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Anemia, Diamond-Blackfan

Diamond-Blackfan anemia (DBA) is a congenital erythroid aplasia that usually presents in infancy. DBA patients have low red blood cell counts (anemia). The rest of their blood cells (the platelets and the white blood cells) are normal. A variety of other congenital abnormalities may also occur. more...

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Clinical Features

Diamond-Blackfan anemia is characterized by anemia (low red blood cell counts) with decreased erythroid progenitors in the bone marrow. This usually develops during the neonatal period. About 47% of affected individuals also have a variety of congenital abnormalities, including craniofacial malformations, thumb or upper limb abnormalities, cardiac defects, urogenital malformations, and cleft palate. Low birth weight and generalized growth retardation are sometimes observed. DBA patients have a modest risk of developing leukemia and other malignancies.

Diagnosis

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. About 20-25% of DBA patients may be identified with a genetic test for mutations in the RPS19 gene.

History

Diamond and Blackfan described congenital hypoplastic anemia in 1938. In 1961, Diamond and colleagues presented longitudinal data on 30 patients and noted an associated with skeletal abnormalities. In 1997 a region on chromosome 19 was determined to carry a gene mutated in DBA. In 1999, mutations in the ribosomal protein S19 gene (RPS19) were found to be associated with disease in 42 of 172 DBA patients. In 2001, it was determined that a second DBA gene lies in a region of chromosome 8 although evidence for further genetic heterogeneity was uncovered.

Genetics

Approximately 10-25% of DBA cases have a family history of disease, and most pedigrees suggest an autosomal dominant mode of inheritance. The disease is characterized by genetic heterogeneity, with current evidence supporting the existence of at least three genes mutated in DBA. In 1997, a patient was identified who carried a rare balanced chromosomal translocation involving chromosome 19 and the X chromosome. This suggested that the affected gene might lie in one of the two regions that were disrupted by this cytogenetic anomaly. Linkage analysis in affected families also implicated this region in disease, and led to the cloning of the first DBA gene. About 20-25% of DBA cases are caused by mutations in the ribosome protein S19 (RPS19) gene on chromosome 19 at cytogenetic position 19q13.2. Interestingly, some previously undiagnosed relatives of DBA patients were found to carry mutations. These patients also had increased adenosine deaminase levels in their red blood cells but no other overt signs of disease. A subsequent study of families with no evidence of RPS19 mutations determined that 18 of 38 families showed evidence for involvement of an unknown gene on chromosome 8 at 8p23.3-8p22. The precise genetic defect in these families has not yet been delineated. In a further 7 families, both the chromosome 19 and chromosome 8 loci could be excluded for involvement, suggesting the existence of at least one other DBA locus in the human genome.

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Lab creates babies for donor tissue
From Deseret News (Salt Lake City), 5/5/04 by Lindsey Tanner Associated Press

CHICAGO -- In a growing practice that troubles some ethicists, a Chicago laboratory helped create five healthy babies so that they could serve as stem-cell donors for their ailing brothers and sisters.

The made-to-order infants were screened and selected when they were still embryos to make sure they would be compatible donors. Their siblings suffered from leukemia or a rare and potentially lethal anemia.

The Chicago doctors said the healthy embryos that were not matches were frozen for potential future use. But some ethicists said such perfectly healthy embryos could end up being discarded.

"This was a search-and-destroy mission," said Richard Doerflinger of the U.S. Conference of Catholic Bishops. The chosen embryos "were allowed to be born so they could donate tissue to benefit someone else."

Valparaiso University professor Gilbert Meilaender, a member of the President's Council on Bioethics, called the practice "morally troubling."

The council recently called for increased scrutiny of the largely unregulated U.S. infertility industry.

The cases involved prenatal tests called preimplantation HLA testing, pioneered at Chicago's Reproductive Genetics Institute.

The tests are an offshoot of preimplantation genetic diagnosis, which has been done for more than 1,000 couples worldwide to weed out test-tube embryos with genetic diseases such as Down syndrome, or, more recently, for sex selection.

The institute's doctors made headlines four years ago after performing embryo tissue typing plus genetic disease screening for a Colorado couple who wanted to create another baby to save their daughter, who had a rare inherited disease called Fanconi anemia. The resulting baby boy, Adam Nash, donated bone marrow in an operation doctors said was a success.

Since then, embryo tissue typing with genetic disease testing has been performed more than three dozen times worldwide, with most of the cases done at the Chicago institute, said the center's Dr. Ander Kuliev.

Kuliev said the latest cases are the first instances in which embryos were tissue-typed but not screened genetically for diseases.

The cases, reported in Wednesday's Journal of the American Medical Association, involved nine couples who submitted embryos that underwent tissue-typing tests during 2002 and 2003. Five had infants considered suitable donors.

So far, stem cells from the umbilical cord blood of one infant have been donated to an ailing sibling, said the institute's Dr. Anver Kuliev. He called the operation a success but said the older child will need continued monitoring to be sure.

Another baby was born last June to an English couple who traveled to Chicago after British fertility authorities denied them permission to undergo the procedure in England, said Dr. Mohammed Taranissi, a London doctor who co-authored the JAMA report. The couple's older child has Diamond-Blackfan anemia, a rare blood ailment that can lead to leukemia. Taranissi said a transplant from the baby boy's umbilical cord blood is scheduled soon.

Kuliev said the institute has done HLA embryo testing alone for more than a dozen other couples and demand is growing.

More than 13,000 U.S. residents are diagnosed yearly with one of the leukemias involved in the research -- acute myeloid leukemia and acute lymphoid leukemia, the most common childhood leukemia.

Taranissi disagreed with ethicists concerned about discarding disease-free embryos. He noted that it often happens with in vitro fertilization, when doctors frequently create more test-tube embryos than are needed.

With tissue-typing embryos, "you're doing this as a lifesaving procedure most of the time," Taranassi said.

For years, families with sick children have conceived babies without costly test-tube procedures, taking a 1-in-4 chance that the child will be a match for the ailing sibling, said University of Wisconsin medical ethicist Norman Fost, who wrote a JAMA editorial.

Some have had abortions when standard prenatal testing showed the child would not be a suitable donor, he said.

The new procedure, he noted, does not involve abortion and poses no known risks to the embryos. Furthermore, parents seeking donor babies typically are well-intentioned and love the donor children, Fost said.

"Of all the reasons people have babies, this would seem to be a wonderful reason. Most reasons are either mindless sex or selfish reasons," he said.

Copyright C 2004 Deseret News Publishing Co.
Provided by ProQuest Information and Learning Company. All rights Reserved.

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