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

• Published in: Pediatric blood & cancer Vol. 61; no. 6; pp. 1041 - 1048
• Main Authors: Roques, Gaëlle, Munzer, Martine, Barthez, Marie-Anne Carpentier, Beaufils, Sandrine, Beaupain, Blandine, Flood, Terry, Keren, Boris, Bellanné-Chantelot, Christine, Donadieu, Jean
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.06.2014; Wiley Subscription Services, Inc
• Subjects: Adaptor Proteins, Signal Transducing - chemistry; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - physiology; Atrophy; Bacterial Infections - etiology; Brain - pathology; Child; Child, Preschool; Consanguinity; Developmental Disabilities - genetics; Developmental Disabilities - pathology; encephalopathy; Ethnic Groups - genetics; Exons - genetics; Female; France; Genes, Recessive; Granulocyte Colony-Stimulating Factor - therapeutic use; HAX1; Hematology; 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; Oncology; Pakistan - ethnology; Pediatrics; Pedigree; Polymorphism, Single Nucleotide; Protein Isoforms - chemistry; Protein Isoforms - genetics; Protein Isoforms - physiology; Sequence Deletion; severe congenital neutropenia; France; Pakistan; encephalopathy; severe congenital neutropenia; HAX1
• ISSN: 1545-5009; 1545-5017; 1545-5017
• DOI: 10.1002/pbc.24964

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 × 109/L, associated with monocytosis (2 × 109/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. Pediatr Blood Cancer 2014;61:1041–1048. © 2014 Wiley Periodicals, Inc.