Rare Classroom: Systemic Mastocytosis

Welcome to the Rare Classroom, a new series from Patient Worthy. Rare Classroom is designed for the curious reader who wants to get informed on some of the rarest, most mysterious diseases and conditions. There are thousands of rare diseases out there, but only a very small number of them have viable treatments and regularly make the news. This series is an opportunity to learn the basics about some of the diseases that almost no one hears much about or that we otherwise haven’t been able to report on very often.

Eyes front and ears open. Class is now in session.

The rare disease that we will be learning about today is:

Systemic Mastocytosis

What is Systemic Mastocytosis?

  • Mastocytosis is a disease characterized by an abnormal accumulation of mast cellsa type of white blood cell, located in peripheral tissues and organs. 
    • Mast cells typically infiltrate the bone marrow and consequently affect the peripheral blood and coagulation system. 
  • Mast cells store components that mediate inflammatory and allergic responses. 
  • There are several subtypes of the disease, and outcomes can vary significantly by subtype
  • While the exact number of patients suffering from all forms of mastocytosisincluding urticaria pigmentosa, is not known, it is estimated that about 3,000 patients are newly diagnosed each year in the United States, and about 30,000 patients live with the disease in the United States
    • SM affects between 1 in 20,000 and 1 in 40,000
  • In advanced SM, mast cells accumulate in such high quantities that they lead to organ damage and dysfunction, bone fractures, and anemia.​
  • Subtypes of advanced SM include aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL) and SM with an associated hematologic neoplasm (SM-AHN)

How Do You Get It?

  • The uncontrolled proliferation of mast cells is caused in many people by a KIT mutation.6 D816V is the most common mutation in SM, occurring in ~90% of SM patients 
  • Most cases of mastocytosis are caused by changes (mutations) in the KIT gene. This gene encodes a protein that helps control many important cellular processes such as cell growth and division; survival; and movement. This protein is also important for the development of certain types of cells, including mast cells (immune cells that are important for the inflammatory response).
  • Certain mutations in the KIT gene can lead to an overproduction of mast cells. In mastocytosis, excess mast cells accumulate in the skin and/or internal organs, leading to the many signs and symptoms of the condition.
  • Most cases of mastocytosis are not inherited. They occur spontaneously in families with no history of the condition and are due to somatic changes (mutations) in the KIT gene. Somatic mutations occur after conception and are only present in certain cells. Because they are not present in the germ cells (egg and sperm), they are not passed on to the next generation.
  • Mastocytosis can rarely affect more than one family member. In some of these cases, the condition is inherited in an autosomal dominant manner. This means that to be affected, a person only needs a change (mutation) in one copy of the responsible gene in each cell. A person with familial mastocytosis has a 50% chance with each pregnancy of passing along the altered gene to his or her child.

What Are The Symptoms?

  • Systemic mastocytosis can lead to a number of symptoms such as:
    • Skin lesions
    • Fatigue
    • Enlarged spleen
    • Enlarged liver
    • Darier’s sign (distinct reaction to scratching lesions)
    • Malabsorption
    • Peptic ulcers
    • Abdominal discomfort
    • Ocular discomfort
    • Nausea, vomiting
    • Depression
    • Diarrhea
    • Olfactive intolerance
    • Headache
    • Changes in bone density
    • Inflammation (ear, nose, throat)
    • Bone and muscle pain
    • Very low blood pressure
    • Anaphylactic shock

How Is It Treated?

  • Treatment is tailored towards each individual patient and their disease
  • The major goal of treatment is to control mast cell growth and expansion
    • Anti-mediator therapies
      • Antihistamines
        • Block histamine targeted receptors the are released by mast cells
      • Leukotriene antagonists
        • Block leukotriene targeted receptors
      • Mast cell stabilizers
        • These prevent mast cells from releasing chemicals. Examples include Ketotifen and cromoglicic acid
      • Proton-pump inhibitors
      • Epinephrine
      • Salbutamol
      • Corticosteroids
    • Antidepressants
    • UV light can reduce skin symptoms, but skin cancer risk is increased
    • Cytoreductive therapies
      • Typically introduced in advanced cases where more serious symptoms and complications are present
      • α-interferon
      • Cladribine
        • Chemotherapy administered subcutaneously
      • Tyrosine kinase inhibitors
        • Midostaurin, masitinib, imatinib, avapritinib (in trials)
  • Survival in patients with indolent systemic mastocytosis (ISM), with a median survival of 198 months, is not significantly different from the general population. However, median survival with aggressive systemic mastocytosis (ASM) is 41 months and that with SM-AHNMD (associated hematological non– mast cell disorder) is 24 months. Mast cell leukemia (MCL) has the poorest prognosis with a median survival of 2 months.
  • Early evolution into acute leukemia may occur in as many as 32% of patients with aggressive mastocytosis.  Leukemic transformation is rare with indolent systemic mastocytosis. ​

Where Can I Learn More???

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