Clinical Diagnosis

The diagnosis of classic Diamond-Blackfan anemia (DBA), a congenital red blood cell aplasia, is made when all four of the following diagnostic criteria are met [Vlachos et al 2008, Vlachos & Muir 2010]:

• Age younger than one year
• Macrocytic anemia with no other significant cytopenias
• Reticulocytopenia
• Normal marrow cellularity with a paucity of erythroid precursors

The following laboratory findings are observed in most, but not all, individuals with DBA [Glader & Backer 1988, Willig et al 1999b]:

• Increased red cell mean corpuscular volume (MCV)
• Elevated erythrocyte adenosine deaminase activity (eADA) (observed in 80%-85%) [Glader & Backer 1988, Vlachos et al 2008]
• Elevated hemoglobin F (HbF) concentration

Other findings include:

• Growth retardation (observed in 30%)
• Congenital malformations (observed in ~30%-50%), in particular craniofacial, upper-limb, heart, and genitourinary malformations [Ball et al 1996, Willig et al 1999b, Lipton et al 2006]

The following are major supporting diagnostic criteria:

• Identification of a disease-causing mutation in one of the genes known to be associated with DBA
• Family history consistent with autosomal dominant inheritance

The following are minor supporting diagnostic criteria:

• Elevated eADA
• Elevated HbF concentration
• One or more congenital anomalies described in classic DBA
• No evidence of another inherited disorder of bone marrow function (see Differential Diagnosis) [Vlachos et al 2008]

If the family history is positive for other individuals with DBA and the family-specific mutation is known, any relative with the family-specific mutation should be considered to have non-classic DBA regardless of the presence of phenotypic findings.

Within families, some affected individuals may exhibit “non-classic” DBA, which is characterized by:

• Mild or absent anemia with only subtle indications of erythroid abnormalities such as macrocytosis, elevated eADA, and/or elevated HbF concentration
• Onset later in life [Willig et al 1999b, Lipton et al 2006]
• A phenotypically normal parent of an affected offspring
• Congenital anomalies or short stature consistent with DBA and minimal or no evidence of abnormal erythropoiesis [Lipton & Ellis 2010]

Persons with simplex cases (i.e., a single occurrence in a family) who do not meet clinical diagnostic criteria, but who have a disease-causing mutation in one of the genes known to be associated with DBA, should be considered to have non-classic DBA [Vlachos et al 2008].

Testing

Bone marrow aspirate shows normocellular bone marrow with:

• Erythroid hypoplasia;
• Marked reduction in normoblasts;
• Persistence of pronormoblasts on occasion;
• Normal myeloid precursors and megakaryocytes.

Molecular Genetic Testing

Genes. DBA has been associated with mutations in the nine following genes that encode ribosomal proteins. A mutation in one of these nine genes is identified in approximately 53% of individuals with DBA [Doherty et al 2010].

• RPS19 mutations were found in approximately 25% of probands [Draptchinskaia et al 1999, Matsson et al 1999, Willig et al 1999a, Cmejla et al 2000, Ramenghi et al 2000, Proust et al 2003, Gazda et al 2004, Orfali et al 2004].
• RPL5 mutations were found in approximately 6.6% of probands in one cohort [Gazda et al 2008], in six of 28 families studied in the second cohort [Cmejla et al 2009], and in 12 of 92 families in Italian population [Quarello et al 2010].
• RPL11 mutations were found in approximately 4.8% of probands in one cohort [Gazda et al 2008], in two of 28 families studied in the second cohort [Cmejla et al 2009], and in 12 of 92 families in Italian population [Quarello et al 2010].
• RPL35A mutations were found in approximately 3% of probands [Farrar et al 2008].
• RPS24 nonsense and splice-site mutations were found in approximately 2% of RPS19-negative individuals [Gazda et al 2006].
• RPS17 mutations were found in three unrelated individuals in three separate cohorts [Cmejla et al 2007, Gazda et al 2008, Song et al 2010]; approximately 1% of individuals with DBA [Doherty et al 2010].
• RPS7 mutation was found in one family [Gazda et al 2008]; approximately 1% of individuals with DBA [Doherty et al 2010].
• RPS10 mutations were identified in approximately 6.4% of people with DBA. Doherty et al [2010] reported mutations in RPS10 in five probands; two mutations were found each in a single family, while one mutation was identified in three unrelated kindreds [Doherty et al 2010].
• RPS26 mutations were identified in approximately 2.6% of individuals with DBA. Nine different mutations were detected in twelve probands [Doherty et al 2010].

