eMedicine Specialties > Ophthalmology > Iris & Ciliary Body

Juvenile Xanthogranuloma

Theodore Curtis, MD, Assistant Professor, Department of Ophthalmology, University of Colorado; Consulting Staff, Rocky Mountain Lions Eye Institute
David T Wheeler, MD, Associate Professor, Departments of Ophthalmology and Pediatrics, Oregon Health & Science University

Updated: Jan 26, 2010

Introduction

Background

Juvenile xanthogranuloma (JXG) primarily is a self-limited dermatologic disorder that is associated rarely with systemic manifestations. Infants and small children are mainly affected.

JXG consists of lesions that may be single or multiple and appear as firm, slightly raised papulonodules several millimeters in diameter. They are tan-orange in color and occur frequently on the head and neck, but many extracutaneous sites have been reported.

The eye, particularly the uveal tract, is the most frequent site of extracutaneous involvement. Approximately one half of patients with ocular involvement have skin lesions. JXG is the most frequent cause of spontaneous hyphema in children and can result in secondary glaucoma and eventual blindness.

Pathophysiology

The etiology of JXG is unknown. JXG is believed to result from a disordered macrophage response to a nonspecific tissue injury, resulting in a granulomatous reaction. JXG is on a spectrum of histiocytic disorders that includes benign cephalic histiocytosis, generalized eruptive histiocytosis, adult xanthogranuloma, and progressive nodular histiocytosis. These diseases are less common than the related Langerhans cell histiocytoses.

Frequency

United States

The frequency is unknown, but it may be higher than reported, since lesions occur early in life, may be misdiagnosed, and spontaneously regress. In those affected, 92% of ocular involvement occurs before age 2 years.^{[1 ]}

Mortality/Morbidity

Cutaneous lesions generally are self-limited and rarely require treatment. The risk of morbidity is high with ocular involvement and can include hyphema, glaucoma, corneal blood staining, cataract, vascular occlusion, and retinal detachment, all of which can lead to amblyopia in childhood. Rarely, death has been reported among children with visceral JXG.

Race

No reported predilection of race exists in JXG, although few African American patients have been described.

Sex

Cutaneous JXG is reported 1.5 times more in male children, but no sex predilection exists in adults. Both sexes are equally at risk for ocular involvement.

Age

JXG may be present at birth (in about 10%) but most often arises in infancy. Children younger than 6 months are more likely to have multiple lesions.^{[1 ]}Zimmerman reported 64% of cutaneous lesions to be present by age 7 months and 85% before 1 year. Adult onset is reported infrequently.

Clinical

History

• Most patients with juvenile xanthogranuloma (JXG) are asymptomatic.
• Ocular lesions usually are discovered incidentally or following spontaneous hyphema. They may be noted by observant parents or primary care physicians.
• Screening for ocular involvement generally is not performed because of its low incidence. The eye probably is affected in only about 0.5% of patients with cutaneous JXG,^{[2 ]}although some early studies found an incidence as high as 10%.^{[3,4 ]}
• Those at greatest risk are children younger than 2 years with multiple skin lesions.^{[1 ]}
• The most common ocular presentation involves the iris. Iris tumors may be diffuse or localized and lead to heterochromia, uveitis, spontaneous hyphema, and secondary glaucoma.
• Other ocular tissues are involved much less frequently, and orbital tumors are rare.
• Nearly all cases are unilateral, and spontaneous regression of lesions is uncommon.
• An association with neurofibromatosis type 1 (NF-1) and juvenile chronic myelogenous leukemia (JCML) has been reported. A recent retrospective review by Cambiaghi of 77 patients younger than 3 years with NF-1 yielded 17 (22%) with JXG, but none developed JCML or other hematologic abnormalities.^{[5 ]}

Physical

• Skin lesions are well demarcated, rubbery, tan-orange papulonodules ranging from 1-20 mm in size. They may be single or multiple and usually occur on the head and neck, but they may appear at any site on the body surface.
• Extracutaneous involvement occurs in 4% of children and in 5-10% overall. Extracutaneous involvement has been reported in every organ system in the body, including central nervous system, eye, salivary glands, larynx, lung, pericardium, myocardium, liver, spleen, colon, retroperitoneum, kidney, adrenal gland, gonads, bone, periosteum, muscle, and mucous membranes.
• Ocular lesions usually involve the iris, but they may occasionally be seen in the eyelids, conjunctiva, cornea, limbal tissue, sclera, retina, choroid, optic nerve, and orbit. Cases are usually unilateral, but bilateral cases have been reported.
• Iris lesions most often resemble isolated cutaneous lesions in color and appearance. They may be single or multiple and localized or diffuse. Tumors have been described to increase in thickness and lighten in color with maturation.
• Iris JXG also may present as diffuse conjunctival injection with uveitis, congenital or acquired heterochromia iridis, spontaneous hyphema, or secondary glaucoma. Involvement of other uveal tissue is very uncommon.
• The second most commonly affected ocular site is the eyelid. Lesions appear as typical cutaneous tumors. Subcutaneous forms are rare, but they can mimic a recurrent/nonresolving chalazion. They can cause deprivational amblyopia or refractive amblyopia if they induce significant astigmatism.
• Intraocular lesions rarely have been reported in the posterior pole.
• Orbital lesions are extremely uncommon. They usually appear as infiltrative soft tissue tumors and often cause proptosis of the globe. At least one case has been described as a locally aggressive lesion causing bony destruction with intracranial extension.

