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.
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
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,
- 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)
- 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)
- 1% never received steroid therapy
- 1% are being transfused for reasons unknown
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.
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.
The first DBA gene was identified as RPS19 on chromosome 19q13.2. Approximately 25% of DBA patients have a mutation in the RPS19 gene. Mutation and deletions affecting sixteen more ribosomal protein genes, RPL5, RPL11, RPL35a, RPS26, RPS24, RPS17, RPS7, RPS10, RPL19, and RPL26, RPS29, RPL31, RPS28, RPS20, RPL15, RPL17 have been identified, as well as mutations to GATA1 and TSR2.
- RPS19, seen in ~25% of patients;
- RPL5, seen in ~7% of patients;
- RPL11, seen in ~5% of patients;
- RPL35a, seen in ~3% of patients;
- RPS26, seen in ~6% of patients;
- RPS24, seen in ~2% of patients;
- RPS17, seen in ~1% of patients;
- RPS7, seen in ~1% of patients;
- RPS10, seen in ~3% of patients;
- RPL19, unknown,
- RPL26, unknown,
- RPS29, unknown,
- RPL31, unknown,
- RPS28, unknown,
- RPS20, unknown,
- RPL15, unknown,
- RPL17, unknown,
- GATA1, unknown; and
- TSR2, unknown.
The remainder of the patients will have a gene defect in genes yet to be determined.
Approximately 20% 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).
The DBAR collaborated with Drs. Blanche Alter and Phil Rosenberg of the National Cancer Institute to confirm DBA as a cancer predisposition syndrome with a cumulative incidence of cancer in 22% of patients by age 46 years. 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 2y, 17y, 45y, 51y)
- Osteogenic Sarcoma (ages 4y, 13y, 22y)
- Soft Tissue Sarcoma (age 30y)
- Acute Myelogenous Leukemia (age 44y, 45y)
- Breast Cancer (ages 34y, 43y)
- Colon Cancer (ages 34y, 43y,49y)
- Oral Squamous Cell Carcinoma (age 69y)
- Vaginal Squamous Cell Carcinoma (age 45y)
- Rectal Cancer (age 28y)
- Uterine Cancer (age 64y)
- Cervical Cancer (age 27y)
- Testicular Cancer (age 62y)
- Lung Cancer (age 21y)
- Melanoma (age 50y)
- Non Hodgkin Lymphoma (age 41y)
- Basal Cell Cancer (age 30y)