Diamond Blackfan Anemia - Cause, Symptoms, and Management

Introduction

Diamond-Blackfan anemia (DBA) is an inherited type of anemia. It mostly presents during the first year of life. It is characterized by a failure to develop red blood cells (RBCs), also called red cell aplasia, and bone abnormalities. It has an autosomal dominant pattern of inheritance (even one copy of the mutated gene can cause a disorder in the offspring) in about 45 percent of the patients.

What Is the Cause of Diamond Blackfan Anemia?

The cause of DBA is a genetic mutation. The most common mutation is on chromosome 11, involving a ribosomal protein (ribosomes are cell structures that synthesize proteins). The mutation leads to defective protein synthesis. Hence, it causes premature death of the RBC-forming cells in the bone marrow. Mutations in approximately twenty ribosomal proteins have been found to date. Also, GATA1 is a transcription factor that undergoes mutation. It has a vital role in RBC production. Further, patients with GATA1 mutation have more severe anemia symptoms. One must note that DBA patients have a higher risk of cancer.

How Common Is Diamond Blackfan Anemia?

DBA is an uncommon congenital condition. The new number of cases (incidence rate) is seven per million live births. The median age of diagnosis is two to three months. However, almost 95 percent of cases are diagnosed before age five. There is no ethnic or gender predisposition. DBA is also called inherited bone marrow failure syndrome (IBMFS).

What Are the Symptoms of Diamond Blackfan Anemia?

The condition affects various systems of the body.

1. Blood Disorders: Anemia is the primary condition in DBA. It may be moderate or severe. The precursor RBCs are typically large (macrocytic) and do not regenerate. In anemia, a lack of RBCs leads to inadequate oxygen supply to the organs. Hence, a patient has frequent fatigue, dyspnea (shortness of breath), and pallor (pale skin).

2. Physical Abnormalities: Physical abnormalities are present in about 50 percent of the patients. They are described below.

• Craniofacial: Craniofacial pertains to the skull and face. A DBA patient has a small skull, wide-set eyes, a flat nasal bridge, a cleft lip, a cleft palate, a small jaw, drooping of the eyelids, and small and low-set ears. All these findings lead to a distinct facial appearance.

• Eyes: DBA patients may have congenital glaucoma (fluid buildup that leads to a damaged optic nerve) and cataract (cloudy lens). Another condition is strabismus (a disorder in which eyes do not point the same way).

• Neck: DBA patients have short and webbed necks. Sprengel and Klippel- Feil deformities are also present. The Sprengel deformity occurs when a shoulder blade is at a higher level than the other. Klippel Feil deformity occurs when two or more neck bones fuse.

• Thumbs: The thumbs have three phalanges (the thumb usually has two phalanges, i.e., bones). Patients have two thumbs in one hand (bifid thumb). DBA patients also have an absent thenar eminence (the bulge present at the thumb base).

• Heart: DBA patients have many heart anomalies. Atrial and ventricular septal defects (ASD and VSD; depict a hole in the heart) are frequent.

• Urinary System: Absent and horseshoe kidneys are some findings. Hypospadias is an abnormality in which the urethral opening is not at the penis tip. It is mainly found in male DBA patients.

• Musculoskeletal: DBA patients have growth retardation and short stature.

• Neurological: These patients have delayed milestones. Hence, they have learning difficulties.

How Is Diamond Blackfan Anemia Diagnosed?

The International Consensus Conference (2008) on diagnosing and treating Diamond Blackfan anemia arrived at major and minor diagnostic criteria.

1. Diagnostic Criteria for Classical DBA: These include the age of onset less than 12 months, macrocytic anemia, reticulocytopenia (reticulocytes are immature RBCs; cytopenia is a decrease in the number of cells), and bone marrow with a lack of RBC precursor cells.

2. Major Criteria: A gene mutation for DBA and a positive family history are the major criteria.

3. Minor Criteria: Adenosine deaminase (ADA) is an enzyme in the metabolism of deoxyribonucleic acid (DNA). Elevated erythrocyte (RBC) ADA levels (eADA) contribute to diagnosing DBA. Other minor supporting criteria are congenital anomalies, elevated fetal hemoglobin (HbF), and no evidence of any other IBMFS.

After evaluating the major and minor criteria, various investigations are done.

1. Blood Workup: A complete blood workup includes a peripheral blood smear (PBS) and a complete blood count (CBC). PBS shows a macrocytic and normochromic (in which the color of RBCs is red) anemia. Platelets and white blood cells (WBCs) are in the normal range. Low reticulocyte counts can also be found. CBC is done as a part of PBS or separately to evaluate hemoglobin, RBCs, WBCs, and platelets. Assessment of HbF, eADA, erythropoietin (a hormone that stimulates RBC production) level, and reticulocytes is also done.

2. Bone Marrow Aspiration: Bone marrow examination shows low RBC levels.

3. Molecular Testing: The first step in molecular diagnosis is identifying the patient’s clinical presentation (phenotype). It includes the family history, pregnancy complications, congenital abnormalities, and bone marrow evaluation for anemia. Then, molecular tests are done to identify the genes involved in DBA.

What Is the Treatment of Diamond Blackfan Anemia?

Different treatment options are used for DBA.

1. Steroids: Corticosteroids are the mainstay of the treatment. The exact mechanism of action is unknown. However, it may have a role in preventing cell death of the precursor RBCs. However, steroids have many side effects. It is crucial to ensure that corticosteroids are given after age one.

2. Blood Transfusions: Chronic blood transfusions with iron chelation therapy are given to patients who are intolerant of the long-term side effects of steroids. Blood transfusions are given every 35 weeks. Also, the goal is to reach a hemoglobin of 8 grams per deciliter (g/dL). Furthermore, iron chelation is essential to prevent iron toxicity.

3. Hematological Stem Cell Transplantation (HSCT): HSCT is the only curative option for DBA. The success rate is higher in less than ten-year-old patients with identical donors. It is an alternative to DBA patients who are unresponsive to blood transfusions.

4. Gene Therapy: It is the introduction of genetic material in a patient for therapeutic purposes. The source of stem cells is different in gene therapy. The mutated gene can be removed and replaced with a normal gene copy. Gene editing is another novel modality for DBA.

5. Newer Drugs: Pharmacological management is essential in patients ineligible for HSCT. Examples of some drugs that are being tested are Galunisertib (an experimental cancer drug) and Sotatercept (in a clinical trial).

Conclusion

Diamond-Blackfan anemia is an uncommon congenital disorder that affects various body systems. The prognosis is good. However, cancer development or disease complications may affect the patient's quality of life. Patients need long-term medications. Further, an integrated approach to managing the disorder can achieve optimal results.