INTRODUCTION — Juvenile xanthogranuloma (JXG) is a benign, proliferative disorder of histiocytic cells of the dermal dendrocyte phenotype. JXG belongs to the broad group of non-Langerhans cell histiocytoses and is typically a disorder of early childhood. JXG typically presents in the first two years of life as a solitary, reddish or yellowish skin papule or nodule (picture 1D), most often on the head, neck, or upper trunk. Histologically, JXG is characterized by the presence of histiocytes, foam cells, and Touton giant cells. JXG generally follows a benign course with spontaneous resolution over a period of a few years. Less commonly, skin lesions can be multiple (picture 2B). Extracutaneous or systemic forms are exceedingly rare and can be associated with considerable morbidity.

An overview of JXG will be presented here. Langerhans cell histiocytosis is discussed separately. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis".)

EPIDEMIOLOGY — Juvenile xanthogranuloma (JXG) is the most common of the non-Langerhans cell histiocytoses [1]. The incidence is unknown. In a large tumor registry spanning 35 years, JXG accounted for 129 of 24,600 pediatric tumors (0.5 percent) [2]. However, this figure may be an underestimate of the relative frequency of JXG since many cases are diagnosed on clinical grounds without histologic confirmation. In a survey of 122 dermatologists with an average of 12 years of practice, 2371 cases of JXG were reported (an average of less than two cases per dermatologist per year); only seven cases had ocular involvement [3].

JXG may be present at birth [4]. A case series and literature review found 47 cases of congenital JXG, 66 percent with isolated cutaneous involvement and 34 percent with systemic involvement [5]. Between 40 and 70 percent of JXG arise in the first year of life [6]. The median ages of onset in two large case series were 5 months (range 0 to 244 months) and 1 year (range 0 to 20 years) [2,7]. The male to female ratio was approximately 1.4:1.

PATHOGENESIS — The cause of juvenile xanthogranuloma (JXG) is unknown. It is a member of the group of histiocytoses, disorders of the mononuclear phagocytic system, which have a broad range of clinical presentations and prognoses.

All histiocytoses arise from CD34⁺ stem cells, which develop, based on the cytokine milieu, into CD14⁺ or CD14^- cells. Langerhans cells and Langerhans cell histiocytoses derive from CD14^- cells. CD14⁺ cells may become monocyte/macrophage lineage or dermal/interstitial dendrocytes, the latter considered to be the precursor cell of non-Langerhans cell histiocytoses [1,8].

Genomic analysis with molecular inversion probe array searching for copy number variation or loss of heterozygosity in 21 cases of JXG found that most solitary cutaneous JXG (19 out of 21) lacked identifiable genetic changes [9]. Genomic alterations appear more common in the setting of systemic JXG. In a series of 12 JXG cases with systemic involvement, 7 had mutations in several MAPK pathway genes, including ARAF, KRAS, MAP2K1, and NRAS [10].

PATHOLOGY — Classic histology of juvenile xanthogranuloma (JXG) shows a mixed dermal infiltrate of mononuclear cells, multinucleated giant cells with or without the features of Touton giant cells (characterized by a ring or wreath of nuclei surrounded by a foamy cytoplasm), and spindle cells. Lymphocytes, eosinophils, neutrophils, and mast cells can be seen. The lesion is nonencapsulated but well demarcated, with dense sheets of cells infiltrating the dermis and the upper portion of the subcutaneous fat. Epidermis and adnexae are spared, though the epidermis can be thinned and, rarely, ulcerated.

The microscopic appearance depends upon the age of the lesion. Early JXG shows only histiocytes, or spindle-shaped fibrohistiocytic cells, minimally lipidized. More mature JXG shows foamy, lipid-laden, vacuolated mononuclear cells and Touton giant cells. Regressing lesions show progressive replacement by fibrous tissue [6].

Immunostaining is important in establishing the diagnosis. JXG stains positively for Factor XIIIa, a marker of interstitial dendrocytes, CD68, CD163, CD14, and fascin. Stains for S100 and CD1a, the latter of which is specific for Langerhans cells, are negative.

CLINICAL MANIFESTATIONS

Clinical presentation — Juvenile xanthogranuloma (JXG) typically presents as a reddish or yellowish to brown papule, plaque, or nodule (picture 1D). A size of 0.5 to 2 cm is typical. The lesions can occur in any location and are most common on the head, neck, and upper trunk. Early lesions tend to be more red and raised, but as they mature and become progressively more lipidized, they appear more yellow and will often flatten. Fine telangiectasias occasionally can be seen overlying the lesion. The lesions usually are solitary (picture 1A-D), but multiple lesions (picture 2A-B) and extracutaneous and systemic involvement may occur. All organs and systems can be affected.

