Novel compound heterozygous variants of TBXAS1 presenting with Ghosal hematodiaphyseal dysplasia treated with steroids

Abstract

Background: Homozygous or compound heterozygous pathogenic variants in the thromboxane A synthase 1 (TBXAS1) gene are associated with Ghosal hematodiaphyseal dysplasia (GHDD) which is characterized by defective hematopoiesis and increased bone density of long bones.

Methods: Patients 1 and 2 are identical twins, who presented with red blood cell transfusion-dependent normocytic anemia and thrombocytopenia with bone marrow fibrosis and cortical bone thickening of long bones on plain radiograph. To clarify the etiology of their anemia and thrombocytopenia, whole blood was used for the DNA extraction and analyzed using next-generation sequencing (NGS) on an in-house bone marrow failure syndrome panel.

Results: The NGS results indicated that these two patients carried two heterozygous variants in TBXAS1, exon7, c.583_584del, p.Ala195Leufs*12, and exon12, c.1420G>T, p.Gly474Trp, which were inherited from their mother and father, respectively. Patients 1 and 2 have been on chronic oral steroids with normalization of hemoglobin and platelet count after steroid initiation. Patient 3 is their sister who has normal blood counts but also has the same variants in TBXAS1 as her brothers. Radiographs showed cortical bone thickening and she has not required any treatment or transfusion.

Conclusion: We report three Caucasian siblings from non-consanguineous parents with novel compound heterozygous variants of TBXAS1 presenting with the phenotypes of GHDD. These three cases illustrate the variable clinical expressivity of the GHDD from two-compound heterozygous pathogenic variants of TBXAS1.

Keywords: TBXAS1; Ghosal hematodiaphyseal dysplasia; anemia; thromboxane synthase 1.

FIGURE 1

Peripheral blood and bone marrow morphologic findings. (a) The peripheral blood smear revealed moderate normocytic anemia and many dacrocytes, suggestive of fibrosis in the bone marrow (Wight‐Giemsa stain, original magnification × 1,000). (b) The bone marrow core biopsy showed diffuse fibrosis and reduced hematopoiesis (H&E stain, original magnification × 200). (c) Reticulin stain demonstrated moderately increased (grade 2/4) reticulin fibers (Arrow). (d) Trichrome stain showed that collagen fibers were also mildly increased (Arrows)

FIGURE 2

A, Patient 1. (a) skeletal survey revealed dense appearance of the long bones with diaphyseal and metaphyseal widening, particularly involving the femurs. (b) Patient 2. Dense appearance of the lone bones with diaphyseal and metaphyseal widening, especially involving femurs. (c). Patient 3. Patchy sclerosis and some cortical thinning involving the proximal to mid femoral diaphysis