Thrombocytopenia, X-Linked, With Or Without Dyserythropoietic Anemia

A number sign (#) is used with this entry because X-linked thrombocytopenia with or without dyserythropoietic anemia (XLTDA) is caused by mutation in the GATA1 gene (305371) on chromosome Xp11.

Description

XLTDA is an X-linked recessive hematologic disorder characterized by thrombocytopenia and abnormal platelet morphology and function due to defective platelet maturation. Some patients have a variable severity of dyserythropoietic anemia (summary by Millikan et al., 2011).

Clinical Features

Nichols et al. (2000) described a woman with mild chronic thrombocytopenia who had 2 pregnancies complicated by severe fetal anemia requiring in utero red blood cell transfusions. The offspring were male half-sibs who were anemic and severely thrombocytopenic from birth. Each ultimately required a bone marrow transplant. Before transplant, peripheral blood showed a paucity of platelets and abnormal erythrocyte size and shape (poikilocytosis and anisocytosis). Bone marrow biopsy showed dyserythropoiesis and numerous small, dysplastic megakaryocytes. Electron microscopy revealed abnormal megakaryocytes with an abundance of smooth endoplasmic reticulum, eccentric nucleus, and a paucity of granules. Platelets also had a paucity of granules, abundant smooth endoplasmic reticulum, and abnormal membranous complexes. White blood cells were unaffected. Both boys had cryptorchidism. There were 3 asymptomatic female sibs.

Mehaffey et al. (2001) described a family in which 4 males in 2 generations related through female carriers had thrombocytopenia characterized by macrothrombocytopenia, profound bleeding, and mild dyserythropoiesis with no measurable anemia.

Freson et al. (2001) described a family with isolated X-linked macrothrombocytopenia without anemia (but with some dyserythropoietic features) in 13 males in 9 sibships of 3 generations connected through carrier females. Electron microscopy of the patients' platelets showed giant platelets with cytoplasmic clusters consisting of smooth endoplasmic reticulum and abnormal membrane complexes. Patient platelets also showed functional defects and low expression of certain membrane glycoproteins.

Freson et al. (2002) reported a family with X-linked thrombocytopenia and dyserythropoietic anemia in which 6 boys died of the disorder before age 2 years. One surviving boy and his mother were available for study. Peripheral blood smear from the boy showed decreased numbers of normal to giant platelets and abnormal erythrocytes, with anisocytes and poikilocytes. Electron microscopy of the platelets showed paucity of alpha-granules and clusters of smooth endoplasmic reticulum. Bone marrow biopsy showed dyserythropoiesis, dysmorphic erythroblasts, and dysplastic megakaryocytes. The mother had only a small number of enlarged platelets, but no anemia and no thrombocytopenia.

Inheritance

The transmission pattern of XLTDA in the family reported by Nichols et al. (2000) was consistent with X-linked recessive inheritance. The mother had mild features of the disorder, which may have resulted from skewed X inactivation.

Molecular Genetics

In 2 male half-sibs with X-linked congenital thrombocytopenia with dyserythropoietic anemia, Nichols et al. (2000) identified a hemizygous mutation in the GATA1 gene (V205M; 305371.0001). The mother, who had mild chronic thrombocytopenia and mild anemia, was heterozygous for the mutation. The findings indicated an important role for GATA1 in erythropoiesis, megakaryocyte development, and platelet formation.

In affected members of a family with X-linked macrothrombocytopenia without anemia, Mehaffey et al. (2001) identified a mutation in the GATA1 gene (G208S; 305371.0003).

In affected members of a family with X-linked macrothrombocytopenia without anemia, Freson et al. (2001) identified a mutation in the GATA1 gene (D218G; 305371.0002).

In a family with XLT with anemia, Freson et al. (2002) identified a mutation in the GATA1 gene (D218Y; 305371.0005).

Genotype/Phenotype Correlations

Compared to XLT individuals with the D218G mutation who did not have anemia (Freson et al., 2001), Freson et al. (2002) found that those with the D218Y mutation who had anemia had more disturbed platelet and erythrocyte morphology and disturbed expression levels of the platelet GATA1-target gene products. The more severe D218Y allele (as opposed to the D218G allele) was not expressed in the platelets of an unaffected female carrier, and her leukocytes showed a skewed X-inactivation pattern. The authors concluded that the nature of the amino acid substitution at position 218 of GATA1 may be of crucial importance in determining the severity of the phenotype in X-linked macrothrombocytopenia patients, and possibly also in inducing skewed X inactivation.