DIAMOND-BLACKFAN ANEMIA 1; DBA1

#105650
DIAMOND-BLACKFAN ANEMIA 1; DBA1

Alternative titles; symbols
DBA
BLACKFAN-DIAMOND SYNDROME; BDS
ANEMIA, CONGENITAL HYPOPLASTIC, OF BLACKFAN AND DIAMOND
ANEMIA, CONGENITAL ERYTHROID HYPOPLASTIC
RED CELL APLASIA, PURE, HEREDITARY
AREGENERATIVE ANEMIA, CHRONIC CONGENITAL
ERYTHROGENESIS IMPERFECTA
AASE-SMITH SYNDROME II
AASE SYNDROME

TEXT
A number sign (#) is used with this entry because Diamond-Blackfan anemia-1 (DBA1) is caused by heterozygous mutation in the gene encoding ribosomal protein S19 (RPS19; 603474) on chromosome 19q13.

Description
Diamond-Blackfan anemia (DBA) is an inherited red blood cell aplasia that usually presents in the first year of life. The main features are normochromic macrocytic anemia, reticulocytopenia, and nearly absent erythroid progenitors in the bone marrow. Patients show growth retardation, and approximately 30 to 50% have craniofacial, upper limb, heart, and urinary system congenital malformations. The majority of patients have increased mean corpuscular volume, elevated erythrocyte adenosine deaminase activity, and persistence of hemoglobin F. However, some DBA patients do not exhibit these findings, and even in the same family, symptoms can vary between affected family members (summary by Landowski et al., 2013).

Genetic Heterogeneity of Diamond-Blackfan Anemia

A locus for DBA (DBA2; 606129) has been mapped to chromosome 8p23-p22. Other forms of DBA include DBA3 (610629), caused by mutation in the RPS24 gene (602412) on 10q22; DBA4 (612527), caused by mutation in the RPS17 gene (180472) on 15q; DBA5 (612528), caused by mutation in the RPL35A gene (180468) on 3q29; DBA6 (612561), caused by mutation in the RPL5 gene (603634) on 1p22.1; DBA7 (612562), caused by mutation in the RPL11 gene (604175) on 1p36; DBA8 (612563), caused by mutation in the RPS7 gene (603658) on 2p25; DBA9 (613308), caused by mutation in the RPS10 gene (603632) on 6p; DBA10 (613309), caused by mutation in the RPS26 (603701) gene on 12q; DBA11 (614900), caused by mutation in the RPL26 gene (603704) on 17p13; DBA12 (615550), caused by mutation in the RPL15 gene (604174) on 3p24; and DBA13 (615909), caused by mutation in the RPS29 gene (603633) on 14q.

Boria et al. (2010) reviewed the molecular basis of Diamond-Blackfan anemia, emphasizing that it is a disorder of defective ribosome synthesis.

Gazda et al. (2012) completed a large-scale screen of 79 ribosomal protein genes in families with Diamond-Blackfan anemia and stated that of the 10 known DBA-associated genes, RPS19 accounts for approximately 25% of patients; RPS24, 2%; RPS17, 1%; RPL35A, 3.5%; RPL5, 6.6%; RPL11, 4.8%; RPS7, 1%; RPS10, 6.4%; RPS26, 2.6%; and RPL26, 1%. Gazda et al. (2012) stated that in total these mutations account for approximately 54% of all DBA patients.

Clinical Features
Diamond et al. (1961) observed triphalangeal thumbs in 1 of 30 patients with congenital erythroid hypoplastic anemia. Alter (1978) pointed out that triphalangeal thumbs occurred in 6 of 133 cases of congenital hypoplastic anemia. In all, 45 of the 133 cases (34%) had associated hand anomalies of some kind.

Cathie (1950) described a similar facial appearance in 4 unrelated affected children with erythrogenesis imperfecta, including snub noses, thick upper lips, and widely separated eyes.

A propensity for the development of leukemia has been reported (Krishnan et al., 1978; Wasser et al., 1978).

