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

Noonan-Like Syndrome With Or Without Juvenile Myelomonocytic Leukemia (CBL Mutation-Associated Syndrome) [Q87.0]

OMIM numbers: 613563165360 (CBL)

Dr. rer. biol. hum. Soheyla Chahrokh-Zadeh

Scientific Background

The CBL gene (Cas-Br-M (murine) ecotropic retroviral transforming sequence) is a proto-oncogene whose protein, E3 ubiquitin protein ligase CBL, functions as negative regulator of several signal transduction pathways, among others in the RAS/MAP kinase signal transduction pathway. Somatic mutations and translocations of this gene are found in many types of cancer, for example in acute myeloid leukemia. It is located on chromosome 11q23.

Juvenile myelomonocytic leukemia (JMML) is a rare form of leukemia, occurring during infancy and early childhood and characterized by malignant transformation in the hematopoietic stem cell compartment. 30% of all cases of myelodysplastic syndrome and 2% of all cases of leukemia are juvenile myelomonocytic leukemia. 10 to 15% of all children affected by neurofibromatosis type 1 with the respective mutations in the neurofibromin gene develop JMML. Patients with the Noonan syndrome (NS) or Noonan-like diseases caused by germline mutations in the genes PTPN11, KRAS and NRAS are predisposed to JMML as well. Somatic PTPN11 as well as homozygous CBL mutations can, among others, be detected in an isolated form of JMML.

Germline mutations in the CBL gene can be detected in a small number of patients who display signs and symptoms of the Noonan-like diseases and who do not have mutations in the genes typically affected in NS. They predominantly occur de novo. These patients may also suffer from JMML. It was shown that this is due to subsequent somatic LOH (loss of heterozygosity) on chromosome 11q23, the gene location of CBL.