Diamond Blackfan Anemia -

DiamondBlackfanAnemia

A RareAnemiaofInfancy,Childhood& Adulthood

Diamond Blackfan Anemia Foundation, Inc.P. O. Box 1092

West Seneca, New York 14224

e-mail: [email protected]

DIAMONDBLACKFANANEMIA

I. THEDISEASE

Diamond Blackfan Anemia (DBA) is a rare anemiamanifesting itself during infancy and childhood. It resultsfrom the failure of the bone marrow to produce red bloodcells.The first two caseswere described in 1936, followed bya more detailed report of four cases by Drs. Diamond andBlackfan in 1938. Many other names have been applied tothis syndrome including Congenital Hypoplastic Anemia,Chronic Congenital Aregenerative Hypoplastic Anemia, andErythrogenesisImperfecta.

Presently there are over 350 known DBA patients in theUnited States and Canada alone. There are approximately400 casesreported in the literature. Of the reported cases,malesand females are equally affected.

This disorder is very heterogeneous. Its etiology is stillunclearalthough the red blood cell defect seems to lie withinthe progenitors for red cell production.

Aside from anemia, many DBA patients also reportvarious physical anomalies. Of the patients from whom dataare available, 48% have at least one physical anomaly, with23% of the patients having more than one anomaly. Forty-one percent have face/head anomalies, and 36% have upperlimb and hand anomalies, mostly involving the thumb. Thirty-three percent have genitourinary anomalies, and 27% havecardiac anomalies. Twenty-one percent of these patientsreport short stature including 11% percent which are notrelated to steroid therapy.

II. THE DIAGNOSIS

For those affected by DBA, anemia is usually profound atthe time of diagnosis. For example, at The Hospital for SickChildren in Toronto, Canada, hemoglobin levels averaged 6.5g/dl in patients diagnosed in the first two months of life and4.0 g/dl in those diagnosed later.

To date there are no definite tests to diagnose DBA.However, the uniform diagnostic criteria for all cases are:(1) normochromic-macrocytic anemia presenting in 90% ofcases in the first 12 months of life; (2) profoundreticulocytopenia; (3) normocellular marrow with a selective,marked deficiency of red cell precursors; (4) increased serumlevels of erythropoietin; (5) normal or slightly decreasedwhite cell counts; and (6) normal or increased plateletcounts. Fetal hemoglobin is usually increased.

DBA is not due to a deficiency of iron, vitamin B-12,folate, or the blood cell stimulating factor - erythropoietin,sinceall are found to be elevated in these patients.

In addition, one red cell enzyme, Adenosine Deaminase(ADA), is increased in many DBA patients, but this is not adiagnostic test for DBA. At present, this test can helpdistinguish DBAfrom other anemic disorders.

III. THE TREATMENT

Steroids

Steroids are the initial treatment for DBA patientsfollowing diagnosis of DBA. Patients usually are started onprednisone at doses from 2-4 mg/kg/day and then slowlyweaned to the lowest dose at which the hemoglobinconcentration is stable. Initially, 81% of patients respond tosteroids. An acceptable dose of prednisone for the long termshould be .5 mg/kg/day or less.

The function of steroids in maintaining acceptablehemoglobin is still unclear. DBApatients may be particularlysensitive to corticosteroids even at low doses.

Steroids can have many potential side effects, especiallyat high doses. These include weight gain, water/saltretention, hypertension, muscle weakness, osteoporosis,impaired wound healing, headaches, suppression of growth,cataracts, glaucoma, and endocrine abnormalities. Everyother day dosing, at low doses, can alleviate many of theseside effects.

BloodTransfusions

When steroids are either ineffective or toxic, transfusiontherapy is the mainstay of treatment. Filtered packed redblood cell transfusions are recommended to reducetransfusion reactions. Usually patients require transfusions at3 to 6 week intervals.

