Chronic multifocal Langerhans cell histiocytosis, previously known as Hand–Schüller–Christian disease, is a type of

Langerhans cell histiocytosis Langerhans cell histiocytosis (LCH) is an abnormal clonal proliferation of Langerhans cells, abnormal cells deriving from bone marrow and capable of migrating from skin to lymph nodes. Symptoms range from isolated bone lesions to multisystem d ...

(LCH), which can affect multiple organs. The condition is traditionally associated with a combination of three features; bulging eyes, breakdown of bone (lytic bone lesions often in the skull), and

diabetes insipidus Diabetes insipidus (DI) is a condition characterized by large amounts of dilute urine and increased thirst. The amount of urine produced can be nearly 20 liters per day. Reduction of fluid has little effect on the concentration of the urine. ...

(excessive thirst and passing urine), although around 75% of cases do not have all three features. Other features may include a fever and weight loss, and depending on the organs involved there may be rashes, asymmetry of the face,

ear infections Otitis is a general term for inflammation in ear or ear infection, inner ear infection, middle ear infection of the ear, in both humans and other animals. When infection is present, it may be viral or bacterial. When inflammation is present due to ...

, signs in the mouth and the appearance of advanced gum disease. Features relating to lung and liver disease may occur. It is due to a

genetic mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosis ...

in the MAPKinase pathway that occurs during early development. The diagnosis may be suspected based on symptoms and

MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and rad ...

and confirmed by

tissue biopsy A biopsy is a medical test commonly performed by a surgeon, an interventional radiologist, or an interventional cardiologist. The process involves the extraction of sample cells or tissues for examination to determine the presence or extent o ...

. Blood tests may show

anaemia Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availab ...

, and less commonly a low white blood cell count and low platelet count. Treatment may involve surgery,

chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...

radiation therapy Radiation therapy or radiotherapy (RT, RTx, or XRT) is a therapy, treatment using ionizing radiation, generally provided as part of treatment of cancer, cancer therapy to either kill or control the growth of malignancy, malignant cell (biology), ...

, and certain medicines. Updated 2017 Hand–Schüller–Christian disease was named for the American pediatrician Alfred Hand Jr., the Austrian neuroradiologist Arthur Schüller, and the American internist Henry Asbury Christian, who described it in 1893, 1915 and 1919, respectively. Before the Histiocyte Society classified histiocytoses in the 1980s, the condition was also known as "Histiocytosis X", where "X" denoted the then unknown cause. It is now known as chronic multifocal Langerhans cell histiocytosis, a subtype of LCH. The disease is rare. Most present between the ages of two and six. The outlook depends on how many and how much organs are affected. In some people the condition is life-threatening.

Signs and symptoms

The traditional combination of three features are seen in 25% of people with the condition, which usually presents between the ages of two and six; one or both bulging eyes, breakdown of bone (lytic bone lesions often in the skull in a 'punched out' pattern), and

(excessive thirst and passing urine). The skin can be affected with rashes, bumps and

ulcers An ulcer is a discontinuity or break in a bodily membrane that impedes normal function of the affected organ. According to Robbins's pathology, "ulcer is the breach of the continuity of skin, epithelium or mucous membrane caused by sloughing ...

, and bones can be painful. There may be large lymph nodes and signs of lung and

liver disease Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Liver diseases File:Ground gla ...

. Affected people may present with fever and weight loss. The face may look asymmetrical and

are common. Between 5 and 75% of cases have been reported to present with signs in the mouth. These include mouth ulcers,

bad breath Bad breath, also known as halitosis, is a symptom in which a noticeably unpleasant breath odour is present. It can result in anxiety among those affected. It is also associated with depression and symptoms of obsessive compulsive disorder. Th ...

, swollen gums, loose teeth and an unpleasant taste. Destruction of part of the jaw bone may give the appearance of advanced gum disease.

Cause

The cause is a

in the MAPKinase pathway that occurs during early development. The origin is a

dendritic cell A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...

, although previously thought to be a

histiocyte A histiocyte is a vertebrate cell that is part of the mononuclear phagocyte system (also known as the reticuloendothelial system or lymphoreticular system). The mononuclear phagocytic system is part of the organism's immune system. The histiocy ...

, a term still used. The mutations causes white blood cells (lymphocytes, macrophages, and eosinophils) to move towards dendritic cells, resulting in damage in any organ except the heart and kidneys. The disease was once thought to be a lipid storage disease as the lesions have a high cholesterol content, but the

blood cholesterol Blood lipids (or blood fats) are lipids in the blood, either free or bound to other molecules. They are mostly transported in a phospholipid capsule, and the type of protein embedded in this outer shell determines the fate of the particle and its ...

is usually normal. Some sources such as the

National Cancer Institute The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health (NIH), which is one of eleven agencies that are part of the U.S. Department of Health and Human Services. ...

describe it as a type of

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

, while other sources specifically state it is not a type of cancer.

