What are the other Names for this Condition? (Also known as/Synonyms)

• Hashimoto-Pritzger Disease
• Langerhans Cell Granulomatosis
• LCH (Langerhans Cell Histiocytosis)

What is Langerhans Cell Histiocytosis? (Definition/Background Information)

• Langerhans Cell Histiocytosis (LCH) is a rare, complicated, and non-heritable genetic disorder that can result in tumor formation in many different body parts
• The disorder affects children under the age of 15, predominantly in the 2-3 years age range. LCH can also affect adults, with lungs being the chief organs affected
• The Langerhans cells are the immune cells of the bone marrow that help control the immune system. They are distributed throughout the body, including in the spleen, liver, lungs, skin, and lymph nodes, apart from the bone marrow
• Carrying non-heritable mutations in the BRAF gene, viral infections, smoking, exposure to toxins, and belonging to the Caucasian race increase the risk for being affected by Langerhans Cell Histiocytosis
• Individuals with this disorder carry a mutation in the BRAF gene. This gene codes for a protein known as B-Raf, which is involved in monitoring cellular growth in response to chemical signals. The BRAF gene is a proto-oncogene, which means that it is a normal gene that can turn cancerous when mutations cause it to be overexpressed
• The BRAF gene mutations can cause the protein B-Raf to be overactive, giving signals for growth and development in the absence of chemical cues from the immediate environment. When the mutations affect Langerhans cells, these cells start multiplying without control
• These immature immune cells form tumors, known as granulomas. These granulomas can affect different parts of the body, such as the bones, brain, skin, lymph nodes, liver, lungs, pituitary gland, and the bone marrow
• The severity of symptoms and the manifestation of disorder are known to vary widely. In about 80% of the affected children, the tumors appear in the bones, which can be in the skull, hip bone, leg bones, and the ribs. Approximately 15-20% of lesions occur in the lungs, liver, and the bone marrow. Langerhans Cell Histiocytosis can affect the skin as well
• The symptoms of Langerhans Cell Histiocytosis can be wide-ranging including pain in the abdomen, anemia, skin rashes, jaundice, breathing problems, vulnerability to infections, hormonal imbalances, swollen lymph nodes, and affecting growth and fertility
• The potential complications include hearing impairment, development of diabetes insipidus, permanent scarring of skin, intellectual deficiency, infertility, and organ failure
• A physical examination with assessment symptoms, evaluation of medical history, tests for hearing, evaluation of organ functions and structure (via imaging tests), and biopsy of the affected tissue are typically required for an accurate diagnosis of Langerhans Cell Histiocytosis
• Although in a few cases, the condition resolves by itself; in others, chemotherapy is often required. It must be noted that Langerhans Cell Histiocytosis is not considered to be a form of cancer
• The prognosis of Langerhans Cell Histiocytosis depends on whether the granulomas are solitary or multiple, if they affect vital organs, and how they respond to treatment. It is imperative that individuals with this disorder get suitable supportive care; a lifelong management of the disorder has to be undertaken

Who gets Langerhans Cell Histiocytosis? (Age and Sex Distribution)

• Langerhans Cell Histiocytosis is a rare genetic disorder, occurring primarily in children. It is believed that the disorder may be underdiagnosed owing to asymptomatic or misdiagnosed cases
• The disorder affects children under the age of 15 years, with symptoms manifesting between 2-3 years of age, in a majority of them
• The incidence rate for the condition is reported to be 1:200,000 among children. In newborns, it is rarer, with 1 in 1-2 million children being affected
• Although predominantly seen in children, the condition can also affect adults. In adult onset disorder type, the disorder is most prevalent amongst past or active smokers
• There is a gender bias in the occurrence of LCH; males are affected twice as frequently as females
• Caucasians are more susceptible to this disorder than individuals from other races and ethnicities

What are the Risk Factors for Langerhans Cell Histiocytosis? (Predisposing Factors)

The following factors may increase the risk for being affected by Langerhans Cell Histiocytosis:

• Non-heritable (somatic) mutations in the BRAF proto-oncogene
• Exposure to toxins in the environment
• Viral infections
• Belonging to the male gender
• Being of Caucasian descent
• History of smoking

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Langerhans Cell Histiocytosis? (Etiology)

Langerhans Cell Histiocytosis is caused by mutations in the BRAF gene. Langerhans cells are immune cells originating in the bone marrow. They modulate the immune functions in the body, and apart from the bone marrow, are distributed in many organs/parts of the body, such as the spleen, liver, skin, lungs, and lymph nodes.

• Under normal circumstances, the BRAF gene codes for a protein known as the B-Raf protein. The B-Raf protein is involved in signal transduction mechanisms to regulate growth of cells. Thus, when there is a chemical signal conducive to cell growth, the BRAF gene is turned “on,” resulting in the B-Raf protein synthesis
• When there is a mutation in the BRAF gene in Langerhans cells, such that the gene is permanently ‘switched on’ irrespective of the chemical cues in the immediate environment, cell growth and multiplication occur without control. These results in the formation of tumors/granulomas made up of immature immune cells
• The BRAF gene mutations causing Langerhans Cell Histiocytosis are not passed from parent to offspring; these are known as somatic or non-heritable mutations. Thus, the disorder does not typically run in families
• However, in the scientific literature, a few families have been reported involving multiple cases of Langerhans Cell Histiocytosis. The exact mode of inheritance of this disorder in such cases is unknown
• The onset of Langerhans Cell Histiocytosis symptoms depend on the type of mutation in an individual, and several variants of the disorder (known as LCH variants) exist

Note: LCH is not considered to be a form of cancer; the tumors that form are considered to be benign.

