Gray Platelet Syndrome Presenting With Pancytopenia, Splenomegaly, and Bone Marrow Fibrosis

Abstract

Objectives Gray platelet syndrome (GPS) is a rare platelet storage pool disorder associated with a marked decrease or absence of platelet α-granules and their contents. It is characterized clinically by mild to moderate bleeding; moderate macrothrombocytopenia with large, agranular platelets; splenomegaly; and bone marrow fibrosis. Electron microscopy confirms markedly reduced or absent α-granules in platelets and megakaryocytes. The classic description of GPS is caused by homozygous mutations in NBEAL2 (neurobeachinlike 2). Methods A 28-year-old Hispanic man with a history of easy bruising and occasional episodes of epistaxis sought treatment for pancytopenia and splenomegaly. Peripheral blood smear and bone marrow analysis, electron microscopy, and next-generation sequencing were performed. Results Large and agranular platelets were present in the peripheral blood. There was bone marrow fibrosis. Electron microscopy of the platelets showed absence of α-granules. Next-generation sequencing revealed a germline apparently homozygous nonsense variant in the NBEAL2 gene: c.5674C>T, p.Gln1892X (p.Q1829X). Conclusions The differential diagnosis of GPS includes a myeloid neoplasm such as myelodysplastic syndrome with bone marrow fibrosis. The availability of diagnostic genetic panels for hereditable platelet disorders can assist in the recognition of GPS and other platelet disorders. We also describe a previously unreported pathogenic germline homozygous nonsense variant in the NBEAL2 gene: c.5674C>T, p.Gln1892X (p.Q1829X) in a patient with GPS.

Inherited Platelet Disorders: An Updated Overview

“…This is a progressive syndrome, such that usually evolves towards severe thrombocytopenia during adolescence and adulthood, accompanied by a gradual degree of myelofibrosis and, in some cases, splenomegaly. Very recently, these patients have been reported to exhibit leukopenia, predisposition to autoimmune diseases, defective NETosis and to developing autoantibodies [ 51 , 53 , 158 , 159 ].…”

A Deep Dive into the Pathology of Gray Platelet Syndrome: New Insights on Immune Dysregulation

“…Heterozygous NBEAL2 variants may be found in unaffected carriers, who may display a mild decrease in α-granule content, although they are not thrombocytopenic. 10 Genetic diagnosis may be approached by Sanger sequencing of the NBEAL2 gene, when the diagnosis of GPS is suspected based on the phenotypic features, or by high-throughput sequencing, including gene panels for inherited platelet disorders 19 or whole-exome sequencing. 17 …”