An Intertriginous Rash in an Infant

A 4-month-old boy presents to the dermatology clinic with a rash on his neck, axilla, and inguinal folds since 2 months of age (Fig 1). The patient was born at term, and birthweight was appropriate for gestational age. Birth and medical histories were normal, with no prenatal, perinatal, or postnatal complications. His developmental milestones and growth velocity are normal. Because the rash was presumed to be due to infection, he had been treated with mupirocin 2% ointment, clindamycin 1% topical solution, clotrimazole 2% cream, and, finally, a 10-day course of oral cephalexin. He had also been treated with topical corticosteroids of varying potencies for suspected contact dermatitis, but the lesions continued to worsen.His physical examination reveals macerated, erythematous, and scaly patches in the axillae, neck, and inguinal folds. The patient has no other systemic findings. Complete blood cell count and complete metabolic panel are normal. A skeletal survey is also normal. Given multiple treatment failures, a skin biopsy is performed on a yellow-brown papule on the leg, which confirms the diagnosis.The differential diagnosis includes irritant contact dermatitis, seborrheic dermatitis, psoriasis, atopic dermatitis, streptococcal perianal dermatitis, candidiasis, and acrodermatitis enteropathica. The biopsy revealed a dense lichenoid lymphohistiocytic infiltrate positive for CD45, CD68, CD1a, S-100, and langerin, consistent with Langerhans cell histiocytosis (LCH).LCH is an inflammatory neoplasm of myeloid-lineage progenitor cells. This condition was originally classified into 4 distinct entities, including Letterer-Siwe disease, Hashimoto-Pritzker disease, eosinophilic granuloma of bone, and Hand-Schuller-Christian disease. (1) Due to overlapping radiologic and histologic findings, Lichtenstein and Jeffe (1) grouped them under the term histiocytosis X in 1953. With the introduction of electron microscopy, Nezelof et al (2) identified Birbeck granules as specific components of normal epidermal Langerhans cells and of histiocytosis X lesions. Hence, the disease was renamed LCH. (3)LCH is most commonly due to the BRAF V600 mutation, which activates the MAPK-ERK pathway and causes rapid proliferation of cells. It affects 1 in 200,000 children each year, with a median age at diagnosis of 3.5 years, although it is also seen in the elderly. (4)(5)LCH can affect different organs and can be clinically classified as unisystem or multisystem, depending on the number of organs affected by the disease. It is also classified as unifocal or multifocal, depending on the number of lesions seen. Multisystem LCH is associated with the worst prognosis of any of these subtypes. (6)LCH most commonly affects the bones in up to 80% of patients, presenting as lytic lesions in the skull and in the vertebrae. (7) It is frequently associated with localized, tender, soft, and raised spots, although asymptomatic cases are also seen. (7)(8) Skin involvement is seen in approximately 33% of patients and is the second most common organ manifestation. (7) It presents as erythematous, scaly, or crusted papules and patches, mimicking a seborrheic dermatitislike or eczematouslike rash. (9) It may also present with erythematous or flesh-colored, ulcerated or umbilicated papules and plaques, as well as pustules, vesicles, and purpura. (9) Lesions are commonly located on the scalp, trunk, neck, inguinal folds, axillae, and perineum. Other organs less commonly affected include the pituitary gland, liver, spleen, lungs, lymph nodes, and central nervous system. (7) Therefore, evaluation should include a complete blood cell count, a complete metabolic panel, an erythrocyte sedimentation rate, coagulation studies, abdominal ultrasonography, chest radiography, and a skeletal radiographic survey to assess for systemic involvement. (7)Our patient developed skin lesions in the axillae, followed by the neck and inguinal folds. Although there are many cases that describe LCH involving the axillae, there is currently limited information regarding the number of cases in which this is the initial area involved. (9)It is important to identify and diagnose early skin manifestations because 87% to 93% of patients with cutaneous LCH also present with systemic involvement, which is associated with a mortality rate of approximately 20%. (6)(10) Rarely, patients with cutaneous LCH lack systemic involvement, as in our