January 2015: Post summaries and take home points

JAK2 is a helper protein that helps other molecules send signals to make more cells and to increase inflammation.
JAK2 mutation V617F makes some cells more responsive to growth factors, so they grow too much. These cells include red blood cells, platelets and mast cells.
Marker associated with other myeloproliferative diseases essential thrombocythemia (too many platelets), polycythemia vera (too many red blood cells), myelofibrosis (fibrosis of bone marrow).
About 5% of SM patients have JAK2 V617F mutation. Indicates higher probability of developing another myeloproliferative disease.
Doesn’t necessary mean lifespan is shorter.

About 75% of MCAD patients have at least one first degree relative with MCAD.
The CKIT D816V mutation is not known to be heritable, but other CKIT mutations have been found in multiple family members.

Life expectancy with indolent systemic mastocytosis (ISM) is normal.
Average age at diagnosis of ISM is 49.
Type and severity of symptoms vary and do not correlate with disease type, presence of CKIT D816V mutation or tryptase level.
Mediator related symptoms are not indicative of aggressive or progressing disease.
Organ swelling is not always indicative of ASM. Organs can be swollen for many years without functional damage or C findings.

5-10 years from diagnosis with ISM, 1.7% of patients progressed to SSM/ASM.
20-25 years from diagnosis with ISM, 8.5% of patients progressed to SSM/ASM.
Risk of transformation of ISM to acute leukemia or ASM was less than 1% and 3% respectively.
ASM and MCL are associated with accumulation of neoplastic mast cells in organs, impairment of organ function, drug resistance, poor prognosis and organ failure.
In most SSM patients, disease stays stable over years or decades.
SSM patients have higher incidence of anemia, constitutional symptoms and mast cell mediator levels than ISM patients.
SSM is diagnosed later than ISM, around 64 years.
ASM can be slow progressing and stable for many years or rapidly progressing.
During progression of ASM and MCL, some patients lose the CKIT D816V mutation.
Slow progression ASM can be kept under control for several months or even years with interferon and cladribine.
In a group of 342 patients, 0.6% ISM patients developed MCL or AML, 6.5% ASM, and 13% SM-AHNMD.
It is possible for disease to convert to less severe category.

Mast cell accumulation is mostly due to decrease in apoptosis (cell death) rather than excessive proliferation.
20-30% of SM patients have tryptase below 20 ng/ml.
If you test negative for CKIT D816V in blood, you may still be positive.
Bone marrow test for CKIT D816V is most accurate.
Histamine intolerance has been proposed as deficiency of enzymes to metabolize histamine. There is no evidence that this occurs in mast cell disease.
33% of MCAS patients are positive for elevated tryptase, 56% n-methylhistamine, 44% PGD2.
66% of patients with MCAS have major or complete regression in symptoms after one year of treatment.

ISM is not life threatening in and of itself. Anaphylaxis, a symptom of ISM, is life threatening.
49% of SM patients experience anaphylaxis in their lifetime. 48% of anaphylaxis episodes in ISM patients were severe.
There is no consensus on what is a normal count of mast cells in GI tract. Some healthy patients have more than 20 mast cells/hpf.
Most patients with adult onset cutaneous mastocytosis also have systemic mastocytosis.
Early studies indicated CM and MCAD were different, but frequency of CKIT mutations the same in patients with CM, SM and MCAS (about 86% in each group in one study). NOTE: The CKIT mutations were not always the D816V mutation.
Patients with MMAS (monoclonal mast cell activation syndrome) and MCAS (mast cell activation syndrome) never have CM.
ASM and MCL patients frequently lack CM.

55% of pediatric mastocytosis cases occur in the first two years of life.
35% occur between ages of 15 and 18.
Cutaneous mastocytosis can result in mediator release symptoms without having systemic mastocytosis.
2/3 of childhood mastocytosis patients had complete resolution of cutaneous disease and symptoms before adulthood. They were not treated with steroids, PUVA or chemo drugs.
Bone marrow biopsies of children with CM often show more mast cells than normal. High bone marrow mast cells in these children does not affect resolution.
In a study of 50 pediatric CM patients, 86% had a CKIT mutation and36% had the D816V mutation.

TET2 is mutated in 20.8-29% of SM patients.
Several mutations are seen.
TET2 is involved in DNA methylation which affects gene expression.
96% of SM patients with major blood abnormalities had mutations in at least two genes regardless of SM subtype.

SRSF2 is a protein that affects gene expression.
An SRSF2 mutation was found in 24-37% of SM patients.
Most common mutation in SM after CKIT D816V.
Strongly associated with SM-AHNMD.
Also found in other cell types besides mast cells. In SM-AHNMD, may cause both mast cell disease and associated blood disorder.

People who took higher amounts of anticholinergics had an increased risk of dementia.
Some medications used to treat mast cell disease are strong anticholinergics, like diphenhydramine and doxepin.
It is not clear if the medications caused dementia or if the conditions that required those medications caused dementia.