Diamond Blackfan Anemia: New Paradigms for a “Not So Pure” Inherited Red Cell Aplasia
Section snippets
Pathophysiology and Genetics: Is DBA a Disorder of Ribosome Biosynthesis?
A number of theories regarding the pathophysiology of DBA have been proposed and discarded.15, 16, 17, 18 Widely accepted is that the disorder results from an intrinsic cellular defect in which erythroid progenitors and precursors are highly sensitive to death by apoptosis.19, 20, 21, 22 Familial DBA appears to be inherited as an autosomal dominant. No instance of autosomal recessive inheritance has been confirmed, and apparent recessive inheritance is likely a consequence of non-penetrance2
Making the Diagnosis of Diamond Blackfan Anemia
The median age at presentation and diagnosis of classical DBA are 8 weeks (range, birth to 6 years) and 12 weeks (range, birth to 26 years), respectively.40 Ninety-three percent of DBA patients present in the first year of life, but as in the other inherited bone marrow failure syndromes, DBA may present in adulthood,52 when it is often misdiagnosed. The differential diagnosis of DBA in children presenting with red cell failure, anemia, reticulocytopenia, and decreased or absent marrow
Congenital Anomalies
Birth defects have long been known to be a feature of DBA. A distinct facial appearance and triphalangeal thumbs have been classically described in DBA as the Cathie facies56 and Aase syndrome,57 respectively. A cute snub nose and wide-spaced eyes, as originally described by Cathie, and other craniofacial anomalies, some as already discussed quite severe, are the most common physical anomalies of DBA. Abnormal thumbs are classic.58 In all, congenital anomalies were found in 30% to 47% of the
Cancer: Is DBA a Cancer Predisposition Syndrome?
At least 26 cases of cancer in patients with DBA have been reported in the literature. Sixteen were hematopoietic malignancies: 10 acute myeloid leukemia (AML), two myelodysplastic syndrome (MDS), two Hodgkin disease, one non-Hodgkin lymphoma, and one acute lymphoblastic leukemia. Ten solid tumors have been reported: three osteogenic sarcoma, two breast cancer, two hepatocellular carcinoma, and one each of gastric carcinoma, vaginal melanoma, and malignant fibrous histiocytoma.3 A number of
Corticosteroids and Red Cell Transfusions
Corticosteroids and red cell transfusions are the mainstays of therapy for DBA. Since 1951,67 it has been known that the anemia of DBA can be ameliorated by corticosteroids. The initial suggestion to use corticosteroids was based on the theory that DBA was an “allergic” disorder. The response to corticosteroids further perpetuated the erroneous notion of DBA as an autoimmune disease, even when only miniscule doses were required to maintain adequate erythropoiesis. The almost unlimited use of
Conclusions: Where Are We Going?
Progress in the understanding of the inherited bone marrow failure syndromes and in particular DBA has resulted from the combination of clinical and research laboratory science. Patient registries have permitted the more precise description of congenital anomalies, suggesting a possible connection between DBA and TCS; similarities between them strongly support their classification as disorders of ribosome biosynthesis. Other disorders have been postulated to involve defects in ribosome assembly
Acknowledgment
The progress described in this review is testament to the commitment of the patients with DBA, their families, clinicians who care for the patients, and the dedicated scientists, clinical and laboratory-based, with whom I have the privilege to work. The author would also like to thank Adrianna Vlachos, MD, Johnson Liu, MD, Hanna Gazda, MD, and Eva Atsidaftos, MA, for their invaluable advice and assistance.
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Cited by (27)
A new murine Rpl5 (uL18) mutation provides a unique model of variably penetrant Diamond-Blackfan anemia
2021, Blood AdvancesCitation Excerpt :Among the ribosomopathies, Diamond-Blackfan anemia (DBA) is the disorder most often linked to anemia. However, many nonhematopoietic phenotypes, particularly in the skeleton and heart, are also found in DBA, as is an increased risk of developing malignancies at a young age.4-8 Inherited heterozygous mutations in genes encoding ribosomal proteins (RPs) lead to most cases of DBA.7
Neonatal Erythrocyte Disorders
2018, Avery's Diseases of the Newborn: Tenth EditionNeonatal Erythrocyte Disorders
2017, Avery's Diseases of the Newborn, Tenth EditionNeonatal manifestations of inherited bone marrow failure syndromes
2016, Seminars in Fetal and Neonatal MedicineCitation Excerpt :Congenital anomalies have been reported in 40–50% patients (Table 1) [1,32]. Craniofacial dysmorphism includes widely separated eyes, ‘snub’ nose, thick upperlip, and rarely cleft lip/palate; upper limb deformities include triphalangeal, bifid or subluxed thumbs with subtle thenar eminence flattening and normal radius [33]. The thumb abnormalities are important to differentiate from FA.
P53 and ribosome biogenesis stress: The essentials
2014, FEBS LettersCitation Excerpt :Diamond-Blackfan anemia (DBA) is the paradigm for this type of disorders. DBA is characterized by hypoplastic macrocytic anemia and specific developmental defects [34]. DBA patients are predisposed to the development of myelodysplastic syndrome (MDS) as well as acute myeloid leukemia and solid malignancies [35].
Congenital Disorders of Ribosome Biogenesis and Bone Marrow Failure
2010, Biology of Blood and Marrow TransplantationCitation Excerpt :DBA is also considered a cancer predisposition syndrome. In a recent review by Lipton and Ellis [21], of the 30 cases of cancer in DBA patients, 15 were hematopoietic malignancies. Although cancer is rare, the incidence is higher than what would be expected for the specific age group [21].
Supported by grants from the Daniella Maria Arturi Foundation, Diamond Blackfan Anemia Foundation, Pediatric Cancer Foundation, National Institutes of Health RO1 HL 079571, and the Feinstein Institute for Medical Research at the NSLIJ General Clinical Research Center MO1 RR018535.