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Diamond Blackfan anaemia

This is part of Rare diseases.

Diagnosis: Diamond Blackfan anaemia

Synonyms: DBA, Blackfan Diamond anaemia, Congenital hypoplastic anaemia

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Publication date: 2012-06-19
Version: 1.0

ICD 10 code

D61.0

The disease

Diamond Blackfan anaemia (DBA) was first described in 1938, by the American paediatricians Louis Klein Diamond and Kenneth Blackfan. Blackfan Diamond anaemia and congenital hypoplastic anemia are other names for the disorder. The condition is characterised by impaired red blood cell production, which results in anaemia (low haemoglobin, Hb). DBA is also associated with certain congenital malformations.

Occurrence

In Sweden, 1-2 children per year are born with Diamond Blackfan anaemia, and there are approximately 30 people with the disorder in Sweden, most under the age of 30.

Cause

Diamond Blackfan anaemia is caused by a mutation in one of the genes coding for ribosomal proteins. There are 79 different ribosomal proteins. Ribosomes are the protein builders of the cell. The correlation between anaemia and the underlying anomalous gene is still unclear, but it is likely that the mutation causes a defect in blood stem cells in the (blood) bone marrow, preventing them from maturing into red blood cells.

To date, more than 10 different genes have been associated with Diamond Blackfan anaemia. Mutations in one of these genes represent more than half of all known cases of the disorder. Some of these mutations are associated with particular congenital malformations. It is expected that several more genes underlying the condition will be identified. Mutations in the RPS19 gene on chromosome 19 (19q13.2) are most common, representing approximately 25 per cent of all cases. The identification of new genes has made it possible to diagnose many cases of non-classical DBA forms. People with these forms may have mild blood production abnormalities (haematological abnormalities) and DBA-associated congenital malformations, or they may be completely asymptomatic, despite being carriers of a mutation. It is also possible that the disorder does not manifest until adulthood.

Type Chromosome  Gene
DBA1 19q13.2 RPS19
DBA2 8p23-p22 -
DBA3 10q22-q23 RPS24
DBA4 15q RPS17
DBA5 3q29-qter RPL35A
DBA6 1p22.1 RPL5
DBA7 1p36.1-p35 RPL11
DBA8 2p25 RPS7
DBA9 6p RPS10
DBA10  12q RPS26

Table: Genes associated with Diamond Blackfan anaemia.

Heredity

The inheritance pattern of Diamond Blackfan anaemia is autosomal dominant. This means that one of the parents has the disease, and so has one normal gene and one mutated gene. Sons and daughters of this parent have a 50 per cent risk of inheriting the disease. Children who do not inherit the mutated gene do not have the disease and do not pass it down.

Figure: Autosomal dominant inheritance

In most cases Diamond Blackfan anaemia is caused by a new mutation. This means that the genetic mutation occurs in an individual for the first time and is not inherited from either parent. Consequently, parents with a child with a new mutation generally do not have an increased risk of having another child with the disorder. However, the new genetic mutation will be hereditary and an adult with this mutation risks passing on the mutated gene to his/her children.

There are also cases in which the inheritance pattern is autosomal recessive. This means that both parents are healthy carriers of a mutated gene. When two healthy carriers have a child, there is a 25 per cent risk that the child will inherit the mutated genes (one from each parent) in which case he or she will have the disease. In 50 per cent of cases the child inherits only one mutated gene (from one parent only) and, like both parents, will be a healthy carrier of the mutated gene. In 25 per cent of cases the child will not have the disease and will not be a carrier of the mutated gene.

Figure: Autosomal recessive inheritance

A person with an inherited autosomal recessive disease has two mutated genes. If this person has a child with a person who is not a carrier of the mutated gene, all the children will inherit the mutated gene but they will not have the disorder. If a person with an inherited autosomal recessive disease has children with a healthy carrier of the mutated gene (who has one mutated gene) there is a 50 per cent risk of the child having the disorder, and a 50 per cent risk of the child being a healthy carrier of the mutated gene.

Symptoms

Diamond Blackfan anaemia is associated with many different symptoms, but all people with the disease have a low blood count (are anaemic). This condition gives rise to symptoms early in life, for example fatigue, poor appetite, paleness and failure to thrive. The heart also has to work harder, resulting in an elevated pulse. The increased rate of blood flow is often noticed as a heart murmur.

The child may also have low muscle tone (hypotonia).

