Kostmann disease contributes to approximately 15% of SCN (severe congenital neutropenia) with a preponderance in the Turkish and Middle Eastern population (PMID:24145314).
HAX1 gene has two different isoforms: isoform A and B.
While neurological signs are not present in mutations associated with isoform A (Trp44X, Glu59X, Glu60fs), neurological abnormalities
including mental retardation, epilepsy and development retardation are seen in mutations associated with both isoforms (Arg86X, Gln123fs,
Val144fs, Gln190X) (PMID:26994629).
Severe congenital neutropenia-3 is an autosomal recessive bone marrow failure disorder characterized by low numbers of neutrophils, increased susceptibility to bacterial and fungal infections, and increased risk of developing myelodysplastic syndrome or acute myeloid leukemia. In addition, patients ... Severe congenital neutropenia-3 is an autosomal recessive bone marrow failure disorder characterized by low numbers of neutrophils, increased susceptibility to bacterial and fungal infections, and increased risk of developing myelodysplastic syndrome or acute myeloid leukemia. In addition, patients with HAX1 mutations affecting both isoform A and B of the gene develop neurologic abnormalities (summary by Boztug et al., 2010). The Swedish physician Rolf Kostmann (1956) described an autosomal recessive hematologic disorder, termed infantile agranulocytosis, with severe neutropenia with an absolute neutrophil count below 0.5 x 10(9)/l and early onset of severe bacterial infections. The disorder was later termed Kostmann syndrome (Skokowa et al., 2007). Lekstrom-Himes and Gallin (2000) discussed severe congenital neutropenia in a review of immunodeficiencies caused by defects in phagocytes. In addition to Kostmann agranulocytosis, recessively inherited neutropenic syndromes include congenital neutropenia with eosinophilia (257100), Chediak-Higashi syndrome (214500), and Fanconi pancytopenic syndrome (see 227650). For a phenotypic description and a discussion of genetic heterogeneity of severe congenital neutropenia, see SCN1 (202700).
Infantile agranulocytosis was first clearly delineated by Kostmann (1956). Starting with 19 sibships collected by Kostmann (1975), Iselius and Gustavson (1984) assembled evidence that a single founder was responsible for the cases observed in Sweden. The likely origin ... Infantile agranulocytosis was first clearly delineated by Kostmann (1956). Starting with 19 sibships collected by Kostmann (1975), Iselius and Gustavson (1984) assembled evidence that a single founder was responsible for the cases observed in Sweden. The likely origin of the gene was thought to be the parish of Overkalix in the county of Norrbotten in the most northern part of Sweden. Carlsson et al. (2008) provided follow-up of 5 affected individuals from the original family reported by Kostmann (1956). All those who survived beyond infancy had evidence of neurologic involvement with developmental delay and decreased cognitive function. Two of 4 patients who reached age 10 years also developed epilepsy. Olofsson et al. (1976) reported 2 patients, a boy and his niece. In each instance the parents were consanguineous. On the first day of life, 1 of the 2 patients had granulocytopenia; complete agranulocytosis developed in 3 weeks after an interval during which the patient had normal or even increased neutrophil levels, due possibly to meningitis. In addition to persistent severe absolute neutropenia (500 neutrophils per microliter or fewer) and bone marrow morphology that suggests maturational arrest of neutrophil precursors at the promyelocyte stage, variable degrees of monocytosis, eosinophilia, hypergammaglobulinemia, and thrombocytosis may be found. In a retrospective survey of 162 patients in whom bone marrow transplantation was performed in 14 European centers between 1969 and 1985, Fischer et al. (1986) found 1 patient with Kostmann syndrome. Corcione et al. (1993) characterized a spontaneous lymphoblastoid cell line raised from the peripheral blood of a patient with Kostmann congenital neutropenia. Neutropenia had first been discovered at the age of 1 month. When examined at the age of 2 years and 9 months, the girl had a history of recurrent bacterial infections (pneumonitis, otitis media, cutaneous furuncles, and tonsillitis) since the age of 3 months. Her general condition was poor, and mild hepatosplenomegaly and diffuse lymph node enlargement were found. Corcione et al. (1993) found that the lymphoblastoid cell line was composed of EBV-infected polyclonal B cells. The supernatant contained a colony-inhibiting activity that was demonstrated to be transforming growth factor beta-1 (TGFB1; 190180). Corcione et al. (1993) hypothesized that the B cells latently infected by EBV in vivo, and possibly expanded as a consequence of the infection, contributed to the inhibition of the patient's granulopoiesis by releasing TGF-beta-1. Koren et al. (1989) reported a family in which a male and female sib with first-cousin parents had what was called congenital dysgranulopoietic neutropenia. The female suffered from omphalitis due to enterobacter at age 2 weeks and subsequently died from sepsis at age 1 month. The male was admitted at age 2 months with an abscess in the right inguinal region due to Pseudomonas aeruginosa. He suffered from frequent severe pyogenic infections. At the time of the report by Koren et al. (1994) he was 11 years old and had been treated successfully with granulocyte colony-stimulating factor (GCSF; 138970) from the age of 8. In 1992, the mother became pregnant and sonographically guided fetal blood sampling was performed by cordocentesis. The results of the blood studies indicated that the fetus was not at risk. The newborn baby was indeed healthy with normal neutrophil