patient. This uncommon subtype occurs in approximately 2% of patients and is called isolated cutaneous LCH (IC-LCH). It mostly affects infants aged 0 to 2 years and generally has a good prognosis. (11) Evolution of lesions is variable. Lesions may remain stable in size, grow proportionately with the patient, or involute spontaneously, typically healing with scarring or pigmentation changes such as hyperpigmentation or hypopigmentation. (12)(13)(14)(15)Diagnosing this condition may be challenging because cutaneous manifestations can mimic some of the most common dermatoses observed in the pediatric population. The rates of misdiagnosis seen in LCH have been reported to be as high as 16%, resulting in a delay of care and contributing to morbidity and mortality. (9) For instance, scalp lesions may be misdiagnosed as seborrheic dermatitis. (13) Meanwhile, groin lesions may be confused with treatment-resistant diaper dermatitis, psoriasis, atopic dermatitis, intertrigo, streptococcal intertrigo, irritant contact dermatitis, and candidiasis, among others. (13) Therefore, it is not surprising that our patient received treatment for some of these conditions before visiting our clinic, all of which were futile. This highlights the importance of considering LCH in the differential diagnosis for intertriginous rashes seen in children. Prompt and appropriate treatment of their condition may be lifesaving and prevent long-term sequelae. (16)There is no standard treatment protocol for IC-LCH. (17) Thus, treatment varies from patient to patient. Current strategies are supported by case series rather than by prospective controlled trials. (17) For instance, the use of systemic therapy in IC-LCH is limited to patients with progressive disease. (18)(19) For unifocal IC-LCH, surgical resection of the lesion is both diagnostic and curative. For low-quantity multifocal IC-LCH, as seen in our patient, first-line therapy is medium- to high-potency topical corticosteroids. (17) However, lesions may not respond to topical corticosteroids and tend to recur on discontinuation. (20)(21) Other agents used as second-line therapy in children include topical calcineurin inhibitors, nitrogen mustard, phototherapy, and imiquimod. (17)Recent studies have shown that topical imiquimod therapy can be effective for skin lesions seen in LCH in both children and adults. (21)(22) This immunomodulator acts by augmenting the type 1 T helper cell–mediated immune response and inducing the release of interferon-α, tumor necrosis factor α, and interleukin-1, among others. (22) It also enhances antigen presentation by Langerhans cells. Topical imiquimod has proved to be effective in lesions unresponsive to topical corticosteroids, all the while sparing patients from corticosteroid-induced adverse effects seen with long-term treatment, especially in flexural areas. It has been mainly used in adult patients with LCH for up to 6 months. (21) A single case report describes the use of topical imiquimod in the pediatric population, with resolution of lesions 5 months after initiating therapy and no recurrence 2 years after discontinuing imiquimod. (22) Minimal adverse effects were noted in both groups in the form of local skin irritation. (21)(22)Once the diagnosis was confirmed, the potency of topical corticosteroids was increased. However, triamcinolone acetonide 0.1% ointment was not effective. Tacrolimus 0.03% ointment was begun but was discontinued due to skin irritation. The patient was then started on imiquimod 5% cream daily, with resolution of lesions in 2 months (Fig 2). This therapy was tolerated well, with only mild skin irritation. She was referred to oncology for further management. Chemotherapy was not recommended because the skin lesions improved with topical therapy and the patient had no systemic findings. The patient was treated with imiquimod 5% cream 3 times daily once lesions resolved for 6 months, and treatment was then discontinued, with no evidence of recurrence of lesions after 9 months. Results of routine laboratory tests and imaging have been negative for systemic disease for the past year, including complete blood cell count, complete metabolic panel, abdominal ultrasonography, and skeletal radiographic survey. Patients with LCH should be followed for at least 5 years after the end of therapy; 5 years after the last disease reactivation in those who did not receive systemic therapy, as in our patient; and through the end of puberty. (7)