Causes

• The etiology of JXG is unknown, but a genetic basis has been suggested given the multiple sites of occurrence. However, familial cases have not been observed.
• The transformation of benign cephalic histiocytosis (a related disorder) into JXG has been reported infrequently. A recent report postulated this progression could be virally mediated.

Differential Diagnoses

Workup

Laboratory Studies

• Juvenile xanthogranuloma (JXG) is mainly a clinical diagnosis, which can be confirmed histologically. Histology of excised lesions and cytology of aqueous fluid may be used.
• Routine screening for metabolic or hematologic abnormalities is not recommended.

Imaging Studies

• High-frequency ultrasound of the anterior segment can aid in identifying lesions, which typically appear as solid homogeneous masses, especially when hyphema is present. Ocular ultrasound may also be used to help confirm the location of the intraocular or orbital lesions.
• CT scan and MRI are rarely indicated.

Other Tests

• Biomicroscopy is the main technique used in ocular diagnosis.

Procedures

• Anterior chamber paracentesis to obtain cytologic material has been described and can be useful in cases where the diagnosis is uncertain.
• Gonioscopy is helpful to identify peripheral lesions and to look for causes of secondary glaucoma.

Histologic Findings

Lesions contain dense polyhedral histiocytes with large amounts of cytoplasm that often contain vacuoles. Touton giant cells are present in 85% of cases.^{[1 ]}They have a wreath of nuclei surrounding a homogenous eosinophilic cytoplasmic center.

Immunohistochemistry shows the lesions to be positive for factor XIIIa, CD68, CD163, fascin, and CD14 but negative for S100 and CD1. This can be used to differentiate these lesions from Langerhans cell histiocytoses.

A prominent vascular network is often present. Evidence of tissue inflammation is seen in the swelling and degeneration of epithelial cells and redundant capillary basement membranes with perivascular edema.

Treatment

Medical Care

• Pharmacotherapy: Topical, subconjunctival, intralesional, and systemic corticosteroids are used for intraocular and orbital juvenile xanthogranuloma (JXG). Orbital lesions may respond to intralesional steroid injections. Iris lesions are treated with topical prednisolone or subconjunctival steroids. These are followed by sub-Tenon steroids if no improvement occurs in several weeks.
• Radiotherapy: Low-dose radiation may be the treatment of choice for diffuse uveal lesions, especially if glaucoma is present, or if there is poor response to steroid treatment. Typically, 100-200 cGy is administered per dose over a 2- to 3-week period. The total is usually kept under 500 cGy, but higher doses are used for poorly responsive tumors.
• Antimetabolites are sometimes used as adjuvants to radiotherapy.
• Appropriate glaucoma medications should be used in the setting of hyphema and increased intraocular pressure.

Surgical Care

• Occasionally, surgery is indicated for localized iris lesions involving less than one quadrant. However, the risks to normal ocular structures may outweigh the benefits.
• The surgeon should be prepared to deal with massive amounts of bleeding, which can occur with iridectomy in this setting.

Consultations

• Discussion with a pediatric dermatologist or radiation oncologist may be helpful to document the extent of the disease and plan treatment.

Diet

• No dietary restrictions are indicated for this disorder.

Activity

• Standard activity restrictions should be put in place for patients who develop spontaneous hyphema. These restrictions generally include bed rest with bathroom privileges and elevation of the head of the bed 30° from the horizontal.
• Small children should have a protective shield over the eye at all times to prevent rubbing.
• Eye protection, especially during sports, should be prescribed for older children who have known ocular tumors.

Medication

Topical, oral, or intralesional corticosteroids are used in the treatment of ocular JXG. Because of risk of spontaneous hemorrhage, all ocular tumors probably should be treated. Specific medications used include the treatments described below.

Corticosteroids

Minimize the activity of inflammatory cells and formation of granulomas. Used in symptomatic patients and commonly provides symptomatic improvement.

Prednisolone acetate 1% (Pred Forte)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. DOC for lesions involving the anterior segment.

