Systemic mastocytosis (SM) - KIT, ASXL1, DNMT3A, RUNX1, SRSF2, and TET2 genes

Systemic mastocytosis (SM), or systemic mast cell disease, is a blood disorder that can affect many different body systems. The signs and symptoms of this disease can develop at any age, but usually appear after adolescence, and include fatigue, redness and heat of the skin, nausea, abdominal distention and pain, diarrhea, gastroesophageal reflux, nasal congestion, hypotension, dizziness and headache. Other less common signs may include attention or memory problems, anxiety or depression, urticaria pigmentosa and anaphylaxis.

Five subtypes of systemic mastocytosis have been described, which differ in severity, and signs and symptoms. The mildest forms are the indolent and smoldering types. Individuals affected by these forms usually suffer only from the general signs and symptoms described above, although individuals suffering from smoldering type may have more affected organs and more serious characteristics. The indolent type is the most frequent form of systemic mastocytosis.

The severe types include aggressive systemic mastocytosis, systemic mastocytosis with associated hematologic malignancy (SM-AHN), and mast cell leukemia. In addition to the general signs and symptoms discussed above, these types typically involve impaired function of an organ, such as the liver, spleen or lymph nodes. The liver dysfunction can cause ascites. On the other hand, aggressive systemic mastocytosis is associated with a loss of bone tissue (osteoporosis and osteopenia) and multiple bone fractures. SM-AHN (systemic mastocytosis with an associated hematologic malignancy) and mast cell leukemia both involve blood cell dissorders or blood cell cancer (leukemia). Mast cell leukemia is the rarest and most severe type of systemic mastocytosis.

Individuals with the milder forms of the condition generally have a normal or near normal life expectancy, while those with the most severe forms typically survive months or a few years after diagnosis.

Systemic mastocytosis occurs when mast cells abnormally accumulate in one or more tissues. It is estimated that more than 80 percent of individuals with systemic mastocytosis have a mutation in the KIT (KIT proto-oncogene receptor tyrosine kinase) gene, located on the long arm of chromosome 4 (4q12). This gene encodes a protein tyrosine kinase that plays an important role in the development and activity of mast cells. The KIT protein stimulates the chemical signaling pathways that are involved in the growth and proliferation of many cell types, including germ cells, hematopoietic cells, mast cells, interstitial cells of Cajal (ICCs) and melanocytes. The mutation identified in 80 percent of cases replaces the amino acid aspartic acid with the amino acid valine at position 816 of the protein (Asp816Val or D816V). This and other mutations of the KIT gene result in the synthesis of altered proteins that are constitutively activated. As a consequence, the signaling pathways that promote cell proliferation are hyperactive, which causes an increase in mast cell production and its accumulation in various tissues.

In addition KIT gene mutations, other genes also appear to be involved in the severity of systemic mastocytosis, often resulting in a more aggressive disease and shorter survival. These genes play a primary role in the control of cell proliferation or in the regulation of the activity of other genes that are important in development. These genes include: ASXL1 (ASXL transcriptional regulator 1), DNMT3A (DNA methyltransferase 3 alpha), RUNX1 (runt related transcription factor 1), SRSF2 (serine and arginine rich splicing factor 2) and TET2 (tet methylcytosine dioxygenase 2).

In affected individuals there are certain triggers that can activate mast cells. These include changes in temperature, friction and minor trauma, surgery, insect stings, vaccines, anxiety, and stress. In addition, certain medications can also be triggers, such as aspirin, opioids or nonsteroidal anti-inflammatory drugs (NSAIDs).

Systemic mastocytosis is generally not inherited, but arises from a somatic mutation in the body's cells that occurs after conception.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with the systemic mastocytosis (SM), by means of the complete PCR amplification of the exons of the KIT, ASXL1, DNMT3A, RUNX1, SRSF2, and TET2 genes, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).