Other loci. In three unrelated individuals with DBA, rare variants of unknown significance were identified in three other genes that encode ribosomal proteins, RPL36, RPS15, and RPS27A.^* These three sequence changes may be pathogenic mutations [Gazda et al 2008].

*Note that RPS27A is expressed as a fusion protein with ubiquitin at its N-terminal part. After translation, the ubiquitin part is processed to free ubiquitin monomer and RPS27A. Because the identified variant localizes to the ubiquitin part of the fusion protein and not to the RPS27A part, it is possible that this sequence change does not cause DBA.

Clinical testing

• Sequence analysis
  • The mutation detection rate of sequence analysis for RPS19 is 90% [Quarello et al 2008].
    
    Note: The other 10% of mutations are allelic or exonic deletions identifiable by multiplex ligation-dependent probe amplification (MLPA) [Quarello et al 2008].
  • The mutation detection rate of sequence analysis for all other genes associated with DBA is unknown at this time.
• Deletion/duplication analysis. Cases of deletions of an RPS19 exon(s) or of an entire gene have also been reported.

Table 1. Summary of Molecular Genetic Testing Used in Diamond-Blackfan Anemia

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Gene Symbol	% of DBA Attributed to Mutations in This Gene	Test Method	Mutation Detection Frequency by Gene and Test Method 1	Test Availability
RPS19	~25%	Sequence analysis	90%	Clinical
		Deletion / duplication analysis 2	~10%
RPL5	~6.6%	Sequence analysis	Unknown	Clinical
RPS10	~6.4%			Clinical
RPL11	~4.8%			Clinical
RPL35A	~3%			Clinical
RPS26	~2.6%			Clinical
RPS24	~2% 3			Clinical
RPS17	~1%			Clinical
RPS7	~1%			Clinical

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, MLPA, or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

3. Approximately 2% of RPS19-negative individuals [Gazda et al 2006]

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm the diagnosis in a proband the following tests should be performed:

• Complete blood count with reticulocyte count
• Erythrocyte adenosine deaminase activity
• Fetal hemoglobin
• Bone marrow aspiration and biopsy
• Molecular genetic testing of RPS19
• Molecular genetic testing of the remaining eight genes in which mutation is known to cause DBA.
• Deletion/duplication testing of RPS19

The following should be ruled out prior to a DBA diagnosis [Vlachos et al 2008] (see Differential Diagnosis):

• Transient erythroblastopenia of childhood
• Fanconi anemia
• Shwachman-Diamond syndrome
• Pearson syndrome
• Dyskeratosis congenita
• Parvovirus B19
• Human immunodeficiency virus (HIV)
• Other infections
• Drugs and toxins
• Immune-mediated diseases

Predictive testing for at-risk asymptomatic adult family members:

• Molecular genetic testing is indicated if the disease-causing mutation in the family has been identified.
• If the family-specific mutation is not known, other testing such as mean corpuscular volume, eADA, and/or fetal hemoglobin concentration should be considered in the evaluation of relatives at risk, especially relatives being considered as bone marrow donors [Vlachos et al 2008].

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in RPS19, RPL5, RPL11, RPL35A, RPS24, RPS17, RPS7, RPS10, or RPS26.

Natural History

The primary hematologic feature of Diamond-Blackfan anemia (DBA) is a profound isolated normochromic and usually macrocytic anemia with normal leukocytes and platelets [Alter & Young 1998, Dianzani et al 2000]. The hematologic complications of DBA occur in 90% of affected individuals during the first year of life: the median age at presentation is two months and the median age at diagnosis is three months [Bagby et al 2004, Ohga et al 2004]. Treatment with corticosteroids is recommended in children over age twelve months [Vlachos & Muir 2010] (see Management). Eventually, 40% of affected individuals are steroid dependent, 40% are transfusion dependent, and 20% go into remission [Chen et al 2005, Vlachos et al 2008].

