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A newborn boy born via normal vaginal delivery at 38.6 weeks gestation to a 33-year-old G5P2022 mother presented at birth with an asymptomatic 8-mm red, papulonodule with central crusting on the right cheek . What's the diagnosis?
A newborn boy born via normal vaginal delivery at 38.6 weeks gestation to a 33-year-old G5P2022 mother presented at birth with an asymptomatic 8-mm red, papulonodule with central crusting on the right cheek (Figure 1). Pregnancy had been complicated by maternal type 2 diabetes mellitus and obesity. Delivery was uncomplicated and the patient was otherwise healthy.
Mother was otherwise healthy and the pregnancy was uneventful. Medications that were used during the pregnancy included prenatal vitamins, insulin, ranitidine, and diphenhydramine. All antenatal ultrasounds, serologies, and labs were unremarkable. Mother reported no relevant personal or family history, specifically no history of herpes simplex virus (HSV) infection, other viral infections, leukemia/lymphoma, or immunodeficiencies.
Initial physical examination revealed a well appearing infant. The Apgar scales were 9, 9, and 9 at 1, 5, and 10 minutes respectively. Patient weighed 3485 grams, an appropriate weight for his gestational age. Vital signs were within normal limits upon delivery.
Skin examination revealed an asymptomatic, round, red, non-blanching, 8-mm firm papulonodule on the right cheek. The lesion had an erythematous base with no drainage or crusting on initial exam. Central crusting later developed on the first day of life. The patient did not appear bothered by the lesion. Physical exam was otherwise unremarkable.
The patient received all routine neonatal labs. Hemoglobin and hematocrit levels were within normal limits. He required 2 oral glucose gels prior to glucose normalization. Metabolic screens were within normal limits. At 24 hours of life, C-reactive protein and a complete blood count were drawn and returned with no abnormalities.
Imaging and consultation
Ultrasound of the lesion of the right cheek demonstrated a heterogeneous, hypoechoic lesion with no evidence of increased vascularity. Pediatric dermatology was consulted for further evaluation of the lesion and performed a biopsy that revealed Langerhans cells with surrounding inflammatory cells and eosinophils (Figures 2 and 3). A cutaneous proliferation of CD1a, CD68, and S100 positive cells was also confirmed via immunohistochemical staining (Figures 4 and 5). Fungal cultures, aerobe-anaerobe cultures, and an acid-fast bacilli culture were negative. These findings were typical of cutaneous Langerhans cell histiocytosis.
The initial differential diagnosis included several infectious and noninfectious etiologies that could account for such a skin lesion (Table). Infantile hemangiomas were high on the differential, as these are the most common skin neoplasms presenting in infancy.1 These are benign vascular tumors with a prevalence of 4%-10% worldwide.1 Ultrasound imaging may demonstrate an increase in internal vascularity. Ultrasound of our patient on day 1 of life indicated no prominent internal vascularity, making the diagnosis of infantile hemangioma less likely. Moreover, the presence of a nodule at birth and uniform blanching erythema with central crusting would not be typical of a classic infantile or congenital hemangioma.
Langerhans cell histiocytosis (LCH) was another diagnosis considered as it has a variable clinical presentation. Manifestations of this hematologic disorder can range from single cutaneous lesions to multiple cutaneous lesions, and to a multi-organ disease. Skin involvement is present in 33% of patients and appearance can vary from dry scaly lesions to crusted vesicles and red papules.2,3 Biopsy confirms characteristic histologic and immunohistochemistry findings.4
Biopsy is also critical to exclude other diagnoses such as congenital juvenile xanthogranuloma. This is a form of non-Langerhans cell histiocytosis which can present as subcutaneous masses with overlying skin changes, papules, or nodules that are erythematous at presentation and become yellow in color over weeks to months.5 These lesions vary from a few mm in diameter to over 3cm, and most commonly involve the head, neck, or trunk.5
Leukemia cutis describes skin manifestations that arise as a result of an underlying leukemia. These lesions can also have a variable presentation including red or violet papules, plaques, nodules or hemorrhagic lesions.6 These lesions commonly appear after a diagnosis of leukemia has already been made, but may also appear before there is any involvement of the peripheral blood or any systemic symptoms arise.7 Approximately two-thirds of patients presenting with neonatal acute myeloid leukemia also present with skin lesions, but lesions may be limited to the skin and resolve without treatment. However, these patients usually have other findings including hepatosplenomegaly or a high systemic tumor burden.8 Confirmation of this diagnosis is also completed via skin biopsy.
