Langerhans cell histiocytosis: Presentation in a preterm neonate

Abstract Background Langerhans cell histiocytosis (LCH) is a rare disorder in which Langerhans cells (LC) accumulate in the skin or other organs and cause tumor formation or organ damage. Cutaneous lesions can vary widely and do not predict extent of systemic disease or prognosis. Case We present a premature infant with skin findings, multisystem involvement, and immunohistochemical markers consistent with multisystem LCH. Conclusion Limited data from preterm neonates with LCH suggest that prognosis is particularly poor, with even limited cutaneous disease often rapidly progressing to become fatal, although diagnosis is not always prompt. Early diagnosis and treatment may affect prognosis.


| INTRODUCTION
Langerhans cell histiocytosis (LCH) is a rare disorder characterized by proliferation of Langerhans cells (LC), myeloid histiocytes originating from bone marrow that reside in the skin. LC function similarly to dendritic cells, playing a role in antigen recognition and presentation. 1,2 LCH occurs with abnormal proliferation and accumulation of immature LCs in the skin or other organs, leading to tumor formation or organ damage. 3 Etiology is unknown but detection of specific genetic mutations, including BRAF-V600E, support classification of LCH as neoplastic. 1,4,5 LCH is primarily a pediatric disease. Incidence of neonatal or congenital LCH (NCLCH) is 1-2/1 000 000 newborns. 6 Disease in premature infants is rare, with only case reports published; presentation and prognosis vary significantly. 3,[7][8][9][10] Disease is classified as single-system (SS-LCH) or multisystem (MS-LCH). In neonates, cutaneous disease is the most common form of SS-LCH and accounts for about 5% of all LCH. 6,11 NCLCH most often presents as MS-LCH, defined by involvement of two or more organ systems. Cutaneous lesions are the predominant presentation in neonates with SS-LCH and MS-LCH. 6 Presence of Birbeck granules (ultrastructural cytoplasmic inclusions) is pathognomonic. Currently, diagnosis is made by immunohistochemical detection of dendritic cell markers CD1a, S100, and langerin (CD207). 11,12 Prognosis is variable and depends on multiple factors, including involvement of "risk organs" (RO; liver, spleen, and/or hematopoietic system), presence of central nervous system (CNS)-risk lesions (involvement of skull bones), and response to therapy. 11,13 We present a preterm infant with skin findings, multisystem involvement, and immunohistochemical markers consistent with MS-LCH.
Informed parental consent was obtained and properly documented. On DOL 17, skin biopsy demonstrated infiltrating epithelioid cells with immunohistochemical staining positive for S100 and CD1a, consistent with LCH ( Figure 2). BRAF-V600E staining was negative.

| CASE DESCRIPTION
Oncology was consulted and intravenous methylprednisolone was ini-

| DISCUSSION
Diffuse congenital purpuric cutaneous lesions, or a "blueberry muffin rash," can represent infectious, vascular, or hematologic/oncologic etiologies. Fetal dermal erythropoiesis is prolonged in infectious or hematologic etiologies in an attempt to compensate for increased blood cell production. 14 The rash is classically associated with rubella and CMV. Congenital CMV is the most common congenital infection worldwide, with prevalence of 0.4% to 0.5% in the United States. 15,16 TORCH and other infections were considered due to our patient's "blueberry muffin rash," premature birth, hepatosplenomegaly, and thrombocytopenia.
Cutaneous metastases from underlying neoplastic processes can present with congenital rash. Leukemia, LCH, and neuroblastoma are the three most common etiologies. 14 Normal levels of urine vanillylmandelic acid and homovanillic acid excluded neuroblastoma.
Leukemia cutis, a dermal infiltration of leukemic cells, presents as reddish-purple nodules and occurs in 25% to 30% of congenital leukemia cases. 17 Leukemia was unlikely with a normal peripheral smear.
With LCH, cutaneous lesions can vary widely and do not predict extent of systemic involvement. 18 Skin and radiographic findings prompted consideration of LCH in our patient.
While congenital infections are more prevalent in premature neo- Medicine, University of Texas Health Science Center at Houston) provided the raw images of the pathology slides used in Figure 2. None of the authors has financial relationships relevant to this article to disclose.

CONFLICT OF INTEREST
The authors have no potential conflicts of interest to disclose.

ETHICS STATEMENT
This case report has been written with institutional approval, and informed, written parental consent was obtained prior to the initiation of the case report.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.