Malignant histiocytosis  is a rare hereditary disease found in the Bernese Mountain Dog and humans, characterized by histiocytic infiltration of the lungs and lymph nodes. The liver, spleen, and central nervous system can also be affected. Histiocytes are a component of the immune system that proliferate abnormally in this disease. In addition to its importance in veterinary medicine, the condition is also important in human pathology. Histiocytic disorders
A histiocyte is a differentiated tissue cell that has its origin in the bone marrow. The source for histiocytes is the monocyte/macrophage line. Monocytes (found in the blood) and macrophages (found in tissue) are responsible for phagocytosis (ingestion) of foreign material in the body. Langerhans cells are dendritic cells found in the skin and function by internalizing antigens (foreign particles) and presenting them to T cells. They arise from monocytes. Histiocytic disorders refer to diseases that are caused by abnormal behavior of these cells. They include the following:

Reactive diseases of Langerhans cells (most important feature in immune histochemistry is expression of E-cadherin)
Histiocytomas
Reactive histiocytosis (immunohistochemical features show that interstitial/dermal DCs are involved)
Cutaneous histiocytosis (CH)
Systemic histiocytosis (SH)
Reactive diseases of macrophages
Hemophagocytic syndrome – a condition where macrophages phagocytose myeloid and erythroid precursors (similar to hemophagocytic lymphohistiocytosis in humans)
Histiocytic sarcoma complex (immunohistochemical features of dendritic cells, possibly interdigitating or perivascular DCs)
Malignant histiocytosis
Diffuse histiocytic sarcoma
Localized histiocytic sarcoma
Malignant diseases of macrophages
Histiocytic lymphoma

Breed disposition
Up to 25 percent of Bernese Mountain Dogs may develop malignant histiocytosis in their lifetime.
As a result, genetic testing is the only way to confirm the syndrome.BHC is caused by a single-nucleotide substitution mutation in TITF1, which encodes thyroid transcription factor 1 (TTF-1) and is inherited in an autosomal dominant pattern. This gene is also known as NK2 homeobox 1 (NKX2-1) The single-nucleotide substitution mutation then ultimately has drastic effects on the maturation processes of TITF-1In some cases, additional developmental abnormalities of lung and thyroid tissue are found in BHC, leading to the suggested alternative name brain-lung-thyroid syndrome. Genetics
Benign Hereditary Chorea is an autosomal dominant disorder. It is believed to be caused by a single-nucleotide substitution in TITF1, located on chromosome 14. A wide spectrum of mutations have been reported, drawing a potential association between amount of subsequently deleted nucleotides to severity of symptoms. These mutations lead to protein truncation, prevent DNA binding, and a loss-of-function. Mutations of the gene affect namely the lungs, brain, and thyroid. This is because during embryonic development, NKX2.1 plays a key role in binding to transcriptional regulatory elements and proteins within those respective organs. Diagnosis
BHC begins showing symptoms during childhood, and is commonly a familial disorder. This is a disorder that is correlated with mutations in the thyroid transcription factor gene (TITF-1). The disorder was discovered in the 1960s. During the time of its discovery, there were no tests that could be used to confirm a diagnosis of the disorder, and the phenotype was not easy to distinguish from other disorders. This resulted in the existence of the disorder being questioned.