Ball et al. (1996) analyzed retrospective data from 80 cases of DBA (33 male, 47 female) born in the U.K. in a 20-year period (1975-1994), representing an annual incidence of 5 per million live births. Ten children from 7 families had an apparently familial disorder. Thirteen percent were anemic at birth, and 72.5% had presented by the age of 3 months. Sixty-seven percent had macrocytosis at presentation, 72% responded initially to steroids, and at the time of study, 61% were transfusion-dependent, 45% were steroid-dependent, and 39% required regular transfusions. Unequivocal physical anomalies, predominantly craniofacial, were present in 37%, and were more likely in boys (52%) than girls (25%). Eighteen percent had thumb anomalies. Height was below the third centile for age in 28%; 31% had neither short stature nor physical anomalies. In 4 children without physical abnormalities, red cell indices were normal and steroid-independent remission was achieved, suggesting transient erythroblastopenia of childhood (227050) rather than DBA. The birth month distribution of children with sporadic DBA and craniofacial dysmorphism suggested a possible seasonality, consistent with a viral etiology. In the familial cases, affected males had unequivocal anomalies, whereas females had only short stature or equivocal anomalies. In 3 families, 2 generations were affected; in 1 family, 3 generations were affected.

Willig et al. (1999) reported 42 probands with DBA caused by mutation in the RPS19 gene. The mean age at presentation was 2 months, and approximately 40% had associated physical anomalies, including triphalangeal thumb, duplication of thumb, short stature, ventricular septal defects, kidney hypoplasia, low hairline, and congenital glaucoma.

Clinical Variability

Anur et al. (2009) reported a patient with nonclassical Diamond-Blackfan anemia. She presented at age 17 years with progressive pancytopenia and bone marrow hypoplasia diagnosed after nausea and vomiting following outpatient surgery for correction of a flexion contracture of the finger. She became transfusion-dependent and the disorder was steroid-resistant. Erythrocyte adenosine deaminase was increased, consistent with the diagnosis. She underwent bone marrow transplantation, but died of complications. Molecular studies were not performed on this patient. Anur et al. (2009) emphasized the unusual and late clinical presentation of DBA in this patient, who had rapidly progressive aplastic anemia and did not show typical physical stigmata of the disorder.

Inheritance
Willig et al. (1999) stated that although the majority of DBA cases are sporadic, approximately 10 to 25% are familial, with most showing autosomal dominant inheritance.

Gazda et al. (2012) stated that approximately 40 to 50% of DBA cases are familial and show autosomal and commonly dominant inheritance.

Familial cases of congenital erythroid hypoplastic anemia were reported by Burgert et al. (1954) and by Diamond et al. (1961). Wallman (1956) described a father and daughter with erythroid hypoplasia, but the ages of onset (34 and 6 years, respectively) were beyond the usual limits of the Diamond-Blackfan syndrome. Forare (1963) observed affected brother and sister with the same father but different mothers. Although he referred to them as ‘step-sibs,’ they are actually half-sibs. Mott et al. (1969) reported a similar situation of 3 affected children from 2 mothers and the same father. Falter and Robinson (1972) described affected mother and daughter. Only the mother had aminoaciduria, suggesting that it was unrelated to the hematologic disorder. Lawton et al. (1974) described father and son with documented erythroid anemia from infancy. The father’s anemia remitted at age 6 years, but he continued to have macrocytosis, reticulocytosis, and raised fetal hemoglobin. Hamilton et al. (1974) described affected mother and daughter. Other families with possible autosomal dominant transmission were reported by Hunter and Hakami (1972), Wang et al. (1978), and Gray (1982).

Sensenbrenner (1972) described affected brother and sister. Pallor was first noted in the male at age 4 months and heart failure from anemia occurred at 10 months. Prednisone effectively controlled the anemia, but the brother developed aseptic necrosis of the left hip. Both patients had height below the 3rd percentile; at age 16, the brother was 147 cm tall, and at age 11, the sister was 127 cm tall. Both patients showed appropriate sexual maturation.

Viskochil et al. (1990) reported a kindred with 7 affected members in 4 sibships spanning 3 generations, with several instances of male-to-male transmission. Hurst et al. (1991) described a mother and son with congenital erythroid hypoplastic anemia; the son had a right radial club hand with absent thumb and conjoined radius and ulna on the right with small, useless thumb on the left. Gojic et al. (1994) reported a family in which 4 males in 3 successive generations had congenital hypoplastic anemia. None of these individuals had malformations; specifically, the thumbs and radii were normal. Two brothers were of short stature: 162 and 156 cm.