The diagnosis is sometimes made in neonates, and in most cases before the age of three months. Only rarely is classic DBA diagnosed after the age of one.

Other symptoms vary widely. Some children have lip and palate clefts. In approximately 30-40 per cent the condition is accompanied by other types of malformations, particularly skeletal anomalies. These include thumb abnormalities, which are considered characteristic of the disorder, but bone anomalies may also be noticed as skin folds on the throat, caused by fused vertebrae. Short stature occurs in about one third of cases. Diamond Blackfan anaemia may also be associated with characteristic facial features.

Diamond Blackfan anaemia is associated with an increased risk of developing myelodysplastic syndrome (MDS), and certain types of cancer. In MDS, the ability of the bone marrow to produce blood cells is impaired, a condition referred to as pre-leukaemia.

Diagnosis

Blood analyses and bone marrow evaluations are used to establish the diagnosis, sometimes in combination with clinical findings.

DNA-based diagnostics is often possible, and if the mutation in the family is known, prenatal diagnostics is possible.

Treatment/interventions

A small number of cases of Diamond Blackfan anaemia may not require medical treatment. Cases of pronounced anaemia are treated with corticosteroids. In almost 50 per cent of all cases, corticosteroids in low doses work well. If high doses are required there will be side effects such as metabolic changes, brittle bones and psychological symptoms, including mood swings and sleep disturbances. Sometimes corticosteroids lose their effectiveness. In these cases it may be worth re-initiating the treatment, as effectiveness may return.

In half of all cases, corticosteroid therapy is not effective enough and regular blood transfusions are required. The need for blood varies, but as a rule blood transfusions are scheduled every two to four weeks, and take between 2 and 4 hours. To facilitate regular blood transfusions, children with DBA may receive an intravenous (port) access, a small metal device surgically implanted beneath the skin with a tube connected to the bloodstream. Blood transfusions, however, do not restore blood counts to normal.

One of the drawbacks of having regular blood transfusions is iron build-up in the body. Over time, there is a risk of developing chronic iron toxicity, as excess iron aggregates in the body and causes organ damage, for example in the liver, heart and lungs. Iron overload requires treatment with desferrioxamine, an agent that binds excess iron in the body so that it can be excreted in urine. Desferrioxamine is infused under the skin (subcutaneous infusion), and this treatment can usually be managed in the home, during sleep. As desferrioxamine may also have side effects that can impair vision or hearing, it is important to have regular medical check-ups. Other medical treatment may also be used to optimize iron elimination. Desferasirox tablets are sometimes administered as an alternative, or a complement to, desferrioxamine therapy.

Spontaneous remission occurs in approximately one fifth of all cases of Diamond Blackfan anaemia. Remission may occur many years after the diagnosis was first made.

Congenital anomalies associated with Diamond Blackfan anaemia vary considerably, and it is therefore difficult to provide general guidelines for treatment. Cleft lip or palate can be treated with surgery, which should be carried out early in life. Plastic surgery clinics have multidisciplinary teams (craniofacial teams or cleft teams) with established routines for treatment and follow-up of children and adolescents with cleft lip, jaw, or palate. These teams include a plastic surgeon, a speech pathologist, an oral and maxillofacial surgeon, an orthodontist, and a psychologist.

As a consequence of treatment, children with DBA may often be absent from school. Educational support may be required, for example in the form of assignments to carry out at home when absence is inevitable owing to blood transfusions. Psychological and social support are also important.

Other therapies that aim to repair the immune system have also been tried, with limited effect. Transplantation of blood stem cells (haematopoietic stem cell transplantation; 'bone marrow transplantation') is considered when medical treatment proves insufficient, when a large number of transfusions are required, and when there is considerable risk of developing chronic iron toxicity. Haematopoietic stem cell transplantation fully restores bone marrow function, but in some cases medication is needed to treat the iron overload that has accumulated before the transplantation was carried out.

Haematopoietic stem cell transplantation

All blood cells are produced from blood stem cells (haematopoietic stem cells) in the bone marrow. Blood-forming stem cells can develop into red blood cells (erythrocytes), different kinds of white blood cells including lymphocytes and blood platelets (thrombocytes). A stem cell transplantation provides the opportunity to replace a sick person's bone marrow with that of a healthy person. To optimise the chances of successful transplantation, the recipient of the marrow should be as free from infection as possible and in good physical condition. For this reason, it is important to carry out the transplantation at an early stage. The intervention itself is fairly simple, but the preparations, aftercare and major risks make it a highly demanding procedure.