counts at 2 and 4 months of age. Germeshausen et al. (2008) reported 6 unrelated patients with SCN3, 5 of whom were of Turkish origin. All presented in infancy with recurrent bacterial infections associated with neutropenia. One patient developed acute lymphoblastic leukemia at age 7 months, and another developed a myelodysplastic syndrome at age 7 years. Two patients had neurologic involvement, including psychomotor retardation and seizures. Germeshausen et al. (2008) noted that some patients with SCN3 develop neurologic deficits. Boztug et al. (2010) reported a consanguineous Turkish family in which 2 girls had SCN3 and neurologic deficits. One patient was diagnosed with the disorder at age 19 years and was treated with recombinant GCSF. She had global developmental delay since early childhood. She had impaired motor function without evidence of spasticity or ataxia, mental retardation, combined conductive and inner ear hearing loss, and severe epilepsy. Examination at age 28 years suggested a peripheral neuropathy. The second patient was diagnosed with SCN at age 5 years. This patient showed delayed motor development, hearing loss, and mental retardation. At age 26 years, the clinical neurologic examination was normal except for clumsiness. Genetic analysis in both patients revealed a homozygous 2-kb deletion within the HAX1 gene that removed exons 4-7, and Western blot analysis showed complete absence of the HAX1 protein. Quantitative brain MRI showed a general reduction of cerebral proton density in the white and gray matter, although no major abnormalities were seen on MRI scans, except for mild cerebellar atrophy in 1 patient. Similar studies in another unrelated patient with SCN3 and severe neurologic deficits also showed a reduction of proton density both in the cerebral white and gray matter, but these changes were not observed in an SCN3 patient without neurologic involvement. Boztug et al. (2010) suggested that the decreased proton density may reflect a reduction in neuronal cell density and microstructural brain changes. The findings again confirmed that mutations that affect both isoforms of HAX1 result in SCN3 with neurologic deficits.
Germeshausen et al. (2008) identified 5 different mutations in the HAX1 gene (see, e.g., 605998.0003; 605998.0004) in 6 unrelated patients with autosomal recessive SCN3. HAX1 mutations affecting exclusively the full-length isoform A only (see, e.g., 605998.0002) resulted in ... Germeshausen et al. (2008) identified 5 different mutations in the HAX1 gene (see, e.g., 605998.0003; 605998.0004) in 6 unrelated patients with autosomal recessive SCN3. HAX1 mutations affecting exclusively the full-length isoform A only (see, e.g., 605998.0002) resulted in neutropenia without neurologic symptoms. In contrast, mutations affecting both HAX1 isoforms A and B (see, e.g., 605998.0001 and 605998.0003) were associated with an additional neurologic phenotype (p less than 0.001).
Autosomal recessive severe congenital neutropenia constitutes a primary immunodeficiency syndrome associated with increased apoptosis in myeloid cells. Using a positional cloning approach and candidate gene evaluation, Klein et al. (2007) identified a recurrent homozygous germline mutation in HAX1 ... Autosomal recessive severe congenital neutropenia constitutes a primary immunodeficiency syndrome associated with increased apoptosis in myeloid cells. Using a positional cloning approach and candidate gene evaluation, Klein et al. (2007) identified a recurrent homozygous germline mutation in HAX1 (605998.0002) in 3 Kurdish pedigrees. Through molecular screening of other individuals with severe congenital neutropenia, they identified 19 additional affected individuals with homozygous HAX1 mutations, including 3 belonging to the original Swedish pedigree described by Kostmann (1956) (605988.0001). HAX1 encodes the mitochondrial HS1-associated protein X1, which functions in signal transduction and cytoskeletal control. Klein et al. (2007) showed that HAX1 is critical to maintaining the inner mitochondrial membrane potential and protecting against apoptosis in myeloid cells. Their findings suggested that HAX1 is a major regulator of myeloid homeostasis and underlined the significance of genetic control of apoptosis in neutrophil development. Klein et al. (2007) sequenced the ELA2 gene (130130), previously associated with cyclic (Horwitz et al., 1999) and congenital (Dale et al., 2000) neutropenia in all individuals. No affected individual was found with mutations in both ELA2 and HAX1, suggesting that these genes defined 2 mutually exclusive groups of individuals with severe congenital neutropenia. Severe congenital neutropenia is a premalignant condition, as up to 21% of affected individuals develop a clonal proliferative disease leading to myelodysplastic syndrome or overt acute leukemia, often preceded by mutations in the gene encoding the granulocyte colony-stimulating factor receptor (CSF3R; 138971) (Dong et al., 1995). To determine whether HAX1 mutations predispose to somatic CSF3R mutations, Klein et al. (2007) sequenced CSF3R in all affected individuals with documented HAX1 mutations and reanalyzed the data of the SCN Registry. In 3 HAX1-deficient individuals, they identified somatic mutations in CSF3R. In 5 (28%) of 18 Japanese patients with severe congenital neutropenia, Ishikawa et al. (2008) identified homozygous or compound heterozygous mutations in the HAX1 gene (605998.0005; 605998.0006). All had developmental delay, and 3 had seizures. These neurologic clinical findings were not observed in 11 (61%) patients who were found to have mutations in the ELA2 gene. Smith et al. (2008) identified homozygous mutations in the HAX1 gene (see, e.g., 605998.0007; 605998.0008) in 4 (4%) of 109 probands with SCN.