Association of Neurodevelopmental Abnormalities Is a Common Clinical Character in Japanese Patients with Severe Congenital Neutropenia Due to HAX1 Deficiency.

Severe congenital neutropenia (SCN) is characterized by early childhood onset of profound neutropenia and recurrent life-threatening infections. The bone marrow usually shows a reduced number of mature myeloid cells with an arrest at the promyelocyte-myelocyte stage. SCN includes a variety of hematological disorders caused by the different genetic abnormality. Genetic analysis in individuals with SCN indicates that 60% of cases are attributable to heterozygous mutation in ELA2, encoding neutrophil elastase. Recently, homozygous mutation in HAX1 encoding HAX1, mitochondrial protein associates with HS1 which is a substrate for Src family tyrosine kinase, was identified in individuals with autosomal recessive forms of SCN and the original Kostmann family in Sweden. In this study, we examined involvement of HAX1 and ELA2 in 17 Japanese cases with SCN. Ten patients had heterozygous mutations, including two novel mutations in ELA2. Five patients had homozygous or compound heterozygous mutations in HAX1. A homozygous single-base-pair substitution at nucleotide 256 (256C>T) HAX1 mutation causing a nonsense change R86X was detected in three patients. Two sibling cases showed compound heterozygous mutation of 256C>T and 59-bp deletion at nucleotide 376–434. This 59-bp deletion was a novel mutation leading to a frameshift and a premature stop codon at nucleotide 441–443 (R126fsX128). All heterozygous carriers had no detectable phenotype. HAX1 protein was undetectable in both homozygous and compound heterozygous patients by immunoblot analysis of leukocytes. Notably, all patients with HAX1 deficiency showed failure to thrive and mild to severe developmental delay. Further, three patients carrying homozygous R86X mutation had epilepsy. Two of three patients had complex partial seizures, and another had atypical absence. An Iranian patient carrying homozygous R86X mutation of HAX1 was described to show failure to thrive in the original report of HAX1 deficiency, and three of six cases of the original Kostmann family showed neurological deficits. In contrast, no SCN patients with a heterozygous mutation in ELA2 displayed the association of neurodevelopmental abnormalities. Thus, R86X mutation in HAX1 is a common abnormality in Japanese SCN patients with HAX1 deficiency and may lead to neurodevelopmental abnormalities as well as severe myelopoietic defects. Because HAX1 is a ubiquitously expressed gene, further accumulation of the patients should be needed to characterize the clinical features of HAX1 deficiency.