central areas contain intracytoplasmic ‘molluscum bodies’, which may enter the tear film. As such, the presenting symptom is often a follicular conjunctivitis. Symptomatic patients or those at risk for corneal injury benefit from surgical excision.

Verruca vulgaris, or a wart, is caused by the human papillomavirus and can be seen on the eyelid. Similar to molluscum, lesions near the lid margin may cause a secondary conjunctivitis. Most cases are also self-limiting, but those that persist can be surgically removed with or without cryotherapy.

Allergic conjunctivitis

The most common cause of chronic conjunctivitis is allergy. The eyelid may show secondary lichenification or scaling dermatititis in such cases. Allergic conjunctivitis in children may be due to vernal or perennial causes.

mandates a careful ophthalmologic examination and may reveal underlying pathology not seen at the skin surface.

Summary

Pathology of the human eyelid can affect the development of vision in several ways. Various congenital syndromes include eyelid malformations as part of the constellation of findings. Tumors involving the eyelid or orbit can potentially be fatal. Trauma to the eyelid may indirectly result in subsequent injury to the eye, surrounding structures, or lacrimal system. Infectious etiologies require prompt recognition and follow-up before central dissemination occurs. As such, careful evaluation of the eyelids and ocular adnexa is a key component in ophthalmic evaluation of a child and may demonstrate the sentinel signs of visual compromise or systemic disease.

•Introduction

•Cystinosis

•Marfan’s syndrome

•Homocystinuria

•Wilson’s disease

•Fabry disease

Introduction

Ocular abnormalities may primarily involve the eye or represent findings secondary to systemic disease. In either case, ocular disease can negatively impact on vision and the quality of life. Because the internal anatomy of the eye may be easily and rapidly evaluated, an ocular examination should always be included in the assessment of the pediatric patient. A delay in diagnosis of the ocular component of systemic diseases may be significant, resulting in permanent vision loss and also compromising

•Osteogenesis imperfecta

•The mucopolysaccharidoses

•Sickle cell disease

•Albinism

•Congenital rubella

the early academic years. At times, even a prompt diagnosis will not ensure a good outcome, as there may be few therapeutic options available to improve vision. In severe cases, we may be limited to prescribing proper visual aids, guiding parents to select the scholastic path that will best meet their child’s needs, and also helping them to manage the implications of their child’s visual disability. It is therefore imperative to maintain good communication between the pediatrician and ophthalmologist in order to optimize the proper medical care of these children.

Cystinosis

DEFINITION/OVERVIEW AND ETIOLOGY

Cystinosis, first described in 1903 by Abderhalden,1 is a generalized lysosomal storage disease caused by mutations in the CTNS gene, which codes for cystinosin.2–4 Cystinosin is a lysosomal carrier protein that transports cystine out of the lysosome. There are three clinical phenotypes that are identified by the age of onset of symptoms: nephropathic (infantile), intermediate (adolescent onset), and benign (adult onset).

The most common and the most severe is the nephropathic (infantile) form. Infants are asymptomatic at birth. At about 6 months of age, affected infants develop anorexia, vomiting, polyuria, constipation, and failure to thrive. This is accompanied by a renal Fanconi syndrome with normoglycemic glycosuria, generalized aminoaciduria, and proteinuria. Hypophosphatemia, hypokalemia, hyponatremia, and metabolic acidosis are also related to the renal tubular dysfunction. Endstage renal disease (ESRD) usually occurs between the ages of 6 and 12 years. Kidney transplantation results in resolution of the renal Fanconi syndrome. Late symptoms that have become more apparent due to increased survival with the advent of cysteamine therapy include ocular complications, hypothyroidism, gonadal dysfunction (more common in males), insulindependent diabetes due to abnormal endocrine pancreatic function, hepatomegaly, splenomegaly, generalized muscle weakness and atrophy, seizures, and central nervous system (CNS) involvement (i.e. hypotonia, swallowing difficulties, speech difficulties, pyramidal signs, cerebellar signs, and progressive intellectual deterioration).

Intermediate (or adolescent) onset cystinosis is a milder form of the disorder that is characterized by later clinical onset and ESRD by about age 15 years. First symptoms appear between the ages of 6 and 8 years. It is much rarer than the infantile form. Extrarenal symptoms may not develop.

The adult onset (or benign) form is generally diagnosed after cystine crystals are identified in the cornea. The levels of cystine found in leukocytes are intermediate between those seen

in homozygotes and heterozygous individuals.5 Other systemic manifestations of the disease are not seen. Affected individuals are usually found to have one severe mutation (either a deletion or nonsense mutation) and a mild mutation such that some residual transport activity is present.6

Cystinosis is inherited in an autosomal recessive (AR) fashion. Ocular deposition of cystine crystals in heterozygous individuals has not been described, although leukocytes from heterozygotes have been found to have substantially increased intracellular levels of free cystine than those from unaffected individuals.7 Mutations in the CTNS gene result in an absent or abnormal membrane protein that is involved in cystine transport out of the lysosome. Diagnosis is made by measuring free cystine levels in white blood cells. This is a very specialized test requiring specialized handling. Mutation analysis is also clinically available.

