and bleeding/exudation. The findings are usually worse temporally. Milder cases may only show straightening of the far temporal peripheral retinal vessels. Temporal dragging of the macular vessels is an ominous sign. If a child is fully vascularized without leakage or traction on first examination, then he or she will not develop retinopathy.




Figure 15.4 Incontinentia Pigmenti (Bloch-Sulzberger Disease)

In cases of retinopathy, progression to traction retinal detachment can be rapid. Careful periodic follow-up is essential. Other reported signs include optic atrophy, foveal hypoplasia, microphthalmos, cataracts, conjunctival pigmentation, iris hypoplasia, uveitis, nystagmus, strabismus, and whorllike epithelial keratitis. Dental abnormalities are seen in greater than 80% of cases and include absent teeth and conical teeth with supplemental cups.


Figure 15.5 Hypomelanosis of Ito

Patients with hypomelanosis of Ito present with cutaneous abnormalities consisting of hypopigmented patches and streaks. (right image) Brain migration disorders are common and result in brachycephaly and micropolygyria. Ophthalmic manifestations include coloboma, iris heterochromia, microphthalmia, and choroidal atrophy. (left image) Biopsy of affected skin may show mosaicism for one of the many reported associated chromosomal aberrations. This girl had congenital glaucoma, developmental delay, and a mosaic isochromosome 8.


Figure 15.6 Xeroderma Pigmentosa

Xeroderma pigmentosum is a rare disorder that is characterized by skin atrophy, telangiectasia, mottled hypopigmentation and hyperpigmentation, and scarring in the early years of life, and has a high rate of malignant transformation as a result of abnormal repair of DNA damaged by ultraviolet light. Multiple genes have been identified, which are usually inherited in an autosomal recessive pattern. Ophthalmic manifestations are very common, with photophobia and conjunctivitis being the earliest findings, with the later development of blepharitis, symblepharon, madarosis, entropion, ectropion, trichiasis, symblepharon, ankyloblepharon, xerosis, pinguecula, and malignancy. Corneal neovascularization, ulceration, and opacification, along with iris inflammation and atrophy and synechia formation, can also occur. Patients have a higher risk of developing internal tumors. (The authors are grateful for the contributions of Dr. Rupan Trikha to this legend.)




Figure 15.7 Ichthyosis

Ichthyosis comprises a large variety of genetic disorders with abnormal differentiation and desquamation of the epidermis leading to thickening (hyperkeratosis), fissuring, and scaling of the skin. Severity and extent can vary tremendously, ranging from dry skin (left image, note mild ectropions) to more severe desquamation (right image, lamellar ichthyosis) or even a life-threatening multisystem disorder. Ocular manifestations include corneal opacities, conjunctivitis, and keratitis. The nails and hair may also be involved. Keratitis, ichthyosis, and deafness (KID) syndrome is one rare variant. (The authors are grateful for the contributions of Dr. Nick Ulrich to this legend.)


Figure 15.8 Ichthyosis

One severe form of ichthyosis presenting in the neonatal period is the collodion baby syndrome, in which the child may have severe desquamation and a cicatricial, almost glistening tight membrane covering the entire body. Congenital ectropion, as shown here (left image), may occur. With resolution, the child can be left with hypertrophic, atrophic, and scarred skin with variable pigmentation(right image). Hyperkeratosis of the palms, soles, and feet as well as abnormal nails and hair also may occur. Possible treatment options include systemic retinoids (vitamin A preparations) for cutaneous symptoms and topical cyclosporine for vascularizing keratitis.


Figure 15.9 Epidermolysis Bullosa

Epidermolysis bullosa (EB) describes a group of conditions associated with abnormalities of the epidermal basement membrane and mucous membranes. It is typically genetically determined. The characteristic features are skin and mucosal fragility. A tendency to blister occurs after even minor trauma. The involvement of the eye with conjunctival and corneal blistering can lead to progressive scarring with reduced vision and even blindness. There are several genetic subtypes: Dystrophic, junctional, and simplex. Within subtypes clinical variability has been observed. The more severe variants, as shown here, can be associated with scarring, fusion of neighboring areas of skin, and even loss of tissue. This girl suffers from repeated episodes of large corneal abrasion after minimal or no trauma. (The authors are grateful for the contributions of Dr. Wells Reinheimer to this legend.)