Of 6 pedigrees presented by Gustavsson et al. (1997), 2 families suggested autosomal recessive inheritance, and 4 families showed dominant inheritance with variable expressivity. In 1 family, the disease was evident in 3 generations with 2 instances of male-to-male transmission. In 2 families, the mother showed a mild anemia. In a fourth family, no phenotype was detected in the parents but the segregation of haplotypes indicated dominant inheritance from the mother.

Among 38 multiplex families with DBA collected from multiple geographic areas, Gazda et al. (2001) found a pedigree pattern consistent with autosomal dominant inheritance in all but 3. The 3 exceptions were small pedigrees consisting of 2 affected children and unaffected parents.

Diagnosis
Using custom enrichment technology combined with high-throughput sequencing of 80 ribosomal protein genes, Gerrard et al. (2013) identified and validated inactivating mutations in samples from 15 (88%) of 17 patients with Diamond-Blackfan anemia. Mutations in 8 different genes were identified; the most commonly affected gene in this cohort was RPL5 (603634), found in 5 patients, including an affected mother and daughter. The results indicated that this methodology is efficient for diagnosing the disorder.

Prenatal Diagnosis

McLennan et al. (1996) made the prenatal diagnosis of congenital hypoplastic anemia causing hydrops fetalis in a child born to a 26-year-old woman with steroid-dependent Blackfan-Diamond syndrome. The diagnosis of BDS had been made in the mother at the age of 2 years following investigation of short stature and failure to thrive. From the age of 4 years, she had been treated with steroids, titrated to maintain a hemoglobin level between 7 and 8.5 g/dl. There was no relevant family history. Her first pregnancy ended in a spontaneous abortion at 8 weeks. In the second pregnancy, failure to visualize cardiac structures adequately at 22 weeks led to referral to a tertiary center. Cardiomegaly and a small pericardial effusion with structurally normal heart were demonstrated. By 33 weeks, the mother developed severe ascites and enlargement of the heart, which occupied nearly the entire chest. Cordocentesis at that time confirmed severe fetal anemia, and transfusion of packed red cells was undertaken. The infant was delivered by cesarean section at 34 weeks. No physical anomalies were found except for proximal and superior displacement of the first metatarsophalangeal joint of an otherwise normal left great toe. Mild cardiac failure had resolved by day 14. Bone marrow at 3 months of age showed a cellular marrow with normal megakaryocytes and myeloid differentiation but virtual absence of red cell precursors. Prednisolone was introduced at that stage without any significant response over the next 2 months. At 14 months of age, the baby was being managed with intermittent transfusions and continued steroid administration.

Clinical Management
Pfeiffer and Ambs (1983) reported a patient in whom, as in other reported patients, treatment with prednisone was effective.

In 2 out of 6 patients, Dunbar et al. (1991) observed sustained remission following treatment with interleukin-3 (IL3; 147740).

Willig et al. (1999) assembled a registry of 229 DBA patients, including 151 from France, 70 from Germany, and 8 from other countries. Of 222 available for long-term follow-up analysis, 62.6% initially responded to steroid therapy. Initial steroid responsiveness was significantly and independently associated with older age at presentation, family history of DBA, and normal platelet count at the time of diagnosis. Severe evolution of the disease, transfusion dependence or death, was significantly and independently associated with a younger age at presentation and with a history of premature birth. In contrast, patients with a family history of the disease experienced a better outcome. The authors found that reassessing steroid responsiveness during the course of the disease for initially nonresponsive patients was useful. Bone marrow transplantation was successful in 11 of 13 cases. They suggested that HLA typing of probands and sibs should be performed early if patients are transfusion-dependent, and cord blood should be preserved. In families with dominant inheritance, no parental imprinting effect or anticipation phenomenon could be demonstrated.

Pathogenesis
Nathan et al. (1978) suggested that Diamond-Blackfan anemia may be a ‘congenital abnormality of erythropoietin (EPO; 133170) responsiveness that causes a functional, if not absolute, deficiency of erythroid precursors.’