Diagnosis

Tests usually include imaging using

. Findings include breakdown of bone and thickening of the

pituitary stalk The pituitary stalk, also known as the infundibular stalk, infundibulum, or Fenderson's funnel, is the connection between the hypothalamus and the posterior pituitary, the posterior lobe of the pituitary gland. The floor of the third ventricle is ...

. The

perivascular space A perivascular space, also known as a Virchow–Robin space, is a fluid-filled space surrounding certain blood vessels in several organs, including the brain, potentially having an immune system, immunological function, but more broadly a dis ...

may appear prominent, the

pituitary gland The pituitary gland or hypophysis is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the human brain, brain, protruding off the bottom of the hypothalamus. The pituitary gland and the hypothalamus contr ...

cystic and there may be signs in the

white matter White matter refers to areas of the central nervous system that are mainly made up of myelinated axons, also called Nerve tract, tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distr ...

, a mass in the

hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...

and enhancement of the

meninges In anatomy, the meninges (; meninx ; ) are the three membranes that envelop the brain and spinal cord. In mammals, the meninges are the dura mater, the arachnoid mater, and the pia mater. Cerebrospinal fluid is located in the subarachnoid spac ...

X-ray An X-ray (also known in many languages as Röntgen radiation) is a form of high-energy electromagnetic radiation with a wavelength shorter than those of ultraviolet rays and longer than those of gamma rays. Roughly, X-rays have a wavelength ran ...

findings typically demonstrate sharp "punched out" lesions in the skull. The destruction of alveolar bone is usually more generalised and may appear as displaced teeth. Blood tests may show

, and less commonly a low white blood cell count and low platelet count. Other useful tests might include a

PET scan Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in Metabolism, metabolic processes, and in other physiological activities including bloo ...

. Diagnosis is confirmed by

Treatment

Treatment may involve surgery,

, and certain medicines.

Prognosis

The outlook depends on how many and how much organs are affected. The prognosis is poor if the disease presents in a young person with many affected organs, unless a newborn with skin lesions only, when the outlook is better. The prognosis is poor if liver, spleen, lung, or bone marrow is affected. A good response to chemotherapy within the first six weeks of treatment, has been found to indicate a better prognosis. In some people the condition is life-threatening. Hence, follow-up is long-term.

Epidemiology

The disease is rare. 70% of cases present before the age of 15. Around 75% of cases do not have all three traditional features.

History

MRI and

CT scan A computed tomography scan (CT scan), formerly called computed axial tomography scan (CAT scan), is a medical imaging technique used to obtain detailed internal images of the body. The personnel that perform CT scans are called radiographers or ...

findings in a

mummy A mummy is a dead human or an animal whose soft tissues and Organ (biology), organs have been preserved by either intentional or accidental exposure to Chemical substance, chemicals, extreme cold, very low humidity, or lack of air, so that the ...

have revealed evidence of the disease dating back to 900–790. B.C. The historic name of Hand–Schüller–Christian disease was named for the American pediatrician Alfred Hand Jr., the Austrian neuroradiologist Arthur Schüller, and the American pathologist Henry Asbury Christian, who described it in 1893, 1915 and 1919, respectively.H. Christian. Defects in membranous bones, exophthalmos, and diabetes insipidus; an unusual syndrome of dyspituitarism. In: Contributions to medical and biological research, dedicated to Sir William Osler. New York, P. B. Hoeber, 1919, 1: 390-401. Medical Clinics of North America, Philadelphia, PA., 1920; 3: 849-871. Shortly afterwards, Letterer in 1924 and Siwe in 1933 described a fatal condition in children who presented with large livers and spleens, large lymph nodes and bone damage. In 1940, Louis Litchtenstein and Henry L. Jaffe described a self-limiting disease characterised by "isolated bone lesions". A common feature of all these conditions was revealed to be the histological findings of large numbers of

histiocytes A histiocyte is a vertebrate cell that is part of the mononuclear phagocyte system (also known as the reticuloendothelial system or lymphoreticular system). The mononuclear phagocytic system is part of the organism's immune system. The histiocy ...

in the tissue biopsies, leading Litchtenstein to propose that the three described conditions were part of a spectrum of a disease he named "Histiocytosis X", where "X" denoted the unknown cause. In 1973, Christian Nezelof recognised the abnormal cell as a 'Langerhans-like' cell, however it took another ten years for the disease to be accepted as one entity and the term 'Langerhans cell histiocytosis' to be internationally recognised. In 1987, the Histiocyte Society published their classification of the histiocyte disorders together with criteria for diagnosis and clinical assessment of

. Hand–Schüller–Christian disease is now considered a subtype of LCH, chronic multifocal Langerhans cell histiocytosis.

References

External links

{{DEFAULTSORT:Hand-Schuller-Christian disease Monocyte- and macrophage-related cutaneous conditions Medical triads Histiocytosis Rare diseases Diseases named after discoverers