The most common extracutaneous presentation is a solitary nodule or mass in the subcutaneous or deep soft tissues [7]. Systemic lesions may occur in the liver, lung, spleen, lymph nodes, bones, and the gastrointestinal tract [7,11]. Eye involvement is rare in patients presenting with cutaneous JXG, with an estimated prevalence of 0.24 percent (7 out of 2949) in a review of published cases [12]. In the same review, systemic involvement with cutaneous JXG occurred in 0.75 percent of patients (22 out of 2949) [12]. It occurs in young children, often without skin involvement. (See 'Ocular juvenile xanthogranuloma' below.)

In two large case series, the distribution of clinical manifestations was as follows [2,7]:

●Solitary skin lesion – 67 and 71 percent

●Multiple skin lesions – 7 and 10 percent

●Superficial or deep soft tissue lesions – 16 percent and 15 percent

●Systemic involvement (with or without skin lesions) – 4 percent and 5 percent

The most severe cases tend to occur in very young children. In a series of 36 systemic cases, the median age was 0.3 years (range 0 to 12 years) [11]. In a study of 45 cases of fetal and neonatal JXG, systemic involvement was observed in 12 patients, 9 of whom had multiple skin lesions [4]. Liver, lung, spleen, lymph nodes, skeleton, and the gastrointestinal tract were the most common sites involved.

Clinical course — Spontaneous regression is the rule for skin lesions and occurs in approximately one to five years [4], sometimes leaving an atrophic or hyperpigmented scar. Extracutaneous and systemic JXG also spontaneously regress in most cases.

Cases in newborns with multisystem or extensive visceral involvement may require aggressive treatment, but fatalities are exceedingly rare [2,7]. (See 'Management' below.)

Ocular juvenile xanthogranuloma — Ocular JXG typically occurs in young children. The iris (picture 3B) is the most frequent site of ocular involvement, but the lid (picture 3A), orbit, ciliary body, cornea, and episclera may also be affected. Red eye and hyphema (bleeding into the anterior chamber of the eye) are the most common presenting complaints in patients with ocular JXG. Uveitis, heterochromia iridis, or iris masses (picture 3B) can also occur [13].

Secondary unilateral glaucoma can occur as a result of acute rise in intraocular pressure from mass effect of blood or the JXG itself and can cause blindness (see "Overview of glaucoma in infants and children", section on 'Secondary glaucoma'). Posterior segment involvement is rare [14,15].

Cutaneous JXGs are absent in approximately one-half of cases of ocular JXG at the time of presentation but may develop before, simultaneous with, or after ocular lesions [6].

ASSOCIATED CONDITIONS — Juvenile xanthogranuloma (JXG) has been reported in approximately 5 to 10 percent of patients with neurofibromatosis type 1 (NF1) and in approximately 30 percent of NF1 patients younger than two years [16,17]. In young children, the presence of multiple café au lait macules and JXG may be a marker of NF1 even in the absence of other reliable diagnostic signs of NF1 [18]. (See "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)

An association between JXG, NF1, and juvenile myelomonocytic leukemia (a rare form of childhood leukemia) has been described in a few single case reports [18-24]. However, the clinical implications of this triple association are unclear [16,25]. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia", section on 'Juvenile myelomonocytic leukemia'.)

DIAGNOSIS — Diagnosis of juvenile xanthogranuloma (JXG) is made clinically, based on the typical appearance of lesions on physical examination in most cases; biopsy is infrequently performed because the clinical picture is usually so typical and because of the self-healing nature of the disease. When the diagnosis is in doubt, skin biopsy for histology and immunostaining is necessary. (See 'Pathology' above.)

Dermoscopy has been suggested as a potentially useful tool for the diagnosis of JXG. The most characteristic dermoscopic finding in early to fully developed JXG is the so-called "setting sun" sign, which consists of a yellow-orange, central area surrounded by a peripheral, pink border with fine, branched, linear telangiectasias; in older lesions that contain more lipidized cells, dermoscopy shows white and yellow globules [26].

