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Blackfan-Diamond anemia

Orpha number ORPHA124
Synonym(s) Aase syndrome
Aase-Smith II syndrome
Congenital PRCA
Congenital hypoplastic anemia, Blackfan-Diamond type
Congenital pure red cell aplasia
Prevalence Unknown
Inheritance
  • Autosomal dominant
Age of onset Neonatal/infancy
ICD-10
  • D61.0
OMIM
UMLS
  • C1260899
MeSH
  • D029503
MedDRA
  • 10062989
SNOMED CT
  • 234371002
  • 88854002

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.

Expert reviewer(s)

  • Dr Thierry LEBLANC

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Detailed information

Summary information
Emergency guidelines
  • FR (2012,pdf)
Guidance for genetic testing
  • EN (2013,pdf)
Clinical genetics review
  • EN (2014)
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