Figure 15.10 Erythema Multiforme (EM)/Stevens-Johnson/Toxic Epidermal Necrolysis

EM refers to a self-limited, mucocutaneous hypersensitivity reaction that classically presents with a sudden onset of a papular, erythematous rash, with symmetrical distribution and centripetal spread. These cutaneous lesions evolve into target lesions. More severe immunologic responses result in Stevens-Johnson syndrome or toxic epidermal necrolysis. The mucous membranes are particularly involved, including the oropharynx and conjunctiva. Skin desquamation is seen in response to minimal trauma (Nikolsky sign). No genetic predisposition or specific cause has been identified, but many potential triggers have been associated, including herpes viruses, adenovirus, Coxsackie virus, mycoplasma, and many prescribed drugs. (The authors are grateful for the contributions of Dr. Rupan Trikha to this legend.)


Figure 15.11 Stevens-Johnson Syndrome

Destruction of conjunctival goblet cells leads to severe keratitis sicca (dry eye, right image) with the characteristic formation of adhesions between the inside surface of the eyelids (palpebral conjunctiva) and the bulbar conjunctiva or cornea. These symblepharons(left image) portend a poor prognosis, and patients may go on to severe vascularized and keratinized corneal scarring, for which even heroic surgery is often not successful in restoring vision. Daily examination during the acute phase of the illness, possibly with the lysing of early symblepharon, copious lubrication, and in some cases topical steroid use, may reduce the incidence of poor outcomes.


Figure 15.12 Atopic Dermatitis/ Eczema

Atopic dermatitis/eczema describes a chronic, relapsing, pruritic skin condition with clinical features of xerosis, inflammation, scaling, and lichenification. Flexor surfaces of extremities are most commonly involved. Involvement of the lids and adnexa may lead to chronic eye rubbing and surface irritation. The pathogenesis is unknown, but elevated immunoglobulin E levels and eosinophilia are found in most patients. Patients may have other atopic signs including asthma and seasonal allergy and may present within the first 3 to 6 months of life. In more severe cases, punctual stenosis, weeping fissures at the lateral canthi, conjunctival papillae, symblepharon, entropion, trichiasis, punctuate keratitis, and even corneal ulceration, vascularization, and opacification may occur. Atopic dermatitis is also associated with anterior subcapsular cataract and keratoconus. (The authors are grateful for the contributions of Dr. Nick Ulrich to this legend.)




Figure 15.13 Contact Dermatitis

Contact dermatitis is an acute, sometimes patterned response to a local topical irritant. Often the offending substance is never discovered. The response can be very pruritic and may be characterized by edema, erythema, and vesicle formation. Although the appearance may be similar to herpes, the absence of pain helps to differentiate contact dermatitis. This child was evaluated and treated for zoster infection (Chapter 19: Infectious Diseases, Fig. 19.7) before it was recognized that this was a response to a new hair gel.


Figure 15.14 Albinism—Iris Transillumination

Albinism is a group of disorders characterized by abnormalities in pigmentation. The involvement of the eye and the skin can be variable. Patients often present with nystagmus in the first several months of life and decreased vision. The cardinal ocular finding is iris transillumination, which may range from a few punctate dots to a severity that is grossly apparent, as seen here, with the lens edge visible through the iris (arrow). Iris transillumination can also be seen following trauma or infection (e.g., herpes) and in some congenital malformations of the anterior segment, but its presence otherwise indicates that the patient either has or carries a gene mutation for albinism.




Figure 15.15 Albinism—Retina

Almost all patients with albinism have some degree of macular hypoplasia and fundus hypopigmentation. Both are due to a deficiency of melanin in the retinal pigmented epithelium. The abnormal macular development results in a poorly differentiated vascular pattern such that the typical normal arc of the temporal superior and inferior arcades may not be recognizable and vessels encroach upon or even cross what would be the foveal avascular zone. In the right image, it is almost impossible to tell if this is a right or left eye due to the undifferentiated vascular pattern.


Figure 15.16 Albinism—Retina

The pigmentary deficiency becomes more apparent peripherally where the deficiency of choroidal melanocyte pigmentation and absence of other macular pigments (e.g., lipofuscin) results in a direct view of the sclera with the exception of retinal and choroidal vessels. The optic nerve may be gray and small. Multichannel visual-evoked potential usually shows abnormal decussation of the visual pathways such that there is an overabundance of fibers crossing to the contralateral side of the brain.