Males and females are affected equally.

Congenital malformations are observed in approximately 50% of affected individuals and more than one anomaly is observed in up to 25% of individuals. The most commonly reported abnormalities (and their reported frequency) include [Bagby et al 2004, Lipton et al 2006, Vlachos et al 2008, Vlachos & Muir 2010]:

• Face and head (50%). Microcephaly; ocular hypertelorism; epicanthus, ptosis; broad, flat nasal bridge; microtia, low-set ears; cleft lip/palate, high arched palate; micrognathia; low anterior hairline
• Eye. Congenital glaucoma, congenital cataract, strabismus
• Neck. Webbed neck, short neck, Klippel-Feil anomaly, Sprengel deformity
• Upper limb and hand including thumb (38%). Absent radial artery; flat thenar eminence; triphalangeal, duplex, bifid, hypoplastic, or absent thumb
• Genitourinary (19%). Absent kidney, horseshoe kidney; hypospadias
• Heart (15%). Ventricular septal defect, atrial septal defect, coarctation of the aorta, other cardiac anomalies

Low birth weight was reported in 25% of affected infants. Thirty percent of affected individuals have growth retardation. Growth retardation can be influenced by other factors including steroid treatment [Chen et al 2005].

The phenotypic spectrum of DBA is broad. Within the same family, some affected individuals may have classic disease, whereas others may have a non-classic form including (1) mild anemia; (2) no anemia with only subtle erythroid abnormalities such as macrocytosis, elevated eADA, and/or increased HbF concentration; or (3) physical malformations without anemia. Others may show a severe form presenting with fetal anemia that results in non-immune hydrops fetalis [Dunbar et al 2003, Saladi et al 2004]. Onset of non-classic DBA can be later than age one year.

DBA is associated with an increased risk for acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), and solid tumors including osteogenic sarcoma [Janov et al 1996, Vlachos et al 2001].

Pregnancy-associated risks. A study that surveyed 64 pregnancies in women with DBA found a high incidence of complications in both mothers and children. Risks include intrauterine growth retardation, preeclampsia, and retroplacental hematoma. In utero fetal death and preterm delivery have been reported [Faivre et al 2006].

Genotype-Phenotype Correlations

Genotype-phenotype correlation studies of persons with a mutation in RPL5 revealed:

• A phenotype with craniofacial, congenital heart, and thumb defects that is more severe than that seen with mutations in RPL11 and RPS19 [Gazda et al 2008, Quarello et al 2010]
• Cleft lip and/or cleft palate (CL/P) in 45% of affected persons with RPL5 mutations [Gazda et al 2008] and in 50% of an affected group of Italians with RPL5 mutations [Quarello et al 2010].
• Small gestational age in seven of eight individuals with an RPL5 mutation versus 43% of individuals with an RPS19 mutation [Cmejla et al 2009]. None of the eight individuals with an RPL5 mutation had CL/P.

RPL11. Mutations in RPL11 are predominantly associated with thumb abnormalities [Gazda et al 2008, Cmejla et al 2009]. Two persons with RPL11 mutations were identified with CL/P in the Italian group with DBA [Quarello et al 2010]

RPS19. No genotype-phenotype correlations were found in persons with RPS19 mutations [Willig et al 1999a, Cmejla et al 2000, Ramenghi et al 2000, Orfali et al 2004].

RPS10. No genotype-phenotype correlations have been identified in persons with RPS10 mutations to date [Doherty et al 2010].

RPS26. No genotype-phenotype correlations have been identified in persons with RPS26 mutations to date [Doherty et al 2010].

Mutations in other DBA-related genes are rare and no genotype-phenotype correlations have been detected.

Penetrance

Penetrance is incomplete.

Nomenclature

DBA has previously been known as:

• Congenital hypoplastic anemia
• Blackfan-Diamond syndrome
• Aase syndrome
• Aase-Smith syndrome II

Prevalence

The prevalence of DBA is not known.

