Diamond-Blackfan Anemia (Answer: C)
Diamond-Blackfan anemia is the correct answer, as it represents an inherited hematopoietic failure syndrome specifically caused by defective ribosome biogenesis during erythroid differentiation, resulting from germline mutations in ribosomal protein genes. 1
Pathophysiology of Diamond-Blackfan Anemia
Diamond-Blackfan anemia is primarily caused by germline heterozygous pathogenic variants in one of 24 genes coding for small or large ribosomal proteins, inherited as an autosomal dominant trait with more than half of cases due to de novo variants. 1 The faulty ribosome biogenesis leads to:
- Accelerated apoptosis in erythroid progenitors/precursors, creating a block in early committed erythropoiesis 2, 3
- Reduced megakaryocyte/erythroid progenitor (MEP) expansion due to premature downregulation of chromatin regulators during differentiation 4
- Defective maturation of erythroid progenitors with very low numbers of erythropoietic precursors and reduced BFU-E progenitor cells in bone marrow 2
Clinical Presentation
Diamond-Blackfan anemia typically presents with:
- Red cell aplasia appearing in the first year of life with profound isolated anemia 2
- Congenital malformations in approximately 50% of cases, most commonly craniofacial, upper extremity, cardiac, and genitourinary abnormalities 1
- Impaired growth as a characteristic feature 1
- Very low reticulocyte counts despite profound anemia 2
Why Other Options Are Incorrect
Pure Red Cell Aplasia (Option A) is typically an acquired condition, not an inherited disorder of hematopoietic differentiation. 2
Fanconi Anemia (Option B) is an inherited bone marrow failure syndrome, but it represents a DNA repair disorder affecting multiple hematopoietic lineages, not specifically a differentiation defect. 1
Myelodysplastic Syndrome (Option D) is predominantly an acquired clonal disorder, though rare inherited forms exist; it represents dysplasia rather than a primary differentiation failure during hematopoiesis. 1
Clinical Significance
Diamond-Blackfan anemia patients have a cumulative malignancy incidence of 13.7% by age 45 years, with MDS being the most common hematologic malignancy, along with solid tumors including osteosarcoma and colon cancer. 1 International consensus now recommends colonoscopy beginning at age 20 years in addition to hematologic surveillance. 1
When considering hematopoietic stem cell transplantation for MDS originating from inherited germline mutations like Diamond-Blackfan anemia, patients should be referred to specialist centers due to specific sensitivities to conditioning regimens and the need for careful family donor selection who may carry the involved mutation. 1