In order to carry out a stem cell transplantation, a donor must be found whose tissue type (HLA type) matches that of the recipient. Ideally the tissue type should be identical. Tissue type is inherited from both parents, and each child has a 25 per cent chance of having the same tissue type as a sick sibling. The optimal solution is to transplant stem cells from an HLA-identical, healthy sibling. If this is not possible, a suitable donor may be located in national and international bone marrow donor programmes or in stored, frozen blood from umbilical cords. The “Tobias Registry” in Sweden contains approximately 40,000 registered voluntary donors, and the names of more than 18 million other donors can be found in registers outside Sweden.

Preparatory measures are needed to help the new stem cells engraft and minimise the risk of diseased cells attacking the new donor cells. The recipient of the transplanted cells is treated with chemotherapy. This treatment can be extremely exacting, as chemotherapy also impairs the barrier function of the mucous membranes. There is a major risk of developing serious infection and for this reason the child needs to be kept in isolation for a period of weeks, or sometimes months, prior to and after the transplantation.

In a blood stem cell transplantation, bone marrow is drawn from the donor's hip bone and is then administered to the recipient via drip, directly into the bloodstream, much as in a blood transfusion. Blood stem cells can also be collected from the donor's blood. The blood is then filtered in a special kind of centrifuge that separates the stem cells from the rest of the blood, which can then be returned to the donor. A third option is to use umbilical cord blood from newborns, which is particularly rich in blood stem cells. The blood of newborns has very high levels of blood stem cells and the small amount of blood remaining in the umbilical cord of a healthy newborn can be frozen and saved for later transplantations.

Regardless of their source, the transplanted blood stem cells find their way into the bone cavities of the recipient, and grow in the bone marrow to supply the child with a new immune system.

Practical advice

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National and regional resources in Sweden

Diagnostics should be carried out regionally, but supportive treatment can be carried out at county level. However, the condition must be managed at a clinic with experience in administering blood transfusions. As DBA is a very rare disease collaboration is required, both in Sweden and internationally.

Genetic assessment is carried out at the unit for Clinical Genetics at Uppsala University Children's Hospital.

Resource personnel

Professor Niklas Dahl, Clinical Genetics, Uppsala University Children's Hospital, SE-751 85 Uppsala, Sweden. Tel: +46 18 611 00 00, email: niklas.dahl@akademiska.se.

Clinical guidance is offered by paediatricians specialized in haematological diseases in children. There are paediatric cancer centres at the university hospitals in Stockholm, Gothenburg, Uppsala, Lund, Umeå, and Linköping.

Courses, exchanges of experience, recreation

Ågrenska is a national competence centre for rare diseases, and its families' programme arranges stays for children and young people with rare diseases and their families. Ågrenska is open to families from the whole of Sweden and focuses particularly on the needs of children and young people with rare diseases. Every year a number of adults with rare diseases also visit Ågrenska. Information is available from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se, www.agrenska.se.

Organizations for the disabled/patient associations

The Swedish association for parents of children and young people with Diamond Blackfan anaemia is no longer active. Those interested are still welcome to contact Håkan Rosén, Labackavägen 34 E, SE-428 35 Kållered, Sweden. Tel: +46 31795 51 06, or Pål Persson, Grims väg 3, SE-374 50 Asarum, Sweden, tel: +46 454 32 17 51, or Lena-Maria Gestrin, tel: +46 70 350 94 53, email: lena-maria.gestrin@comhem.se.

There is an American Diamond Blackfan Anemia Foundation, www.dbafoundation.org, and there is also the DBA UK, The Diamond Blackfan Anaemia Charity, www.diamondblackfan.org.uk.

Courses, exchanges of experience for personnel

Physicians may contact:
The Swedish Paediatric Society Section for Haematology/Oncology, Working Group for Paediatric Haematology (Vårdplaneringsgruppen för Pediatrisk Hematologi, VPH), chair: Ulf Tedgård, Skåne University Hospital, Malmö, SE-205 02 Malmö, Sweden, www.blf.net/onko/.

The Nordic Society of Pediatric Hematology and Oncology, Working group for Aplastic Anemia in Children, Niels Clausen, Børneafdelingen, Skejby Sygehus, DK-8200 Århus N, Denmark.

During the Ågrenska Family Program weeks, training days are organized for personnel working with the children who are participating. Information is available from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se, www.agrenska.se.

