Information on the following diseases can be found in the Related Disorders section of this report:

• Rosai-Dorfman Disease
• Mastocytosis
• Erdheim-Chester Disease
• Seborrheic Dermatitis
• Lymphoma
• .

Infants often present with extensive seborrhia-like rash on the scalp that mimics persistent cradle cap; an erythematous papular rash mimicking a Candida diaper rash; or deep ulcerative lesions in the groin. A few have purplish-brown lesions 3-6mm in diameter that resemble. Marked hypertrophy of the gingiva with early eruption of teeth is seen. Infiltration of the liver and spleen results in massive organomegaly. Liver dysfunction causes hypoproteinemia with edema and ascites. Lymph nodes in the cervical, axillary, and inguinal areas are most often affected, but mediastinal nodes may enlarge causing wheezing and respiratory compromise. Lung involvement results in tachypnea and pneumothoraces. Bone marrow infiltration causes pancytopenia, but thrombocytopenia is often the most obvious problem with bleeding and anemia that may be exacerbated by hypersplenism. Bone lesions in children or adults present as painful lesions. For children the skull is most often affected, followed by long bones of the upper and lower extremity, ribs and spine. Adults have many more lesions in the madible and maxilla. Also, pulmonary involvement is more prevalent in adults because of the association with smoking. Many adult female patients have ulcerative lesions in the genital tract or groin. Both groups of patients may initially present with diabetes insipidus that may be presumed idiopathic. Patients with cerebellar involvement present with ataxia and thought to have an infectious disease, multisystem atrophy, or Parkinson's disease. Cerebral infiltrations of several types my lead to headaches, behavior changes.

The exact cause of Langerhans cell histiocytosis is unknown. The Langerhans cell is a normal cell that responds to a variety of immune system stimuli. Possible causes also include infections or immune system abnormalities, but these theories have not been proven. Environmental factors may play a role.

Researchers at the Children's Hospital of Philadelphia studied 35 children diagnosed with LCH and determined that the human herpesvirus 6 (HHV-6) was present in 25 of 35 tissue samples. However, more research is necessary to determine what role, if any, HHV-6 plays in the development of LCH in some children.

In rare cases, more than one case of LCH has appeared in the same family, although no clear inheritance pattern has been identified.

Cigarette smoking may be associated with the development of some cases of pulmonary LCH. The exact role smoking plays in the development of pulmonary LCH is not completely understood.

There is no known etiology of LCH. It occurs in approximately 5 children and 2-3 adults per million population. Several cytokines are expressed at higher levels in the LC and surrounding lymphocytes. An underlying immune defect is the likely cause of the disease, but no specific gene mutations or chromosomal abnormalities have been identified although peripheral blood chromosomes are reported to be more fragile than normal. Patients with LCH have a higher incidence of malignancy either before or after the diagnosis of LCH. There are a few cases of concordant disease in presumed monozygotic twins. Family members have a higher incidence of thyroid disease.

Symptoms of the following disorders can be similar to those of Langerhans cell histiocytosis. Comparisons may be useful for a differential diagnosis:

Rosai-Dorfman disease is a rare disorder characterized by histiocytosis affecting the sinuses and the lymph nodes, resulting in abnormal enlargement of the lymph nodes (lymphadenopathy). In some cases, other organ systems of the body may be affected including the central nervous system, skin, and, in rare cases, the kidney or other areas. The exact cause of Rosai-Dorfman disease is unknown. The disorder may also be known as sinus histiocytosis with massive lymphadenopathy. (For more information on this disorder, choose "Rosai-Dorfman" as your search term in the Rare Disease Database.)

Mastocytosis is a rare disorder characterized by abnormal accumulation of mast cells in skin, bone marrow, and internal organs such as the liver, spleen and lymph nodes. The skin abnormalities associated with mastocytosis are known as urticaria pigmentosa and are characterized by small, brownish, flat or elevated spots (lesions) that may be surrounded by reddened, itchy skin. In many cases, only the skin is involved. However, the disorder may also affect various organ systems resulting in abnormally enlarged liver and spleen (hepatosplenomegaly); gastrointestinal problems such as abdominal pain and diarrhea; and cardiovascular problems such as high blood pressure (hypertension). In some cases, bones may be affected resulting in bone pain and fractures. The exact cause of mastocytosis is unknown. (For more information on this disorder, choose "Mastocytosis" as your search term in the Rare Disease Database.)

