First Case of Leukemia in a Child Suffering from Cyclic Neutropenia with ELANE Mutation

Congenital neutropenia (CN) and Cyclic neutropenia (CyN) are rare hematological conditions in which ELANE mutations have been found. The discrimination of Cyn from CN is based on the cycling neutrophil counts which decrease to <0.2 x 10⁹/L, usually at 21 day intervals. Infectious episodes are typically less severe in CyN compared to infections in CN patients. While in patients suffering from ELANE-CN an increased risk of leukemic transformation of more than 10 percent is well documented, no AML has been reported in the European SCNIR cohort of 38 patients with ELANE-CYN so far.

Here we report the first case of AML secondary to ELANE-CyN in a 17 year old girl. Severe neutropenia was first diagnosed at the age of four weeks during a septicemia with pseudomonas, but no serial blood counts were collected. G-CSF treatment was initiated at an age of 2 years after recurrent otitis media, pneumonia and skin abscesses. Infectious events occurred infrequently under G-CSF treatment. At an age of 14 years she was referred to us after a severe infectious event (liver abscess) and an unexplained high range of ANCs (0 to more than 10x10⁹/µl ) under G-CSF treatment with varying doses. Sequential blood counts confirmed the diagnosis of CyN. Molecular genetic testing revealed a heterozygous ELANE mutation, both parents are ELANE negative. Previous bone marrows varied between a maturation arrest on the promyelocyte stage with absence of neutrophils and up to 16 percent segmented neutrophils. No cytogenetic aberrations were detected prior to AML. AML was diagnosed recently when she presented with decreasing platelets and hemoglobin. Bone marrow at this time showed 14% blasts and presence of monosomy 7 plus trisomy 21 in the cytogenetic evaluation.

Molecular genetic evaluation of the bone marrow revealed presence of a CSFR3 and RUNX1 mutations in the leukemic cells.

Conclusion

Our patient presented with a secondary AML after ELANE positive cyclic neutropenia. Cytogenetics, CSFR3 and RUNX1 mutations in the bone marrow at the time of leukemia diagnosis have been described in the pathway of leukemogenesis in Congenital neutropenia with ELANE, HAX1 or other underlying mutation.

Our patient is the first case of leukemia in ELANE-CyN and proofs that ELANE-CyN is another pre-leukemic condition. However, the risk of myeloid transformation is very low.