Diamond-Blackfan anemia; Erythrogenesis imperfecta - Genes RPL5, RPL11, RPL35A, RPS7, RPS10, RPS17, RPS19, RPS24 or RPS26 genes

Diamond-Blackfan anemia, also known as congenital hypoplastic anemia or erythrogenesis imperfecta, is an alteration due to a primary failure in the bone marrow that causes it to be unable to generate enough erythrocytes. The anemia, normochromic macrocytic, consequent, usually becomes apparent during the first year of life accompanied by the symptoms of it: fatigue, weakness and pale skin and mucous membranes. Patients affected by this syndrome tend to have other complications such as the development of a myelodysplastic syndrome, or an increased risk of developing some hematological neoplasms such as acute myeloid leukemia or osteosarcoma. In 30 to 40% of patients there are other congenital anomalies, mainly in the craniofacial region or the upper extremities, including craniofacial anomalies (microcephaly, micrognathia, hypertelorism, palpebral ptosis, broad-based nose, low-set ear pavilions), cleft palate, cleft lip, cataracts, glaucoma, strabismus, hypoplastic or malformed thumbs, and cardiac or genitourinary anomalies (hypospadias). The usual laboratory findings are the increase in the average corpuscular volume, the elevation of erythrocyte adenosine deaminase and the increase in hemoglobin F. The syndrome may present different severity, and in milder forms mild anemia appears in adulthood.

Diamond-Blackfan anemia is due to mutations in several genes, some of which have not been identified. Approximately 25 percent of people with Diamond-Blackfan anemia have mutations in the RPS19 gene, located on the long arm of chromosome 19 (19q13.2); about 25 to 35 percent of affected people have mutations in the RPL5 gene, located on the short arm of chromosome 1 (1p22.1) (6.6%); RPS10, located on the short arm of chromosome 6 (6p21.31) (6.4%); RPL11, located on the short arm of chromosome 1 (1p36.11) (4.8%); RPL35A, located on the long arm of chromosome 3 (3q29) (3%); RPS26, located on the long arm of chromosome 12 (12q13.2) (2.6%); RPS24, located on the long arm of chromosome 10 (10q22.3) (2%); RPS17, located on the long arm of the chromosome 15 (15q25.2) (1%); or RPS7, located on the short arm of chromosome 2 (2p25) (1%).

These genes encode the proteins that are going to be part of the ribosomes (RP: ribosomal Protein), both of their small subunit of 40S (S-proteins -small-) (proteins S7, S10, S17, S19, S24 and S26), and of the large 50S subunit (L-Large- proteins) (proteins L5, L11, L35-A). In the ribosomes cellular proteins are synthesized, and therefore a failure in the structure of the ribosomes affects the elaborated proteins. Some of the ribosomal proteins participate in the stability of the ribosome structure, others participate in the synthesis of proteins, and others can act in intracellular communication pathways, regulation of cell division, or in the cell's own destruction (apoptosis). 

More than 170 mutations have been identified in the RPS19 gene, 70 mutations in the RPL5 gene, 3 mutations in the RPS10, 44 mutations in the RPL11 gene, 14 mutations in the RPL35A gene, 33 mutations in RPS26, 10 mutations in the RPS24 gene, 18 mutations in the RPS17 gene and 1 mutation in the RPS7 gene. Mutations in any of the genes mentioned above are believed to affect the stability or function of ribosomal proteins. In this way, the deficiency of functional ribosomal proteins could increase the cellular self-destruction in the bone marrow causing anemia. It has been demonstrated that the deficiencies of the RPS19 and RPS24 proteins are involved in Diamond-Blackfan anemia, and in a subset of patients the mutation causes the degradation of the RNA transcripts, or they alter their conformation and stability. 

This disease is inherited in an autosomal dominant pattern, which means that a copy of the altered gene in each cell is sufficient for the disease to be expressed. In most cases, an affected person has a father with the disease. In approximately 45% of cases, an affected person inherits the mutation of an affected parent. The remaining cases are due to new mutations in the gene and occur in people with no history of the disease in their family. 

Tests performed in IVAMI: in IVAMI perform the detection of mutations associated with Diamond-Blacckfan anemia, by complete PCR amplification of the exons of the RPL5, RPL11, RPL35A, RPS7, RPS10, RPS17, RPS19, RPS24 or RPS26 genes, respectively, and its subsequent sequencing. Our recommendation is to begin with the study of the RPS19 gene, where the mutations are most frequent, and to continue with those genes that present a similar incidence of mutations (RPL5, RPL11, RPL35A, and RPS10), and if no mutations in these genes were found, perform tests to detect mutations in the remaining genes (RPS24, RPS7, RPS17 and RPS26). 

Recommended samples: blood drawn with EDTA for separation of blood leukocytes, or card impregnated with dried blood sample (IVAMI can mail the card to deposit the blood sample).