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

Abstract

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.

• Authors: Gaëlle Roques, Martine Munzer, Marie-Anne Carpentier Barthez, Sandrine Beaufils, Blandine Beaupain, Terry Flood, Boris Keren, Christine Bellanné-Chantelot, Jean Donadieu
• Journal: Pediatric blood & cancer (Pediatr Blood Cancer) Vol. 61 Issue 6 Pg. 1041-8 (Jun 2014) ISSN: 1545-5017 [Electronic] United States
• PMID: 24482108 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: © 2014 Wiley Periodicals, Inc.

Chemical References

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

Topics

• Adaptor Proteins, Signal Transducing (chemistry, genetics, physiology)
• Atrophy
• Bacterial Infections (etiology)
• Brain (pathology)
• Child
• Child, Preschool
• Congenital Bone Marrow Failure Syndromes
• Consanguinity
• Developmental Disabilities (genetics, 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, physiology)
• Neutropenia (blood, congenital, genetics, pathology, surgery)
• Pakistan (ethnology)
• Pedigree
• Polymorphism, Single Nucleotide
• Protein Isoforms (chemistry, genetics, physiology)
• Sequence Deletion