Other potential etiologies include congenital sarcomas, such as rhabdomyosarcoma. These soft-tissue neoplasms can present as red or violaceous nodules if they metastasize to involve the skin.9 Additionally, extramedullary hematopoiesis, or a “blueberry muffin rash”, can also present as similar papules and nodules that can be the result of an underlying infection (often TORCH infections), hemolysis, or malignancy.9
An infectious etiology also cannot be ruled out when a newborn presents with an abnormal skin lesion. Neonatal HSV needs to be considered due to the high morbidity and mortality rates associated with this infection.10 Patients with neonatal HSV usually present with clusters of vesicles localized to the skin, eyes or mouth. Failure to treat could lead to disseminated disease or spread to the central nervous system.11 Cutaneous lesions can also be the manifestation of infections caused by the other congenital TORCH infections, Staphylococcus aureus, Group A or B Streptococcus, and congenital candidiasis.
Infection could suggest that there is an underlying immunodeficiency such as HIV, malignancy, or a white blood cell disorder. Our patient did not present with any risk factors for these conditions and lab values were reassuring. Additionally, the patient was not exposed to any risk factors that would alter the function of the immune system at this age including maternal illness, prematurity, immunosuppressive medications or inadequate prenatal care.12,13
Langerhans cell histiocytosis has an incidence of 2.6-8.9 cases per million amongst children aged younger than 15 years, and a median age of diagnosis of 3-4 years.3 This disorder is characterized by proliferation of CD1a, S100, CD68, and CD207 myeloid dendritic cells and has a highly variable clinical presentation.4,14 Any organ system can be affected, thus requiring a comprehensive evaluation of affected patients. Commonly affected sites include the bone, skin, central nervous system, pulmonary, hematopoietic, and hepatobiliary systems.
Among patients diagnosed with LCH, 33% present with skin findings.3 Skin lesions usually present as ulcerated, red papules, as was seen in our patient, but may also appear pustular, vesicular, or petechial in nature.2 In infancy skin manifestations may also resemble other skin disorders such as erythema toxicum neonatorum, eczema, or seborrheic dermatitis. As a result, it is important to accurately diagnose this condition to ensure appropriate treatment.
A rare variant of LCH named congenital self-healing reticulocytosis has also been identified. This condition was first described by Hashimoto and Pritzker and presents at birth or within the first few weeks of life.15 Patients may present with brown to violaceous papules located anywhere on the body. As with classic LCH, these lesions can be single or multiple. It is thought that the true incidence of this variant is underreported because most of these lesions resolve without treatment within the first 3-4 months of life.16
Although children with lesions isolated to the skin usually have a good prognosis, patients with LCH who have isolated skin involvement also have an excellent prognosis, however, close observation is still required.2 In 40% of patients with similar isolated cutaneous findings progression to multi system disease or reactivation was observed.17
Initial evaluation of patients with LCH requires determining whether there is single or multisystem involvement. Recommended testing includes a complete blood count with differential, complete metabolic panel including liver function tests, and coagulation studies. Imaging assessment should include a skeletal survey, ultrasound of the liver and spleen, and chest radiography.2 Treatment can then be tailored to the individual patient and extent of their disease.
Treatment for LCH is dependent on the site affected and the number of lesions. For patients presenting with isolated skin involvement, surgical resection can lead to cure. If lesions are multiple then topical corticosteroids are first line therapy, with second line agents including topical nitrogen mustard, oral thalidomide, and oral methotrexate.2 Additional studies need to be completed to further assess the efficacy of second line treatment options.
If skin involvement is diffuse or there are signs of multisystem disease, a systemic steroid with vinblastine for 6-12 months is first-line treatment. For patients with organ involvement (spleen, liver, bone marrow) 6-mercaptopurine may also be added to this treatment regimen.18 Prognosis for patients who fail these first-line treatment options is typically poor, and salvage therapy is indicated in these situations. This includes treatments such as hematopoietic stem cell transplant or a combination of cladribine and cytarabine.19
Recent research has been investigating the use of therapies targeting BRAF-V600E mutations. Patients with this mutation are more likely to have higher risk LCH or have increased resistance to treatment.20 Vemurafenib, a BRAF inhibitor, has been shown to be efficacious, however further studies are required to determine appropriate dosing and duration of therapy.21
Current recommendations for follow up for patients treated for isolated skin findings include evaluation of the lesion every 2 to 4 weeks. This includes monitoring for any signs of progression to multisystem involvement. Once the skin lesions have resolved, follow-up is recommended every 6 months for at least 5 years.22
The cheek lesion was excised by pediatric dermatology and our patient was evaluated by the pediatric hematology-oncology service. Initial skeletal survey to assess for bone involvement showed a calvarial lesion suspicious for LCH. Follow up whole body positron emission tomography scan was completed and showed no findings of bone or other multisystem involvement. As a result, systemic therapy was not indicated as the cheek lesion was previously excised. It was determined that the patient likely had the congenital self-healing reticulocytosis variant of LCH. The patient continues to follow with serial skeletal surveys and labs, and remains in complete remission.
Acknowledgements: The authors thank Dr Kumaran Mudaliar, MD; Dr Wendy Kim, DO; and Dr Natalie Kamberos, DO for their valuable contributions to this case.
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