NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Diamond-Blackfan Anemia

, MS, CGC and , MD, PhD.

Author Information

Initial Posting: ; Last Update: April 7, 2016.

Summary

Clinical characteristics.

Diamond-Blackfan anemia (DBA) in its classic form is characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets, congenital malformations in up to 50% of affected individuals, and growth retardation in 30% of affected individuals. The hematologic complications occur in 90% of affected individuals during the first year of life. The phenotypic spectrum ranges from a mild form (e.g., mild anemia, no anemia with only subtle erythroid abnormalities, physical malformations without anemia) to a severe form of fetal anemia resulting in nonimmune hydrops fetalis. DBA is associated with an increased risk for acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), and solid tumors including osteogenic sarcoma.

Diagnosis/testing.

The diagnosis is established in a proband when all four of the following diagnostic criteria are present:

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

Other causes of bone marrow failure (e.g., Fanconi anemia, Pearson syndrome, dyskeratosis congenita, human immunodeficiency virus infection) need to be considered and ruled out as appropriate. DBA has been associated with pathogenic variants in sixteen genes that encode ribosomal proteins and in GATA1 and TSR2. A pathogenic variant in one of these eighteen genes is identified in approximately 65% of individuals with DBA.

Management.

Treatment of manifestations: Corticosteroid treatment, recommended in children older than age twelve months, initially improves the red blood cell count in approximately 80% of affected individuals. Chronic transfusion with packed red blood cells is initially necessary while the diagnosis is made and in those not responsive to corticosteroids. Hematopoietic stem cell transplantation (HSCT), the only curative therapy for the hematologic manifestations of DBA, is often recommended for those who are transfusion dependent or develop other cytopenias. Treatment of malignancies should be coordinated by an oncologist. Chemotherapy must be given cautiously as it may lead to prolonged cytopenia and subsequent toxicities.

Prevention of secondary complications: Transfusion-related iron overload is the most common complication in transfusion-dependent individuals. Iron chelation therapy with deferasirox orally or desferrioxamine subcutaneously is recommended after ten to 12 transfusions. Corticosteroid-related side effects must also be closely monitored, especially as related to risk for infection, growth retardation, and loss of bone density in growing children. Often individuals will be placed on transfusion therapy if these side effects are intolerable.

Surveillance: Complete blood counts several times a year; bone marrow aspirate/biopsy periodically to evaluate morphology and cellularity in the event of another cytopenia or a change in response to treatment. In steroid-dependent individuals: monitor blood pressure and (in children) growth.

Agents/circumstances to avoid: Deferiprone for the treatment of iron overload, which has led to severe neutropenia in a few individuals with DBA; infection (especially those on corticosteroids).

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

Genetic counseling.

DBA is most often inherited in an autosomal dominant manner; GATA1-related and TSR2-related DBA are inherited in an X-linked manner. Approximately 40% to 45% of individuals with autosomal dominant DBA have inherited the pathogenic variant from a parent; approximately 55% to 60% have a de novo pathogenic variant. Each child of an individual with autosomal dominant DBA has a 50% chance of inheriting the pathogenic variant. Males with GATA1 or TSR2-related DBA pass the pathogenic variant to all of their daughters and none of their sons. Women heterozygous for a GATA1 or TSR2 pathogenic variant have a 50% chance of transmitting the pathogenic variant in each pregnancy: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will usually not be affected. Carrier testing of at-risk female relatives is possible if the GATA1 or TSR2 pathogenic variant has been identified in the family. Prenatal testing for pregnancies at increased risk is possible if the familial pathogenic variant has been identified.

Diagnosis

Suggestive Findings

Diamond-Blackfan anemia (DBA) should be suspected in individuals with the following clinical, laboratory, and histopathologic features:

Clinical features

  • Pallor, weakness, failure to thrive
  • Growth retardation (observed in 30%)
  • Congenital malformations (observed in ~30%-50%), in particular craniofacial, upper-limb, heart, and genitourinary malformations

Laboratory features

  • Macrocytic anemia with no other significant cytopenias
  • Increased red-cell mean corpuscular volume (MCV)
  • Reticulocytopenia
  • Elevated erythrocyte adenosine deaminase activity (eADA) (observed in 80%-85%)
  • Elevated hemoglobin F (HbF) concentration

Histopathology features (bone marrow aspirate)

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

Major supporting diagnostic criteria of classic DBA

  • Identification of a pathogenic variant in one of the genes known to be associated with DBA (see Table 1A and Table 1B)
  • Family history of DBA consistent with autosomal dominant inheritance

Minor supporting diagnostic criteria of classic DBA

  • 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)

Features of non-classic DBA

  • 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 [Lipton et al 2006]
  • Congenital anomalies or short stature consistent with DBA and minimal or no evidence of abnormal erythropoiesis [Lipton & Ellis 2010]

Establishing the Diagnosis

To establish 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

The diagnosis of DBA is established in a proband 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

Note: The following diagnoses should be considered in individuals with a suspected diagnosis of DBA who do not meet all four of the diagnostic criteria and do not have a pathogenic variant in one of the genes listed in Table 1A or Table 1B [Vlachos & Muir 2010]. See Differential Diagnosis.

Molecular testing for identification of a heterozygous pathogenic variant in one of the genes listed in Table 1A or Table 1B establishes the diagnosis of DBA if clinical features are inconclusive.

Molecular testing approaches can include serial single-gene testing, use of a multi-gene panel, and more comprehensive genomic testing.

Serial single-gene testing

1.

Sequence analysis of RPS19 is performed first.

2.

If no pathogenic variant in RPS19 is found, perform sequence analysis of the remaining 17 genes in which pathogenic variants are known to cause DBA (see Table 1A and Table 1B).

3.

If sequence analysis does not reveal a pathogenic variant, deletion/duplication analysis should be performed for the genes in which a deletion/duplication has been previously identified (see Table 1A).

A multi-gene panel that includes the genes in Table 1A and Table 1B and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included and the sensitivity of multi-gene panels vary by laboratory and over time.

More comprehensive genomic testing (when available) including whole-exome sequencing (WES), whole-genome sequencing (WGS), and whole mitochondrial sequencing (WMitoSeq) may be considered if serial single-gene testing (and/or use of a multi-gene panel) fails to confirm a diagnosis in an individual with features of DBA. For issues to consider in interpretation of genomic test results, click here.

See Table 1A for the most common genetic causes (i.e., pathogenic variants of any one of the genes included in this table account for ≥1% of DBA) and Table 1B for less common genetic causes (i.e., pathogenic variants of any one of the genes included in this table are reported in only a few families).

Table 1A.

Molecular Genetics of Diamond-Blackfan Anemia: Most Common Genetic Causes

Gene 1, 2% of DBA Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 3 Detected by Test Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
RPL5~6.6% 6~95% 73 individuals 8
RPL11~4.8% 9~94% 102 individuals 11
RPL35A~3% 124 individuals 134 individuals 14
RPS10~2.6% 158 individuals 16None reported 17
RPS17~1%5 individuals 1813 individuals 19
RPS19~25% 20~95% 216 individuals 22
RPS24~2% 235 individuals 241 individual 25
RPS26~6.4% 26~76% 276 individuals 28

Pathogenic variants of any one of the genes included in this table account for ≥1% of DBS.

1.

Genes are listed in alphanumeric order.

2.
3.

See Molecular Genetics for information on pathogenic allelic variants detected.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

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]

7.
8.
9.

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]

10.
11.

2/72 individuals tested [Quarello et al 2012]

12.
13.

4/205 individuals tested [Farrar et al 2008, Smetanina et al 2015]

14.
15.

