Congenital Self-Healing Reticulohistiocytosis

Pediatric Dermatology
Section Editor: Andrew Krakowski, MD
Assistant Section Editors: Sheila Friedlander, MD; Andrea Zaenglein, MD

This month’s column by Young H. Lee, MD; Mala K. Talekar, MD; Catherine G. Chung, MD; Moshe D. Bell, MD; Andrea L. Zaenglein, MD

The authors are from Penn State/Hershey Medical Center, Hershey, Pennsylvania. Disclosure: The authors report no relevant conflicts of interest.

J Clin Aesthet Dermatol. 2014;7(2):49–53

Congenital self-healing reticulohistiocytosis, also known as congenital self-healing Langerhans cell histiocytosis or Hashimoto-Pritzker disease, is a Langerhans cell histiocytosis. It is characterized by skin lesions in the newborn period in an otherwise healthy infant that show a Langerhans cell infiltrate in the skin on histological analysis. These findings subsequently spontaneously involute. This report describes two newborns who presented at birth with differing presentations of congenital self-healing reticulohistiocytosis. A review of the disorder, including diagnosis and evaluation, is presented.

Congenital self-healing reticulohistiocytosis (CSHR) is a rare benign variant of Langerhans cell histiocytosis, first described by Hashimoto and Pritzker.1 It usually presents as multiple red-brown papules, nodules, or vesicles at birth or in the neonatal period. Solitary lesions are also well described. All lesions tend to involute spontaneously within several months. CSHR is characterized by lack of systemic involvement.[1,2] However, there have been reports of recurrences and multi-organ involvement following the resolution of early Langerhans cell proliferations, highlighting the unpredictable and variable course of the disease and the need for long-term follow-up.[3–6]
Here, the authors describe two cases of newborns who presented with crusted cutaneous papules that soon resolved and were subsequently diagnosed with CSHR.

Case 1
A newborn girl, born at 37 and 3/7 weeks gestation via an induced vaginal delivery for intrauterine growth restriction by ultrasound, was noted to have a solitary 0.8cm brown, crusted papule on her left posterior shoulder that was present at birth (Figure 1A). She was born to a 17-year-old mother with a history of smoking, depression, and bipolar disorder, treated with lithium during the first trimester.
One month after birth, the baby was evaluated in the outpatient dermatology clinic. She was developing well with no signs of systemic disease. Over the past month, the infant’s mother reported that the lesion would occasionally drain opaque pus-like fluid, though manipulating the papule did not seem to cause discomfort to the infant. The remainder of her physical examination was normal; no lymphadenopathy or organomegaly was noted.

A biopsy was performed, which grossly revealed an opaque yellow drainage beneath the crust of the papule. Histological evaluation revealed a diffuse dermal infiltrate composed of large histiocytes with reniform nuclei, many of which expressed CD1a by immunohistochemistry (Figure 2). Given the possibility of multiorgan involvement with Langerhans cell histiocytoses, the baby was referred to pediatric hematology/oncology for evaluation. Imaging and laboratory studies were performed, including a skeletal survey, computed tomography (CT) of the chest, complete blood count with differential, complete metabolic panel, coagulation studies, iron studies and ferritin, uric acid, and erythrocyte sedimentation rate. All were within normal limits.

Eight weeks later, the lesion had completely regressed, leaving postinflammatory hyperpigmentation (Figure 1B). Given the clinical course and histopathological presentation, as well as the negative imaging and laboratory studies, CSHR was diagnosed.

Case 2
A newborn boy was born at 38 and 3/7 weeks gestation via a Caesarean section for breech presentation to a 27-year-old mother with an uncomplicated prenatal course at an outside hospital. He was noted to have multiple brown crusted papules on his trunk and extremities, ranging 1 to 5mm in size (Figure 3). He was also noted to have respiratory distress at birth and required CPAP followed by supportive oxygen for several days. A sepsis work-up was initiated, and he was started on broad-spectrum antibiotics. Dermatology was consulted due to concerns for an infectious etiology, specifically herpes simplex virus. A biopsy was performed, which showed a dense nodular infiltrate composed of numerous eosinophils, lymphocytes, and histiocytes. The histiocytes stained positive for CD1a.

He was then transferred to our neonatology unit for further management, and Pediatric Hematology Oncology was consulted. His exam revealed the skin findings as above and tachypnea. There was no hepatosplenomegaly, pallor, jaundice, oropharyngeal lesions, or signs of neurological involvement.
Imaging and laboratory studies were performed, including a skeletal survey and chest x-ray, CT of the chest, complete blood count with differential, complete metabolic panel, coagulation studies, iron studies and ferritin, uric acid, and erythrocyte sedimentation rate. The laboratory results were within normal limits. The chest x-ray showed fine hazy interstitial opacity throughout the lungs, but the CT of the chest did not reveal any evidence of pulmonary involvement by LCH. The skeletal survey was normal. Given the clinical picture and the supportive laboratory, radiological and histopathological evidence, CSHR was diagnosed. The infant improved clinically over the next few days and was discharged home.

The infant had serial clinical follow-up throughout the first year. The skin lesions completely resolved with only residual postinflammatory hyperpigmentation. No new skin lesions or any signs of systemic involvement with LCH were noted.

