Ophthalmology – Juvenile Xanthogranuloma (Nevoxanthoendothelioma)

Basics

Description

Juvenile xanthogranuloma (JXG) is a benign non-Langerhans cell histiocytic disorder that occurs mainly in infants and young children.

It is usually a self-limited skin disease, producing yellow-tan papules or nodules on the head, neck, trunk, or extremities.

Extracutaneous involvement occurs in a small percentage of patients and may involve:

• Eye
• Lung
• Gastrointestinal tract
• Bone
• Muscle

Ocular involvement can affect:

• Iris
• Eyelid
• Cornea
• Conjunctiva
• Ciliary body
• Choroid
• Episclera
• Orbit
• Posterior segment

The iris is the most important ocular site, because involvement can cause spontaneous hyphema and secondary glaucoma.

Epidemiology

The true incidence of JXG is uncertain because many cutaneous lesions regress spontaneously and may never be diagnosed.

Most cases occur in early childhood.

Approximately:

• 10% are present at birth
• Most develop during the first year of life
• Solitary skin lesions are more common than multiple lesions

Ocular disease occurs predominantly in very young children and is usually unilateral.

Only about half of children with ocular JXG have obvious skin lesions, so absence of a cutaneous lesion does not exclude ocular disease.

Pathophysiology

JXG is believed to result from a reactive proliferation of histiocytes rather than a true neoplasm.

The trigger is uncertain but may involve a nonspecific inflammatory response to physical or infectious stimuli.

Affected tissues accumulate:

• Histiocytes
• Lipid-laden foam cells
• Multinucleated giant cells

The characteristic histologic cell is the Touton giant cell.

Commonly Associated Conditions

Important associations include:

Neurofibromatosis Type 1

JXG may occur in children with NF1.

Children with the combination of:

• NF1
• JXG

have historically been recognized as having an increased association with juvenile myelomonocytic leukemia, although the magnitude of this association varies among studies.

Juvenile Myelomonocytic Leukemia

JMML is a rare myeloproliferative disorder of early childhood.

Because iris infiltration from leukemia can mimic ocular JXG, atypical cases require careful systemic evaluation.

Niemann–Pick Disease

Rarely associated with xanthomatous lesions and systemic storage disease.

Urticaria Pigmentosa

A form of cutaneous mastocytosis that may coexist with other pediatric dermatologic lesions.

Diagnosis

History

Many children are asymptomatic.

Parents may notice:

• Yellow-orange skin nodules
• Change in iris color
• Red eye
• Visible blood in the eye
• Enlarged pupil
• Reduced vision
• Eye pain
• Photophobia

Pain and photophobia may occur when secondary glaucoma develops.

Because children may not report visual symptoms reliably, careful examination is essential.

Cutaneous Findings

Typical skin lesions are:

• Firm
• Tan, yellow, orange, or reddish
• Papular or nodular
• Usually located on the head, neck, trunk, or extremities

They may be solitary or multiple.

Most lesions gradually regress spontaneously.

Ocular Findings

Ocular JXG may produce:

• Spontaneous hyphema
• Vascular yellow-brown iris mass
• Heterochromia
• Unilateral anterior uveitis
• Secondary glaucoma
• Corneal blood staining
• Cataract
• Conjunctival mass
• Proptosis
• Retinal vascular occlusion
• Retinal detachment
• Amblyopia

A young child with unilateral spontaneous hyphema and glaucoma should prompt consideration of JXG.

Iris Involvement

The iris may appear:

• Thickened
• Diffusely infiltrated
• Nodular
• Yellow-brown
• Highly vascular

Fragile abnormal vessels can bleed spontaneously, causing hyphema.

Iris infiltration may also obstruct the anterior chamber angle and elevate IOP.

Secondary Glaucoma

Glaucoma may result from:

• Obstruction of the trabecular meshwork by inflammatory or histiocytic material
• Peripheral anterior synechiae
• Blood in the anterior chamber
• Steroid response
• Structural angle damage

This is one of the most important causes of visual loss in ocular JXG.

Physical Examination

A complete examination should include:

• Skin examination of head, neck, trunk, and extremities
• Visual acuity assessment
• Pupillary examination
• Intraocular pressure
• Slit-lamp examination
• Gonioscopy when feasible
• Dilated fundus examination

In young children, examination under anesthesia may occasionally be required.