In five probands; two pathogenic variants were found each in a single family, while one pathogenic variant was identified in three unrelated kindreds [Doherty et al 2010].

16.

8/17 individuals tested [Doherty et al 2010, Smetanina et al 2015]

17.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

18.
19.
20.
21.
22.
23.

Pathogenic nonsense and splice-site variants were found in approximately 2% of RPS19-negative individuals [Gazda et al 2006].

24.
25.

1/87 individuals tested [Landowski et al 2013]

26.

Nine different pathogenic variants were detected in twelve probands [Doherty et al 2010].

27.
28.

Table 1B.

Molecular Genetics of Diamond-Blackfan Anemia: Less Common Genetic Causes

Gene 1, 2, 3% of DBS Attributed to Pathogenic Variants in This GeneComments
GATA1Rare5 families [Sankaran et al 2012, Klar et al 2014, Ludwig et al 2014, Parrella et al 2014]
RPL15Rare1 individual [Landowski et al 2013]
RPL26Rare1 individual [Gazda et al 2012]
RPL27Rare1 individual [Wang et al 2015]
RPL31Rare1 individual [Farrar et al 2014]
RPS7Rare1 individual [Gazda et al 2008]
RPS27Rare1 individual [Wang et al 2015]
RPS28Rare2 families [Gripp et al 2014]
RPS29Rare2 families [Mirabello et al 2014]
TSR2Rare1 family [Gripp et al 2014]
Unknown 4

Pathogenic variants of any one of the genes listed in this table are reported in only a few families (i.e., <1% of DBS).

1.

Genes are listed in alphanumeric order.

2.
3.

Click here (pdf) for information on allelic variants detected in the genes listed.

4.

Rare variants of uncertain significance were identified in unrelated individuals in three additional genes that encode ribosomal proteins: RPL36, RPS15, and RPS27A [Gazda et al 2008].

Test characteristics. See Clinical Utility Gene Card [Vlachos et al 2013] for information on test characteristics including sensitivity and specificity.

Clinical Characteristics

Clinical Description

Anemia. 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 older than 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].

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 the following [Bagby et al 2004, Lipton et al 2006, Vlachos et al 2008, Vlachos & Muir 2010]:

  • Head and face (50%). Microcephaly; hypertelorism, epicanthus, ptosis; microtia, low-set ears; broad, depressed nasal bridge; cleft lip/palate, high arched palate; micrognathia; low anterior hairline
  • Eye. Congenital glaucoma, congenital cataract, strabismus
  • Neck. Webbing, 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
  • Growth. 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, Vlachos et al 2008].
  • Malignancy. 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, Vlachos et al 2012].
  • Development. Rarely, in children with DBA developmental delay can occur [Willig et al 1999, Tentler et al 2000, Farrar et al 2011, Kuramitsu et al 2012].

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 erythrocyte adenosine deaminase activity (eADA), and/or increased HbF concentration; or (3) physical malformations without anemia. Others may have a severe form presenting with fetal anemia that results in nonimmune hydrops fetalis [Dunbar et al 2003, Saladi et al 2004]. Onset of non-classic DBA can be later than age one year.

Genotype-Phenotype Correlations

RPL5. Craniofacial, congenital heart, and thumb defects were more severe than those seen with pathogenic variants in RPL11 and RPS19 [Gazda et al 2008, Quarello et al 2010]. Cleft lip and/or cleft palate (CL/P) was reported in 45% of affected persons with RPL5 pathogenic variants [Gazda et al 2008] and in 50% of an affected group of Italians with RPL5 pathogenic variants [Quarello et al 2010]. Small gestational age was reported in seven of eight individuals with an RPL5 pathogenic variant versus 43% of individuals with an RPS19 pathogenic variant [Cmejla et al 2009]. None of the eight individuals with an RPL5 pathogenic variant had CL/P.

RPL11. Pathogenic variants in RPL11 are predominantly associated with thumb abnormalities [Gazda et al 2008, Cmejla et al 2009]. In the Italian group with DBA, two persons with RPL11 pathogenic variants were identified with CL/P [Quarello et al 2010].

GATA1. The splice site variants IVS2+1delG and 220G>C (p.Leu74Val) affecting GATA1 exon 2 cause DBA with profound anemia.

RPS10, RPS19, RPS26. No genotype-phenotype correlations were found in persons with pathogenic variants in RPS10, RPS19, and RPS26 [Willig et al 1999, Cmejla et al 2000, Ramenghi et al 2000, Orfali et al 2004, Doherty et al 2010].

RPS29. To date, no genotype-phenotype correlations have been identified in persons with RPS29 pathogenic variants.

RPL27, RPL 31, RPS27. To date, no genotype-phenotype correlations have been identified in persons with RPL27, RPL31, or RPL27 pathogenic variants.

RPS28. Two families with DBA with mandibulofacial dystostosis were described [Gripp et al 2014]

TSR2. One family with DBA with mandibulofacial dystostosis was described [Gripp et al 2014]

Penetrance

Penetrance is incomplete.

Nomenclature

DBA has previously been known as congenital hypoplastic anemia of Blackfan and Diamond, congenital hypoplastic anemia, Blackfan-Diamond syndrome, Aase syndrome, and Aase-Smith syndrome II.

Prevalence

The incidence of DBA is estimated at between 1:100,000 and 1:200,000 live births; it remains consistent across ethnicities [Vlachos et al 2008].

Differential Diagnosis

Because of the difficulty of establishing the diagnosis of Diamond-Blackfan anemia (DBA), in some instances the diagnosis may only be established after other disorders in the differential diagnoses have been ruled out.

Transient erythroblastopenia of childhood (TEC) (OMIM) is characterized by acquired anemia caused by decreased production of red blood cell precursors in a previously healthy child. The etiology of TEC is unknown, although an association with viral infections has been proposed. TEC is almost always self-resolving within one to several months and only requires clinical intervention (e.g., red blood cell transfusion) in severe cases [Alter & Young 1998].

TEC can be distinguished from DBA because in TEC:

  • More than 80% of children are age one year or older at diagnosis, whereas in DBA, 90% of children are younger than age one year at the time of diagnosis [Alter & Young 1998];
  • Only 10% of children have elevated eADA, compared to approximately 85% of individuals with DBA [Glader & Backer 1988, Vlachos et al 2008];
  • Anemia is normocytic, whereas in DBA it is macrocytic [Alter & Young 1998].

Other genetic conditions with bone marrow failure (BMF)

  • Fanconi anemia (FA) is characterized by physical abnormalities, BMF, and increased risk for malignancy. Physical abnormalities, present in 60%-75% of affected individuals, include short stature; abnormal skin pigmentation; malformations of the thumbs, forearms, skeletal system, eyes, kidneys and urinary tract, ear, heart, gastrointestinal system, oral cavity, and central nervous system; hearing loss; hypogonadism; and developmental delay. Progressive BMF with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. By age 40 to 48 years, the estimated cumulative incidence of BMF is 90%; the incidence of hematologic malignancies (primarily acute myeloid leukemia) is 10%-33%; and of non-hematologic malignancies (solid tumors, particularly of the head and neck, skin, GI tract, and genital tract) 25%-30%.

    The diagnosis of FA rests on the detection of chromosome aberrations (breaks, rearrangements, radials, exchanges) in cells after culture with a DNA interstrand cross-linking agent such as diepoxybutane (DEB) or mitomycin C (MMC). Molecular genetic testing is complicated by the presence of at least 18 genes, which are responsible for the FA complementation groups including [A, B, C, D1 (BRCA2), D2, E, F, G, I, J (BRIP1), L, M, and N (PALB2), O (RAD51C), and P (SLX4)] .

