Neurological findings and genetic alterations in patients with Kostmann syndrome and HAX1 mutations

Pediatr Blood Cancer. 2014 Jun;61(6):1041-8. doi: 10.1002/pbc.24964. Epub 2014 Jan 30.


Objectives: To describe the clinical profile and the prevalence of severe congenital neutropenia (SCN) and HAX1 mutations, so-called Kostmann syndrome, in France.

Study design: Two pedigrees were identified from the French registry.

Results: The study included five subjects (three males), which represent 0.7% of the 759 SCN cases registered in France. The age at diagnosis was 0.3 years (range: 0.1-1.2 years) and the median age at the last follow-up was 7.3 years (range: 1.2-17.8 years). A novel large homozygous deletion of the HAX1 gene (exons 2-5) was found in one pedigree; while, a homozygous frameshift mutation was identified in exon 3 (c.430dupG, p.Val144fs) in the second pedigree. Severe bacterial infections were observed in four patients, including two cases of sepsis, one case of pancolitis, a lung abscess, and recurrent cellulitis and stomatitis. During routine follow-up, the median neutrophil value was 0.16 × 10(9)/L, associated with monocytosis (2 × 10(9)/L). Bone marrow (BM) smears revealed a decrease of the granulocytic lineage with no mature myeloid cells above the myelocytes. One patient died at age 2 from neurological complications, while two other patients, including one who underwent a hematopoietic stem cell transplantation (HSCT) at age 5, are living with very severe neurological retardation.

Conclusions: SCN with HAX1 mutations, is a rare sub type of congenital neutropenia, mostly observed in population from Sweden and Asia minor, associating frequently neurological retardation, when the mutations involved the B isoform of the protein.

Keywords: HAX1; encephalopathy; severe congenital neutropenia.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / physiology
  • Atrophy
  • Bacterial Infections / etiology
  • Brain / pathology
  • Child
  • Child, Preschool
  • Congenital Bone Marrow Failure Syndromes
  • Consanguinity
  • Developmental Disabilities / genetics
  • Developmental Disabilities / pathology
  • Ethnicity / genetics
  • Exons / genetics
  • Female
  • France
  • Genes, Recessive
  • Granulocyte Colony-Stimulating Factor / therapeutic use
  • Hematopoietic Stem Cell Transplantation
  • Humans
  • Immunocompromised Host
  • Infant
  • Intellectual Disability / genetics
  • Male
  • Mutation, Missense
  • Myelopoiesis / genetics
  • Myelopoiesis / physiology
  • Neutropenia / blood
  • Neutropenia / congenital*
  • Neutropenia / genetics
  • Neutropenia / pathology
  • Neutropenia / surgery
  • Pakistan / ethnology
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Protein Isoforms / chemistry
  • Protein Isoforms / genetics
  • Protein Isoforms / physiology
  • Sequence Deletion


  • Adaptor Proteins, Signal Transducing
  • HAX1 protein, human
  • Protein Isoforms
  • Granulocyte Colony-Stimulating Factor

Supplementary concepts

  • Neutropenia, Severe Congenital, Autosomal Recessive 3