Figure 15.17 Oculocutaneous Albinism Type 1A (OCA1A)

Oculocutaneous albinism is characterized by the presence of variable skin hypopigmentation, the degree of which depends on the molecular genetic defect involved. The rate-limiting step in melanin synthesis is dependent upon tyrosinase, the first step in tyrosine metabolism. Autosomal recessive mutations in the tyrosinase gene result in OCA type 1. The term “tyrosinase negative” is no longer used. Complete absence or severe deficiency of tyrosinase results in a markedly hypopigmented phenotype (OCA1A), with no visible pigmentation and severe ocular involvement. Vision is usually in the range of 6/60 or worse. Patients have snow white hair and extremely fair skin throughout their lifetime without any increased pigmentation. These patients are susceptible to sun damage and skin cancer.




Figure 15.18 Oculocutaneous Albinism Type 1B (OCA1B)— Yellow Variant

Oculocutaneous albinism type IB is due to specific mutations in the tyrosinase gene that reduce its function but do not create null alleles. Reduced production of the products of tyrosinase leads to a shunting of the metabolic pathway away from the production of the darker pigments (eumelanins) toward the production of the more yellow pigments (pheomelanins). Patients are typically born with white hair and skin, but develop some moderate amounts of pigmentation with age. While doing so the hair goes through a typical “white tipped” phase. In the yellow variant (OCA1B) the hair may develop a yellow or light brown color with fair skin and moderate reductions in visual acuity. Nystagmus and iris transillumination are present but the macular hypoplasia and nystagmus are not as severe as seen in OCA1A.


Figure 15.19 Oculocutaneous Albinism Type TS (OCA TS)— Temperature Sensitive

Temperature-sensitive OCA results from a specific temperature-sensitive tyrosinase mutation that renders the enzyme nonfunctional only in the areas where the temperature is elevated: The groin, scalp, and axillae. On the cooler chest and extremities, the enzyme is fully functional and the hair color is dark. As the eyes are placed within the head, they are subjected to warmer temperatures, resulting in ocular findings similar to OCA1A. Notice white axillary hair (left image) in contrast to darker forearm hair (right image).




Figure 15.20 Oculocutaneous Albinism Type 2 (OCA 2)

Oculocutaneous albinism type 2 is secondary to an abnormality in the p gene located on chromosome 15q11. This gene appears to play a role in transport across the melanosome membrane. Previously these patients were labeled as “tyrosinase positive” because of the normal levels of tyrosine on incubated hair bulbs. But some tyrosinase-related forms of OCA are phenotypically indistinguishable from OCA2. Infants with OCA2 may present in infancy with a similar appearance to OCA1A (Figure 15.17). However, they acquire greater amounts of pigment in early childhood, largely pheomelanins. Vision is less severely affected than with OCA1. There are a wide variety of OCA2 phenotypes, including “brown albinism” and albinism with ephelides.


Figure 15.21 Hermansky-Pudlak Syndrome

Hermansky-Pudlak syndrome is a combination of oculocutaneous albinism of variable severity, bleeding diathesis, and, in some patients, accumulation of ceroidlike material. This disorder is an autosomal recessive trait and most prevalent in Puerto Rico and Switzerland. Multiple causative genes are known, all of which share in common a role in the formation and trafficking of intracellular vessels, which include melanosomes, lysosomes, and platelet-dense bodies. The pigmentary and ocular phenotype is very variable. The bleeding diatheses are secondary to decreased aggregation of platelets. The platelet aggregation defect manifests as easy bruising (seen here), epistaxis, and gingival bleeding. Accumulation of ceroid lipofuscin material in the lungs and gastrointestinal tract can be life threatening. In this family portrait, the two brothers in the first row, center and right, are affected.


Figure 15.22 Chediak-Higashi Syndrome

Like Hermansky-Pudlak syndrome (Fig. 15.21), Chediak-Higashi is an autosomal recessive form of oculocutaneous albinism caused by mutations in one of several genes involved with intracellular vesicular manufacture and function, including melanosomes. In this disorder, it is the intracellular vesicles of white blood cells rather than platelets that are affected and result in impaired neutrophil chemotaxis with a predisposition to infection. The hair has a characteristic metallic gray sheen and other features of mild oculocutaneous albinism are present. Other systemic manifestations include progressive peripheral neuropathy and a lymphohistiocytic proliferative phase. The clinical findings include white skin with a metallic sheen to the hair. The disorder may be fatal.




Figure 15.23 Ocular Albinism

Ocular albinism is most often an X-linked recessive disorder linked to Xp22 (OA1, Nettleship-Falls type). Less commonly, an autosomal recessive form of ocular albinism may be caused by mutations in the tyrosinase or p genes (Fig. 15.20). Patients with OA1 may have darkly pigmented hair and skin or be well pigmented less so than their average family member. Skin biopsy may show macromelanosomes (right image, arrow, electron microscopy), reflecting the role the OA1 gene is felt to play in melanosome biology. The ocular manifestations tend to be more variable.


