Alternative titles; symbols
SNOMEDCT: 718196002; ORPHA: 231393; DO: 0111767;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp11.23 | Thrombocytopenia with beta-thalassemia, X-linked | 314050 | X-linked recessive | 3 | GATA1 | 305371 |
A number sign (#) is used with this entry because X-linked thrombocytopenia with beta-thalassemia (XLTT) is caused by mutation in the gene encoding GATA-binding protein-1 (GATA1; 305371) on chromosome Xp11.
XLTT is an X-linked recessive hematologic disorder characterized by variable thrombocytopenia, hemolytic anemia, splenomegaly, and abnormalities in hemoglobin chain synthesis (summary by Ciovacco et al., 2008 and Millikan et al., 2011).
Thompson et al. (1977) described an unusual family in which 4 and possibly 5 males in multiple generations had splenomegaly and petechiae, moderate thrombocytopenia, prolonged bleeding time due to platelet dysfunction, reticulocytosis and unbalanced (hemo)globin chain synthesis resembling that of beta-thalassemia minor. Minor defects (reticulocytosis, globin synthesis imbalance) were found in some females. The female progenitor was white, but her ethnic extraction was not specified. No linkage to Xg was demonstrated.
Tubman et al. (2007) reported a family in which 3 affected males had thrombocytopenia, increased mean platelet volume, mild microcytosis, and increased red cell distribution consistent with X-linked inheritance. Peripheral blood smear showed so-called 'gray platelets' with decreased alpha-granules (see 139090). One male studied had a mild beta-thalassemia-like phenotype on hemoglobin electrophoresis. The proband was a 1-year-old girl with normal platelet count and no bleeding history who had 2 populations of platelets on peripheral blood smear: one normal and the other large, agranular, and pale.
Clinical Variability
Phillips et al. (2007) reported a 3-year-old boy with XLTT and anemia who presented with a photosensitive bullous dermatosis and was found to have hirsutism, splenomegaly, and increased uroporphyrin with decreased UROS (606938) activity (21% of normal). Although these features were consistent with a clinical diagnosis of congenital erythropoietic porphyria (CEP; 263700), sequencing of the UROS gene was negative. Laboratory studies showed microcytic anemia with increased reticulocytes, thrombocytopenia, increased fetal hemoglobin (59.5%), and beta-thalassemia. Bone marrow biopsy was hypercellular with dyserythropoiesis, nuclear bridging, and occasional multinucleated red cells. Megakaryocytes were decreased in number. He underwent a stem cell transplant, which was successful. The mother had had multiple first-trimester spontaneous abortions, but no signs of porphyria. The grandmother had chronic anemia and thrombocytopenia.
Yu et al. (2002) identified an arg216-to-gln mutation in the N finger of GATA1 (R216Q; 305371.0006) in the family with X-linked thrombocytopenia with beta-thalassemia reported by Thompson et al. (1977).
Tubman et al. (2007) identified an R216Q substitution in affected members of a family with a mild bleeding disorder, thrombocytopenia, and large agranular platelets characteristic of the so-called 'gray platelet syndrome.' In a letter, Balduini et al. (2007) stated that the family reported by Tubman et al. (2007) had a phenotype consistent with XLTT and that the classification as 'X-linked gray platelet syndrome' is a misnomer risking confusion in the literature. They noted that deficiency of platelet alpha-granules can be a feature of XLTT. In response, the original authors (Neufeld et al., 2007) agreed that the disorder in the family may be classified as an example of a unique disorder, i.e., XLTT, but endorsed its classification as 'a unique kind of GPS, inherited in X-linked fashion, with platelets indistinguishable by experts from autosomal GPS (at the light microscope and ultrastructure level).'
In a 3-year-old boy with XLTT, anemia, and clinical features reminiscent of congenital erythropoietic porphyria, Phillips et al. (2007) identified a hemizygous mutation in the GATA1 gene (R216W; 305371.0010). The GATA1 gene regulates expression of UROS in developing erythrocytes, which explained the decreased UROS activity and features of porphyria in this patient. The R216W mutation affects the same residue as that reported by Yu et al. (2002) (R216Q; 305371.0006) in an XLTT family with a less severe phenotype. Phillips et al. (2007) postulated that the larger, more hydrophobic tryptophan in their family would affect GATA1 binding to the UROS promoter more significantly than the smaller glutamine described by Yu et al. (2002). The striking fetal hemoglobin in the patient reported by Phillips et al. (2007) also suggested a role for GATA1 in globin chain switching.
Balduini, C. L., De Candia, E., Savoia, A. Why the disorder induced by GATA1 arg216gln mutation should be called 'X-linked thrombocytopenia with thalassemia' rather than 'X-linked gray platelet syndrome'. (Letter) Blood 110: 2770-2771, 2007. [PubMed: 17881640] [Full Text: https://doi.org/10.1182/blood-2007-03-080978]
Ciovacco, W. A., Raskind, W. H., Kacena, M. A. Human phenotypes associated with GATA-1 mutations. Gene 427: 1-6, 2008. [PubMed: 18930124] [Full Text: https://doi.org/10.1016/j.gene.2008.09.018]
Millikan, P. D., Balamohan, S. M., Raskind, W. H., Kacena, M. A. Inherited thrombocytopenia due to GATA-1 mutations. Semin. Thromb. Hemost. 37: 682-689, 2011. [PubMed: 22102271] [Full Text: https://doi.org/10.1055/s-0031-1291378]
Neufeld, E. J., Tubman, V. N., Levine, J. E., Campagna, D. R., Monahan-Earley, R., Dvorak, A. M., Fleming, M. D. What's in a name? (Letter) Blood 110: 2771 only, 2007.
Phillips, J. D., Steensma, D. P., Pulsipher, M. A., Spangrude, G. J., Kushner, J. P. Congenital erythropoietic porphyria due to a mutation in GATA1: the first trans-acting mutation causative for a human porphyria. Blood 109: 2618-2621, 2007. [PubMed: 17148589] [Full Text: https://doi.org/10.1182/blood-2006-06-022848]
Thompson, A. R., Wood, W. G., Stamatoyannopoulos, G. X-linked syndrome of platelet dysfunction, thrombocytopenia, and imbalanced globin chain synthesis with hemolysis. Blood 50: 303-316, 1977. [PubMed: 871527]
Tubman, V. N., Levine, J. E., Campagna, D. R., Monahan-Earley, R., Dvorak, A. M., Neufeld, E. J., Fleming, M. D. X-linked gray platelet syndrome due to a GATA1 arg216gln mutation. Blood 109: 3297-3299, 2007. [PubMed: 17209061] [Full Text: https://doi.org/10.1182/blood-2006-02-004101]
Yu, C., Niakan, K. K., Matsushita, M., Stamatoyannopoulos, G., Orkin, S. H., Raskind, W. H. X-linked thrombocytopenia with thalassemia from a mutation in the amino finger of GATA-1 affecting DNA binding rather than FOG-1 interaction. Blood 100: 2040-2045, 2002. [PubMed: 12200364] [Full Text: https://doi.org/10.1182/blood-2002-02-0387]