Blackfan-Diamond disease / anemia (DBA)

Blackfan-Diamond disease – click here for US CDC’s brochure

Diamond and Blackfan described a congenital hypoplastic anemia in 1938. In 1961, Diamond and colleagues presented longitudinal data on 30 patients and noted an association with skeletal abnormalities. In 1997 a region on chromosome 19 was determined to carry a gene mutated in DBA. In 1999, mutations in the ribosomal protein S19 gene (RPS19) were found to be associated with disease in 42 of 172 DBA patients. In 2001, it was determined that a second DBA gene lies in a region of chromosome 8 although evidence for further genetic heterogeneity was uncovered.

Diamond–Blackfan anemia (DBA), also known as Blackfan–Diamond anemia and Inherited erythroblastopenia, is a congenital erythroid aplasia that usually presents in infancy. DBA patients have low red blood cell counts (anemia). The rest of their blood cells (the platelets and the white blood cells) are normal. This is in contrast to Shwachman–Bodian–Diamond syndrome, in which the bone marrow defect results primarily in neutropenia, and Fanconi anemia, where all cell lines are affected resulting in pancytopenia.

A variety of other congenital abnormalities may also occur.

Diamond–Blackfan anemia is characterized by anemia (low red blood cell counts) with decreased erythroid progenitors in the bone marrow. This usually develops during the neonatal period. About 47% of affected individuals also have a variety of congenital abnormalities, including craniofacial malformations, thumb or upper limb abnormalities, cardiac defects, urogenital malformations, and cleft palate. Low birth weight and generalized growth delay are sometimes observed. DBA patients have a modest risk of developing leukemia and other malignancies.

Typically, a diagnosis of DBA is made through a blood count and a bone marrow biopsy.

A diagnosis of DBA is made on the basis of anemia, low reticulocyte (immature red blood cells) counts, and diminished erythroid precursors in bone marrow. Features that support a diagnosis of DBA include the presence of congenital abnormalities, macrocytosis, elevated fetal hemoglobin, and elevated adenosine deaminase levels in red blood cells.

Most patients are diagnosed in the first two years of life. However, some mildly affected individuals only receive attention after a more severely affected family member is identified.

About 20–25% of DBA patients may be identified with a genetic test for mutations in the RPS19 gene.

Genetics: approximately 10–25% of DBA cases have a family history of disease, and most pedigrees suggest an autosomal dominant mode of inheritance. The disease is characterized by genetic heterogeneity, with current evidence supporting the existence of at least three genes mutated in DBA.

In 1997, a patient was identified who carried a rare balanced chromosomal translocation involving chromosome 19 and the X chromosome. This suggested that the affected gene might lie in one of the two regions that were disrupted by this cytogenetic anomaly. Linkage analysis in affected families also implicated this region in disease, and led to the cloning of the first DBA gene. About 20–25% of DBA cases are caused by mutations in the ribosome protein S19 (RPS19) gene on chromosome 19 at cytogenetic position 19q13.2. Interestingly, some previously undiagnosed relatives of DBA patients were found to carry mutations. These patients also had increased adenosine deaminase levels in their red blood cells but no other overt signs of disease.

A subsequent study of families with no evidence of RPS19 mutations determined that 18 of 38 families showed evidence for involvement of an unknown gene on chromosome 8 at 8p23.3-8p22. The precise genetic defect in these families has not yet been delineated.

The phenotype of DBA patients suggests a hematological stem cell defect specifically affecting the erythroid progenitor population. This is difficult to reconcile with the known function of the single known DBA gene. The RPS19 protein is involved in the production of ribosomes. As such, loss of RPS19 function would be predicted to affect translation and protein biosynthesis and have a much broader impact. Disease features may be related to the nature of RPS19 mutations. The disease is characterized by dominant inheritance, and therefore arises due to a partial loss of RPS19 protein function. It is possible that erythroid progenitors are acutely sensitized to this decreased function, while most other tissues are unaffected.

Clinical management and treatments: Corticosteroids can be used to treat anemia in DBA. In a large study of 225 patients, 82% initially responded to this therapy, although many side effects were noted.[14] Some patients remained responsive to steroids, while efficacy waned in others. Blood transfusions can also be used to treat severe anemia in DBA. Periods of remission may occur, during which transfusions and steroid treatments are not required. Bone marrow transplantation (BMT) can cure hematological aspects of DBA. This option may be considered when patients become transfusion-dependent because frequent transfusions can lead to iron overloading and organ damage. However, data from a large DBA patient registry indicated that adverse events in transfusion-dependent patients were more frequently caused by BMTs than iron overloading.

An article published on Feb. 10, 2009 [1] reported that an eight year old boy with a DBA-like disease has been successfully treated by supplementing his diet with the amino acids leucine and isoleucine. A 2007 study [15] shows the efficacy of a similar treatment on a different patient. Larger studies are being conducted.