The major complication of transfusion therapy is ironoverload. Liver biopsy or testing with use of a SQUIDmachine (limited availability) provides the most accuratemeasurement of iron stores. Deposition of iron in majororgans can lead to diabetes, heart and liver dysfunction, andgrowth failure as well as other endocrine problems.

Chelation of iron with desferrioxamine (Desferal)subcutaneously should be considered as soon as iron storesare found to be elevated. Easier and less time consumingmodes of administering chelation are currently beingresearched.

BoneMarrowTransplantation

Bone marrow transplantation (BMT) has been attemptedwith limited success in only a small number of DBA patients.Bone marrow transplantation is still considered experimentaland should be pursued cautiously.

Stem cell transplantation for DBA patients with HLAmatched siblings continues to be a viable option. Accordingto the North American Diamond Blackfan Anemia Registry(DBAR), there were 20 stem cell transplants for DBAreported in the U.S. from 1993 through 1999. Fifteen werefrom bone marrow and five from cord blood. Of the twenty,eight were from HLAmatched siblings. Of these eight, sevensurvived. Two transplants involved family donors that didnot have a complete HLA match with the DBA patient. Bothof these patients died. The remaining ten transplants werefrom unrelated persons that had an HLAmatch with the DBApatient. Of these ten, three survived. Given the?e results, itis not surprising that most doctors do not recommend stemcell transplantation unless the donor is a full HLA matchedsibling. Statistics from the North American Diamond BlackfanAnemia Registry (DBAR) indicate the overall survival ratefollowing BMTis 59%.

The statistics from the DBAR differ slightly from thestatistics gathered from the approximately 35 DBAtransplants that have been reported in the literature. Someof these 35 cases have been reported more than once. Ofthe cases in the literature, most of the donors were siblings;one was a mother, and one was a matched unrelated donor.Ten of these have died. From these thirty-five reportedcases, the absolute cure rate is 71%, and the projectedsurvival rate from Kaplan-Meieranalysis is 66%.

IV. QUESTIONSANDANSWERS

Is Remissiona Possibility?

Remissionshave occurred in approximately 17% of DBApatients reported to the DBAR. Remissions occur followingboth steroid and/or transfusion therapies. DBA patients whoare in remission are able to maintain acceptable hemoglobinswithout steroids and/or transfusions.

Is DBAGenetic?

In most instances, there is only one DBA patient in thefamily. In these cases, DBA mayor may not be genetic.In approximately ten percent of cases, there is more thanone affected family member. For example, there could bemore than one affected sibling or both a parent and a childaffected. Where there is more than one family memberaffected, DBA is genetic in that family.

To date, one DBA gene, RPS19(19q13), has beenidentified. Approximately twenty-five percent of DBApatientsare believed to have this gene. Scientists in the United Statesand Europe are currently looking at three otherchromosomes which likely have other DBAgenes.

How can I learn more and helpmyself/others?

1. Contact the Diamond Blackfan Anemia Foundation,Inc. (address provided below) who can put you into contactwith families in the support network.

2. Register with the Diamond Blackfan Anemia Registry(address provided below).

3. Take notes, tape conversations,and ask questionswhen talking with your doctor{s) and other sources.

4. Learn definitions of medical terms (see Glossary) soyou can understand medical terminology.

5. ResearchDBAat a medicallibraryor on a Medlineserviceon the Internet.

6. Join a DBA support group (online or in yourgeographicalarea).

Is DBA a form of cancer?

DBAis not a form of cancer. However, a small number ofDBA patients have developed leukemia or cancers. This rateappears to be at a substantially higher rate than thebackground rate. Of the 355 patients in the DBAR,ten havecancer. The cancers involved are osteosarcoma (4), MDS(2), colon carcinoma (2), and soft tissue sarcoma (1), andmelanoma (1). There have been 23 casesof cancer reportedin the literature some of which are also included in the DBARstudy; the most common of the cancers reported in theliterature are acute non-lymphocytic leukemia (ANNL),myelodysplasia (MDS), and osteogenic sarcoma.

In what activitiescan a DBApatientengage?

