Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Systemic Mastocytosis [C96.2]

OMIM numbers: 154800164920 (KIT)

Dipl.-Ing. (FH) Tanja Hinrichsen

Scientific Background

Systemic mastocytosis (SM) is a rare, clinically heterogeneous condition (frequency 1:100,000) and ranges from skin lesions that may regress spontaneously to highly aggressive neoplasms with multiple organ failure and high lethality. Malignant growth and/or accumulation of clonal mast cells in one or several organs is characteristic. SM is of sporadic, very rarely familial occurrence; inheritance is autosomal dominant. The WHO classification from 2008 distinguishes:

  • Cutaneous mastocytosis (CM)
  • Indolent systemic mastocytosis (ISM)
  • Systemic mastocytosis with an associated clonal hematological non-mast cell lineage disease (SM-AHNMD)
  • Aggressive systemic mastocytosis (ASM)
  • Mast cell leukemia (MCL)
  • Mast cell sarcoma (MCS)
  • Extracutaneous mastocytoma

While CM predominantly occurs in children, SM is only observed in the second decade of life. In approximately 80% of all patients the skin is affected; in SM, most of the time the bone marrow is affected. Clinical diagnosis of SM requires either one major criterion, such as detection of multifocal, dense infiltrates of mast cells (≥ 15 mast cells) in the bone marrow and/or other extracutaneous organ(s) and additionally one minor criterion or three minor criteria, such as atypical mast cell morphology, detection of CD2 and/or CD25 on the mast cells, serum total tryptase > 20 ng/ml or detection of an activating mutation in codon-816 of the KIT gene in the bone marrow, blood or other extracutaneous organ(s).

The proto-oncogene KIT encodes for the tyrosine-kinase receptor KIT (CD117) and is constitutively activated by mutations. In 95% of all SM patients the KIT-D816V mutation can be detected in the mast cells, which is associated with a partial resistance to the tyrosine-kinase inhibitor imatinib. Other activating mutations in exon 17 such as D816Y, D816H and D816F occur less frequently. Due to the small number of circulating mast cells, highly sensitive methods are required for the detection of the D816V mutation (such as allele-specific amplification with suppression of the wild-type allele).