The incidence of DBA is estimated at between 1:100,000 and 1:200,000 live births [Vlachos et al 2008] or 5-7 per million live births [Ball et al 1996, Willig et al 1999b, Campagnoli et al 2004]; it remains consistent across ethnicities [Vlachos et al 2008].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Diamond-Blackfan anemia (DBA), the following are recommended:

• Evaluation by a hematologist
• Evaluation by a clinical geneticist for congenital malformations and to obtain a detailed family history
• Developmental assessment
• Evaluation by a cardiologist including echocardiography
• Ultrasound examination of the kidney and urinary tract
• Evaluation by a nephrologist and a urologist, as appropriate

Treatment of Manifestations

Eventually, 40% of individuals are steroid dependent, 40% are transfusion dependent, and 20% go into remission [Chen et al 2005, Vlachos et al 2008].

Corticosteroids administration. Corticosteroids can initially improve the red blood count in approximately 80% of affected individuals.

• The recommended corticosteroid is prednisone with a starting dose of 2 mg/kg/day given orally once a day in the morning, beginning when the child is at least six months old. An increase in hemoglobin concentration is usually seen in two to four weeks.
• Corticosteroids may be slowly tapered to the minimal effective dose. Monitoring of blood counts is needed to ensure that the red cell hemoglobin concentration remains at 80-100 g/L, the minimum required for transfusion independence.
• The corticosteroid maintenance dose varies and can be extremely low in some individuals. The recommended maximum maintenance dose is ≤0.5mg/kg/day or ≤1 mg/kg every other day.
• If the recommended steroid dose cannot sustain the red cell hemoglobin concentration in an acceptable range (usually one month), the corticosteroids should be tapered and discontinued.

Side effects of corticosteroids include osteoporosis, weight gain, cushingoid appearance, hypertension, diabetes mellitus, growth retardation, pathologic bone fractures, gastric ulcers, cataracts, glaucoma, and increased susceptibility to infection [Alter & Young 1998, Willig et al 1999a, Lipton et al 2006].

Red blood cell transfusion. If the individual is resistant to corticosteroid therapy, chronic transfusion with packed red blood cells is necessary. The goal of transfusion therapy is a red cell hemoglobin concentration of 80-100 g/L, which is usually adequate for maintaining growth and development [Vlachos et al 2008, Vlachos & Muir 2010].

Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for DBA. Persons with DBA who are transfusion-dependent or develop other cytopenias are often treated with HSCT.

In one study of 61 persons with DBA who underwent bone marrow transplantation (BMT), the majority (67%) received their bone marrow grafts from an HLA-matched related donor. The three-year probability of overall survival was 64% (range 50%-74%). Transplantation from an HLA-identical sib donor was associated with better survival [Roy et al 2005].

The Diamond-Blackfan Anemia Registry of North America describes 36 patients who underwent HSCT: 21 HLA-matched sib stem cell transplants and 15 alternative donor stem cell transplants. Survival greater than five years from SCT for allogeneic sib transplants was 72.7% ±10.7% versus survival greater than five years from alternative donor transplants of 17.1% ±11.9% [Lipton et al 2006, Vlachos et al 2008]. Survival was the best (92.3%) for children younger than age ten years transplanted using an HLA-matched sib.

Note: (1) It is recommended that the affected individual, sibs, and parents undergo HLA typing at the time of diagnosis of DBA to identify the most suitable bone marrow donor in the event that HSCT would be required. (2) Because penetrance of DBA is incomplete, it is possible that a relative considered as a bone marrow donor could have a disease-causing mutation but not manifest findings of DBA. (3) Relatives with a DBA-causing mutation, regardless of their clinical status, are not suitable bone marrow donors, because their donated bone marrow may fail or not engraft in the recipient.

Cancer treatment. Treatment of malignancies should be coordinated by an oncologist.

Prevention of Secondary Complications

Transfusion iron overload is the most common complication in transfusion-dependent individuals. The following methods are used both to assess for evidence of transfusion iron overload and to evaluate the effectiveness of iron chelation therapy:

• Measurement of iron concentration in a liver biopsy specimen, which accurately determines total body iron accumulation
• MRI for assessing iron loading in the liver and heart
• Magnetic biosusceptometry (SQUID), which gives a measurement of hepatic iron concentration
  Note: Although the latter two methods of total iron measurement are noninvasive, they are available at only a limited number of centers and should be correlated with the “gold standard” liver biopsy [Cappellini & Piga 2008, Vlachos et al 2008].

