Diamond Blackfan anemia (DBA) was first recognized as a distinct entity in 1938, although it was called “congenital hypoplastic anemia” at that time. The accepted diagnostic criteria for DBA are:

• usually macrocytic anemia (a decreased number of larger than normal red blood cells)
• reticulocytopenia (a decreased number of new young red blood cells)
• normal bone marrow cellularity, but with a selective deficiency in red blood cell precursors
• normal or slightly decreased white blood cell count
• normal or slightly increased platelet count

Although a number of theories regarding the pathophysiology (cause) of DBA have been proposed, it is now widely accepted that the disorder results from an intrinsic progenitor cell defect in which erythroid progenitors and precursors are highly sensitive to death by apoptosis (self-destruction). The first DBA gene has been identified as RPS 19, a gene that codes for a ribosomal protein located at chromosome 19q13.2. The function of this protein is only poorly understood. The existence of other genes has been confirmed, and studies are underway to identify them.

Diamond Blackfan anemia is the preferred name for this disorder but other names for DBA include:

• Blackfan Diamond syndrome
• Congenital pure red cell aplasia
• Congenital hypoplastic anemia
• Aase syndrome (felt to be a subset of DBA in which there is a finger-like thumb, and not a distinct disorder)

Incidence

Incidence is estimated to be in the range of five to ten cases for every million children born. We estimate about 30 new cases per year in the US and Canada. There are an equal number of males and females with the disease. Children usually appear to first be affected at 2 months of age with a range from birth to 6 years, although a few adults have been diagnosed. More than 90% of the patients present during the first year of life. The diagnosis is generally made at 12 weeks, or 3 months, of age with a range from birth to adulthood.

Initial Treatment

Corticosteroids (prednisone and related drugs) and red blood cell transfusions are the mainstays of therapy.

In the DBAR, the initial patient response to steroids is as follows:

• 82% were initially responsive to steroids
• 16% were non-responsive to initial steroids and required transfusion
• 2% of patients were never treated with steroids

Subsequent Treatment

Overall 44% of patients are currently on corticosteroids. Steroid-related side effects were observed in many of the patients.

• 40% of patients had Cushingoid features (puffy face, swelling)
• 12% had pathologic fractures (bone fractures occurring with no or minimal trauma)
• 7% had cataracts

36% of patients are currently receiving chronic (usually monthly) red cell transfusions. Of these,

• 49 % could not be weaned to an acceptable dose of steroids (i.e. only had a response to high doses of steroids with too many side effects)
• 32% were never steroid responsive (i.e. required transfusions initially because they were non-responsive to steroids)
• 17% became steroid refractory (i.e. had been on steroids but lost the response to steroids over time)
• 1% never received steroid therapy
• 1% are being transfused for reasons unknown

Other Treatment

DBA patients have rarely responded to treatment with: Interleukin-3 (no longer available), very high doses of corticosteroid, androgens, cyclosporine A, and metoclopramide (Reglan). All of these medications have toxicities that must be described by the hematologist prior to their use.

Remission

A “remission” is defined as a stable hemoglobin adequate for age, maintained for at least six months, without any corticosteroids, transfusions, or other therapy.

Twenty percent of all patients remitted once in their lifetime, with 77% of these patients remitting during the first decade of life. Many of these patients have sustained remissions.

Genetics

The first DBA gene was identified as RPS 19 on chromosome 19q13.2. Approximately 20-25% of DBA patients have a mutation in the the RPS19 gene. Three more genes, RPS24, RPS17 and RPL35a, have recently been identified, accounting for another 6% of the gene mutations causing DBA.

The remainder of the patients will have a gene defect in genes yet to be determined.

Inheritance

Approximately 10% of families reported to the DBAR have more than one affected individual. Most of these families appear to be of dominant inheritance (meaning transmission from a parent to a child). Within these families there is great variability in the manifestations of DBA (eg. degree of anemia, birth defects, etc.). For example, the parent may have mild anemia while the child is steroid or transfusion dependent, or the parent may be steroid responsive while the child does not respond to steroid and is transfusion dependent. Many different combinations within a family have been seen. In addition some affected members may have birth defects while others do not.

Congenital Anomalies (Birth Defects)

47% of the patients in the DBAR have one or more physical abnormalities (not including short stature). Of these,

• 50% of the abnormalities are of the face and head (including cleft lip and palate)
• 38% are of the upper arm and hand
• 39% are of the kidney, and
• 30% of the heart

21% of patients have more than one abnormality.

Stem Cell Transplant Outcomes

Stem cell transplantation (SCT), also known as bone marrow or cord blood or peripheral blood stem cell transplantation (depending on the donor source), is curative in DBA. However, the role of transplantation for patients with DBA remains complex and controversial. As of the last published analysis, most of the sibling transplants used chemotherapy alone as a conditioning regimen, while most of the alternative donor (mismatched family or unrelated donor) transplants used a combination of chemotherapy with radiation therapy for pre-transplant conditioning. Data from the DBAR show overall survival of 77% for allogeneic sibling SCT (94% for allogeneic sibling SCT age 9 years and less) and 36% for alternative donor SCT (86% for alternative SCT done after 2000).

Cancer Epidemiology

A review of the literature reports cases of leukemia and solid tumors in DBA patients. One important feature of DBA -associated cancers is that they present at a younger age than these cancers are usually found. Thus careful analysis of DBA patients and their families is essential to defining the cancer risk in this population.

The following cancers have been observed in patients that were enrolled in the DBAR:

• Myelodysplastic Syndrome (ages 17y, 45y, 52y)
• Osteogenic Sarcoma (ages 4y, 13y, 22y)
• Soft Tissue Sarcoma (age 30y)
• Acute Myelogenous Leukemia (age 44y)
• Breast Cancer (ages 34y, 43y)
• Colon Cancer (ages 34y, 49y)
• Oral Squamous Cell Carcinoma (age 63)
• Vaginal Squamous Cell Carcinoma (age 41)