Figure 15.24 Ocular Albinism Type 1 (OA1)—Carriers

As OA1 is an X-linked recessive disorder, females are carriers. As a result of lyonization, they will have clones of cells in their eye and skin that will be expressing the OA1 gene copy that is mutated while others use the normal allele. This can be seen clinically either via iris transillumination, the presence of hypopigmented skin macules (left image, lesion surrounded by arrows), or the “mud splattered” fundus (right image) reflecting interspersed cell populations of different pigmentation. However, it is very rare that a manifesting heterozygote has a clinical reduction in vision, nystagmus, or macular hypoplasia.


Figure 15.25 Albinoidism

Albinoidism describes a hypopigmented phenotype that is enough to cause a gross alteration in hair and skin color along with iris transillumination, but yet not enough to result in macular hypoplasia or significantly reduced vision. This patient has a well-developed fovea. Mild nystagmus may be present and sometimes the line of distinction between frank albinism and albinoidism may be difficult to discern. However, albinoidism is an autosomal dominant condition. Multichannel visual-evoked potential does not show an abnormal decussation of optic nerve fibers.




Figure 15.26 Piebaldism

Piebaldism presents with ventral amelanotic patches and, in some patients, a white forelock. The forehead, eyebrows, chin, chest, abdomen, and extremities may be affected. Iris heterochromia has been associated with this condition. Piebaldism is an autosomal dominant disorder. Causative mutations in the cKIT proto-oncogene (4q11-q12) results in a failure of neural crest melanocyte precursors to properly migrate into the affected areas. (Photograph courtesy of Dr. Bernice Krafchik.)


Figure 15.27 Molluscum Contagiosum

Molluscum contagiosum is a common DNA pox viral infection contracted by direct contact or via fomites. Characteristic discrete nodular lesions are approximately 2 to 4 mm and with a central umbilication and an underlying pearly white material that can be expressed but contains active virus. Giemsa stain reveals molluscum bodies (eosinophilic inclusion bodies on a basophilic cytoplasm). Lesions are common on the face, eyelids, neck, axillae, and thighs, often in linear streaks as a result of local spread through scratching. Lid margin involvement can lead to chronic ocular irritation due to virus shedding into the conjunctival sac. Patients can present with chronic follicular blepharoconjunctivitis and superficial punctate keratopathy. The virus can rarely directly involve the conjunctiva, causing molluscum lesions.


Figure 15.28 Granuloma Annulare

Granuloma annulare is a benign annular lesion commonly seen in children. Initially the lesions consist of a small erythematous nodule on the surface of the skin. These lesions spread circumferentially to form an erythematous ring with a discolored center. They most commonly occur on the dorsal surface of the hands and feet but can involve the periorbita. Pathologic examination shows a classic granuloma with areas of central necrosis, deposition of mucin, and peripheral foreign body giant cells and histiocytes. Granuloma annulare can easily be differentiated from tinea corporis by its absence of scales. Spontaneous involution may occur after several months to years. Topical or subcutaneous corticosteroids may shorten the duration.




Figure 29 Juvenile Xanthogranulomatosis

Juvenile xanthogranulomatosis is characterized by firm, dome-shaped, orange lesions (A) that evolve from small macules and papules. Benign histiocytic infiltration characterized by lipid-laden histiocytes, inflammatory cells, and Touton giant cells is seen microscopically. Lesions typically resolve over several years. Involvement of the heart, kidneys, skeletal system, gonads, and salivary glands is uncommon. Ocular manifestations include iris (B), ciliary body, or choroid (C) lesions. Patients may present with spontaneous hyphema under which is a small iris xanthogranuloma. Differential diagnosis must include retinoblastoma. Steroids can be used to reduce the inflammatory component and help reduce vision-threatening complications.


Figure 15.30 Linear Nevus Sebaceum (Nevus of Jadassohn)

Linear nevus sebaceum usually occurs on the face and is associated with ocular malformations in approximately one half of cases including microphthalmia, choristomas, and coloboma of the lids and/or iris/choroid/optic nerve. The most common ocular abnormality is conjunctival choristoma. This skin lesion is also associated with seizures and mental retardation. It is perhaps a type subset of epidermal nevus syndrome. Patients may also have cardiac, renal, and skeletal abnormalities. The skin lesions are enlarged and very yellow at birth, as the infant's sebaceous glands are activated by maternal hormones. They then regress but often reactivate during puberty. Patients are at risk for benign and malignant tumors developing in the lesions. Treatment may involve observation or surgery.