The histiocytoses are a group of disorders characterized by a monoclonal proliferation and infiltration of histiocytes, which includes monocytes/macrophages, dermal dendritic cells, and Langerhans cells, within various organs.[7] The various histiocytoses have been more recently reclassified based on the predominant cell type by the Histiocyte Society, dividing the disorders into dendritic cell disorders, which includes the Langerhans cell histiocytoses (LCH), macrophage-related disorders, and malignant histiocytic disorders (Table 1).[8]

Prior to the reclassification of histiocytoses, LCH was traditionally separated into four subtypes, including Letterer-Siwe disease, Hand-Schüller-Christian disease, eosinophilic granuloma, and Hashimoto-Pritzker disease. Letterer-Siwe disease was described as the acute diffuse form of LCH, a multi-system disease involving the skin, lung, liver, lymph nodes, bone, and the hematopoietic system. Hand-Schüller-Christian disease encompassed the classic triad of diabetes insipidus, bone lesions, and exophthalmos. Eosinophilic granuloma was the localized form of LCH, most commonly manifesting as a single asymptomatic granulomatous lesion within the bone. Finally, Hashimoto-Pritzker disease, or CSHR, was almost always limited to the skin and resolved within several weeks.9 More recently, these LCH disorders have been considered a spectrum of disease rather than distinct entities.

A diagnosis of LCH is typically made with a skin biopsy that shows positive immunohistochemical staining of infiltrative cells in the dermis with CD1a and S-100. These cells also exhibit classic Birbeck granules on electron microscopy, which was once the gold standard for identifying Langerhans cells before immunohistochemistry became more prominent.[8] Langerin (CD 207) is a newer monoclonal antibody directed against a type-II transmembrane C-type lectin protein of Birbeck granules that can also be used to identify Langerhans cells.[10,11]

CSHR is characterized by involvement limited to the skin and spontaneous involution. However, there are rare reports of pulmonary and ocular involvement in CSHR that resolved in concordance with cutaneous findings.[12,13] The clinical presentation of skin findings can vary widely, but classically there are multiple, red-brown papules, nodules, or vesicles found on all parts of the body, at times including the palms and soles, resembling a varioliform rash.[14] These lesions can be crusted, eroded, or ulcerated, and they can also less commonly be found on mucosal surfaces.[2,6] There have also been reports of disseminated brown or violaceous nonblanching macules and papules that raised concerns of congenital infections or other hematological disorders as seen with the “blueberry muffin” lesions.[15,16] Cases of solitary lesions of CSHR are also well documented, such as in Case 1.[17–19] They are often a moist, eroded nodule or plaque. In contrast to CSHR, disseminated forms of LCH tend to be scaly, eczematous patches, often similar to seborrheic dermatitis, most prominent in the intertriginous areas and on the scalp, and these areas can become eroded or ulcerated.[14,20] Given the physical exam findings, CSHR can be suspected over disseminated LCH, but these distinctions are not conclusive. In a small number of cases, the neonates have been found to have CT findings consistent with pulmonary LCH, with or without respiratory symptoms, in addition to skin involvement. It has been suggested that systemic investigation, including chest CT, be done to evaluate this disorder.

There are no definitive criteria other than clinical observation that can distinguish CSHR from the disseminated forms of LCH. There have been several reports of relapses and systemic disease following the resolution of early Langerhans cell histiocytoses, stressing the unpredictable nature of the disease and the necessity for long-term follow-up.[3–6] One infant’s skin and mucosal lesions disappeared by three months of age and had a normal work-up, but at eight months, her skin lesions relapsed, accompanied by anemia, thrombocytopenia, lung involvement, and hepatosplenomegaly.

She ultimately died at 11 months of age.[5] In another report, diabetes insipidus occurred two years after the skin findings resolved.[3] The most common clinical manifestations of systemic involvement include osteolytic bone lesions, particularly of the cranium, and lymphadenopathy, but the bone marrow, liver, spleen, lungs, gastrointestinal tract, central nervous system, and endocrine glands can all be affected.[20]

Once the diagnosis of a Langerhans cell histiocytosis is made, baseline laboratory and radiographic evaluation must be done to determine the extent of organ involvement. In addition to a thorough history and physical examination, a complete blood count with differential, liver function tests, coagulation studies, a skeletal survey, and chest radiography should be completed.[7,20,21] Further studies, such as urine osmolality (to evaluate for diabetes insipidus) can be done if indicated by these studies or symptoms.

Overall, patients with CSHR have an excellent prognosis, with a 100-percent survival with minimal or no treatment, given that it does not progress to multisystem disease.[22] Recognition of this entity at presentation is important as it will potentially prevent administration of systemic toxic therapy to the infant in question. There are no specific recommended treatments for CSHR, but if lesions persist, topical corticosteroids, tacrolimus, or nitrogen mustard can be used, or localized lesions may be excised.[22–24] However, given the potential for later relapse and/or systemic involvement, multidisciplinary long-term follow-up with both Dermatology and Pediatric Hematology-Oncology is indicated.

The new classification of Langerhans cell histiocytoses highlights the variable clinical expression of these diseases. While a diagnosis of CSHR is often strongly suspected by the clinician, it cannot be confirmed until the clinical course is completed. Even then, a suspicion for recurrence must be maintained for years.

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