References:

1. Tchernia, Gilbert; Delauney, J (2000-06). “Diamond–Blackfan anemia”. Orpha.net. http://www.orpha.net/data/patho/Pro/en/BlackfanDiamond-FRenPro429.pdf. Retrieved 1 January 2010.

2. Cmejla R, Cmejlova J, Handrkova H, et al. (February 2009). “Identification of mutations in the ribosomal protein L5 (RPL5) and ribosomal protein L11 (RPL11) genes in Czech patients with Diamond–Blackfan anemia”. Hum. Mutat. 30 (3): n/a. doi:10.1002/humu.20874. PMID 19191325.

3. Diamond LK, Blackfan, KD (1938). “Hypoplastic anemia.”. Am. J. Dis. Child. 56: 464–467.

4. Diamond LK, Allen DW, Magill FB (1961). “Congenital (erythroid) hypoplastic anemia: a 25 year study.”. Am. J. Dis. Child. 102: 403–415. PMID 13722603.

5. Gustavsson P, Willing TN, van Haeringen A, Tchernia G, Dianzani I, Donner M, Elinder G, Henter JI, Nilsson PG, Gordon L, Skeppner G, van’t Veer-Korthof L, Kreuger A, Dahl N (1997). “Diamond–Blackfan anaemia: genetic homogeneity for a gene on chromosome 19q13 restricted to 1.8 Mb.”. Nat. Genet. 16 (4): 368–71. doi:10.1038/ng0897-368. PMID 9241274.

6. Gustavsson P, Skeppner G, Johansson B, Berg T, Gordon L, Kreuger A, Dahl N (1997). “Diamond–Blackfan anaemia in a girl with a de novo balanced reciprocal X;19 translocation.”. J. Med. Genet. 34 (9): 779–82. doi:10.1136/jmg.34.9.779. PMC 1051068. PMID 9321770. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1051068.

7. Draptchinskaia N, Gustavsson P, Andersson B, Pettersson M, Willig TN, Dianzani I, Ball S, Tchernia G, Klar J, Matsson H, Tentler D, Mohandas N, Carlsson B, Dahl N (1999). “The gene encoding ribosomal protein S19 is mutated in Diamond–Blackfan anaemia.”. Nat. Genet. 21 (2): 168–75. doi:10.1038/5951. PMID 9988267.

8. Gazda H, Lipton JM, Willig TN, Ball S, Niemeyer CM, Tchernia G, Mohandas N, Daly MJ, Ploszynska A, Orfali KA, Vlachos A, Glader BE, Rokicka-Milewska R, Ohara A, Baker D, Pospisilova D, Webber A, Viskochil DH, Nathan DG, Beggs AH, Sieff CA (2001). “Evidence for linkage of familial Diamond–Blackfan anemia to chromosome 8p23.3-p22 and for non-19q non-8p disease.”. Blood 97 (7): 2145–50. doi:10.1182/blood.V97.7.2145. PMID 11264183.

9. Gazda H, Lipton JM, Willig TN, et al. (April 2001). “Evidence for linkage of familial Diamond–Blackfan anemia to chromosome 8p23.3-p22 and for non-19q non-8p disease”. Blood 97 (7): 2145–50. doi:10.1182/blood.V97.7.2145. PMID 11264183. http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=11264183.

10. Gazda HT, Grabowska A, Merida-Long LB, et al. (December 2006). “Ribosomal protein S24 gene is mutated in Diamond–Blackfan anemia”. Am. J. Hum. Genet. 79 (6): 1110–8. doi:10.1086/510020. PMC 1698708. PMID 17186470. http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)63474-0.

11. Cmejla R, Cmejlova J, Handrkova H, Petrak J, Pospisilova D (December 2007). “Ribosomal protein S17 gene (RPS17) is mutated in Diamond–Blackfan anemia”. Hum. Mutat. 28 (12): 1178–82. doi:10.1002/humu.20608. PMID 17647292.

12. Farrar JE, Nater M, Caywood E, et al. (September 2008). “Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond–Blackfan anemia”. Blood 112 (5): 1582–92. doi:10.1182/blood-2008-02-140012. PMC 2518874. PMID 18535205. http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=18535205.

13. a b c Gazda HT, Sheen MR, Vlachos A, et al. (December 2008). “Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond–Blackfan anemia patients”. Am. J. Hum. Genet. 83 (6): 769–80. doi:10.1016/j.ajhg.2008.11.004. PMC 2668101. PMID 19061985. http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(08)00589-2.

14. Vlachos A, Klein GW, Lipton JM (2001). “The Diamond Blackfan Anemia Registry: tool for investigating the epidemiology and biology of Diamond–Blackfan anemia.”. J. Pediatr. Hematol. Oncol. 23 (6): 377–82. doi:10.1097/00043426-200108000-00015. PMID 11563775.