    FANCB-related FA is inherited in an X-linked manner. All other types of FA are inherited in an autosomal recessive manner.
  • Shwachman-Diamond syndrome (SDS) is characterized by exocrine pancreatic dysfunction with malabsorption, malnutrition, and growth failure; hematologic abnormalities with single- or multi-lineage cytopenias and susceptibility to myelodysplasia syndrome (MDS) and acute myelogenous leukemia (AML); and bone abnormalities. In almost all affected children, persistent or intermittent neutropenia is a common presenting finding, often before the diagnosis of SDS is made. Short stature and recurrent infections are common.

    The diagnosis of SDS relies on clinical findings, including pancreatic dysfunction and characteristic hematologic problems. SDS is caused by mutation of SBDS and inherited in an autosomal recessive manner.
  • Pearson syndrome is characterized by sideroblastic anemia of childhood, pancytopenia, exocrine pancreatic failure, and renal tubular defects. Typically progressive liver failure and intractable metabolic acidosis result in death in infancy. Those who survive develop neurologic symptoms. Pearson syndrome is most often caused by de novo deletions in mitochondrial DNA (mtDNA), but rearrangements (large-scale partial deletions and duplications) have been found [Morel et al 2009]. Inheritance is maternal (see Mitochondrial DNA Deletion Syndromes).
  • Dyskeratosis congenita (DC), a telomere biology disorder, is characterized by a classic triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia. People with DC are at increased risk for progressive BMF, MDS or AML, solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis. Onset and progression of manifestations of DC vary: at the mild end of the spectrum are those who have only minimal physical findings with normal bone marrow function, and at the severe end are those who have the diagnostic triad and early-onset BMF. Treatment for DC includes androgen therapy and possible bone marrow transplantation [Alter & Young 1998, Alter 2007]. DC can be inherited in an X-linked, autosomal recessive, or autosomal dominant manner.
  • Cartilage-hair hypoplasia (CHH) is characterized by the presence of short tubular bones at birth and variable other findings including fine sparse blond hair; anemia; macrocytosis with or without anemia; and defective T-cell-mediated responses resulting in severe immunodeficiency. The incidence is highest in the Amish and Finnish populations. Treatment includes red blood cell transfusions and steroid therapy [Alter & Young 1998, Hermanns et al 2005]. CHH is caused by mutation of RMRP and is inherited in an autosomal recessive manner.

Acquired conditions with BMF

  • Infections
    • Parvovirus B19 infection; usually asymptomatic, but occasionally can cause red cell aplasia, which is most often mild and self-limited by production of virus-neutralizing antibodies in the host [Parekh et al 2005]. However, in persons with hereditary or acquired anemia, parvovirus infection can be severe and life-threatening, requiring red blood cell transfusions. Seropositivity for parvovirus reaches 50% by age 15 years and 90% in the elderly.
    • HIV; associated with pure red cell aplasia (PRCA) [Alter & Young 1998]
    • Viral hepatitis
    • Mononucleosis and human T-cell lymphotropic virus type 1 [Alter & Young 1998]
  • Drugs and toxins
    • Antiepileptic drugs: diphenylhydantoin, sodium valproate, carbamazepine, sodium dipropylacetate
    • Others: azathioprine; chloramphenicol and thiamphenicol; sulfonamides; isoniazid; procainamide [Alter & Young 1998]
  • Immune-mediated diseases
    • Thymoma, most commonly associated with PRCA. Approximately 5%-10% of persons with thymoma develop PRCA.
    • Myasthenia gravis, systemic lupus erythematosus, and multiple endocrinopathies [Alter & Young 1998]

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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
  • Ophthalmology evaluation for glaucoma and cataract for individuals on steroid therapy
  • Orthopedic evaluation for individuals with clinical findings suggestive of Klippel-Feil anomaly or Sprengel deformity
  • Orthopedic evaluation for individuals with upper limb and/or thumb anomalies
  • Ultrasound examination of the kidney and urinary tract
  • Evaluation by a nephrologist and a urologist, as appropriate
  • Evaluation by a cardiologist including echocardiography
  • Developmental assessment

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].

Corticosteroid 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 after age twelve months. 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 ≤0.5 mg/kg/day or ≤1 mg/kg every other day.
  • If after approximately one month the recommended steroid dose does not sustain the red cell hemoglobin concentration in an acceptable range, 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 1999, 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 individuals 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 pathogenic variant but not manifest findings of DBA. (3) Relatives with a pathogenic variant, 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: (1) 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]. (2) 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 1999, 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].

Surveillance

The following are indicated:

  • Complete blood counts several times a year
  • Bone marrow aspirate/biopsy to evaluate morphology and cellularity periodically and if evidence of another cytopenia or failure of current treatment is noted
  • Monitoring of blood pressure in individuals who are steroid dependent
  • Monitoring of growth individuals who are steroid dependent and in those at risk for transfusion iron overload
  • Evaluation by an endocrinologist; recommended for individuals who are steroid dependent and those at risk for transfusion iron overload

Cancer surveillance includes the following:

  • In individuals with DBA who are otherwise healthy, every four to six months: an interim history, physical examination, and measurement of blood count
  • If red blood-cell, white blood-cell, or platelet counts fall rapidly, 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 individuals are more prone to complications resulting from immune system dysfunction.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual to allow early diagnosis and appropriate monitoring for bone marrow failure, physical abnormalities, and related cancers.

Evaluations include:

  • Molecular genetic testing if the pathogenic variant in the family is known;
  • Consideration of other testing (e.g., mean corpuscular volume, eADA, and/or fetal hemoglobin concentration) if the pathogenic variant in the family is not known – especially of relatives being considered as bone marrow donors [Vlachos et al 2008].

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

Pregnancy Management

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].

A study that surveyed 64 pregnancies in women with DBA found a high incidence of complications in both mothers and children. Risks include the following [Faivre et al 2006]:

  • Intrauterine growth retardation
  • Preeclampsia
  • Retroplacental hematoma
  • In utero fetal death
  • Preterm delivery

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Most often, Diamond-Blackfan anemia (DBA) is inherited in an autosomal dominant manner. GATA1-related DBA and TSR2-related DBA are inherited in an X-linked manner.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

  • Approximately 40%-45% of individuals diagnosed with autosomal dominant DBA inherited a DBA-related pathogenic variant from a parent [Orfali et al 2004].
  • Approximately 55%-60% of cases are caused by a de novo pathogenic variant.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include somatic and/or germline mosaicism [Cmejla et al 2000] in a parent or a de novo pathogenic variant in the proband. The incidence of germline mosaicism is unknown at this time.
  • Recommendations for the evaluation of parents of a proband include molecular genetic testing for the pathogenic variant identified in the proband or, if a pathogenic variant has not been identified in the proband, measurement of MCV, eADA, and fetal hemoglobin levels (see Evaluation of Relatives at Risk).
  • Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation, failure to recognize the disorder in family members, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
  • If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the variant and may be mildly/minimally affected.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents: if a parent of the proband is affected with autosomal dominant DBA, 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 DBA-related pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but 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 autosomal dominant DBA has a 50% chance of inheriting the DBA-related pathogenic variant.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has a DBA-related pathogenic variant, his or her family members may be at risk.

Risk to Family Members — X-Linked Inheritance

Parents of a male proband

  • The father of a male with GATA1 or TSR2-related DBA will not have the disease nor will he be hemizygous for the pathogenic variant; therefore, he does not require further evaluation/testing.
  • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the GATA1 or TSR2 pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism. No data on the possibility or frequency of germline mosaicism in the mother are available.
  • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a de novo pathogenic variant, in which case the mother is not a heterozygote. The frequency of de novo pathogenic variants is not currently known.

