Diamond-Blackfan anemia

Other Names: DBA; Anemia Diamond Blackfan type; Blackfan Diamond syndrome; BDS; Anemia congenital erythroid hypoplastic; Aregenerative anemia chronic congenital; Erythrogenesis imperfecta; Red cell aplasia, pure hereditary; Congenital hypoplastic anemia; Aase syndrome; Blackfan-Diamond anemia; Aase-Smith II syndrome; Congenital PRCA; Congenital hypoplastic anemia, Blackfan-Diamond type; Congenital pure red cell aplasia

Diamond-Blackfan anemia is an inherited blood disorder that affects the ability of the bone marrow to produce red blood cells. The major function of bone marrow is to produce new blood cells. In Diamond-Blackfan anemia, the bone marrow malfunctions and fails to make enough red blood cells, which carry oxygen to the body's tissues. The resulting shortage of red blood cells (anemia) usually becomes apparent during the first year of life. Symptoms of anemia include fatigue, weakness, and an abnormally pale appearance (pallor).

People with Diamond-Blackfan anemia have an increased risk of several serious complications related to their malfunctioning bone marrow. Specifically, they have a higher-than-average chance of developing myelodysplastic syndromes (MDS), which is a disorder in which immature blood cells fail to develop normally. Individuals with Diamond-Blackfan anemia also have an increased risk of developing a bone marrow cancer known as acute myeloid leukemia (AML), a type of bone cancer called osteosarcoma, and other cancers.

Epidemiology

Diamond-Blackfan anemia affects approximately 5 to 7 per million newborn babies worldwide.

Causes

Diamond-Blackfan anemia can be caused by mutations in one of many genes, including the RPL5, RPL11, RPL35A, RPS10, RPS17, RPS19, RPS24, and RPS26 genes. These and other genes associated with Diamond-Blackfan anemia provide instructions for making ribosomal proteins, which are components of cellular structures called ribosomes. Ribosomes process the cell's genetic instructions to create proteins.

Each ribosome is made up of two parts (subunits) called the large and small subunits. The ribosomal proteins produced from the RPL5, RPL11, and RPL35A genes are among those found in the large subunit. The proteins produced from the RPS10, RPS17, RPS19, RPS24, and RPS26 genes are among those found in the small subunit.

Some ribosomal proteins are involved in the assembly or stability of ribosomes. Others help carry out the ribosome's main function of building new proteins. Studies suggest that some ribosomal proteins may have other functions, such as participating in chemical signaling pathways within the cell, regulating cell division, and controlling the self-destruction of cells (apoptosis).

Approximately 25 percent of individuals with Diamond-Blackfan anemia have mutations in the RPS19 gene. About another 25 to 35 percent of individuals with this disorder have mutations in the RPL5, RPL11, RPL35A, RPS10, RPS17, RPS24, or RPS26 gene. Mutations in any of these genes are believed to cause problems with ribosome function. Studies indicate that a shortage of functioning ribosomes may increase the self-destruction of blood-forming cells in the bone marrow, resulting in anemia. Abnormal regulation of cell division or inappropriate triggering of apoptosis may contribute to the other health problems that affect some people with Diamond-Blackfan anemia. Scientists are working to determine why the blood abnormalities and physical problems can vary so much between individuals.

Mutations in many other genes, some of which have not been identified, account for the remaining Diamond-Blackfan anemia cases. While mutations in genes that provide instructions for ribosomal proteins cause most cases of Diamond-Blackfan anemia, gene changes affecting proteins that interact with ribosomal proteins or that play other roles in blood-forming processes have been identified in a few individuals with this disorder.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In approximately 45 percent of cases, an affected person inherits the mutation from one affected parent. The remaining cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

Types

Different subtypes exist and are divided based on the specific gene mutated; however, they have similar features. Patients with mutations in the RPL5 gene have more serious symptoms and about 45% have cleft palate and are smaller than average size. Patients with mutations in the RPL11 gene have thumb anomalies more frequently than people with the other types. Mutations in the GATA1 gene are associated with severe anemia.

Signs and symptoms

Approximately half of individuals with Diamond-Blackfan anemia have physical abnormalities. They may have an unusually small head size (microcephaly) and a low frontal hairline, along with distinctive facial features such as wide-set eyes (hypertelorism); droopy eyelids (ptosis); a broad, flat bridge of the nose; small, low-set ears; and a small lower jaw (micrognathia). Affected individuals may also have an opening in the roof of the mouth (cleft palate) with or without a split in the upper lip (cleft lip). They may have a short, webbed neck; shoulder blades that are smaller and higher than usual; and abnormalities of their hands, most commonly malformed or absent thumbs. About one-third of affected individuals have slow growth leading to short stature.

Other features of Diamond-Blackfan anemia may include eye problems such as clouding of the lens of the eyes (cataracts), increased pressure in the eyes (glaucoma), or eyes that do not look in the same direction (strabismus). Affected individuals may also have kidney abnormalities; structural defects of the heart; and, in males, the opening of the urethra on the underside of the penis (hypospadias).

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Arrhythmia(Abnormal heart rate)
• Pallor

30%-79% of people have these symptoms

• Abnormality of the genital system(Genital abnormalities)
• Abnormality of the hand(Abnormal hands)
• Abnormality of the urinary system(Urinary tract abnormalities)
• Cleft palate(Cleft roof of mouth)
• Delayed puberty(Delayed pubertal development)
• Fatigue(Tired)
• Macrocytic anemia
• Migraine(Intermittent migraine headaches)

5%-29% of people have these symptoms

• Acute leukemia
• Depressed nasal ridge(Flat nose)
• Short nose(Decreased length of nose)
• Short stature(Decreased body height)
• Thick lower lip vermilion(Increased volume of lower lip)

Diagnosis

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

Treatment

Treatment may involve corticosteroids, blood transfusions, a bone marrow transplant or stem cell transplantation.

Corticosteroids: Corticosteroid treatment is recommended in children over 1 year of age; this treatment can initially improve the red blood count in approximately 80% of people with Diamond-Blackfan anemia. Prednisone initial dose is 2 mg / kg / day given orally once a day, at morning time. After a month, if there is no improvement after a month the corticosteroids are tapered-of and suspended.

Two drugs, antithymocyte globulin (ATG) and cyclosporin have been used to treat DBA, but have only provided occasional responses. No study has ever combined these two drugs for the treatment of DBA.

The combined use of ATG and cyclosporine as a rational approach to the treatment of DBA.

However the relapse and failure rate are high, and corticosteroids are associated with many short and long term side effects. Patients who do not respond or who do not tolerate corticosteriods require lifelong red blood cell transfusion and iron chelation therapy.

Allogeneic bone marrow transplantation is an option for those with a related histocompatible donor, but this procedure is associated with high mortality and morbidity. Other therapies have been tried without general success. Occasional responses to either ATG or cyclosporine have been reported, but no study has used both ATG and cyclosporine. In other blood/bone marrow disorders of immune etiology these drugs have synergistic effects. We propose a Phase II study to explore the combined use of ATG and cyclosporine as a rational approach to the treatment of Diamond Blackfan anemia.

NIH genetic and rare disease info

• NIH info on Diamond-Blackfan anemia

Diamond-Blackfan anemia is a rare disease.

Diamond-Blackfan anemia Resources
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