15. Pospisilova D, Cmejlova J, Hak J, Adam T, Cmejla R (2007). “Successful treatment of a Diamond–Blackfan anemia patient with amino acid leucine.”. Haematologica 92 (5): e66. doi:10.3324/haematol.11498. PMID 17562599.

Source: Wikipedia

External resources (to be looked for):

  • Diamond Blackfan Anemia Foundation (USA)
  • Daniella Maria Arturi Foundation Research For The Cure (USA)
  • GeneReviews/NCBI/NIH/UW entry on Diamond–Blackfan Anemia
  • OMIM entries on Diamond–Blackfan Anemia
  • Diamond–Blackfan Anemia research study of Inherited Bone Marrow Failure Syndromes (IBMFS)
  • UK Diamond Blackfan Anaemia Charity
  • Diamond Blackfan Anæmia International Support Group
  • Diamond Blackfan Anemia Registry of North America (DBAR)
  • “‘Designer baby’ bid gets go-ahead” at BBC News, 4 May 2006
  • Diamond Blackfan Anemia and You
  • Diamond–Blackfan anemia Genetics Home Reference

Information for professionals

Orpha number ORPHA124
Prevalence of rare diseases 1-9 / 1 000 000
Inheritance
  • Autosomal dominant
Age of onset Neonatal/infancy
ICD 10 code
  • D61.0
MIM number
Synonym(s) Aase syndrome
Aase-Smith II syndrome
Blackfan-Diamond anemia
Congenital PRCA
Congenital hypoplastic anemia, Blackfan-Diamond type
Congenital pure red cell aplasia

Summary

Blackfan-Diamond anemia (DBA) is a congenital aregenerative and often macrocytic anemia with erythroblastopenia. Annual incidence in the general population of Europe is estimated at around 1/150,000. Both sexes are equally affected and no ethnic predisposition has been identified. The anemia is discovered early in life, usually within the first 2 years; diagnosis after 4 years of age is very unlikely. Pallor and dyspnea, especially during feeding or while sucking, are the principal warning signs. Pallor is isolated, without organomegaly, signs suggestive of hemolysis or involvement of other hematopoietic cell lines. Over half of all DBA patients present with short stature and congenital anomalies, the most frequent being craniofacial (Pierre-Robin syndrome and cleft palate), thumb and urogenital anomalies. Pregnancies in DBA-affected women are now identified as high-risk, for both mother and child. DBA patients may also be at a higher risk of leukemia and cancer. DBA is inherited as an autosomal dominant trait with variable penetrance. At present, disease-causing mutations are identified in 40-45% of patients. All involved genes code for ribosomal proteins (RPs) from either the small (RPS7, RPS17, RPS19, RPS24) or the large (RPL5, RPL11, RPL35a) ribosomal subunit. Mutations in RPS19, RPL5 and RPL11 are found in 25%, 9% and 6.5% of patients respectively, whereas the other genes are each involved in only 1 to 3% of cases. The only clear genotype/phenotype correlation made so far is the frequent occurrence of craniofacial abnormalities in RPL5 and RPL11 mutation carriers and the rarity of these anomalies in RPS19 mutation carriers. In a child with anemia and erythroblastopenia, the diagnosis can be supported by a familial history (10-20% of cases), associated malformations (40% of cases), and elevated erythrocyte adenosine deaminase (EAD), which is a frequent but non-specific sign that may also be elevated in relatives in the absence of other DBA symptoms. Detection of a disease-causing mutation is of diagnostic value. The differential diagnosis should include transient erythroblastopenia (see this term), chronic parvovirus B19 infection, and other congenital anemias. Genetic counseling and prenatal diagnosis are difficult because of the variability of clinical expression and the fact that only 40-45% of patients have an identified mutation within a RP gene. In familial cases, the risk of recurrence is 50%. Close ultrasound follow-up during the pregnancy is recommended in all cases. The two main therapeutic approaches are regular transfusions and long-term corticosteroid therapy. Treatment must be adapted to each case and according to the age of the patient. Steroids should not be administered during the first year of life. Short stature, occurring both as part of the syndrome and due to treatment-related complications (steroids, hemochromatosis), is a major issue for these patients. Allogenic bone-marrow transplantation must be discussed in corticoresistant patients when an unaffected and HLA-identical sib is available. The prognosis is generally good. However, complications of treatment and a higher incidence of cancer may reduce life expectancy. Disease severity depends on the quality and response to treatment. For patients undergoing regular transfusions, quality of life is clearly altered.

Source: Orphanet
Expert reviewer(s)
Dr Thierry LEBLANC
Last update: February 2009

Detailed information

Review article
Guidance for genetic testing

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