Sibs of a male proband. The risk to sibs of a male proband depends on the genetic status of the mother:

  • If the mother of an affected male has a GATA1 or TSR2 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes (carriers) and will usually not be affected.
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism.

Offspring of a male proband. Affected males transmit the GATA1 or TSR2 pathogenic variant to:

  • All of their daughters, who will be heterozygotes (carriers) and will usually not be affected;
  • None of their sons.

Other family members. The proband's maternal aunts may be at risk of being heterozygotes (carriers) for the GATA1 or TSR2 pathogenic variant and the aunts’ offspring, depending on their gender, may be at risk of being heterozygotes or of being affected.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose, information that could help determine the genetic risk status of the extended family.

Heterozygote (Carrier) Detection

Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the GATA1 or TSR2 pathogenic variant has been identified in the proband. Females who are heterozygous for this X-linked disorder will usually not be affected.

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 pathogenic variant. When neither parent of a proband with DBA has the pathogenic variant or clinical evidence of the disorder, the pathogenic variant is likely de novo. 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the DBA-related pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic diagnosis for a pregnancy at increased risk for DBA are possible options.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Daniella Maria Arturi Foundation
    PO Box 1434
    Mattituck NY 11952
    Email: daniellafoundation@dmaf.org
  • Diamond Blackfan Anemia Foundation, Inc. (DBAF)
    PO Box 1092
    West Seneca NY 14224
    Phone: 716-674-2818
    Email: dbafoundation@juno.com
  • My46 Trait Profile
  • National Cancer Institute (NCI)
    6116 Executive Boulevard
    Suite 300
    Bethesda MD 20892-8322
    Phone: 800-422-6237 (toll-free)
    Email: cancergovstaff@mail.nih.gov
  • National Organization for Rare Disorders (NORD)
    RareCareSM
    Phone: 800-999-6673
  • Diamond Blackfan Anemia Registry (DBAR)
    269-01 76th Avenue
    New Hyde Park NY 11040
    Phone: 888-884-DBAR
    Fax: 718-343-2961
    Email: eatsidaf@nshs.edu
  • National Cancer Institute Inherited Bone Marrow Failure Syndromes (IBMFS) Cohort Registry
    Phone: 800-518-8474
    Email: NCI.IBMFS@westat.com

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table B.

OMIM Entries for Diamond-Blackfan Anemia (View All in OMIM)

105650DIAMOND-BLACKFAN ANEMIA 1; DBA1
180468RIBOSOMAL PROTEIN L35A; RPL35A
180472RIBOSOMAL PROTEIN S17; RPS17
300945TSR2, 20S rRNA ACCUMULATION, S. CEREVISIAE, HOMOLOG OF; TSR2
300946DIAMOND-BLACKFAN ANEMIA 14 WITH MANDIBULOFACIAL DYSOSTOSIS; DBA14
305371GATA-BINDING PROTEIN 1; GATA1
602412RIBOSOMAL PROTEIN S24; RPS24
603474RIBOSOMAL PROTEIN S19; RPS19
603632RIBOSOMAL PROTEIN S10; RPS10
603633RIBOSOMAL PROTEIN S29; RPS29
603634RIBOSOMAL PROTEIN L5; RPL5
603658RIBOSOMAL PROTEIN S7; RPS7
603685RIBOSOMAL PROTEIN S28; RPS28
603701RIBOSOMAL PROTEIN S26; RPS26
603702RIBOSOMAL PROTEIN S27; RPS27
603704RIBOSOMAL PROTEIN L26; RPL26
604174RIBOSOMAL PROTEIN L15; RPL15
604175RIBOSOMAL PROTEIN L11; RPL11
606129DIAMOND-BLACKFAN ANEMIA 2; DBA2
607526RIBOSOMAL PROTEIN L27; RPL27
610629DIAMOND-BLACKFAN ANEMIA 3; DBA3
612527DIAMOND-BLACKFAN ANEMIA 4; DBA4
612528DIAMOND-BLACKFAN ANEMIA 5; DBA5
612561DIAMOND-BLACKFAN ANEMIA 6; DBA6
612562DIAMOND-BLACKFAN ANEMIA 7; DBA7
612563DIAMOND-BLACKFAN ANEMIA 8; DBA8
613308DIAMOND-BLACKFAN ANEMIA 9; DBA9
613309DIAMOND-BLACKFAN ANEMIA 10; DBA10
614900DIAMOND-BLACKFAN ANEMIA 11; DBA11
615550DIAMOND-BLACKFAN ANEMIA 12; DBA12
615909DIAMOND-BLACKFAN ANEMIA 13; DBA13

Molecular Genetic Pathogenesis

Ribosomes, consisting of a small 40S subunit and a large 60S subunit, 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, RPS7, RPS27A, RPS10, and RPS26 belong to the small ribosomal subunit, whereas those encoded by RPL5, RPL11, RPL26, 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 variants 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 pathogenic missense RPS19 variants can 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 [Léger-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, RPL11, and RPL26 deficiency, respectively, further indicating that DBA is a disorder of ribosomes [Choesmel et al 2008, Farrar et al 2008, Gazda et al 2008, Gazda et al 2012]. 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 on perturbation of RPS19 expression [Danilova et al 2008].

For a detailed summary of gene and protein information for the following genes, see Table A, Gene.

RPL5

Gene structure. RPL5 has eight exons with the translation start codon in exon 1 (NM_000969).

Pathogenic allelic variants. Thirteen pathogenic variants in RPL5 have been identified in 18 families in one cohort [Gazda et al 2008], and six pathogenic variants have been identified in six families in the second cohort [Cmejla et al 2009]. The pathogenic variants include nonsense and frameshift variants (insertions, deletions), splice-site variants, and two missense variants.

Normal gene product. RPL5 contains 297 amino acids (NP_000960.2). RPL5 is a component of the large ribosomal subunit.

Abnormal gene product. See Molecular Genetic Pathogenesis.

RPL11

Gene structure. RPL11 has six exons with the translation start codon in exon 1 (NM_000975.2).

Pathogenic allelic variants. Eleven pathogenic variants in RPL11 have been described in 13 families in one cohort [Gazda et al 2008] and two variants have been identified in a second cohort [Cmejla et al 2009]. The pathogenic variants include frameshift (insertions, deletions), splice-site, one nonsense, and two missense variants.

Normal gene product. RPL11 contains 178 amino acids (NP_000966.2). RPL11 is a component of the large ribosomal subunit.

Abnormal gene product. See Molecular Genetic Pathogenesis.

RPL35A

Gene structure. RPL35A has five exons with the translation start codon in exon 2 (NM_000996.2).

Pathogenic allelic variants. Five families with pathogenic variants in RPL35A have been described [Table 2; Farrar et al 2008].

Table 2.

Selected RPL35A Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.82_84delCTTp.Leu28delNM_000996​.2
NP_000987​.2
c.97G>Ap.Val33Ile
c.304C>Tp.Arg102Ter

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. RPL35A comprises 110 amino acids. RPL35A is a component of the large ribosomal subunit.

Abnormal gene product. See Molecular Genetic Pathogenesis.

RPS10

Gene structure. RPS10 contains six exons with the start codon in exon 2

Pathogenic allelic variants. Three pathogenic variants have been identified in five families with DBA [Doherty et al 2010]. The pathogenic variants include a small insertion and one missense and one nonsense variant.

Normal gene product. RPS10, which comprises 165 amino acids, is a component of the small ribosomal subunit.

Abnormal gene product. Variants in RPS10 cause abnormal start codon and premature termination codons. They are predicted to result in abnormal truncated protein.

