AA metabolism and the clinical characteristics of 2 patients with Ghosal hematodiaphyseal dysplasia syndrome. (A) A schematic diagram of the AA metabolism pathway. AA is released from the membrane phospholipids by PLA₂ and is metabolized by COX-1 and −2 enzymes, (green oval) first into the unstable intermediate metabolite PGG₂, which is converted to PGH2. PGH₂ serves as a substrate for several PG synthases (PGDS, PGES, PGIS, blue ovals) that generate the following proinflammatory PG metabolites: PGD₂, PGE₂, and PGI₂. PGH₂ can also be converted to TXA₂ through the action of thromboxane synthase (red oval), the gene which is mutated in Ghosal hematodiaphyseal dysplasia syndrome. In addition to the COX-1/2 enzymes, AA is metabolized by 5-LOX (blue oval) to generate various products of hydroperoxyeicosatetraenoic acid, including 5-HETE and leukotrienes, for example, LTE₄. (B) Bone marrow biopsy sections for patient 1 have aspiration artifact but show an apparent reduction in marrow cellularity out of proportion to peripheral counts. On the left, H&E-stained section at an original magnification ×10 additionally shows thickened trabeculae (black arrow), and on the right, the H&E-stained section at an original magnification ×20 highlights disorganized osteocytes (black arrow). (C) A schematic diagram of thromboxane synthase A 1, encoded by the TBXAS1, showing the locations of the variants in the 2 patients reported in this manuscript (shown in red, above the diagram), and those from 13 sequenced cases previously reported in the literature (shown in blue, below the diagram). Diagram created using Domain Graph (DOG, version 2.0). D (for Case 1) and E (for Case 2), show. H&E, hematoxylin and eosin; 5-LOX, 5-lipooxygenase; PLA_2, phospholipase A₂; TXA₂, thromboxane A_2.