DIFFERENTIAL DIAGNOSIS — The clinical differential diagnosis of juvenile xanthogranuloma (JXG) in children includes Langerhans cell histiocytosis, other xanthomatous lesions, mastocytoma, Spitz nevus, and dermatofibroma. In most cases the histologic features and immunohistochemistry staining are diagnostic (table 1):

●Langerhans cell histiocytosis – Langerhans cell histiocytosis typically presents in infancy as a refractory infantile seborrheic dermatitis with petechiae, diaper dermatitis with ulceration and erosion, cutaneous papules, and nodules (picture 4). Diabetes insipidus, hepatosplenomegaly, lymphadenopathy, and bone marrow involvement can occur. Individual lesions are typically smaller than those of JXG. On immunostaining of biopsied tissue, Langerhans cell histiocytosis is S100 and CD1a positive, but JXG is S100 and CD1a negative. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis", section on 'Skin and oral mucosa'.)

●Papular xanthoma – Papular xanthoma (picture 5) is a very uncommon disease that occurs mainly in normolipidemic adults and presents as multiple yellow or red papules or nodules on the trunk and, less frequently, on the head and extremities. Rare pediatric cases have been reported [27-30]. The histologic and immunohistochemical differentiation from JXG is difficult. Papular xanthoma presents a dense infiltrate of foam cells, with fewer Touton cells and inflammatory cells than JXG. Immunostaining for factor XIIIa was negative in a series of 10 cases [27].

●Tuberous xanthoma – Tuberous xanthomas occur most often in areas of pressure, such as the buttocks, knees (picture 6), and elbows (picture 7A-B); they are firm, asymptomatic, reddish-yellow nodules, seen in patients with hypercholesterolemia and high LDL. Histologically, tuberous xanthoma consists of dermal aggregates of foam cells, with absence of Touton cells or other inflammatory cells. (See "Cutaneous xanthomas", section on 'Tuberous xanthomas'.)

●Spitz nevus – Spitz nevi present as a single, dome-shaped, pink to red papule on the face or extremities of children. Histologically, classic Spitz nevi show a symmetrical proliferation of spindle and epithelioid cells, often in nests. Immunostaining confirms the melanocytic origin (S100, Melan-A [Mart-1], and tyrosinase positive) [31]. (See "Spitz nevus and atypical Spitz tumors".)

●Mastocytoma – Mastocytomas are benign collections of mast cells within the dermis that demonstrate urtication with stroking (Darier sign). They are relatively common in children and appear as reddish to golden brown papules or plaques, which can sometimes have a rubbery feel (picture 8A-B). They are generally asymptomatic but can be mildly pruritic with urtication. Pathology shows mast cells in the papillary dermis highlighted by Giemsa stain. (See "Mastocytosis (cutaneous and systemic) in children: Epidemiology, clinical manifestations, evaluation, and diagnosis", section on 'Skin'.)

●Dermatofibroma – Dermatofibromas are benign, generally asymptomatic, tan to reddish-brown papules seen frequently on the extremities. They often arise after minor inflammation or trauma (eg, folliculitis or insect bite). They are seen more commonly in older children and adults than in infants. Histologically, an acanthotic epidermis with an underlying zone of normal papillary dermis is seen. The lesion is unencapsulated, and collagen trapping (spindle cells encasing normal collagen) occurs at the periphery. Spindle cells overlap in fascicles and whorls. (See "Overview of benign lesions of the skin", section on 'Dermatofibroma'.)

The differential diagnosis of JXG in older children and adults includes xanthoma disseminatum and eruptive xanthoma:

●Xanthoma disseminatum – Xanthoma disseminatum is a rare, nonfamilial form of non-Langerhans cell histiocytosis occurring in young adults, with frequent involvement of mucocutaneous sites [32,33]. It is often associated with diabetes insipidus. Numerous erythematous, yellow-brown papules and nodules are symmetrically distributed on the trunk, face, and upper extremities (picture 9). Lesions may become confluent in flexural areas [34]. The histologic and immunohistochemical characteristics are the same as JXG.

●Eruptive xanthomas – Eruptive xanthomas occur in adults in the setting of hypertriglyceridemia, as crops of tiny, yellowish-red papules on a background of erythema (picture 10). Sites of predilection include the buttocks, shoulders, and extensor extremities. Facial and oral involvement can occur. Histologically, eruptive xanthoma consists of a dermal infiltrate of histiocytes, lymphocytes, neutrophils, and, in mature lesions, small foam cells. (See "Cutaneous xanthomas", section on 'Eruptive xanthomas'.)

MANAGEMENT — The management of juvenile xanthogranuloma (JXG) depends upon the site(s) of involvement.

