Congenital Self-Healing Reticulohistiocytosis 

Updated: Jun 26, 2018
Author: David F Butler, MD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Congenital self-healing reticulohistiocytosis has been described as a benign form of Langerhans cell histiocytosis (LCH) that appears during the first 2-3 months of life and then resolves over a period of several months. However, more aggressive forms of LCH have been reported during the neonatal period and may initially be clinically indistinguishable from congenital self-healing reticulohistiocytosis. Continued surveillance and monitoring of patients presumed to have congenital self-healing reticulohistiocytosis is paramount.

LCH, once described as histiocytosis X, is a clonal proliferative disorder of Langerhans cells that stain immunohistochemically with S-100 and CD-1a and demonstrate cytoplasmic Birbeck granules under electron microscopy.[1] Four variants of this disorder have been described: Letterer-Siwe disease, Hand-Schüller-Christian disease, eosinophilic granuloma, and congenital self-healing reticulohistiocytosis, also termed Hashimoto-Pritzker disease.[2]

Letterer-Siwe disease is an acute, sometimes fulminant, multisystem disorder that commonly develops during early infancy. Skin findings often demonstrate multiple scaly papules in a seborrheic distribution. Lesions occur in crops and may be crusted or hemorrhagic. Systemic involvement may include the pulmonary system, the liver, the spleen, bone, bone marrow, the hypothalamus, the gastrointestinal tract, and lymph nodes.[3]

Hand-Schüller-Christian disease is a chronic, progressive, multifocal variant that usually affects adults. This variant has 4 characteristic findings: exophthalmos, diabetes insipidus, bone lesions, and mucocutaneous lesions. Skin lesions often have a xanthomatous appearance.[4]

Eosinophilic granuloma is a more chronic, localized disorder that most often involves bone. The cranium, ribs, vertebrae, pelvis, scapulae, and long bones may be involved.[2] Related articles include Eosinophilic Granuloma (Histiocytosis X), Imaging in Eosinophilic Granuloma of the Skeleton, and Langerhans Cell Histiocytosis Imaging.

Congenital self-healing reticulohistiocytosis was first reported in 1973 by Hashimoto and Pritzker as a benign, self-limited variant of LCH with only skin involvement.[5] This variant usually manifests at birth or during the neonatal period as reddish-brown papules or papulovesicular lesions. Lesions resolve within 3 months. Systemic involvement does not develop.

Because skin manifestations of the more aggressive, systemic forms of LCH may initially be lesions that mimic congenital self-healing reticulohistiocytosis, a thorough evaluation for systemic abnormalities must be undertaken. A recent case report highlights the necessity for close follow-up. A 2-month-old Japanese boy was diagnosed with "skin only Langerhans cell histiocytosis" after developing typical skin lesions positive for CD1a with a negative systemic workup. Complete regression of skin lesions occurred by age 9 months. By age 11 months, the patient developed fever, cough, and a left supraclavicular swelling. Workup revealed a mass in the thymus composed of CD1a-positive histiocytes and the patient underwent multiagent chemotherapy.[6]  A review of several similar cases was published in 2012.[7] One author described two infants who presented with similar clinical manifestations, with one infant having skin lesions involute and remained free of internal involvement but the other infant developed extensive internal involvement.[8]

Congenital self-healing reticulohistiocytosis is truly a diagnosis of exclusion, and long-term follow-up monitoring for possible relapse or progression of the disease is required.

Articles on related topics include Multicentric Reticulohistiocytosis and Langerhans Cell Histiocytosis.

Pathophysiology

Langerhans cells arise from bone marrow precursors to populate the epidermis and act as antigen-presenting cells; they play a key role in immune surveillance and contact sensitivity. By the seventh week of gestation, Langerhans cells are found in the epidermis and are found to start expressing CD1a protein by 60 days of gestation.[9] The clonal, proliferative nature of LCH has long been debated as to whether it represents a reactive or neoplastic process.[10] A virally induced proliferation of Langerhans cells was disproved by extensive polymerase chain reaction screening for 9 different viruses.[11]

Elevated levels of cytokines such as tumor necrosis factor-alpha; interferon gamma; granulocyte-monocyte colony-stimulating factor; and interleukins 1, 2, 4, and 10 have been demonstrated in the tissue of LCH lesions.[12, 13] The actual role of these cytokines in the pathogenesis of the disease remains obscure.

Etiology

The etiology of congenital self-healing reticulohistiocytosis remains unknown. Viral, neoplastic, and immunologic mechanisms have been proposed. Elevated values of cytokines, including interleukins 1 and 2, tumor necrosis factor-alpha, and granulocyte-macrophage colony-stimulating factor, have been reported, suggesting the possibility of deregulated immune stimulation.[14]

Epidemiology

Frequency

United States

Owing to the high rate of spontaneous resolution and lack of clinical recognition, the true incidence of congenital self-healing reticulohistiocytosis may be underreported.[15, 16] The reported prevalence of LCH in children is 5 cases per million population,[2] and the incidence rate of congenital self-healing reticulohistiocytosis is much lower.