Depending on the patient's medical condition and his/herdoctor's advice, most patients are encouraged and able toget some form of physical exercise every day. Normalphysical activity is generally permitted.

V. DBAREGISTRY

There is a Diamond Blackfan Anemia Registry (DBAR) forNorth American DBA patients. The purpose of the registry isto collect data on DBA patients to aid present and futurepatients through effective research.

For more information on the DBAR and/or to obtain apreliminary registration form, please contact:

Diamond Blackfan Anemia RegistryAttn: Adrianna Vlachos, M.D.Schneider Children's Hospital

Division of Pediatric Hematology/Oncology andStem Cell Transplantation

269-01 76th Avenue

New Hyde Park, NY11040

e-mail: [email protected] Phone Number: 1-888-884-DBAR

Phone: 718-470-3460; Fax: 718-343-2961

After you return the preliminary form, you will thenreceive a longer medical form. It is very important that thisform be completed and returned by you and/or yourphysician. Patients are also strongly encouraged to sendcomplete medical records along with or instead of the longform. The DBARguarantees patient confidentiality.

Complete and accurate medical information on all DBApatients will enable scientists to have an effective databasefor DBAresearch.

VI. DIAMONDBLACKFANANEMIAFOUNDATION,INC.

The Diamond Blackfan Anemia Foundation, Inc. (DBAF)was founded in 1994 by parents of children with DBA. It is aS01(c)(3) not-for-profit New York corporation that supportsitself solely through donations and is staffed exclusively byvolunteers.

Since inception, the DBAF has been fighting to find thecauseof andcurefor DBA.The DBAFfunds medicalresearchprojects, provides emotional support to families affected byDBA, and organizes DBA family meetings. It also publishesthe DBANewsletter twice a year.

For more information and/or to receive the DBANewsletter, please contact:

Diamond Blackfan Anemia Foundation, Inc.P.O. Box 1092

West Seneca, New York 14224

e-mail: [email protected]

VII. GLOSSARY

Anemia: Decrease in the oxygen-carrying capacity of the blood;indicated by a low hematocrit (Hct) and hemoglobin (Hb)concentration.Anomaly: Deviation from what is regarded as normal; congenitalmalformation; birth defect.B Cells:Type of lymphocyte especially involved in the production ofantibodies.Basophil: Type of white blood cell; a type of granulocyte involved inallergicreactions; normal value: 0.5-2% or 25-100 per microliter.Bone Marrow: Soft tissue within the bones where blood cells aremanufactured.Bone Marrow Aspiration: Test in which a sample of bone marrowcells is removed from the bone marrow with a needle and examinedunder a microscope.BoneMarrow Transplant (BMT): Procedure in which bone marrow ofthe patient is destroyed by chemotherapy and/or radiation and thenreplacedwith healthy cells from a compatible donor; also known asStemCellTransplant.Chelation: A system to remove excess iron from the blood andtissues.Chronic: Of long duration; designates a condition or diseaseshowing little change or of slow progression.CompleteBlood Count (CBC): Amount or level of blood cells: whitecells,red cells, and platelets in the peripheral blood.Congenital: Present at birth.CrossMatch: Type and cross; test in which the blood cells of a donorand a recipient are determined to be compatible or not compatiblefor a transfusion.Cytokines: Growth factors which promote the proliferation andmaturationof blood cells; chemicals which are produced naturally bythe body and which help to regulate cell growth.DiamondBlackfanAnemia(DBA):A rare pure red bloodcell anemiabeginning in infancy and childhood and resulting from the failure ofthe bone marrow to produce red blood cells.Differential: Percent of different types of white blood cells in theblood.Dominant: In genetics, a trait or characteristic that may beexpressed in the offspring even though it is carried on only one ofthe homologous (parental) chromosomes.Endocrine: System to secrete; the network of ductless glands andother structures that elaborate and secrete hormones directly intothe blood stream, affecting the function of specific target organs.Eosinophil: Type of white blood cell, i.e., neutrophil; involved inallergicreaction; normal value 2-3%.Erythrocyte: A red blood cell.Etiology: The cause of a disease.FetalHemoglobin: Type of oxygen carrying molecule present in thefetus and infant. Forms more than half of the hemoglobin of thefetus and present in minimal amounts in children and adults.Abnormallyelevated in certain blood disorders.Granulocyte: Type of white blood cell; one example is a neutrophil.Hematology: Study of the blood.Hematocrit (Hct): Portion of the blood's total volume that is made upof red blood cells. Normal values vary: men 45% to 57%; women37% to 47%; children (depending on age) 36% to 46%.Hemoglobin (Hgb or Hb): iron-containing molecules in the blood thatimparts the color to blood; combines with oxygen from the lungs andcarries it to the body's cells. Normal values for men: 14 to 16 g/dl;women: 12 to 14 g/dl; children: 12 to 14 g/dl.Hypoplastic: Incomplete or underdevelopment of an organ ortissue.