Diagnostic Tests

Biopsy

Diagnosis can be confirmed by biopsy of:

• Skin lesion
• Iris lesion
• Other involved tissue

For iris disease, biopsy options may include:

• Fine-needle aspiration
• Iridectomy
• Iridocyclectomy

Biopsy is generally reserved for cases in which the clinical diagnosis is uncertain or malignancy cannot be excluded.

Pathological Findings

Classic histology demonstrates:

• Histiocytes
• Foam cells
• Lymphocytes
• Plasma cells
• Multinucleated giant cells

The characteristic finding is the Touton giant cell.

Touton giant cells contain a ring of nuclei surrounded by foamy, lipid-containing cytoplasm.

Immunohistochemistry typically shows positivity for histiocytic markers such as:

• CD68
• CD163
• Factor XIIIa

Cells are generally negative for:

• CD1a
• S-100

This helps distinguish JXG from Langerhans cell histiocytosis.

Differential Diagnosis

Important differential diagnoses include:

• Leukemic iris infiltration
• Iris nevus
• Iris melanoma
• Langerhans cell histiocytosis
• Rhabdomyosarcoma
• Dermoid
• Xanthoma
• Hemangioma
• Neurofibroma
• Molluscum contagiosum
• Juvenile idiopathic arthritis-associated uveitis

The combination of a vascular iris lesion, spontaneous hyphema, and secondary glaucoma in a young child is especially suggestive of JXG.

Treatment

Treatment depends on the site and severity of disease.

Many cutaneous lesions require no treatment because they regress spontaneously.

Ocular disease requires more aggressive management because of the risk of permanent visual loss.

Corticosteroids

Systemic corticosteroids may be used for significant ocular or extracutaneous disease.

Topical corticosteroids may be used for associated anterior segment inflammation.

In selected refractory cases, additional immunomodulatory therapy may be considered.

Management of Hyphema

Spontaneous hyphema should be treated with standard precautions.

Management may include:

• Cycloplegic drops
• Topical corticosteroids
• Eye shield
• Head elevation
• Avoidance of strenuous activity
• Avoidance of unnecessary anticoagulant or antiplatelet exposure

IOP should be monitored closely.

Management of Glaucoma

Elevated IOP should be treated promptly.

Initial treatment may include topical pressure-lowering medications.

If glaucoma is severe or uncontrolled, surgical management may be necessary.

Because these are young children, prolonged elevation of IOP can cause rapid and permanent optic nerve damage.

Amblyopia Treatment

Amblyopia is an important secondary complication.

It can result from:

• Cataract
• Corneal blood staining
• Strabismus
• Anisometropia
• Glaucoma
• Prolonged visual deprivation

Treatment may include:

• Refractive correction
• Patching
• Atropine penalization
• Treatment of the underlying ocular lesion

Early treatment is essential.

Surgery

Surgical procedures may be required for:

• Local resection of persistent lesions
• Cataract extraction
• Glaucoma surgery
• Removal of visually significant iris or conjunctival masses

Surgery is individualized according to the affected structure and visual threat.

Follow-Up

Children with ocular JXG should be followed by an ophthalmologist, often with pediatric ophthalmology involvement.

Monitoring should include:

• Visual acuity
• IOP
• Anterior chamber inflammation
• Hyphema recurrence
• Cataract
• Corneal blood staining
• Optic nerve appearance
• Amblyopia

A primary care physician or dermatologist should follow associated skin lesions.

Patient Education

Parents should understand that most skin lesions are benign and self-limited.

However, ocular involvement can be serious.

They should seek prompt ophthalmic evaluation for:

• Red eye
• Eye pain
• Photophobia
• Visible blood in the eye
• Change in iris color
• New squint
• Reduced visual behavior

Prognosis

The systemic prognosis is generally excellent.

Most children have:

• Normal development
• Normal intelligence
• Normal lifespan
• Spontaneous regression of cutaneous lesions

The ocular prognosis depends on early recognition and control of complications.

Vision can be permanently reduced if secondary glaucoma, cataract, corneal blood staining, or amblyopia develops.

Complications

Important complications include:

• Secondary glaucoma
• Recurrent hyphema
• Corneal blood staining
• Cataract
• Amblyopia
• Retinal detachment
• Severe permanent visual loss

The key clinical pearl is: a young child with unilateral spontaneous hyphema, a vascular yellow-brown iris lesion, and secondary glaucoma should raise strong suspicion for juvenile xanthogranuloma.