Genetic Test Detects Rare Bone Disorder Before X-Ray Changes

Researchers reported a genetically confirmed case of Ghosal hematodiaphyseal dysplasia in an 18-month-old boy before the onset of characteristic radiographic changes. Published in the Egyptian Journal of Medical Human Genetics, this case report and literature review highlights the critical role of early molecular testing in diagnosing rare hematological disorders. The study demonstrates that whole exome sequencing can identify the underlying genetic cause of bone marrow failure even when skeletal surveys appear normal, potentially allowing for earlier intervention and improved clinical outcomes for affected children.

Ghosal hematodiaphyseal dysplasia is a rare autosomal recessive condition first described in 1957. It is characterized by increased bone density in the long bones, predominantly affecting the diaphyseal regions, alongside a regenerative corticosteroid-sensitive anemia caused by bone marrow fibrosis. The disorder is caused by biallelic pathogenic variants in the TBXAS1 gene, located on chromosome 7q34, which encodes thromboxane synthase, an enzyme involved in the arachidonic acid cascade. Approximately 30 cases have been reported worldwide, with the majority originating from India, Pakistan, and the Middle East. Notably, prior to this report, no cases had been diagnosed prior to the appearance of characteristic radiographic changes.

The patient was an 18-month-old male, the first-born child of a non-consanguineous couple from northern India. He presented with a history of progressive pallor starting at six months of age, which required three red blood cell transfusions. There was no history of bleeding, bony pain, fractures, visual problems, developmental delay, or jaundice. Initial examination revealed severe pallor, frontal bossing, and a solitary café-au-lait macule on the abdomen measuring less than 0.5 cm. The child was severely underweight at 12 kg, which is -3.11 standard deviations, and moderately stunted at 80 cm, which is -2.74 standard deviations. No skeletal deformities, facial dysmorphism, icterus, lymphadenopathy, or organomegaly were noted during the systemic examination.

Initial laboratory investigations revealed severe anemia with a hemoglobin level of 5.3 g/dL, compared to the normal range of 10.9–13.7 g/dL. The patient also exhibited thrombocytopenia with a platelet count of 94,000/mm³, well below the normal range of 150,000-450,000/mm³, while the leukocyte count remained normal at 7,530/mm³. A peripheral smear showed normocytic hypochromic anemia with a decreased reticulocyte count. Iron profile, Vitamin B12, folic acid, and Vitamin D levels were all within normal ranges. High-performance liquid chromatography showed no abnormalities in hemoglobin fractions. A skeletal survey performed at this stage showed no abnormalities, which is a key distinction in this case compared to typical presentations of the disease.

Given the growth failure, bicytopenia, and low reticulocyte count, the medical team considered the possibility of a bone marrow failure syndrome. Bone marrow aspiration and biopsy were performed to investigate further. The bone marrow aspirate was paucicellular, and the biopsy revealed 2+ reticulin fibrosis with prominence of lymphocytes and plasma cells. Secondary myelofibrosis, hemophagocytic lymphohistiocytosis, and storage disorders were excluded through clinical evaluation and diagnostic investigations. Normal levels of Vitamin D, negative HIV status, normal viral markers, and normal malignancy screening helped rule out these alternative diagnoses.

Whole exome sequencing was subsequently performed and identified a compound heterozygous mutation in the TBXAS1 gene. The mutations included c.122_135del p.Lys41Thrfs47 located in exon 2 and c.748G > T p.Glu250Ter located in exon 8. The frameshift mutation affects the N-terminal region of the protein, likely resulting in early truncation and loss of function, while the nonsense mutation further supports a null effect on protein synthesis. This finding expands the mutational spectrum of Ghosal hematodiaphyseal dysplasia, as most previously reported cases involved homozygous missense mutations or combinations clustered toward the C-terminal region of the gene. Carrier testing of the parents could not be performed due to financial constraints, which limits accurate recurrence risk estimation and comprehensive genetic counseling for the family.

