TBXAS1 – Ghosal hematodiaphyseal dysplasia

Ghosal hematodiaphyseal dysplasia (GHDD) is a rare autosomal recessive disorder caused by biallelic variants in TBXAS1, encoding thromboxane A synthase. Affected individuals present with bone marrow fibrosis leading to pancytopenia, metadiaphyseal dysplasia of long bones, normocytic anemia, thrombocytopenia, myelofibrosis, short stature, and developmental delay.

Autosomal recessive inheritance is supported by multiple sibling pairs and compound heterozygous cases. Two adult siblings with pancytopenia responded to steroids (PMID:31395426); a middle-aged woman with bone pain harbored homozygous c.1235G>A (p.Arg412Gln) (PMID:39220787); two Indian children exhibited c.722G>A (p.Arg241Gln) and recurrent c.1235G>A (p.Arg412Gln) (PMID:35395429); and adult and pediatric patients in a targeted NSAID study carried loss-of-function alleles (PMID:36574346).

The variant spectrum includes missense substitutions (p.Arg412Gln, p.Arg241Gln), frameshift alleles (c.583_584del (p.Ala195LeufsTer12)), and other novel changes (p.Val89Ala, p.Leu283Pro, p.Ile88Thr) identified across eight independent families (PMID:33595912; PMID:28868793). Recurrent founder alleles have not been described.

Functional assays demonstrate that mutation of active site residues, notably Arg-413 (c.1234C>T (p.Arg412Trp) and c.1235G>A (p.Arg412Gln)), abolishes enzyme activity in transfected cells, confirming a loss-of-function mechanism (PMID:8702713). NSAID treatment in GHDD patients normalized prostaglandin metabolites and resolved cytopenias, consistent with modulation of excess PGH2 in the absence of TXAS (PMID:36574346).

Corticosteroid therapy has repeatedly demonstrated rapid correction of anemia and improvement in bone lesions across pediatric and adult cohorts, underscoring the clinical utility of molecular diagnosis for guiding treatment (PMID:39277773; PMID:31395426). No conflicting evidence has been reported.

Integration of robust genetic and functional data over three decades supports a Definitive gene–disease association. Early genetic testing for TBXAS1 in patients with refractory anemia and long-bone dysplasia enables targeted steroid and NSAID interventions, reduces transfusion requirements, and improves skeletal outcomes.

Key take-home: Diagnosis of TBXAS1-related GHDD informs precision therapy with corticosteroids and NSAIDs, transforming management of this rare bone marrow failure syndrome.

References

• Transfusion and apheresis science • 2019 • Ghosal hematodiaphyseal dysplasia with autoimmune anemia in two adult siblings. PMID:31395426
• Radiology case reports • 2024 • Middle-aged women with hematodiaphyseal dysplasia: Ghosal syndrome: Case report. PMID:39220787
• Journal of tropical pediatrics • 2024 • Steroid-responsive anemia with bony dysplasias: What lurks behind! PMID:39277773
• European journal of medical genetics • 2022 • Novel TBXAS1 variants in two Indian children with Ghosal hematodiaphyseal dysplasia: A concise report. PMID:35395429
• Blood • 2023 • Nonsteroidal anti-inflammatory drugs as a targeted therapy for bone marrow failure in Ghosal hematodiaphyseal dysplasia. PMID:36574346
• Pediatric blood & cancer • 2018 • Chronic steroid-response pancytopenia and increased bone density due to thromboxane synthase deficiency. PMID:28868793
• Molecular genetics & genomic medicine • 2021 • Novel compound heterozygous variants of TBXAS1 presenting with Ghosal hematodiaphyseal dysplasia treated with steroids. PMID:33595912
• The Journal of biological chemistry • 1996 • Identification of thromboxane A2 synthase active site residues by molecular modeling-guided site-directed mutagenesis. PMID:8702713

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