Hypertension: A common, often asymptomatic disordercharacterized by elevated blood pressure persistently exceeding140/90 mm Hg in adults; and for children, exceeding what is normalfor the child's age.Leukocyte: White blood cell; includes granulocytes, lymphocytes,basophils, and eosinophils.Liver Biopsy: A needle is inserted into the liver and a sample takento determine iron liver stores.Lymphocyte: A white blood cell formed in lymphoid tissuethroughout the body, e.g., lymph nodes, spleen, thymus, tonsils, andsometimes in bone marrow.Macrocytes: Abnormally large erythrocytes.Megakaryocytes: Large cells in the bone marrow from which piecesbreak off to form platelets.Neutropenia: Low neutrophil (poly) count.Neutrophil: Type of white blood cell that fights infection; also calledpolymorphonuclear leukocyte (poly). Normal values depend on agebut are generally 50-60 percent of 4,000 to 10,000 in number. Forthose under age 5, normal values are less than 50%.Normocellular: Having a normal number of cellular elements ingeneral; not devoid of cells.Normochromic: Normal color of erythrocytes; normal amount ofhemoglobin in each red cell.Osteoporosis: Loss of bone calcareous matter and increased boneporosity.Pancytopenia: Low number of all blood cells.Parvovirus B-19: The cause of a usually benign disease known asFifth disease; in immunocompromised patients, may cause aplasticanemia.Platelets: Blood cells which form clots thereby preventing bleedingand bruising. Normal values range from 150,000 to 400,000 permicroliter of blood. A count below 50,000 can result in spontaneousbleeding; a count below 5,000 can put the patientat risk of severelife-threatening bleeds.Precursors: A substance that precedes another substance.Progenitor: Those young cells that should normally mature into redcells; anything that originates or precedes.Red Blood Cell (RBC): Oxygen-carrying cell in the blood that containsthe pigment hemoglobin, produced in the bone marrow; erythrocyte.Counts refer to the number of cells in a microliter of blood. Normalranges vary according to sex and age.Reticulocyte (Retic) Count: Number of young red blood cells.Immature RBCsjTotal RBCsx 100%=reticcount.Reticulocytopenia: Deficiency of reticulocytes in the blood.SQUID: A non-invasive machine that uses magnetic principles todetermine liver iron stores.Stem Cell: Cell from which platelets, red blood cells, and/or whitecells grow in the bone marrow.Thrombocyte: Platelet, clotting factor in the blood.Thrombocytopenia: Low platelet count.Thymocytes: T cells; lymphocytes arising in the thymus.White Blood Cells (WBC): Blood cells that fight infection. Normalvalues range from 4,000 to 10,000 cells per microliter of blood butcan be greatly altered by factors such as stress, exercise anddisease.

The Diamond Blackfan Anemia Foundation, Inc., its officers,directors,and volunteers are not responsible for the information inthis brochure. This brochure is for informational purposes only anddoes not constitute medical opinion or advice. Consult your personalphysician as to whether any information in this brochure may beuseful in your specific case.

Printed in 2001.