Fiona Poyer, Austria
St. Anna Kinderspital Pediatric Hematology and OncologyPresenter of 1 Presentation
MYELODYSPLASTIC SYNDROME LEADING TO THE DIAGNOSIS OF A RARE PRIMARY IMMUNODEFICIENCY (NHEJ1-DEFICIENCY)
Abstract
Background and Aims
The correct repair of DNA double strand breaks by non-homologous end joining is vital for antibody and lymphocyte receptor diversity. NHEJ1 represents its most recently discovered component with less than 20 published cases of NHEJ1 deficiency worldwide.
Methods
We identified a 22-year old patient with recurrent pulmonary infections and mild pancytopenia who had been diagnosed with a hypocellular myelodysplastic syndrome at 6 years of age. At diagnosis, cytogenetics showed a premalignant monosomy 7-positive clone. Hematopoietic stem cell donor search remained unsuccessful. Intriguingly, patient blood counts stabilized, and repeat bone marrow punctures showed a complete resolution of the premalignant clone several weeks later. At 14 years of age, a 20q12 deletion clone became apparent and remains detectable with varying relative contribution to date.
Results
To identify disease etiology, we employed our previously established, targeted NGS-based panel for hematological disorders (Kager et al., Br J Haematol 2017) and identified a novel mutation of the NHEJ1 gene (NM_024782.2:c236T>C, p.Leu79Pro), coding for the XRCC4 binding site of the protein and predicted highly damaging by CADD (score 31.0) and other computational gene prediction tools. The patient’s phenotype (microcephaly, short stature) as well as his progressive lymphopenia with telomere shortening fit the diagnosis of NHEJ1 deficiency.
Conclusions
This is the first patient worldwide described with myelodysplastic syndrome due to NHEJ1 deficiency, and only the second patient with NHEJ1 deficiency reaching adulthood without allogeneic HSCT. This case underlines the utility of NGS-based approaches for efficient identification of genetic etiologies of unresolved hematological and immunological disorders.