Dosing

Adult

1 gtt to affected eye qid

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Concurrent ocular infection, especially viral

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Prolonged use may contribute to development of cataract and glaucoma

Prednisolone (Delta-Cortef, Econopred)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. For ocular lesions not responsive to topical steroids.

Dosing

Adult

1-2 mg/kg/d PO divided tid/qid for up to 2 wk

Pediatric

Administer as in adults; usually given in liquid form

Interactions

Decreases effects of salicylates and toxoids (for immunizations); phenytoin, carbamazepine, barbiturates, and rifampin decrease effects of corticosteroids

Contraindications

Systemic infection; recent or planned exposure to live or attenuated vaccines; known exposure to chickenpox or measles

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Multiple adverse effects involving nearly all organ systems reported; in particular, suppression of HPA axis and reduced growth velocity can occur with prolonged use, although probably not in a 2-wk period; in children, oral corticosteroids are best prescribed in conjunction with a neonatologist or pediatrician

Dexamethasone (Decadron, AK-Dex) and betamethasone suspension (Celestone)

Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability. To be injected subconjunctivally (for intraocular lesions) or intralesionally (for orbital lesions).

Dosing

Adult

2 mL of 50:50 mixture

Pediatric

Administer as in adults

Interactions

None reported

Contraindications

Concurrent ocular infection or known steroid-responsive glaucoma

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Significant bleeding can occur with injection into a vascular lesion, such as JXG; increased risk of cataract or glaucoma

Follow-up

Further Inpatient Care

• Patients with juvenile xanthogranuloma (JXG) rarely are admitted, except for management of acute hyphema or extensive visceral involvement. Follow-up care is dictated by the clinical situation.

Further Outpatient Care

• Patients with known cutaneous lesions should be seen regularly and screened for the development of ocular or other noncutaneous lesions.
• Patients with iris tumors should undergo prompt treatment.
• Patients presenting with hyphema should be monitored closely after acute management for ocular sequelae and management of amblyopia when appropriate.

Inpatient & Outpatient Medications

• Patients prescribed topical or oral steroids, as well as those receiving steroid injection, should be observed for development of cataract and glaucoma, as well as tumor response.

Complications

• The primary complication of ocular JXG is spontaneous hyphema and its sequelae, especially glaucoma and amblyopia.

Prognosis

• Spontaneous regression of skin lesions is the natural course, but in ocular disease, regression has only been infrequently documented.
• JXG is an important cause of spontaneous hyphema in childhood, the sequelae of which include secondary glaucoma and blindness.
• Visual prognosis of iris JXG depends upon prompt diagnosis and treatment prior to intraocular hemorrhage. Once hyphema occurs, visual morbidity increases substantially.
• In patients with other ocular or orbital involvement, prognosis varies with the extent of the disease and its response to treatment.

Patient Education

• Patients with cutaneous lesions should be made aware of the importance of a screening eye examination and regular follow-up care.
• Patients with known ocular disease should undergo prompt treatment as appropriate. They should avoid any situation where ocular trauma could occur until resolution of the ocular disease is achieved.
• Patients should be made aware of the signs and symptoms of spontaneous hyphema and seek ophthalmic attention as soon as possible if these are noted to occur.

Miscellaneous

Medicolegal Pitfalls

• The following situations may create unnecessary provider risk:
  • Failure to perform a complete ocular examination in a patient referred with known cutaneous JXG
  • Failure to treat or recommend treatment of intraocular or orbital JXG
  • Failure to examine the fellow eye of a patient with spontaneous hyphema, particularly in the event of subsequent discovery of bilateral disease

Special Concerns

• The ophthalmologist treating pediatric patients with JXG always must be mindful of the risk of irreversible visual impairment from inadequately treated amblyopia. Preverbal or uncooperative patients in whom acceptable visual acuity cannot be documented on several attempts should be referred to a pediatric ophthalmologist or certified orthoptist.

References

1. Cypel TK, Zuker RM. Juvenile xanthogranuloma: Case report and review of the literature. Can J Plast Surg. Fall 2008;16(3):175-7. [Medline]. [Full Text].

2. Liang S, Liu YH, Fang K. Juvenile xanthogranuloma with ocular involvement. Pediatr Dermatol. Mar-Apr 2009;26(2):232-4. [Medline].

3. Karcioglu ZA, Mullaney PB. Diagnosis and management of iris juvenile xanthogranuloma. J Pediatr Ophthalmol Strabismus. Jan-Feb 1997;34(1):44-51. [Medline].

4. Vendal Z, Walton D, Chen T. Glaucoma in juvenile xanthogranuloma. Semin Ophthalmol. Jul-Sep 2006;21(3):191-4. [Medline].

5. Cambiaghi S, Restano L, Caputo R. Juvenile xanthogranuloma associated wiht neurofibromatosis 1: patients without evidence of hematologic malignancies. Pediatr Dermatol. 2004;21(2):97-101. [Medline].