Based on the molecular diagnosis and evidence from previous reports, the child was initiated on oral prednisolone at a dose of 2 mg/kg/day. The treatment led to a significant rise in hemoglobin to 9.8 g/dL over a two-month period. Steroid tapering was initiated after three months, following the development of steroid facies. The child has been followed for the past year and continues to show good clinical progress, with appropriate gain in weight and height. Hematologic parameters have remained stable, with a current hemoglobin of 10.8 g/dL and a platelet count of 311,000/mm³. The only noted complication was steroid facies, which is a known side effect of long-term corticosteroid use.

The fibrosis observed in this case differs from that seen in primary myelofibrosis, which is driven by somatic mutations in genes such as JAK2, MPL, CALR, and TET2. While these mutations are established drivers in primary myelofibrosis, TBXAS1 variants are associated with a rare hereditary marrow failure syndrome that may phenotypically overlap but arises from a distinct molecular etiology. The identification of TBXAS1 mutations provides a logical explanation for the anemia and increased bone density associated with this dysplasia, linking the genetic defect to the pathophysiological mechanisms of the disease.

The hallmark of Ghosal hematodiaphyseal dysplasia is the gradual development of anemia and thrombocytopenia, often beginning in early childhood. Thrombocytopenia was present in only 50% of previously reported patients. The time lag between hematological symptoms and bony involvement ranged from 0 to 60 months, with a mean duration of 14.5 months. In this case, the child developed progressive pallor by six months of age, a crucial time for early diagnosis before the appearance of skeletal changes. The absence of skeletal deformities in the early stages contrasts with findings in the literature, where diagnosis was typically established only after the appearance of skeletal changes.

This case underscores the importance of considering bone marrow failure syndromes and rare diagnoses like Ghosal hematodiaphyseal dysplasia in cases of unexplained anemia and thrombocytopenia. Early genetic confirmation can guide clinical practice, enable proactive management, and preserve growth potential. The successful treatment with corticosteroids in this case is consistent with previous reports of successful management in affected patients. However, it is crucial to monitor the child for long-term side effects and maintain ongoing follow-up, as seen in this case where the child has maintained stable hemoglobin levels for the past eight months.

The study highlights the significance of early molecular diagnosis in improving outcomes for children with rare genetic disorders. This approach emphasizes the value of genetic testing in the diagnostic workup of pediatric bone marrow failure syndromes.

Despite the positive outcome, the lack of parental genetic testing due to financial constraints remains a limitation of the case. This limits the ability to provide accurate recurrence risk estimation and comprehensive genetic counseling to the family.

In conclusion, this case report demonstrates the utility of whole exome sequencing in the diagnosis of Ghosal hematodiaphyseal dysplasia prior to the onset of radiographic changes. It reinforces the importance of considering rare genetic disorders in the differential diagnosis of pediatric bone marrow failure syndromes. Early molecular diagnosis and treatment significantly improve outcomes in affected children, highlighting the critical role of genetic testing in modern pediatric hematology.

Subject of Research: Genetically confirmed case of ghosal hematodiaphyseal dysplasia prior to onset of radiographic changes: case report and review of literature

Article Title: Genetically confirmed case of ghosal hematodiaphyseal dysplasia prior to onset of radiographic changes: case report and review of literature

Article References: Uvais, K. K. M., Mandal, P., Suresh, C. N., Chandan, S., & Singh, S. (2026). Genetically confirmed case of ghosal hematodiaphyseal dysplasia prior to onset of radiographic changes: case report and review of literature. Egyptian Journal of Medical Human Genetics, 27(1), Article 53. https://doi.org/10.1186/s43042-026-00880-2

Image Credits: AI Generated

DOI: 10.1186/s43042-026-00880-2

Keywords: Genetically, confirmed, case, ghosal, hematodiaphyseal, dysplasia, prior, onset, radiographic, changes, report, review