Treatment is available in the form of both specific and supportive therapies. Treatment of renal symptoms is best performed by a nephrologist and includes following renal tubular losses with special attention to hydration status, acid–base status, electrolyte status, and phosphorus and calcium status. Carnitine supplementation is common to correct carnitine depletion. ESRD is treated with transplantation. Hypothyroidism is treated with levothyroxine and growth failure is treated with growth hormone. Hypersplenism with resulting thrombocytopenia or leucopenia may lead to splenectomy. Portal hypertension can develop and is treated by portal bypass.

Specific therapy with cysteamine bitartrate with monitoring of leukocyte cystine levels is beneficial and has been shown to slow development of the nephropathy. Ocular instillation of the medication has been described. The major difficulty with this treatment revolves around unpleasant sideeffects (nausea, vomiting, and unpleasant odors) and the need for frequent dosing.

CLINICAL PRESENTATION

Burki (1941) was the first to describe the pathognomonic crystal accumulation in the cornea and conjunctiva.8 This accumulation starts at birth and has been reported to be clinically evident by 16 months of age.9 It affects all layers of the cornea (243). The accumulation starts in the anterior peripheral surface of the

cornea and spreads centrally and posteriorly. The typical ground glass appearance of the cornea, which is observable by the naked eye, only becomes recognizable in older, untreated patients.10 Initially, corneal crystals are asymptomatic. Dureau et al. (2003) reported the appearance of photophobia secondary to this crystal deposition at a mean age of 7.7 years.11 They also reported that by age 10 most children complain of photophobia, which becomes severe after 15 years of age. Blepharospasm may also accompany the photophobia. Sneezing in response to bright light, also know as the ‘photic sneeze reflex’, has been observed in 26% of patients with nephropathic cystinosis.12 As the cornea becomes more infiltrated, patients can experience a superficial punctate keratopathy with foreign body sensation and pain.13 This typically does not occur until age 10 or greater. In children older than 15 years, recurrent erosions and corneal edema may occur, necessitating corneal grafting.13

Visual acuity is not usually affected by the presence of the corneal crystals and typically remains better than 20/40 unless there is an occurrence of corneal erosions, corneal edema, or retinal pathology.

The most commonly encountered retinal abnormality is a hypopigmentation of the retinal pigment in the periphery with pigmentary stippling. Tsilou et al. (2006) found this abnormality as early as 6 months.10 Dureau et al. (2003) noted a mean age of 10.19 years of patients with this finding.11 As the child grows, these changes progress posteriorly toward the macula. Macular changes, which affect the central vision, have been found as early as 6 years of age. The cause of this retinal degeneration remains unclear. Several histopathologic studies have also shown crystal accumulation in the retinal pigment.14

Other nonspecific retinal changes have been reported in 9% of patients studied by Tsilou et al. (2006).10 One such abnormality resembled retinitis pigmentosa (RP). In their study of 208 nephropathic cystinosis patients, Tsilou et al. (2006) tested visual fields in patients older than 11 years of age.10 Half of these patients had mild to moderate abnormalities. The frequency of the visual field abnormality increased with age. These changes are felt to be secondary to both corneal and retinal changes.

243

243 Cystinosis.

DIAGNOSIS AND MANAGEMENT/TREATMENT

Ophthalmologists are often consulted once the diagnosis of nephropathic cystinosis has been established. Although oral cysteamine is efficacious in reducing most of the systemic symptoms associated with cystinosis, it has no effect on the symptoms associated with the corneal accumulation of crystals.

Topical lubricants and sunglasses can help moderate some of the symptoms. Topical cysteamine treatment (0.55% [50 mM] cysteamine hydrochloride solution with benzalkonium chloride 0.01% as a preservative) has been proven to be safe and ameliorate the symptoms of photophobia, blepharospasm, corneal erosions, corneal edema, and eye pain in single and multicenter studies.15 Topical cysteamine is typically administered 6–12 times per day. The frequency of the dosing can pose a compliance issue to patients and parents. It is only stable at room temperature for up to 1 week, which can further compound compliance.

Corneal transplantation is reserved for the patient with severe symptoms that are unaided by topical lubricants and/or cysteamine drops.

Tsilou et al. (2006) have shown that early initiation of oral cysteamine therapy can reduce the frequency of retinal complications.10 They recommend continuation of the medication even after renal transplantation because of its extrarenal therapeutic effects.