Halperin and Freedman (1989) noted that erythroid stem cells in DBA are partly or completely refractory to EPO. However, they noted that patients have normal EPO structure and no anti-EPO antibodies, suggesting that there may be an abnormality in EPO receptor expression, EPO binding, or EPO signal transduction.

Glader et al. (1983) found increased adenosine deaminase (ADA; 608958) activity in red cells of patients with DBS. Whitehouse et al. (1984) found heterogeneity in DBS with respect to erythrocyte ADA activity and concluded that increased ADA activity was not limited to erythroid cells. Two sibs in 1 family showed increased red cell ADA activity over 4 months of multiple blood sampling. Both patients had the ADA 2-1 electrophoretic pattern and both allelozymes showed hyperactivity, indicating that there was not a mutation at the ADA locus.

Abkowitz et al. (1991) cultured marrow and blood mononuclear cells from 10 Diamond-Blackfan patients with various hematopoietic growth factors in the presence or absence of stem cell factor (SCF; mast cell growth factor; Steel factor; SF; 184745). Because of erythroid bursts observed in cultures containing SCF, the authors speculated that the SCF axis may be involved in the pathogenesis of Diamond-Blackfan anemia, and suggested that a therapeutic trial of SCF in patients would be worthwhile. Similar results were obtained by Bagnara et al. (1991) and by Carow et al. (1991). Sieff et al. (1992) investigated whether DBA was due to hyporesponsiveness to or hypoproduction of Steel factor. By studying long-term bone marrow cultures, they found that the DBA patients studied responded to SCF and produced SCF mRNA normally, indicating that SCF itself was not involved in DBA pathophysiology. Olivieri et al. (1991) found no gross abnormalities in the structure of either stem cell factor or its tyrosine kinase receptor (KIT; 164920) in 10 DBA patients. Spritz and Freedman (1993) found no mutations in either the SCF or KIT genes in patients with DBA.

Dianzani et al. (1996) stated that there was neither molecular nor clinical evidence for the involvement of stem cell factor or interleukin-3 (IL3; 147740) in the pathogenesis of DBA. Dianzani et al. (1996) also found no abnormality of the coding sequence of the EPOR gene (133171) in 23 DBA patients using SSCP. A Southern blot hybridization with an EPOR probe was negative in 7 patients. Furthermore, linkage studies showed that the disorder did not segregate with the EPOR gene in 2 informative DBA families.

Using gene expression profiling, Gazda et al. (2006) found that erythroid precursors of 3 patients with RPS19-association DBA in remission showed downregulation of multiple ribosomal protein genes, as well as downregulation of genes involved in transcription and translation compared to cells from 6 control individuals. DBA cells also showed upregulation of several proapoptotic genes, including TNFRSF10B (603612) and TNFRSF6 (134637). In addition, DBA cells showed downregulation of MYB (189990) and changes in expression of other cancer-related genes. Some of these changes were validated by RT-PCR studies. Gazda et al. (2006) concluded that DBA results from impaired ribosome biogenesis and decreased protein translation.

Using small interfering RNA (siRNA), Flygare et al. (2007) showed that reduced expression of RPS19 in a human erythroleukemia cell line led to a defect in maturation of the 40S ribosomal subunits, affected erythroid differentiation, and increased apoptosis. Cells expressing siRNA targeting RPS19 failed to efficiently cleave 21S pre-rRNAs at the E site within internal transcribed sequence-1, which would normally lead to formation of the mature 3-prime end of the 18S rRNA. CD34 (142230)-negative and CD34-positive bone marrow cells from DBA patients with mutations in RPS19 showed an increased ratio of 21S to 18SE pre-rRNA compared with healthy controls, and the defect was more pronounced in CD34-negative patient cells. The findings indicated that RPS19 is required for efficient maturation of 40S ribosomal subunits. The results showed that cells from patients with DFA have a defect in pre-rRNA processing, and Flygare et al. (2007) concluded that the disorder results from defects in ribosome synthesis.