RPS17

Gene structure. RPS17 has five exons with the translation start codon in exon 1.

Pathogenic allelic variants. Three pathogenic variants of RPS17 have been described, including two missense variants (c.2T>G) [Cmejla et al 2007] and (c.1A>G) [Song et al 2010] and one small deletion (c.200_201 delGA) [Gazda et al 2008].

Table 3.

Selected RPS17 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.2T>GSee footnote 1NM_001021​.3
NP_001012​.1
c.200_201delGAp.Gly68TyrfsTer19

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Nucleotide change eliminates the translation initiation codon for methionine, resulting in utilization of a downstream start codon and giving rise to a short peptide of four amino acids [Cmejla et al 2007].

Normal gene product. RPS17 comprises 135 amino acids. RPS17 is a component of the small ribosomal subunit.

Abnormal gene product. Pathogenic alleles result in loss of function of the normal protein.

RPS19

Gene structure. RPS19 has six exons with the translation start codon in exon 2 (reference sequence NM_001022.3).

Pathogenic allelic variants. The pathogenic alleles of RPS19 are numerous and include frameshift, missense, nonsense, and splice-site variants. In addition, individuals with deletions of an RPS19 exon(s) or of an entire allele have also reported. The pathogenic variants differ between affected families [Draptchinskaia et al 1999, Matsson et al 1999, Willig et al 1999, Cmejla et al 2000, Ramenghi et al 2000, Proust et al 2003, Campagnoli et al 2004, Gazda et al 2004, Orfali et al 2004].

Normal gene product. RPS19 comprises 145 amino acids (NP_001013.1). RPS19 is a component of the small ribosomal subunit.

Abnormal gene product. See Molecular Genetic Pathogenesis.

RPS24

Gene structure. Human RPS24 has five isoforms: a, b, c, d, and e. The translation start codon in all isoforms is in exon 1. Isoforms a (NM_033022.3) and b (NM_001142282.1) comprise six exons, while isoforms c (NM_001026.4) and d (NM_001142285.1) comprise five exons. Isoform e (NM_001142283.1) comprises seven exons.

Pathogenic allelic variants. Three pathogenic variants of RPS24 have been described [Gazda et al 2006].

Table 4.

Selected RPS24 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.46C>Tp.Arg16TerNM_033022​.3
NP_148982​.1
c.316C>Tp.Gln106Ter
c.4_6delACCinsTACGGATAGp.Asn1_Met23del 1

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

In-frame deletion resulting from skipping of exon 2 [Gazda et al 2006]

Normal gene product. RPS24 has five isoforms – a, b, c, d, and e – which comprise between 130 and 289 amino acids. RPS24 encodes a ribosomal protein that is a component of the 40S ribosomal subunit.

Abnormal gene product. See Molecular Genetic Pathogenesis.

RPS26

Gene structure. RPS26 contains four exons with the start codon in exon 1.

Pathogenic allelic variants. Nine pathogenic variants have been identified in 12 families with DBA [Doherty et al 2010]. The pathogenic variants include a small insertion and a missense and splice site variant.

Normal gene product. RPS26, which comprises 115 amino acids, is a component of the small ribosomal subunit.

Abnormal gene product. The reported variants result in abnormal truncated protein and, in one individual (variant c.97G>A), in a substitution (p.Asp33Asn).

Click here (pdf) for details on some of the less commonly mutated genes from Table 1B.