Erdheim-Chester disease (ECD) is a rare multisystem disorder of adulthood. It is characterized by excessive production and accumulation of histiocytes within multiple tissues and organs. Histiocytes are large phagocytic cells (macrophages) that normally play a role in responding to infection and injury. (A phagocytic cell is any "scavenger cell" that engulfs and destroys invading microorganisms or cellular debris.) In those with ECD, sites of involvement may include the long bones, skin, tissues behind the eyeballs, lungs, brain, pituitary gland, and/or additional tissues and organs. Associated symptoms and findings and disease course depend on the specific location and extent of such involvement. The specific underlying cause of ECD is unknown. (For more information on this disorder, choose "Erdheim-Chester" as your search term in the Rare Disease Database.)

Seborrheic dermatitis is a skin disorder characterized by reddish, scaly patches affecting the scalp. The disorder may spread to affect the neck, face, and other areas of the body. Individuals with LCH that present with skin symptoms may be misdiagnosed with seborrheic dermatitis. The exact cause of seborrheic dermatitis is not known.

Lymphoma is a general term for cancer affecting the lymphatic system. Functioning as part of the immune system, the lymphatic system helps to protect the body against infection and disease. It consists of a network of tubular channels (lymph vessels) that drain a thin watery fluid known as lymph from different areas of the body into the bloodstream. Lymph accumulates in the tiny spaces between tissue cells and contains proteins, fats, and certain white blood cells known as lymphocytes. Abnormal enlargement of the lymph nodes, liver, and spleen may occur. A malignant lymphoma may spread to affect other areas of the body such as the central nervous system and gastrointestinal tract. Affected individuals may experience fevers, fatigue, and weight loss. Some cases of Letterer-Siwe disease may mimic some forms of malignant lymphoma.

Diagnosis
Xrays of the skull, a complete skeletal bone survey and bone scan, chest xray, complete blood count and differential, erythrocyte sedimentation rate, liver function tests including AST, ALT, bilirubin, and akaline phophatase; electrolytes and urinalysis. CT of the skull if mastoids involved. Pulmonary disease: high resolution CT. Brain:MRI. Diabetes insipidus: water deprivation test or serum and urine osmolality.

Treatment
Patients should be treated on protocols of the Histiocyte Society so the biology and therapy of these rare patients can be advanced. Treatments vary depending on the extent of disease and involve chemotherpy with prednisone, velban with or without 6-mercaptopurine and methotrexate. Those patients with liver, spleen, lung, or bone marrow involvement are considered to be of "higher risk" for not responding to therapy. Patients with lesions in multiple bones or more than one "risk" organ have an excellent chance for responding to combination chemotherapy. If a patient does not respond to the standard therapy by the sixth week (or twelfth week for a partial response) they should be changed to the salvage therapy (2-CdA/Ara-C) on the LCH-S protocol.
A separate protocol exists for following and treating patients with central nervous system involvement.

Anti-cytokine therapy is being tried in a limited number of institutions.
Contact the Histiocytosis Association of America for details of treatment protocols:
800-858-2758 or www.histo.org

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

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Bhatia S, Nesbit ME, Egeler RM et al. Epidemiology study of Langerhans cell histiocytosis in children. J Pediatr 1997; 130:774-784.

Geissman G, Lepelletier Y, Fraitag S, et al. Differentiation of Langerhans cells in Langerhans cell histiocytosis. Blood 2001;97:1241-1248.

Baugartner I, von Hochstetter A, Baumert B, Luetolf U, Follath F. Langerhans'-Cell Histiocytosis in Adults. Med Ped Oncol 1997; 28:9-14.