Severe developmental delay and epilepsy in a Japanese patient with severe congenital neutropenia due to HAX1 deficiency

Abstract

HAX1 deficiency has recently been identified as a cause of severe congenital neutropenia (SCN), but little is known about the phenotype. We described an SCN patient with a homozygous 256C-to-T transition causing an R86X mutation in the HAX1 gene. Notably, the patient has been complicated by epilepsy and severe delay of motor, cognitive, and intellectual development; each developmental quotient was 21–26 at 7 years old. Growth failure and dental development delay were also noted. Neurodevelopmental delay in this patient expands the clinical phenotype of HAX1 deficiency and suggests an important role of HAX1 on neural development as well as myelopoiesis.

Severe congenital neutropenia (SCN) is a rare disorder of myelopoiesis resulting in recurrent life-threatening infections due to a lack of neutrophils.1 Individuals with SCN have characteristic bone marrow findings of myeloid hypoplasia with arrest of myelopoiesis at the promyelocyte/myelocyte stage.1 This disorder was first described in Kostmann’s seminal paper in 1956.2 Recent evidence has indicated that SCN is a heterogeneous disorder involving mutations in various genes, including those encoding granulocyte colony stimulating factor receptor (G-CSFR) (CSF3R),3 neutrophil elastase (ELA2),4 Wiskott-Aldrich syndrome protein (WAS),5 and GFI-1.6 More recently, Klein et al. identified homozygous HAX1 mutations as a cause of an autosomal recessive SCN in 20 Middle Eastern patients and 3 classical Kostmann family members.7 They suggested that HAX1 is critical for maintaining the inner mitochondrial membrane potential and protecting against apoptosis in myeloid cells.7

HAX1 has been initially described as an interacting partner with HS-1, a signal-transduction protein in hematopoietic cells.8 HAX1 mRNA is ubiquitously expressed,8, 9 and therefore its deficiency could theoretically result in dysfunction of several organs other than hematopoietic systems. Given that the precise function of HAX1 is not fully defined, clinical phenotypes of patients with deficiency of the responsible gene may be helpful. Here, we described an SCN patient caused by homozygous R86X mutations in HAX1, who presented with severe developmental delay followed by refractory epilepsy. This case may expand the phenotype of HAX1 deficiency in human and may provide a novel function of this gene.