Cutaneous juvenile xanthogranuloma — No treatment is needed for cutaneous JXG. Reassurance to patients and the parents or caregivers of affected children about the benign course and spontaneous regression of the disease is usually all that is necessary. Involution usually occurs one to five years after onset [35]. Most resolve without scarring, though atrophic scarring is possible and likely more common in larger lesions.

Routine referral of all patients with cutaneous JXG for ophthalmologic evaluation is not recommended [3]. Most patients with ocular involvement present with acute ocular complaints; asymptomatic eye involvement is rare. There are no prospective studies of the benefits of routine ophthalmologic evaluation for children with cutaneous JXG. It is reasonable to consider referral to ophthalmology for patients under age two presenting with multiple micronodular (<10 mm) JXG, as they may have a higher risk of ocular involvement [3], though yield of routine eye examination is low in the absence of ocular complaints or signs [12].

Subcutaneous and soft tissue juvenile xanthogranuloma — Subcutaneous and soft tissue lesions also resolve spontaneously and do not require treatment.

Ocular juvenile xanthogranuloma — Children with ocular and periocular lesions should be referred to an ophthalmologist for diagnosis and management. The treatment depends upon the type of ocular involvement and complications.

Whether children with cutaneous JXG should be referred for ophthalmologic evaluation is discussed above. (See 'Cutaneous juvenile xanthogranuloma' above.)

Symptomatic systemic juvenile xanthogranuloma — Systemic lesions that are associated with symptoms (eg, mass effect) may require treatment if they do not spontaneously regress [11]. Treatment decisions for patients with symptomatic systemic JXG should be made on a case-by-case basis. Referral to an oncologist may be warranted. Treatment may involve excision, radiotherapy, and/or systemic chemotherapy [36-40].

There is no standard chemotherapeutic regimen for systemic JXG. A variety of regimens have been tried with variable results [36]. Most of these regimens included agents that are used in the treatment of Langerhans cell histiocytosis (eg, vinblastine, prednisone, methotrexate, and mercaptopurine). Central nervous system involvement has been successfully treated with cladribine (2-chlorodeoxyadenosine) [41,42]. In one patient, extracutaneous JXG was successfully treated with thalidomide after failure of other chemotherapeutic regimens [43].

PROGNOSIS — Prognosis of cutaneous juvenile xanthogranuloma (JXG) is uniformly good; spontaneous regression of skin lesions over a few years is the rule. Patients may have residual hyperpigmentation, minimal atrophy, or anetoderma (loss of elastic fibers in the dermis) following regression [6].

Extracutaneous JXG most often regress spontaneously as well, although treatment may be needed to relieve symptoms due to mass effect. Long-term sequelae are rarely reported. Fatalities are extremely rare, typically in infants with central nervous system or massive hepatic involvement and liver failure [2,7,11,44-46].

SUMMARY AND RECOMMENDATIONS

●Juvenile xanthogranuloma (JXG) is a rare, benign, proliferative histiocytic disorder of dermal dendrocyte origin and is the most common of the non-Langerhans cell histiocytoses. It occurs predominantly in young children. (See 'Epidemiology' above.)

●Typical skin lesions appear as reddish to yellow papules, plaques, or nodules, most often on the head, neck, and upper trunk (picture 1D). Extracutaneous or systemic JXG is rare, occurring in up to 4 percent of all cases, and may involve every organ or system, including the eye (picture 3A-B). (See 'Clinical presentation' above.)

●Ocular JXG may occur in the absence of skin lesions and usually presents with ocular manifestations (hyphema, uveitis, iris or corneal lesions) (picture 3A-B). (See 'Ocular juvenile xanthogranuloma' above.)

●The diagnosis is clinical in most cases. In difficult cases, histology and immunohistochemistry are diagnostic. (See 'Diagnosis' above.)

●The differential diagnosis of cutaneous JXG includes Langerhans cell histiocytosis (picture 4), other xanthomatous lesions (such as papular xanthoma, tuberous xanthoma, xanthoma disseminatum, and eruptive xanthoma), Spitz nevus, mastocytoma, and dermatofibroma. (See 'Differential diagnosis' above.)

●Cutaneous JXG generally regresses spontaneously; reassurance about the benign course is usually all that is necessary. Patients with ocular JXG should be referred to an ophthalmologist. Systemic JXG may require treatment (excision, radiotherapy, and/or chemotherapy) if it causes symptoms. (See 'Management' above.)