6. Cadera W, Silver MM, Burt L. Juvenile xanthogranuloma. Can J Ophthalmol. Jun 1983;18(4):169-74. [Medline].

7. Chang MW. Update on juvenile xanthogranuloma: unusual cutaneous and systemic variants. Semin Cutan Med Surg. Sep 1999;18(3):195-205. [Medline].

8. DeBarge LR, Chan CC, Greenberg SC, et al. Chorioretinal, iris, and ciliary body infiltration by juvenile xanthogranuloma masquerading as uveitis. Surv Ophthalmol. Jul-Aug 1994;39(1):65-71. [Medline].

9. Harley RD, Romayananda N, Chan GH. Juvenile xanthogranuloma. J Pediatr Ophthalmol Strabismus. Jan-Feb 1982;19(1):33-9. [Medline].

10. Hernandez-Martin A, Baselga E, Drolet BA, Esterly NB. Juvenile xanthogranuloma. J Am Acad Dermatol. Mar 1997;36(3 Pt 1):355-67; quiz 368-9. [Medline].

11. Kaur H, Cameron JD, Mohney BG. Severe astigmatic amblyopia secondary to subcutaneous juvenile xanthogranuloma of the eyelid. J AAPOS. Jun 2006;10(3):277-8. [Medline].

12. Miszkiel KA, Sohaib SA, Rose GE, et al. Radiological and clinicopathological features of orbital xanthogranuloma. Br J Ophthalmol. Mar 2000;84(3):251-8. [Medline].

13. Shields JA, Shields CL. Clinical spectrum of histiocytic tumors of the orbit. Trans Pa Acad Ophthalmol Otolaryngol. 1990;42:931-7. [Medline].

14. Tanz WS, Schwartz RA, Janniger CK. Juvenile xanthogranuloma. Cutis. Oct 1994;54(4):241-5. [Medline].

15. Weitzman S, Jaffe R. Uncommon histiocytic disorders: The non-Langerhans cell histiocytoses. Pediatr Blood Cancer. 2005;44:1-9. [Medline].

16. Zvulunov A, Barak Y, Metzker A. Juvenile xanthogranuloma, neurofibromatosis, and juvenile chronic myelogenous leukemia. World statistical analysis. Arch Dermatol. Aug 1995;131(8):904-8. [Medline].

Keywords

juvenile xanthogranuloma, JXG, Langerhans cell histiocytosis, uvea, hyphema, glaucoma, amblyopia, vision loss, blindness

Contributor Information and Disclosures

Author

Theodore Curtis, MD, Assistant Professor, Department of Ophthalmology, University of Colorado; Consulting Staff, Rocky Mountain Lions Eye Institute
Theodore Curtis, MD is a member of the following medical societies: American Academy of Ophthalmology and American Association for Pediatric Ophthalmology and Strabismus
Disclosure: Nothing to disclose.

Coauthor(s)

David T Wheeler, MD, Associate Professor, Departments of Ophthalmology and Pediatrics, Oregon Health & Science University
David T Wheeler, MD is a member of the following medical societies: American Academy of Ophthalmology, American Association for Pediatric Ophthalmology and Strabismus, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Medical Editor

Gerhard W Cibis, MD, Clinical Professor, Director of Pediatric Ophthalmology Service, Department of Ophthalmology, University of Kansas, Kansas City
Gerhard W Cibis, MD is a member of the following medical societies: American Academy of Ophthalmology, American Association for Pediatric Ophthalmology and Strabismus, and American Ophthalmological Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Simon K Law, MD, PharmD, Assistant Professor of Ophthalmology, Jules Stein Eye Institute; Chief of Section of Ophthalmology Surgical Services, Department of Veterans Affairs Healthcare Center, West Los Angeles
Simon K Law, MD, PharmD is a member of the following medical societies: American Academy of Ophthalmology, American Glaucoma Society, and Association for Research in Vision and Ophthalmology
Disclosure: Nothing to disclose.

Managing Editor

J James Rowsey, MD, Former Director of Corneal Services, St Luke's Cataract and Laser Institute, Florida
J James Rowsey, MD is a member of the following medical societies: American Academy of Ophthalmology, American Association for the Advancement of Science, American Medical Association, Association for Research in Vision and Ophthalmology, Florida Medical Association, Pan-American Association of Ophthalmology, Sigma Xi, and Southern Medical Association
Disclosure: Nothing to disclose.

CME Editor

Lance L Brown, OD, MD, Ophthalmologist, Affiliated With Freeman Hospital and St John's Hospital, Regional Eye Center, Joplin, Missouri
Disclosure: Nothing to disclose.

Chief Editor

Hampton Roy Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences
Hampton Roy Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, and Pan-American Association of Ophthalmology
Disclosure: Nothing to disclose.

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