Rare Disease Basics
Rare Diseases
What is Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL)?
Acute lymphoblastic leukemia (ALL) is a fast-growing malignant disorder resulting from proliferation of white blood cells that fail to mature and accumulate in the bone marrow, destroying and replacing cells that produce normal blood cells. Prognosis declines with increasing age and is most unfavorable when the Philadelphia chromosome (Ph) is present.
What causes Ph+ ALL?
Changes in chromosomes (genetic material) are a major cause of abnormal genetic conditions in humans. If a change involves a translocation, part of a chromosome breaks off and attaches to another chromosome. The Philadelphia chromosome results from a reciprocal translocation between chromosomes 9 and 22 in which a gene segment on chromosome 9 is inserted into one of several regions of a gene on chromosome 22. The new gene resulting from this translocation produces an abnormal protein that adversely impacts normal cellular processes, resulting in an increased proliferation of leukemic cells.
What is Myelodysplastic/Myeloproliferative disease (MDS/MPD)?
The myelodysplastic syndromes (MDS) are a diverse collection of blood disorders. characterized by an ineffective production of blood cells. The myeloproliferative diseases (MPDs) are a group of diseases of the bone marrow in which excess cells are produced. Myelodysplastic/myeloproliferative overlap disorders (MDS/MPD) are malignant stem cell disorders that have both dysplastic and proliferative features at the time of initial presentation, resulting in increased numbers of immature cells in the bone marrow and a decrease in mature functional cells in the blood.
What causes MDS/MPD?
While patients with MDS/MPD lack the Philadelphia chromosome that is common to chronic myeloid leukemia (CML), chromosomal damage is common in patients with this disease, including gene rearrangements involving the platelet-derived growth factor receptor gene known as PDGFR. The new gene resulting from this kind of rearrangement produces an abnormal protein that adversely impacts normal cellular processes, causing cells to multiply out of control.
What is aggressive systemic mastocytosis (ASM)?
Aggressive systemic mastocytosis (ASM) is a myeloproliferative disorder characterized by the abnormal growth, proliferation, and accumulation of mast cells in one or more organs that can, in some cases, lead to organ failure. There is usually severe involvement of the bone marrow, liver, spleen, and lymphatic system. Mast cells are produced in the bone marrow and contain chemical mediators, like histamine, that are released in response to inflammatory and allergenic events.
What causes ASM?
Changes in chromosomes (genetic material) are a major cause of abnormal genetic conditions in humans. If the change involves a mutation in a gene, then the protein produced by the gene will usually not function as intended. If the change involves a deletion within a gene, there is a loss of genetic information, resulting in a shorter than normal protein that will also usually not function as intended. ASM is associated with a specific mutation within the c-Kit gene on chromosome 4 or a deletion within the chromosome that causes abnormal activation of the platelet-derived growth factor receptor gene, known as PDGFR. This new gene makes an abnormal protein that adversely impacts normal cellular processes, causing cells to multiply out of control.
What is hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL)?
Hypereosinophilic syndrome (HES) is a blood disorder characterized by unexplained, higher than normal levels of eosinophils, a type of white blood cell, and evidence of organ dysfunction due to eosinophilic tissue infiltration. In some cases, it can additionally be characterized by elevated levels of immature mast cells in the bone marrow and mast cell products in the blood. When associated with chromosomal abnormalities, the disease is then called chronic eosinophilic leukemia (CEL).
What causes HES/CEL?
An overproduction of eosinophils in the bone marrow with migration into the blood stream and various organs are upstream events associated with the disease. Changes in chromosomes (genetic material) associated with HES/CEL usually involve translocations of the platelet-derived growth factor receptor gene known as PDGFR. They are a major cause of abnormal genetic conditions in humans. If a change involves a translocation, part of a chromosome breaks off and attaches to another chromosome. Adjacent to the PDGFR gene are a number of genes important in the growth and maturation of eosinophils. The normal function of these genes may be adversely impacted by the PDGFR translocation process, causing the unexplained eosinophilia.
What is dermatofibrosarcoma protuberans (DFSP)?
Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive cutaneous tumor of intermediate malignancy that is characterized by slow infiltrative growth and a strong tendency toward local recurrence after surgery.
What causes DFSP?
Changes in chromosomes (genetic material) are a major cause of abnormal genetic conditions in humans. If a change involves a translocation, part of a chromosome breaks off and attaches to another chromosome. In rare cases, the broken parts can attach to themselves forming ring structures. Chromosomal translocations and/or ring chromosomes that fuse the collagen gene on chromosome 17 to the platelet-derived growth factor gene, known as PDGFR, on chromosome 22 are present in nearly all cases of DFSP. Abnormal activation of the platelet-derived growth factor receptor gene produces an abnormal protein that adversely impacts normal cellular processes, causing cells to multiply out of control.
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