References

Literature Cited

  1. Alter BP, Kumar M, Lockhart LL, Sprinz PG, Rowe TF. Pregnancy in bone marrow failure syndromes: Diamond-Blackfan anaemia and Shwachman-Diamond syndrome. Br J Haematol. 1999;107:49–54. [PubMed: 10520024]
  2. Alter BP, Young NS. The bone marrow failure syndromes. In: Nathan DG, Orkin HS, eds. Hematology of Infancy and Childhood. Vol 1. Philadelphia, PA: Saunders; 1998:237-335.
  3. Alter BP. Diagnosis, genetics, and management of inherited bone marrow failure syndromes. Hematology Am Soc Hematol Educ Program. 2007:29–39. [PubMed: 18024606]
  4. Angelini M, Cannata S, Mercaldo V, Gibello L, Santoro C, Dianzani I, Loreni F. Missense mutations associated with Diamond-Blackfan anemia affect the assembly of ribosomal protein S19 into the ribosome. Hum Mol Genet. 2007;16:1720–7. [PubMed: 17517689]
  5. Bagby GC, Lipton JM, Sloand EM, Schiffer CA. Marrow failure. Hematology Am Soc Hematol Educ Program. 2004;2004:318–36. [PubMed: 15561690]
  6. Campagnoli MF, Garelli E, Quarello P, Carando A, Sv SV, Nobili B, Dl DL, Pecile V, Zecca M, Dufour C, Ramenghi U, Dianzan I. Molecular basis of Diamond-Blackfan anemia: new findings from the Italian registry and a review of the literature. Haematologica. 2004;89:480–9. [PubMed: 15075082]
  7. Cappellini MD, Piga A. Current status in iron chelation in hemoglobinopathies. Curr Mol Med. 2008;8:663–74. [PubMed: 18991652]
  8. Chae H, Park J, Lee S, Kim M, Kim Y, Lee JW, Chung NG, Cho B, Jeong DC, Kim J, Kim JR, Park G. Ribosomal protein mutations in Korean patients with Diamond-Blackfan anemia. Exp Mol Med. 2014;46:e88. [PMC free article: PMC3972785] [PubMed: 24675553]
  9. Chen S, Warszawski J, Bader-Meunier B, Tchernia G, Da Costa L, Marie I, Dommergues JP. Diamond-blackfan anemia and growth status: the French registry. J Pediatr. 2005;147:669–73. [PubMed: 16291361]
  10. Choesmel V, Bacqueville D, Rouquette J, Noaillac-Depeyre J, Fribourg S, Cretien A, Leblanc T, Tchernia G, Da Costa L, Gleizes PE. Impaired ribosome biogenesis in Diamond-Blackfan anemia. Blood. 2007;109:1275–83. [PMC free article: PMC1785132] [PubMed: 17053056]
  11. Choesmel V, Fribourg S, Aguissa-Toure AH, Pinaud N, Legrand P, Gazda HT, Gleizes PE. Mutation of ribosomal protein RPS24 in Diamond-Blackfan anemia results in a ribosome biogenesis disorder. Hum Mol Genet. 2008;17:1253–63. [PubMed: 18230666]
  12. Cmejla R, Blafkova J, Stopka T, Zavadil J, Pospisilova D, Mihal V, Petrtylova K, Jelinek J. Ribosomal protein S19 gene mutations in patients with diamond-blackfan anemia and identification of ribosomal protein S19 pseudogenes. Blood Cells Mol Dis. 2000;26:124–32. [PubMed: 10753603]
  13. Cmejla R, Cmejlova J, Handrkova H, Petrak J, Petrtylova K, Mihal V, Stary J, Cerna Z, Jabali Y, Pospisilova D. Identification of mutations in the ribosomal protein L5 (RPL5) and ribosomal protein L11 (RPL11) genes in Czech patients with Diamond-Blackfan anemia. Hum Mutat. 2009;30:321–7. [PubMed: 19191325]
  14. Cmejla R, Cmejlova J, Handrkova H, Petrak J, Pospisilova D. Ribosomal protein S17 gene (RPS17) is mutated in Diamond-Blackfan anemia. Hum Mutat. 2007;28:1178–82. [PubMed: 17647292]
  15. Danilova N, Sakamoto KM, Lin S. Ribosomal protein S19 deficiency in zebrafish leads to developmental abnormalities and defective erythropoiesis through activation of p53 protein family. Blood. 2008;112:5228–37. [PubMed: 18515656]
  16. Delaporta P, Sofocleous C, Stiakaki E, Polychronopoulou S, Economou M, Kossiva L, Kostaridou S, Kattamis A. Clinical phenotype and genetic analysis of RPS19, RPL5, and RPL11 genes in Greek patients with Diamond Blackfan anemia. Pediatr Blood Cancer. 2014;61:2249–55. [PubMed: 25132370]
  17. Dianzani I, Garelli E, Ramenghi U. Diamond-Blackfan Anaemia: an overview. Paediatr Drugs. 2000;2:345–55. [PubMed: 11022796]
  18. Doherty L, Sheen MR, Vlachos A, Choesmel V, O'Donohue MF, Clinton C, Schneider HE, Sieff CA, Newburger PE, Ball SE, Niewiadomska E, Matysiak M, Glader B, Arceci RJ, Farrar JE, Atsidaftos E, Lipton JM, Gleizes PE, Gazda HT. Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-Blackfan anemia. Am J Hum Genet. 2010;86:222–8. [PMC free article: PMC2820177] [PubMed: 20116044]
  19. Draptchinskaia N, Gustavsson P, Andersson B, Pettersson M, Willig TN, Dianzani I, Ball S, Tchernia G, Klar J, Matsson H, Tentler D, Mohandas N, Carlsson B, Dahl N. The gene encoding ribosomal protein S19 is mutated in Diamond-Blackfan anaemia. Nat Genet. 1999;21:169–75. [PubMed: 9988267]
  20. Dunbar AE 3rd, Moore SL, Hinson RM. Fetal Diamond-Blackfan anemia associated with hydrops fetalis. Am J Perinatol. 2003;20:391–4. [PubMed: 14655096]
  21. Faivre L, Meerpohl J, Da Costa L, Marie I, Nouvel C, Gnekow A, Bender-Götze C, Bauters F, Coiffier B, Peaud PY, Rispal P, Berrebi A, Berger C, Flesch M, Sagot P, Varet B, Niemeyer C, Tchernia G, Leblanc T. High-risk pregnancies in Diamond-Blackfan anemia: a survey of 64 pregnancies from the French and German registries. Haematologica. 2006;91:530–3. [PubMed: 16537118]
  22. Farrar JE, Nater M, Caywood E, McDevitt MA, Kowalski J, Takemoto CM, Talbot CC Jr, Meltzer P, Esposito D, Beggs AH, Schneider HE, Grabowska A, Ball SE, Niewiadomska E, Sieff CA, Vlachos A, Atsidaftos E, Ellis SR, Lipton JM, Gazda HT, Arceci RJ. Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond-Blackfan anemia. Blood. 2008;112:1582–92. [PMC free article: PMC2518874] [PubMed: 18535205]
  23. Farrar JE, Quarello P, Fisher R, O'Brien KA, Aspesi A, Parrella S, Henson AL, Seidel NE, Atsidaftos E, Prakash S, Bari S, Garelli E, Arceci RJ, Dianzani I, Ramenghi U, Vlachos A, Lipton JM, Bodine DM, Ellis SR. Exploiting pre-rRNA processing in Diamond Blackfan anemia gene discovery and diagnosis. Am J Hematol. 2014;89:985–91. [PMC free article: PMC4332597] [PubMed: 25042156]
  24. Farrar JE, Vlachos A, Atsidaftos E, Carlson-Donohoe H, Markello TC, Arceci RJ, Ellis SR, Lipton JM, Bodine DM. Ribosomal protein gene deletions in Diamond-Blackfan anemia. Blood. 2011;118:6943–51. [PMC free article: PMC3245214] [PubMed: 22045982]
  25. Flygare J, Aspesi A, Bailey JC, Miyake K, Caffrey JM, Karlsson S, Ellis SR. Human RPS19, the gene mutated in Diamond-Blackfan anemia, encodes a ribosomal protein required for the maturation of 40S ribosomal subunits. Blood. 2007;109:980–6. [PMC free article: PMC1785147] [PubMed: 16990592]
  26. Gazda HT, Grabowska A, Merida-Long LB, Latawiec E, Schneider HE, Lipton JM, Vlachos A, Atsidaftos E, Ball SE, Orfali KA, Niewiadomska E, Da Costa L, Tchernia G, Niemeyer C, Meerpohl JJ, Stahl J, Schratt G, Glader B, Backer K, Wong C, Nathan DG, Beggs AH, Sieff CA. Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia. Am J Hum Genet. 2006;79:1110–8. [PMC free article: PMC1698708] [PubMed: 17186470]
