A new NDE1/PDGFRB fusion transcript underlying chronic myelomonocytic leukaemia in Noonan Syndrome

A 35-year-old female patient with Noonan Syndrome (NS) presented with leukocytosis and splenomegaly. Recent medical history included malaise, lack of appetite and moderately painful, tender red nodules with central ulceration on face, neck and arms. Skin biopsy showed marked oedema and superficial and deep derma granulocyte infiltration, with some eosinophils. Blood counts were: white blood cells, 386_109/l (neutrophils 55%, lymphocytes 7%, monocytes 34%, eosinophils 4%); haemoglobin: 13.5 g/dl; platelets, 336_109/l. Chronic myelomonocytic leukaemia (CMML) was diagnosed on bone marrow aspirate. Bone marrow karyotype was: 46,XXt(5;16)(q33;p13). In all cells bearing t(5;16)(q33;p13), fluorescent in situ hybridization (FISH) indicated PDGFRB was rearranged. In our patient, candidates as PDGFRB gene partners were selected on the basis of FISH findings. As NDE1 was in the correct orientation and contained an N-terminal oligomerization domain, we sought an NDE1-PDGFRB fusion. Amplifying the NDE1-PDGFRB transcript by RT-PCR yielded a specific product which, upon sequencing, showed in-frame fusion of NDE1 exon 5 (GenBank no. NM_017668) with PDGFRB exon 11 (GenBank no. NM_002609) (Figure 1e). NDE1-PDGFRb is predicted to contain the 174 amino acids (including the oligomerization domain) of the NDE1 N-terminal fused to the C-terminal transmembrane and split tyrosine kinase domains of PDGFRb. Amplification and sequencing of the der(5) genomic breakpoint confirmed NDE1 intron 5 and PDGFRB intron 10 were fused (Genbank accession no. DQ317513). Denaturing high-performance liquid chromatography analysis identified a G1784T (NM_002834) nucleotide germline substitution in exon 3 of PTPN11, which given our patient’s phenotype, is most probably the congenital cause of NS. Our study shows for the first time a case of CMML with an NDE1-PDGFRB fusion in addition to a missense mutation in exon 30 of PTPN11 underlying NS. The PTPN11 gain-of-function mutation in association with the constitutively phosphorylated tyrosine kinase NDE1-PDGFRB may have triggered CMML in this patient with NS.