Note: Routine measurement of serum ferritin concentration is not reliable in detecting iron overload because the serum ferritin concentration does not always correlate with total body iron accumulation.

Iron chelation therapy is usually started after ten to 12 transfusions (170-200 mL/kg of packed red blood cells), when serum ferritin concentration reaches 1000-1500 µg/L, or when hepatic iron concentration reaches 6-7 mg/g of dry weight liver tissue.

• Deferasirox is recommended in individuals age two years or older. It is administered once daily in an oral dose of 20-30 mg/kg/day.
  Side effects are usually mild and include rash, nausea, creatinine elevation, and rarely proteinuria and transaminase elevation. Patient satisfaction with deferasirox is greater than with desferrioxamine, mostly because of ease of administration [Cappellini & Piga 2008, Porter et al 2008, Vlachos et al 2008].
• Desferrioxamine is administered four to seven nights a week in an eight- to 12-hour subcutaneous infusion via a portable pump. The recommended initial dose is 40 mg/kg/day; the maximum dose is 50-60 mg/kg/day. The dose and frequency of infusion may be modified using the serum ferritin concentration or the hepatic iron concentration as a guide [Cappellini & Piga 2008, Vlachos et al 2008].
  Side effects include ocular and auditory toxicity and growth retardation. Compliance rate is hampered by the demanding administration route and schedule.

Note: Deferiprone is not recommended in the treatment of iron overload in individuals with DBA [Vlachos et al 2008] because its side effects include neutropenia [Henter & Karlen 2007].

Side effects of corticosteroids include osteoporosis, weight gain, cushingoid appearance, hypertension, diabetes mellitus, growth retardation, pathologic bone fractures, gastric ulcers, cataracts, glaucoma, and increased susceptibility to infection [Alter & Young 1998, Willig et al 1999a, Lipton et al 2006].

One of the critical side effects of corticosteroids is growth retardation. If growth is severely impaired, corticosteroids should be stopped and replaced by a short-term red blood cell transfusion regimen [Vlachos et al 2008].

Pregnancy. Management of pregnancy in marrow failure disorders requires obstetricians with expertise in high-risk pregnancies and hematologists with experience with marrow failure syndromes [Alter et al 1999].

During pregnancy the maternal hemoglobin level must be monitored.

Use of low-dose aspirin up to 37 weeks’ gestation may help prevent vasculo-placental complications in women with a history of a previous problematic pregnancy [Faivre et al 2006].

Surveillance

Complete blood counts must be performed several times a year.

Perform bone marrow aspirate/biopsy to evaluate morphology and cellularity periodically and if evidence of another cytopenia or failure of current treatment is noted.

Blood pressure must be monitored in individuals who are steroid dependent.

Growth must be monitored in patients who are steroid dependent and those at risk for transfusion iron overload.

Evaluation by an endocrinologist is recommended for patients who are steroid dependent and those at risk for transfusion iron overload.

Cancer surveillance. In individuals with DBA who are otherwise healthy: every four to six months obtain an interim history, perform a physical examination, and measure blood count.

If red blood-cell, white blood-cell, or platelet counts fall rapidly, perform bone marrow aspirate with biopsy and cytogenetic studies, including karyotype and FISH analysis, to look for acquired abnormalities in chromosomes 5, 7, and 8 that are associated with certain cancers [Vlachos et al 2008].

Agents/Circumstances to Avoid

Deferiprone is not recommended in the treatment of iron overload in persons with DBA because its side effects include neutropenia [Vlachos et al 2008].

Individuals with DBA, especially those on corticosteroid treatment, should take reasonable precautions to avoid infections, as steroid-dependent patients are more prone to complications resulting from immune system dysfunction.