  27. Gazda HT, Preti M, Sheen MR, O'Donohue MF, Vlachos A, Davies SM, Kattamis A, Doherty L, Landowski M, Buros C, Ghazvinian R, Sieff CA, Newburger PE, Niewiadomska E, Matysiak M, Glader B, Atsidaftos E, Lipton JM, Gleizes PE, Beggs AH. Frameshift mutation in p53 regulator RPL26 is associated with multiple physical abnormalities and a specific pre-ribosomal RNA processing defect in diamond-blackfan anemia. Hum Mutat. 2012;33:1037–44. [PMC free article: PMC3370062] [PubMed: 22431104]
  28. Gazda HT, Sheen MR, Vlachos A, Choesmel V, O'Donohue MF, Schneider H, Darras N, Hasman C, Sieff CA, Newburger PE, Ball SE, Niewiadomska E, Matysiak M, Zaucha JM, Glader B, Niemeyer C, Meerpohl JJ, Atsidaftos E, Lipton JM, Gleizes PE, Beggs AH. Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients. Am J Hum Genet. 2008;83:769–80. [PMC free article: PMC2668101] [PubMed: 19061985]
  29. Gazda HT, Zhong R, Long L, Niewiadomska E, Lipton JM, Ploszynska A, Zaucha JM, Vlachos A, Atsidaftos E, Viskochil DH, Niemeyer CM, Meerpohl JJ, Rokicka-Milewska R, Pospisilova D, Wiktor-Jedrzejczak W, Nathan DG, Beggs AH, Sieff CA. RNA and protein evidence for haplo-insufficiency in Diamond-Blackfan anaemia patients with RPS19 mutations. Br J Haematol. 2004;127:105–13. [PubMed: 15384984]
  30. Glader BE, Backer K. Elevated red cell adenosine deaminase activity: a marker of disordered erythropoiesis in Diamond-Blackfan anaemia and other haematologic diseases. Br J Haematol. 1988;68:165–8. [PubMed: 3348976]
  31. Gregory LA, Aguissa-Toure AH, Pinaud N, Legrand P, Gleizes PE, Fribourg S. Molecular basis of Diamond-Blackfan anemia: structure and function analysis of RPS19. Nucleic Acids Res. 2007;35:5913–21. [PMC free article: PMC2034476] [PubMed: 17726054]
  32. Gripp KW, Curry C, Olney AH, Sandoval C, Fisher J, Chong JX. UW Center for Mendelian Genomics, Pilchman L, Sahraoui R, Stabley DL, Sol-Church K. Diamond-Blackfan anemia with mandibulofacial dystostosis is heterogeneous, including the novel DBA genes TSR2 and RPS28. Am J Med Genet A. 2014;164A:2240–9. [PMC free article: PMC4149220] [PubMed: 24942156]
  33. Hamaguchi I, Ooka A, Brun A, Richter J, Dahl N, Karlsson S. Gene transfer improves erythroid development in ribosomal protein S19-deficient Diamond-Blackfan anemia. Blood. 2002;100:2724–31. [PubMed: 12351378]
  34. Henter JI, Karlen J. Fatal agranulocytosis after deferiprone therapy in a child with Diamond-Blackfan anemia. Blood. 2007;109:5157–9. [PubMed: 17344464]
  35. Hermanns P, Bertuch AA, Bertin TK, Dawson B, Schmitt ME, Shaw C, Zabel B, Lee B. Consequences of mutations in the non-coding RMRP RNA in cartilage-hair hypoplasia. Hum Mol Genet. 2005;14:3723–40. [PubMed: 16254002]
  36. Idol RA, Robledo S, Du HY, Crimmins DL, Wilson DB, Ladenson JH, Bessler M, Mason PJ. Cells depleted for RPS19, a protein associated with Diamond Blackfan Anemia, show defects in 18S ribosomal RNA synthesis and small ribosomal subunit production. Blood Cells Mol Dis. 2007;39:35–43. [PubMed: 17376718]
  37. Janov AJ, Leong T, Nathan DG, Guinan EC. Diamond-Blackfan anemia. Natural history and sequelae of treatment. Medicine (Baltimore) 1996;75:77–8. [PubMed: 8606629]
  38. Klar J, Khalfallah A, Arzoo PS, Gazda HT, Dahl N. Recurrent GATA1 mutations in Diamond-Blackfan anaemia. Br J Haematol. 2014;166:949–51. [PubMed: 24766296]
  39. Konno Y, Toki T, Tandai S, Xu G, Wang R, Terui K, Ohga S, Hara T, Hama A, Kojima S, Hasegawa D, Kosaka Y, Yanagisawa R, Koike K, Kanai R, Imai T, Hongo T, Park MJ, Sugita K, Ito E. Mutations in the ribosomal protein genes in Japanese patients with Diamond-Blackfan anemia. Haematologica. 2010;95:1293–9. [PMC free article: PMC2913077] [PubMed: 20378560]
  40. Kuramitsu M, Hamaguchi I, Takuo M, Masumi A, Momose H, Takizawa K, Mochizuki M, Naito S, Yamaguchi K. Deficient RPS19 protein production induces cell cycle arrest in erythroid progenitor cells. Br J Haematol. 2008;140:348–59. [PubMed: 18217898]
  41. Kuramitsu M, Sato-Otsubo A, Morio T, Takagi M, Toki T, Terui K, Wang R, Kanno H, Ohga S, Ohara A, Kojima S, Kitoh T, Goi K, Kudo K, Matsubayashi T, Mizue N, Ozeki M, Masumi A, Momose H, Takizawa K, Mizukami T, Yamaguchi K, Ogawa S, Ito E, Hamaguchi I. Extensive gene deletions in Japanese patients with Diamond Blackfan anemia. Blood. 2012;119:2376–84. [PubMed: 22262766]
  42. Landowski M, O'Donohue MF, Buros C, Ghazvinian R, Montel-Lehry N, Vlachos A, Sieff CA, Newburger PE, Niewiadomska E, Matysiak M, Glader B, Atsidaftos E, Lipton JM, Beggs AH, Gleizes PE, Gazda HT. Novel deletion of RPL15 identified by array-comparative genomic hybridization in Diamond-Blackfan anemia. Hum Genet. 2013;132:1265–74. [PMC free article: PMC3797874] [PubMed: 23812780]
  43. Léger-Silvestre I, Caffrey JM, Dawaliby R, Alvarez-Arias DA, Gas N, Bertolone SJ, Gleizes PE, Ellis SR. Specific Role for Yeast Homologs of the Diamond Blackfan Anemia-associated Rps19 Protein in Ribosome Synthesis. J Biol Chem. 2005;280:38177–85. [PubMed: 16159874]
  44. Lipton JM, Atsidaftos E, Zyskind I, Vlachos A. Improving clinical care and elucidating the pathophysiology of Diamond Blackfan anemia: an update from the Diamond Blackfan Anemia Registry. Pediatr Blood Cancer. 2006;46:558–64. [PubMed: 16317735]
  45. Lipton JM, Ellis SR. Diamond Blackfan anemia 2008-2009: broadening the scope of ribosome biogenesis disorders. Curr Opin Pediatr. 2010;22:12–9. [PMC free article: PMC2886588] [PubMed: 19915471]
  46. Ludwig LS, Gazda HT, Eng JC, Eichhorn SW, Thiru P, Ghazvinian R, George TI, Gotlib JR, Beggs AH, Sieff CA, Lodish HF, Lander ES, Sankaran VG. Altered translation of GATA1 in Diamond-Blackfan anemia. Nat Med. 2014;20:748–53. [PMC free article: PMC4087046] [PubMed: 24952648]
  47. Matsson H, Klar J, Draptchinskaia N, Gustavsson P, Carlsson B, Bowers D, de Bont E, Dahl N. Truncating ribosomal protein S19 mutations and variable clinical expression in Diamond-Blackfan anemia. Hum Genet. 1999;105:496–500. [PubMed: 10598818]
  48. Mirabello L, Macari ER, Jessop L, Ellis SR, Myers T, Giri N, Taylor AM, McGrath KE, Humphries JM, Ballew BJ, Yeager M, Boland JF, He J, Hicks BD, Burdett L, Alter BP, Zon L, Savage SA. Whole-exome sequencing and functional studies identify RPS29 as a novel gene mutated in multicase Diamond-Blackfan anemia families. Blood. 2014;124:24–32. [PMC free article: PMC4125351] [PubMed: 24829207]
  49. Miyake K, Utsugisawa T, Flygare J, Kiefer T, Hamaguchi I, Richter J, Karlsson S. Ribosomal protein S19 deficiency leads to reduced proliferation and increased apoptosis but does not affect terminal erythroid differentiation in a cell line model of Diamond-Blackfan anemia. Stem Cells. 2008;26:323–9. [PubMed: 17962699]
  50. Morel AS, Joris N, Meuli R, Jacquemont S, Ballhausen D, Bonafe L, Fattet S, Tolsa JF. Early neurological impairment and severe anemia in a newborn with Pearson syndrome. Eur J Pediatr. 2009;168:311–5. [PubMed: 18553104]
  51. Ohga S, Mugishima H, Ohara A, Kojima S, Fujisawa K, Yagi K, Higashigawa M, Tsukimoto I., Aplastic Anemia Committee Japanese Society of Pediatric Hematology. Diamond-Blackfan anemia in Japan: clinical outcomes of prednisolone therapy and hematopoietic stem cell transplantation. Int J Hematol. 2004;79:22–30. [PubMed: 14979474]
