Anemia, X-Linked, With Or Without Neutropenia And/or Platelet Abnormalities

A number sign (#) is used with this entry because X-linked anemia with or without neutropenia and/or platelet abnormalities (XLANP) is caused by mutation in the GATA1 gene (305371) on chromosome Xp11.

Description

XLANP is an X-linked recessive hematologic disorder characterized by early-onset anemia and bone marrow erythroid hypoplasia with variable neutropenia. Some patients may have low platelets or platelet abnormalities. The severity is variable. Some patients have shown a favorable response to corticosteroid treatment (summary by Hollanda et al., 2006 and Sankaran et al., 2012).

In some cases, the disorder may resemble Diamond-Blackfan anemia (see, e.g, DBA1; 105650) (Sankaran et al., 2012; Parrella et al., 2014; Klar et al., 2014).

Clinical Features

Hollanda et al. (2006) described a Brazilian family in which 8 males in 2 generations had moderate to severe anemia without thrombocytopenia. Some affected individuals had variable degrees of neutropenia and some had increased fetal hemoglobin. Peripheral blood films showed abnormal erythrocyte morphology, including anisocytosis, macrocytosis, poikilocytosis, elliptocytes, and fragmented red blood cells. Bone marrow biopsy showed trilineage dysplasia with hypocellularity of erythroid and granulocytic lineages, and with normal or increased numbers of micromegakaryocytes. Platelet analysis of 2 affected males showed impaired platelet aggregation, and ultrastructural studies showed round platelets with a paucity of alpha- and dense body granules. Two patients had mild anemia without relevant clinical symptoms, 2 were in remission after bone marrow transplant due to severe anemia and neutropenia, 2 received monthly transfusions, 1 died of pneumonia, and 1 died of an unrelated cause. All heterozygous females were clinically normal with normal hematologic parameters.

Clinical Variability/Diamond-Blackfan Anemia-Like Phenotype

Sankaran et al. (2012) reported a family in which 2 boys had congenital macrocytic anemia, low reticulocyte counts, and a modest elevation of fetal hemoglobin. They showed a good clinical response to corticosteroid therapy. Both also had occasional reductions in the neutrophil count, and 1 boy developed a low platelet count at age 17 years. Neither showed increased bleeding or an increased propensity for infection. Bone marrow biopsy showed erythroid hypoplasia without abnormalities of the other hematopoietic lineages, and the boys were given a diagnosis of Diamond-Blackfan anemia (DBA; 105650). However, erythrocyte adenosine deaminase in the boys was not elevated, as is usually observed in DBA. Weiss et al. (2012) commented on the findings of Sankaran et al. (2012), noting that the patients reported by Hollanda et al. (2006) were not diagnosed with DBA, although their features overlapped those in the patients reported by Sankaran et al. (2012). Weiss et al. (2012) discussed the controversy that DBA is often a clinical diagnosis, but that genetic studies have identified it as a disorder of ribosomes. They noted that it is unclear whether GATA1 should be considered a 'new DBA gene,' particularly because mutations in GATA1 can cause a wide range of hematologic phenotypes and because GATA1 has an uncertain role in ribosome function.

Klar et al. (2014) reported 3 Swedish brothers, 1 of whom was a maternal half-brother, who presented with anemia in the first 3 months of life. Laboratory studies showed macrocytic anemia and erythroid hypoplasia in the bone marrow with otherwise normal cellularity. Two had increased erythrocyte adenosine deaminase, suggesting a clinical diagnosis of Diamond-Blackfan anemia. The patients initially responded to steroid treatment, but became refractory as adults, necessitating red cell transfusions.

Parrella et al. (2014) reported an Italian boy who developed severe anemia at age 9 months. Erythrocyte adenosine deaminase activity was slightly increased and bone marrow aspirate showed a selective deficiency in erythroid precursors without abnormalities of the other lineages. The patient was diagnosed clinically with DBA and responded to steroid treatment. At age 4 years, he developed a progressive 3-lineage hypoplasia and myelodysplastic syndrome and underwent successful hematopoietic stem cell transplantation.

Inheritance

The transmission pattern of anemia with or without neutropenia and/or platelet abnormalities in the family reported by Hollanda et al. (2006) was consistent with X-linked recessive inheritance.

Mapping

X-linked anemia without thrombocytopenia is caused by mutation in the GATA1 gene, which was mapped to chromosome Xp11.23 by Caiulo et al. (1991).

Molecular Genetics

In 8 affected males in 2 generations of a family with macrocytic anemia, with or without neutropenia and/or platelet abnormalities, Hollanda et al. (2006) identified a germline splice site mutation in the GATA1 gene (332G-C; 305371.0008), resulting in the synthesis of only the short variant, GATA1s. The data suggested that GATA1s alone, produced in low or normal levels, is not sufficient to support normal erythropoiesis. Acquired somatic mutations in the GATA1 gene that result in synthesis of GATA1s have been found in individuals with Down syndrome with both transient myeloproliferative disorder and acute megakaryoblastic leukemia (see 190685). However, none of the patients reported by Hollanda et al. (2006) developed leukemia.

In 2 brothers with congenital anemia, occasional reductions in neutrophil count, and low platelet count in 1 patient, Sankaran et al. (2012) identified the same GATA1 splice site mutation (305371.0008) found by Hollanda et al. (2006). RT-PCR studies of patient samples showed that most of the GATA1 mRNA was for GATA1s, although there were trace amounts of the full-length protein. Their unaffected mother, who also carried the mutation, had about 53% levels of the full-length protein. Another GATA1 mutation resulting in the GATA1s isoform (305371.0009) was found in 1 of 62 additional boys with a clinical diagnosis of Diamond-Blackfan anemia without known mutations.

In 3 Swedish brothers with a clinical diagnosis of Diamond-Blackfan anemia, Klar et al. (2014) identified a hemizygous splice site mutation in the GATA1 gene that was identical to the mutation found by Sankaran et al. (2012) in brothers with a phenotype resembling DBA. Haplotype analysis indicated that the mutation occurred independently in the 2 families.

In an Italian boy with X-linked anemia, Parrella et al. (2014) identified a hemizygous mutation in the initiation codon of the GATA1 gene (305371.0011). The mutation, which was found by direct sequencing of the GATA1 gene among 23 Italian patients with a clinical diagnosis of Diamond-Blackfan anemia, was inherited from the unaffected mother. The mutation was predicted to result in loss of the long GATA1 isoform.

Ludwig et al. (2014) found that the transcriptional signature of GATA1 target genes was globally and specifically decreased in cells from patients with Diamond-Blackfan anemia-1 (DBA1; 105650) due to mutation in the RPS19 gene (603474). The mRNA level of GATA1 was not decreased, but protein and activity levels of GATA1 were decreased, likely reflecting decreased protein translation due to ribosomal abnormalities caused by mutation in RPS19. Similar results were observed with mutations in other DBA-associated ribosomal genes, again reflecting impaired translation. Ludwig et al. (2014) characterized the 5-prime end of GATA1 mRNA and found that it was highly structured, which influences translation efficiency. Further in vitro studies demonstrated that the defective erythropoiesis in patients with DBA associated with ribosomal protein haploinsufficiency could be partially overcome by increasing GATA1 levels. The findings provided a mechanistic link between mutations in GATA1 and phenotypes resembling DBA, which is usually associated with mutations in ribosomal subunit genes, and also suggested that dysregulated GABA1 protein translation may be a key factor in mediating the erythroid-specific defect observed in DBA.