HAX1-related congenital neutropenia: Long-term observation in paediatric and adult patients enrolled in the European branch of the Severe Chronic Neutropenia International Registry (SCNIR)

Denys Pogozhykh*, Deniz Yilmaz Karapinar, Maksim Klimiankou, Natali Gerschmann, Georg Ebetsberger-Dachs, Jan Palmblad, Göran Carlsson, Tania Masmas, Sally Kinsey, Marije Bartels, Sabine Mellor-Heineke, Karl Welte, Julia Skokowa, Cornelia Zeidler

*Corresponding author for this work

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Abstract

HAX1-related congenital neutropenia (HAX1-CN) is a rare autosomal recessive disorder caused by pathogenic variants in the HAX1 gene. HAX1-CN patients suffer from bone marrow failure as assessed by a maturation arrest of the myelopoiesis revealing persistent severe neutropenia from birth. The disorder is strongly associated with severe bacterial infections and a high risk of developing myelodysplastic syndrome or acute myeloid leukaemia. This study aimed to describe the long-term course of the disease, the treatment, outcome and quality of life in patients with homozygous HAX1 mutations reported to the European branch of the Severe Chronic Neutropenia International Registry. We have analysed a total of 72 patients with different types of homozygous (n = 68), compound heterozygous (n = 3), and digenic (n = 1) HAX1 mutations. The cohort includes 56 paediatric (<18 years) and 16 adult patients. All patients were initially treated with G-CSF with a sufficient increase in absolute neutrophil counts. Twelve patients required haematopoietic stem cell transplantation for leukaemia (n = 8) and non-leukaemic indications (n = 4). While previous genotype–phenotype reports documented a striking correlation between two main transcript variants and clinical neurological phenotypes, our current analysis reveals novel mutation subtypes and clinical overlaps between all genotypes including severe secondary manifestations, e.g., high incidence of secondary ovarian insufficiency.

Original languageEnglish
Pages (from-to)393-411
Number of pages19
JournalBritish Journal of Haematology
Volume202
Issue number2
DOIs
Publication statusPublished - Jul 2023

Keywords

  • acute leukaemia
  • bone marrow failure
  • HAX1 mutation
  • MDS
  • neutropenia

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