International

An annual prevalence of 4-5.4 cases per million population is reported for all forms of LCH, and, since Hashimoto and Pritzker first described congenital self-healing reticulohistiocytosis in 1973, more than 100 cases have been reported.

Race

The prevalence of LCH seems to be higher among whites than persons of other races.

Sex

The sex distribution is equal.

Age

The cutaneous lesions of congenital self-healing reticulohistiocytosis typically manifest at birth or during the first 2 months of life. One case report documents the presentation of an 8-year-old girl in Japan who had multiple asymptomatic, reddish-brown papules over her face and upper limbs.[17] Skin lesions normally resolve over a 3- to 4-month period.

New papules that develop after age 2 months are not typical of congenital self-healing reticulohistiocytosis and should be investigated as possibly being a more aggressive form of LCH. Aggressive forms of LCH may manifest during the neonatal period.

Prognosis

Overall, the prognosis is good, with complete resolution of lesions within 3-4 months of their onset. Some lesions heal with residual hypopigmented, hyperpigmented, or atrophic scars.[18]

Congenital self-healing reticulohistiocytosis has been regarded as the benign end of the spectrum of LCH. By definition, congenital self-healing reticulohistiocytosis is a self-limited disorder and clinical features should completely resolve over a period of months. The few reports of relapses or the development of systemic LCH after a diagnosis of congenital self-healing reticulohistiocytosis actually represent systemic disease that initially manifested in a manner similar to congenital self-healing reticulohistiocytosis.

 

Presentation

History

Skin lesions typically are present at birth or develop during the neonatal period. Papules are most often asymptomatic. Most commonly, a history of a normal delivery following a normal-term pregnancy is reported. In one report, urticaria developed a few days after the development of the papules.[19]

Physical Examination

The development of multiple reddish-brown papules is the most common presentation of congenital self-healing reticulohistiocytosis (see the images below).[20] Solitary lesions are reported in 25% of the cases.[21, 22] Papules tend to be located on the head, neck, and distal extremities. The papules may become crusted.[23]

Urticarial patches on the leg of a 3-month-old inf Urticarial patches on the leg of a 3-month-old infant and several reddish-brown papules on the foot typical of congenital self-healing reticulohistiocytosis.
Reddish-brown papules of congenital self-healing r Reddish-brown papules of congenital self-healing reticulohistiocytosis on the foot of a 3-month-old infant.

Other manifestations may include vesicles, pustules, plaques, scaling patches, blue nodular skin infiltrates, hemorrhagic bullae, and hemangiomalike lesions.[24, 25, 26, 27] Two cases that presented with extensive erosive superficial lesions, including nasal and oral mucosa erosions, have been reported.[28] One case of intense residual pigmentation (due to hemosiderin deposition) at the sites of resolving skin lesions has been reported.[29]

A two-month-old infant was reported to manifest multiple hypopigmented flat-topped papules that histologically showed features of congenital self-healing reticulohistiocytosis and no internal involvement.[30]

Newborns have been described as "blueberry muffin babies".[31]

Eye involvement that resolved concurrently with the skin lesions has been reported.[32] Another newborn was described as having acute glaucoma secondary to a pseudo-inflammatory membrane with typical histocytic cells occluding the iridocorneal angle.[33]

Additionally, one infant with congenital self-healing reticulohistiocytosis demonstrated multiple lung cysts that completely resolved within 1 year.[34] Another infant was described as having a lung lesion that resolved with the skin lesions.[35]

Finally, although hepatomegaly has been noted in some infants, the clinical significance of this is uncertain.

The lesions of congenital self-healing reticulohistiocytosis have been reported to urticate after physical manipulation (pseudo-Darier sign); this occurs because of the increased numbers of mast cells in lesional skin along with the Langerhans cells.[19]

Particular attention should be given during examination to look for signs of extracutaneous involvement, such as the following:

  • Lymphadenopathy

  • Hepatosplenomegaly

  • Soft tissue mass

  • Neurologic deficits

  • Pathologic fractures

  • Pulmonary

The skin lesions of congenital self-healing reticulohistiocytosis may be localized or widely disseminated. Although a solitary lesion or a limited number of lesions is more common, disseminated crusted papules of congenital self-healing reticulohistiocytosis have been reported.[36]

 

DDx

Diagnostic Considerations

Congenital self-healing reticulohistiocytosis should also be differentiated from the following other histiocytic disorders known to spontaneously regress in infancy:

  • Juvenile Xanthogranuloma (Nevoxanthoendothelioma)

  • Generalized eruptive histiocytoma

  • Indeterminate cell histiocytosis

Note the following differential diagnoses reported by Zunino-Goutorbe et al[37] :

  • Congenital fibrosarcoma

  • Infantile fibrous hamartoma

  • Infantile myofibroma

  • Ulcerated hemangioma

Differential Diagnoses

 

Workup

Laboratory Studies

The diagnosis of congenital self-healing reticulohistiocytosis depends on the presence of the histopathologic features of the disease and either CD-1a–positive staining of cells or the finding of Birbeck granules using electron microscopy.

