Why the disorder induced by GATA1 Arg216Gln mutation should be called “X-linked thrombocytopenia with thalassemia” rather than “X-linked gray platelet syndrome”

To the editor:

GATA1 mutations induce 2 X-linked thrombocytopenias: dyserythropoietic anemia with thrombocytopenia (Online Mendelian Inheritance in Man [OMIM] 300367) and X-linked thrombocytopenia with thalassemia (XLTT; OMIM314050). The former has been described in 6 families with 5 different GATA1 mutations,^1,2  whereas the latter has been identified in 3 pedigrees with the 216R>Q substitution.^3,–5  In both illnesses, patients present mild dyserythropoiesis, red cell hemolysis, severely defective maturation of megakaryocytes, macrothrombocytopenia with α-granule deficiency, and abnormalities of the cytoplasmic membrane system. Unbalanced globin-chain synthesis resembling β-thalassemia has been described only in patients with XLTT, whereas severe anemia and thrombocytopenia have only been observed in dyserythropoietic anemia with thrombocytopenia. These 2 disorders are therefore closely related and are the unique inherited thrombocytopenias that constitutively present abnormalities of red cell line.

Tubman et al⁶  identified a family with X-linked thrombocytopenia, large agranular platelets, and increased erythrocyte hemoglobin F (HbF) deriving from the 216R>Q mutation in GATA1 and recently reported it in this journal under the title “X-linked gray platelet syndrome due to a GATA1 216R>Q mutation.” Because genotype and phenotype of this pedigree are completely superimposable with those observed in previous patients with XLTT, their decision to classify them as “X-linked gray platelet syndrome” risks producing further confusion in the field of inherited thrombocytopenias, which is already per se complex and confusing. It is perfectly true that the large platelets with α-granule deficiency observed in XLTT are in some respects similar to those typical of Gray platelet syndrome⁷  (GPS; OMIM 139090), but it is also unquestionable that several other findings differentiate the former from the latter. For instance, the red cell defect of XLTT has never been described in GPS, whereas the bone marrow emperipolesis of GPS^8,9  is not present in XLTT. Moreover, different expression and localization of α-granule proteins, such as differences in the spectrum of functional defects of platelets, distinguish these 2 disorders. Finally, the gene responsible for the classical GPS has not yet been identified, and it may be everywhere except in chromosome X, because an X-linked transmission has been never observed, whereas autosomal dominant inheritance has been well documented in some pedigrees. So GPS and XLTT are different disorders presenting the common finding of large platelets with α-granule deficiency. Furthermore, applying the term GPS to all conditions with pale platelets due to severe α-granule deficiency would also imply that other genetic thrombocytopenias with this finding (Medich giant platelet disorder, white platelet syndrome) have to be considered GPS. On the contrary, some affected members of GPS pedigrees who, due to the variable penetrance of this disorder, have very mild α-granule deficiency (despite full expression of other platelet defects)⁹  could no longer be classified as GPS.

So, to avoid confusion, we suggest that (1) the disorder deriving from GATA1 216R>Q mutation is not an “X-linked gray platelet syndrome” but rather XLTT, and (2) the term GPS should be used to indicate the illness (or the syndrome) that several reports and reviews⁷  have well described in the past.