What are the Signs and Symptoms of Langerhans Cell Histiocytosis?

The signs and symptoms of Langerhans Cell Histiocytosis are varied in their severity and complexity. Some individuals with the disorder may be asymptomatic. In about 80% of cases, the granuloma tumors affect the bones; in the rest of the cases, the tumors may affect the liver, bone marrow, and lungs.

Single or multiple granulomas in many organs are known to arise simultaneously. The symptoms associated with each organ are described below:

• Bones (involving the skull, hipbone, long bones of the limbs, ribs, etc.)
  • Pain and swelling in the bones
  • Fragility and fractures
  • Protruding eyeballs
• Skin
  • Blisters
  • Rashes
  • Eczema
  • Psoriasis
• Lungs
  • Inflammation in airways
  • Stiffening of airways
  • Difficulty in breathing
  • Coughing up blood
  • Fibrosis of the lungs
  • Increased risk of infections
• Pituitary gland - which regulates the synthesis of many hormones modulating many body functions
  • Hormonal imbalance
  • Growth retardation; short stature
  • Delayed puberty
  • Infertility
  • Diabetes insipidus (production of copious amounts of dilute urine)
  • Thyroid gland malfunction, which can affect regulation of body temperature, health of skin and hair, and one’s moods
• Liver
  • Enlargement of the liver (hepatomegaly)
  • Yellowing of the skin and whites of eyes
• Enlargement of the spleen (splenomegaly)
• Brain
  • Headaches
  • Confusion, irritability
  • Compromised intellectual development
  • Seizures
• Central nervous system
  • Lack of coordination
  • Difficulty in swallowing
  • Tremors
  • Speech problems
• Swollen lymph nodes
• Bone marrow
  • Overall reduction in the numbers of different blood cell types (pancytopenia)
  • Issues with blood clotting
  • Anemia
  • Fatigue, dizziness
  • Feeling of ill health
  • Fever
• Ears
  • Structural defects
  • Middle ear infections
  • Pus formation

How is Langerhans Cell Histiocytosis Diagnosed?

Diagnostic tests that are performed for Langerhans Cell Histiocytosis may include:

• Physical exam with evaluation of medical history
• Blood and urine sample analysis
• Liver function test
• Radiographic studies (involving the chest, skeletal survey) including CT, MRI scan of the brain (chiefly of the hypothalamus-pituitary organs)
• Other tests include: Skin/tissue biopsy, lung function test, hormonal studies, auditory and visual testing, etc.

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Langerhans Cell Histiocytosis?

Complications due to Langerhans Cell Histiocytosis may include:

• Diabetes insipidus
• Hearing impairment can lead to deafness
• Permanent skin scarring
• Decreased intellectual ability; depression and anxiety
• Organ damage that could include liver cirrhosis, chronic lung dysfunction, etc.
• Acute leukemia
• Physical growth retardation

How is Langerhans Cell Histiocytosis Treated?

Individuals with granulomas in the bones, skin, lymph nodes and pituitary gland are collectively grouped in the “multisystem low risk” category. Those with involvement of vital organs, such as the lungs, bone marrow, spleen and liver, fall in the “multisystem high risk” category. These categorizations help with the treatment plans.

Treatment of Langerhans Cell Histiocytosis is based on the course, severity, and extent of the disorder. The treatment options include:

• Administration of non-steroidal anti-inflammatory drugs (NSAIDs) for pain
• Steroid injection inside the lesion, if it is a solitary tumor
• Topical steroids and methotrexate (oral) for skin lesions
• Phototherapy with psoralen and ultraviolet irradiation (PUVA) therapy to treat skin lesions
• Surgical excision of solitary lesions, when possible
• 2 chlorodeoxyadenosine treatment for low-risk disorder; high-dosage 2 chlorodeoxyadenosine treatment for children with high-risk disorder
• Chemotherapy, for lesions that involve the central nervous system (the therapy for children may be for a period up to 1 year)
• Low-dose radiation therapy

Clinical trials conducted by the US-based “Histiocyte Society” may be an important avenue for new treatment methods and modalities.

How can Langerhans Cell Histiocytosis be Prevented?

• Currently, there are no specific methods or guidelines to prevent Langerhans Cell Histiocytosis, since it is a genetic condition
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as Langerhans Cell Histiocytosis

Regular (long-term) medical screening at periodic intervals with tests and physical examinations are highly recommended.

What is the Prognosis of Langerhans Cell Histiocytosis? (Outcomes/Resolutions)

The prognosis of Langerhans Cell Histiocytosis depends on the severity and extent of the disorder and the response to therapy.

• Generally, individuals with “low risk” category of disorder involving the skin, bones, and pituitary gland, respond better to treatment than those with the “high risk” category disorder (with spleen, liver, bone marrow, and lung involvement).
• 50% of the children under the age of 2 years, diagnosed with some organ dysfunction die of the disorder
• Long-term medical and supportive care may be needed for individuals with severe developmental, cognitive, and neurological abnormalities

Additional and Relevant Useful Information for Langerhans Cell Histiocytosis:

Langerhans Cell Histiocytosis has been variously described as ‘Hashimoto-Pritzger Disease’ and ‘Langerhans Cell Granulomatosis’.