Research and development (R&D)

Medical research in the fields of genetics and molecular biology is ongoing at the Department of Genetics and Pathology, Uppsala University (Professor Niklas Dahl). Collaboration is established between leading researchers worldwide.

There is a working group for Diamond Blackfan anaemia within the European Society for Paediatric Haematology and Immunology, DBA working group of ESPHI, Dr Gil Tchernia, Centre Hospitalier de Bicêtre, Laboratoire d’Hématologie, 78 Rue du Général Leclerc, F-94270 Le Kremlin-Bicêtre, France.

Information material

An information leaflet on Diamond Blackfan anaemia summarising the information in this database text is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2011-11-13.) Address: SE-120 88 Stockholm, Sweden. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se. Postage will be charged for bulk orders.

The Ågrenska National Competence Centre for Rare Diseases has published a newsletter on Diamond Blackfan anaemia, nr 272 (2006). Newsletters are edited summaries of lectures delivered at family and adult visits to Ågrenska. They may be ordered from Ågrenska, Box 2058, SE-436 02 Hovås, Sweden. Tel: +46 31 750 91 00, fax: +46 31 91 19 79, email: agrenska@agrenska.se. They are also available at www.agrenska.se.

Literature

Alter BP, Young NS. The bone marrow failure syndromes. In: Nathan and Oski’s hematology of infancy and childhood, 6 ed. David G Nathan, Stuart H Orkin, A Thomas Look, David Ginsburg, Eds. Philadelphia; W B Saunders Company 2003.

Draptchinskaia N, Gustavsson P, Andersson B, Pettersson M, Willig TN, Dianzani I et al. The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia. Nature Genet 1999; 21: 169-175.

Flygare J, Aspesi A, Bailey JC, Miyake K, Caffrey JM, Karlsson S, Ellis S. Human RPS19, the gene mutated in Diamond-Blackfan anemia, encodes a ribosomal protein required for the maturation of 40S ribosomal subunits. Blood 2007; 109: 980-986.

Gazda H, Sieff CA. Recent insights into the pathogenesis of Diamond-Blackfan anaemia. Br J Haematol 2006; 135: 149-157.

Gazda H, Grabowska A, Merida-Long LB, Latawiec E, Schneider HE, Lipton J et al. Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia. Am J Hum Genet 2006; 79: 1110-1118.

Gazda H, Lipton JM, Willig TN, Ball S, Niemeyer CM, Tchernia G et al. Evidence for linkage of familial Diamond-Blackfan anemia to chromosome 8p23.3-p22 and for non-19q non-8p disease. Blood 2001; 97: 2145-2150.

Gustavsson P, Willig T-N, van Haeringen A, Tchernia G, Dianzini I, Donnér M et al. Diamond-Blackfan anaemia: genetic homogeneity for a gene on chromosome 19q13 restricted to 1.8 Mb. Nature Genet 1997; 16: 368-371.

Lipton J. Diamond Blackfan anemia: New paradigms for a “not so pure” inherited red cell aplasia. Semin Hematol 2006; 43: 167-177.

Matsson H, Klar J, Draptchinskaia N, Gustavsson P, Carlsson B, Bowers D et al. Truncating ribosomal protein S19 mutations and variable clinical expression in Diamond-Blackfan anemia. Hum Genet 1999; 105: 496-500.

Roy V, Perez W, Eapen M, Marsh JC, Pasquini M, Pasquini R et al. Bone marrow transplantation for Diamond-Blackfan anemia. Biology Blood Marrow Transplant 2005; 11: 600-608.

Vlachos A, Muir E. How I treat Diamond Blackfan anemia. Blood 2010; 116: 3715-3723.

Vlachos A, Ball S, Dahl N, Alter BP, Sheth S, Ramenghi V et al. Diagnosing and treating Diamond Blackfan anemia: results of an international clinic consensus conference. Br J Haematol 2008; 142: 859-876.

Database references

OMIM (Online Mendelian Inheritance in Man)
www.ncbi.nlm.nih.gov/omim 
Search: diamond-blackfan anemia; dba

GeneReviews (University of Washington)
www.genetests.org (find GeneReviews, then Titles)
Search: diamond-blackfan anemia

Document information

The Swedish Information Centre for Rare Diseases produced and edited this information material.

The medical expert who wrote the draft of this information material is senior physician Gunnar Skeppner, Örebro University Hospital, Sweden.

The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Publication date: 2012-06-19
Version: 1.0
Publication date of the Swedish version: 2011-12-29

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

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