  52. Orfali KA, Ohene-Abuakwa Y, Ball SE. Diamond Blackfan anaemia in the UK: clinical and genetic heterogeneity. Br J Haematol. 2004;125:243–52. [PubMed: 15059149]
  53. Parekh S, Perez A, Yang XY, Billett H. Chronic parvovirus infection and G6PD deficiency masquerading as Diamond-Blackfan anemia. Am J Hematol. 2005;79:54–7. [PubMed: 15849759]
  54. Parrella S, Aspesi A, Quarello P, Garelli E, Pavesi E, Carando A, Nardi M, Ellis SR, Ramenghi U, Dianzani I. Loss of GATA-1 full length as a cause of Diamond-Blackfan anemia phenotype. Pediatr Blood Cancer. 2014;61:1319–21. [PMC free article: PMC4684094] [PubMed: 24453067]
  55. Porter J, Galanello R, Saglio G, Neufeld EJ, Vichinsky E, Cappellini MD, Olivieri N, Piga A, Cunningham MJ, Soulières D, Gattermann N, Tchernia G, Maertens J, Giardina P, Kwiatkowski J, Quarta G, Jeng M, Forni GL, Stadler M, Cario H, Debusscher L, Della Porta M, Cazzola M, Greenberg P, Alimena G, Rabault B, Gathmann I, Ford JM, Alberti D, Rose C. Relative response of patients with myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox (ICL670): a 1-yr prospective study. Eur J Haematol. 2008;80:168–76. [PMC free article: PMC2268958] [PubMed: 18028431]
  56. Proust A, Da Costa L, Rince P, Landois A, Tamary H, Zaizov R, Tchernia G, Delaunay J. Ten novel Diamond-Blackfan anemia mutations and three polymorphisms within the rps19 gene. Hematol J. 2003;4:132–6. [PubMed: 12750732]
  57. Quarello P, Garelli E, Brusco A, Carando A, Mancini C, Pappi P, Vinti L, Svahn J, Dianzani I, Ramenghi U. High frequency of ribosomal protein gene deletions in Italian Diamond Blackfan anemia patients detected by Multiplex Ligation-dependent Probe Amplification (MLPA) assay. Haematologica. 2012;97:1813–7. [PMC free article: PMC3590087] [PubMed: 22689679]
  58. Quarello P, Garelli E, Carando A, Brusco A, Calabrese R, Dufour C, Longoni D, Misuraca A, Vinti L, Aspesi A, Biondini L, Loreni F, Dianzani I, Ramenghi U. Diamond-Blackfan anemia: genotype-phenotype correlations in Italian patients with RPL5 and RPL11 mutations. Haematologica. 2010;95:206–13. [PMC free article: PMC2817022] [PubMed: 19773262]
  59. Ramenghi U, Campagnoli MF, Garelli E, Carando A, Brusco A, Bagnara GP, Strippoli P, Izzi GC, Brandalise S, Riccardi R, Dianzani I. Diamond-Blackfan anemia: report of seven further mutations in the RPS19 gene and evidence of mutation heterogeneity in the Italian population. Blood Cells Mol Dis. 2000;26:417–22. [PubMed: 11112378]
  60. Roy V, Perez WS, Eapen M, Marsh JC, Pasquini M, Pasquini R, Mustafa MM, Bredeson CN. Bone marrow transplantation for diamond-blackfan anemia. Biol Blood Marrow Transplant. 2005;11:600–8. [PubMed: 16041310]
  61. Saladi SM, Chattopadhyay T, Adiotomre PN. Nomimmune hydrops fetalis due to Diamond-Blackfan anemia. Indian Pediatr. 2004;41:187–8. [PubMed: 15004307]
  62. Sankaran VG, Ghazvinian R, Do R, Thiru P, Vergilio JA, Beggs AH, Sieff CA, Orkin SH, Nathan DG, Lander ES, Gazda HT. Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia. J Clin Invest. 2012;122:2439–43. [PMC free article: PMC3386831] [PubMed: 22706301]
  63. Smetanina NS, Mersiyanova IV, Kurnikova MA, Ovsyannikova GS, Hachatryan LA, Bobrynina VO, Maschan MA, Novichkova GA, Lipton JM, Maschan AA. Clinical and genomic heterogeneity of Diamond Blackfan anemia in the Russian Federation. Pediatr Blood Cancer. 2015;62:1597–600. [PMC free article: PMC4515145] [PubMed: 25946618]
  64. Song MJ, Yoo EH, Lee KO, Kim GN, Kim HJ, Kim SY, Kim SH. A novel initiation codon mutation in the ribosomal protein S17 gene (RPS17) in a patient with Diamond-Blackfan anemia. Pediatr Blood Cancer. 2010;54:629–31. [PubMed: 19953637]
  65. Tentler D, Gustavsson P, Elinder G, Eklöf O, Gordon L, Mandel A, Dahl N. A microdeletion in 19q13.2 associated with mental retardation, skeletal malformations, and Diamond-Blackfan anaemia suggests a novel contiguous gene syndrome. J Med Genet. 2000;37:128–31. [PMC free article: PMC1734524] [PubMed: 10662814]
  66. Tsangaris E, Klaassen R, Fernandez CV, Yanofsky R, Shereck E, Champagne J, Silva M, Lipton JH, Brossard J, Michon B, Abish S, Steele M, Ali K, Dower N, Athale U, Jardine L, Hand JP, Odame I, Canning P, Allen C, Carcao M, Beyene J, Roifman CM, Dror Y. Genetic analysis of inherited bone marrow failure syndromes from one prospective, comprehensive and population-based cohort and identification of novel mutations. J Med Genet. 2011;48:618–28. [PubMed: 21659346]
  67. Vlachos A, Ball S, Dahl N, Alter BP, Sheth S, Ramenghi U, Meerpohl J, Karlsson S, Liu JM, Leblanc T, Paley C, Kang EM, Leder EJ, Atsidaftos E, Shimamura A, Bessler M, Glader B, Lipton JM. Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference. Br J Haematol. 2008;142:859–76. [PMC free article: PMC2654478] [PubMed: 18671700]
  68. Vlachos A, Dahl N, Dianzani I, Lipton JM. Clinical utility gene card for: Diamond - Blackfan anemia - update 2013. Eur J Hum Genet. 2013 Mar 6; Epub ahead of print. [PMC free article: PMC3778360] [PubMed: 23463023]
  69. Vlachos A, Klein GW, Lipton JM. The Diamond Blackfan Anemia Registry: tool for investigating the epidemiology and biology of Diamond-Blackfan anemia. J Pediatr Hematol Oncol. 2001;23:377–82. [PubMed: 11563775]
  70. Vlachos A, Muir E. How I treat Diamond-Blackfan anemia. Blood. 2010;116:3715–23. [PMC free article: PMC2981532] [PubMed: 20651069]
  71. Vlachos A, Rosenberg PS, Atsidaftos E, Alter BP, Lipton JM. Incidence of neoplasia in Diamond Blackfan anemia: a report from the Diamond Blackfan Anemia Registry. Blood. 2012;2012;119:3815–9. [PMC free article: PMC3335385] [PubMed: 22362038]
  72. Wang R, Yoshida K, Toki T, Sawada T, Uechi T, Okuno Y, Sato-Otsubo A, Kudo K, Kamimaki I, Kanezaki R, Shiraishi Y, Chiba K, Tanaka H, Terui K, Sato T, Iribe Y, Ohga S, Kuramitsu M, Hamaguchi I, Ohara A, Hara J, Goi K, Matsubara K, Koike K, Ishiguro A, Okamoto Y, Watanabe K, Kanno H, Kojima S, Miyano S, Kenmochi N, Ogawa S, Ito E. Loss of function mutations in RPL27 and RPS27 identified by whole-exome sequencing in Diamond-Blackfan anaemia. Br J Haematol. 2015;168:854–64. [PubMed: 25424902]
  73. Willig TN, Draptchinskaia N, Dianzani I, Ball S, Niemeyer C, Ramenghi U, Orfali K, Gustavsson P, Garelli E, Brusco A, Tiemann C, Perignon JL, Bouchier C, Cicchiello L, Dahl N, Mohandas N, Tchernia G. Mutations in ribosomal protein S19 gene and diamond blackfan anemia: wide variations in phenotypic expression. Blood. 1999;94:4294–306. [PubMed: 10590074]

Chapter Notes

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

  • 7 April 2016 (sw) Comprehensive update posted live
  • 16 January 2014 (cd) Revision: mutation of RPL15 causative of DBA12
  • 25 July 2013 (me) Comprehensive update posted live
  • 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
Copyright © 1993-2016, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2016 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK7047PMID: 20301769

Views

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...