Evaluation of Relatives at Risk

Molecular genetic testing of at-risk relatives of a proband with a known pathogenic mutation allows for early diagnosis and appropriate monitoring for bone marrow failure, physical abnormalities, and related cancers.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

Diamond-Blackfan anemia (DBA) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Approximately 40%-45% of individuals diagnosed with DBA have a parent who has the same disease-causing mutation [Orfali et al 2004]; approximately 55%-60% of cases are caused by de novo mutations.
• If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, two explanations are possible: somatic and/or germline mosaicism [Cmejla et al 2000] in a parent or a de novo mutation in the proband. The incidence of germline mosaicism is unknown at this time.
• If a pathogenic mutation can be identified in the proband, both parents are tested for this family-specific mutation.
• If no disease-causing mutation can be identified in the proband, both parents and other first-degree relatives can be evaluated by measuring MCV, eADA, and fetal hemoglobin levels.
• Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: (1) Although approximately 45% of individuals diagnosed with DBA have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, or late onset of the disease in the affected parent. (2) If the parent has somatic mosaicism for the mutation, she or he may be mildly/minimally affected.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the parents.
• If a parent of the proband is affected, the risk to the sibs is 50%.
• The sibs of a proband with clinically unaffected parents are still at increased risk for the disorder because of the possibility of reduced penetrance in a parent.
• If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low. However, the risk remains greater than that of the general population because of the possibility of germline mosaicism. The incidence of germline mosaicism is currently unknown.

Offspring of a proband. Each child of an individual with DBA has a 50% chance of inheriting the mutation.

Other family members of a proband

• The risk to other family members depends on the status of the proband's parents and sibs.
• If a parent and/or sib is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation has been identified in the family by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. If no laboratory offering prenatal testing is listed in the GeneTests Laboratory Directory, such testing may be available through laboratories offering custom mutation prenatal testing. See .

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

Ribosomes consist of a small 40S subunit and a large 60S subunit and catalyze protein synthesis. Small and large subunits are composed of four RNA species and approximately 80 structurally distinct proteins. The proteins encoded by RPS19, RPS24, RPS17, RPS15, RPS27A, RPS10 and RPS26 belong to the small ribosomal subunit, whereas those encoded by RPL5, RPL11, RPL35A, and RPL36 are components of the large ribosomal subunit.

Haploinsufficiency of RPS19 and RPS24 has been shown to be the basis for DBA. In a subset of affected individuals, frameshift mutations lead to degradation of the mutated transcripts [Hamaguchi et al 2002, Campagnoli et al 2004, Gazda et al 2004, Gazda et al 2006]. Recent studies have also demonstrated that DBA-causing missense RPS19 mutations affect RPS19 conformation and stability, triggering proteasome-mediated degradation or blocking its incorporation into pre-ribosomes [Angelini et al 2007, Gregory et al 2007, Kuramitsu et al 2008].

RPS19 protein has been demonstrated to play an important role in 18S rRNA maturation in yeast and in human cells [Leger-Silvestre et al 2005, Choesmel et al 2007, Flygare et al 2007, Idol et al 2007]. Similarly, alterations of pre-RNA processing and small or large ribosomal subunit synthesis were demonstrated in human cells with RPS24 and RPS7 deficiency and with RPL35A, RPL5, and RPL11 deficiency, respectively, further indicating that DBA is a disorder of ribosomes [Choesmel et al 2008, Farrar et al 2008, Gazda et al 2008]. Deficiency of RPS19 and RPL35A was shown to cause increased apoptosis in hematopoietic cell lines and in bone marrow cells [Farrar et al 2008, Miyake et al 2008], and imbalance of the p53 family proteins has been suggested as a mechanism of abnormal embryogenesis and anemia in zebrafish upon perturbation of RPS19 expression [Danilova et al 2008].

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Acknowledgments

We would like to acknowledge and thank Elizabeth Taylor DeChene, MS, CGC; Alan Beggs, PhD; Colin Sieff, MB, BCh; and Peter Newburger, MD for careful reading of the manuscript and very helpful suggestions. In addition, the authors wish to thank The Manton Foundation for funding of our studies on Diamond-Blackfan anemia.

Revision History

• 27 January 2011 (me) Comprehensive update posted live
• 24 November 2009 (cd) Revision: deletion/duplication analysis for RPS19 available clinically
• 13 October 2009 (cd) Revision: sequence analysis and prenatal testing available for RPL5, RPL11, RPL35A, RPS7, RPS17 mutations; prenatal testing available for RPS24 mutations
• 25 June 2009 (et) Review posted live
• 17 February 2009 (hg) Original submission