A skin biopsy is required for the diagnosis; a punch biopsy is preferable. Laboratory studies should include a CBC count, serum chemistries, liver function tests, coagulation studies, and urine osmolarity.[38] Depending on the clinical presentation, other studies to consider would include the following:

  • Gram stain

  • Skin scrapings for scabies

  • Potassium hydroxide and Tzanck preparations

  • Bacterial, viral, and fungal cultures

  • TORCH (toxoplasmosis, other infections, rubella, cytomegalovirus infection, and herpes) serologies

Imaging Studies

The following imaging studies may be warranted:

  • Abdominal ultrasound

  • Chest, skull, and long bone radiographs

  • MRIs of the chest and abdomen

Other Tests

Bone marrow aspiration may be needed.

Histologic Findings

The histologic findings are often indistinguishable from Langerhans cell histiocytosis (LCH). Hematoxylin and eosin–stained sections demonstrate a polymorphous infiltrate of histiocytes, mononuclear cells, neutrophils, eosinophils, and mast cells involving the papillary and reticular dermis (see image files below).[39] Extension of the infiltrate to the fat is rare. Crusting and epidermal ulceration are common. Infiltrating Langerhans cells often exhibit indented or kidney-shaped nuclei (see image files below). Epidermotropism and the formation of intraepidermal microabscesses of Langerhans cells may be seen (see image below). Usually, Langerhans cell histiocytes have a scant amount of cytoplasm, but, on occasion, large mononuclear or multinucleated histiocytes may have abundant eosinophilic ground-glass cytoplasm that may mimic the giant cells of reticulohistiocytosis. An increased number of mast cells may be noted.

Hematoxylin and eosin–stained section (400X) showi Hematoxylin and eosin–stained section (400X) showing hemorrhage and infiltration of papillary dermis and epidermis with mononuclear and histiocytic (Langerhans) cells with reniform nuclei.
Hematoxylin and eosin–stained section (400X) showi Hematoxylin and eosin–stained section (400X) showing an intraepidermal collection of histiocytic (Langerhans) cells with prominent reniform nuclei.

The histologic diagnosis should be confirmed with immunohistochemical stains. Langerhans cells stain positive for CD-1a (see image below) and S-100. Other stains available are peanut agglutinin (PNA), placental alkaline phosphatase (PLAP), and interferon-gamma receptor. These stains are not specific for congenital self-healing reticulohistiocytosis; they stain all forms of LCH.

Immunohistochemical staining with CD-1a shows posi Immunohistochemical staining with CD-1a shows positive staining of cells within intraepidermal microabscesses.

No significant differences in the expression of E-cadherin, PHH3, and Ki-67 have been found in comparisons of cases of congenital self-healing reticulohistiocytosis and disseminated LCH.[15]

Langerhans cells also demonstrate the presence of Birbeck (tennis racket) granules on electron microscopy (see image below). CD207 or Langerin is a new immunostain that can also identify Birbeck granules.[38]

Electron microscopy demonstrating cytoplasmic Birb Electron microscopy demonstrating cytoplasmic Birbeck (tennis racket) granules.

Some differences have been noted ultrastructurally between congenital self-healing reticulohistiocytosis and systemic forms of LCH. Electron microscopy reveals approximately 50% of cells in LCH have Birbeck granules, compared with only 10-30% of congenital self-healing reticulohistiocytosis cells. Transformation of Birbeck granules to laminated dense bodies is noted in congenital self-healing reticulohistiocytosis and may reflect degenerative changes. Some authors regard the coexistence of laminated dense bodies and Birbeck granules as indicative of congenital self-healing reticulohistiocytosis.[40]

Currently, however, no histologic or laboratory means is available to distinguish congenital self-healing reticulohistiocytosis from LCH. Spontaneous regression of the lesions and lack of systemic disease are the only means to differentiate these disorders.

 

Treatment

Medical Care

Because congenital self-healing reticulohistiocytosis is a self-limited disorder that is asymptomatic, no specific treatment is required.

Consultations

Consultation with a pediatric dermatologist may be required to confirm the diagnosis. Consultation with a pediatric hematologist/oncologist is important in the systemic evaluation of the patient.

Long-Term Monitoring

Congenital self-healing reticulohistiocytosis patients must be evaluated at regular intervals for signs of progression or recurrence. Any signs of extracutaneous involvement must be investigated. Long-term follow up may include laboratory studies and other tests included in the initial evaluation.