Mapping
Gustavsson et al. (1997) reported a female patient with a de novo balanced translocation t(X;19)(p21;q13) who presented with constitutional erythroblastopenia as well as short stature and left kidney hypoplasia. By analysis of 26 families with DBA, Gustavsson et al. (1997) found linkage to chromosome 19q13 with a peak lod score at D19S197 (maximum lod = 7.08, theta = 0.00). Within this region, a submicroscopic de novo deletion of 3.3 Mb was identified in a patient with DBA. The deletion coincided with the translocation breakpoint observed in the patient mentioned earlier and, together with key recombinations, restricted the DBA gene to a 1.8-Mb region.

Using polymorphic 19q13 markers, including a short-tandem repeat in the critical DBA locus region, Gustavsson et al. (1998) studied 29 multiplex DBA families and 50 families with sporadic DBA cases. In 26 of the 29 multiplex families, DNA analysis yielded results consistent with a DBA gene on 19q within a 4.1-cM interval restricted by D19S200 and D19S178; however, in 3 multiplex families, the DBA candidate region on 19q13 was excluded from the segregation of marker alleles. This result suggested genetic heterogeneity for DBA, but indicated that the gene region on 19q segregates with the majority of familial cases. Among the 50 families comprising sporadic DBA cases, Gustavsson et al. (1998) identified 2 de novo and overlapping microdeletions on 19q13. In combination, the 3 known microdeletions associated with DBA restricted the critical gene region to approximately 1 Mb.

Genetic Heterogeneity

In 5 of 12 Italian families with DBA, Ramenghi et al. (1999) excluded the locus on 19q.

Costa et al. (2002) described piebaldism in a patient with DBA who did not have a mutation in the RPS19, KIT, or SCF genes. RPS19 is involved in approximately 25% of patients with DBA, KIT is a basis for piebald trait, and SCF is the KIT ligand. Costa et al. (2002) suggested that DBA with piebaldism may represent a novel phenotype due to mutation in a gene not previously identified.

Molecular Genetics
In 10 of 40 probands with DBA, Draptchinskaia et al. (1999) identified 9 different heterozygous mutations in the RPS19 gene (see, e.g., 603474.0001-603474.0002). Twenty-one patients had a family history of the disorder and 19 were sporadic cases. Six of the patients with mutations had a family history of the disorder. No mutations were found in the 5-prime untranslated region sequence or in the coding sequence in the 30 other probands.

Willig et al. (1999) identified heterozygous mutations in the RPS19 gene in 42 (24.4%) of 172 index patients with DBA. Mutations in the RPS19 gene were also found in some apparently unaffected individuals from DBA families who presented only with increased ADA levels. The authors found no genotype/phenotype correlations. For example, in 1 family, a pair of monozygotic twins had the same mutation, but only 1 of them had a thumb malformation.

Gazda et al. (2006) stated that mutation in the RPS19 gene occurs in an estimated 25% of probands with DBA. The authors identified de novo nonsense and splice site mutations in another ribosomal protein, RPS24 (602412), in 3 families with DBA. This finding strongly suggests that DBA is a disorder of ribosome synthesis and that mutations in other ribosomal proteins or associated genes that lead to disrupted ribosomal biogenesis and/or function may also cause DBA.

Landowski et al. (2013) performed array CGH for copy number variation in 87 probands with Diamond-Blackfan anemia who were negative for mutation in 10 known DBA-associated ribosomal protein genes, and identified large deletions in 6 (7%) of the patients, including a deletion in the RPS19 gene (603474.0009) in a steroid-dependent male patient with a webbed neck. Large deletions were also identified in the RPS24, RPS17, RPS26, and RPL15 genes; Landowski et al. (2013) proposed screening of all 80 ribosomal protein genes for copy number changes in DBA patients.

Genotype/Phenotype Correlations
Gazda et al. (2008) screened 196 probands with DBA for mutations in 25 genes encoding ribosomal proteins and identified mutations in the RPL5 (603634), RPL11 (604175), and RPS7 (603658) genes that segregated with disease in multiplex families and were associated with defects in the maturation of ribosomal RNAs in vitro. Mutations in RPL5 were associated with craniofacial abnormalities, particularly cleft lip and/or palate, in 9 of 14 patients with known malformations; the authors noted that none of the 12 DBA patients with RPL11 mutations and associated malformations had craniofacial abnormalities (p = 0.007) nor did any of the 35 previously reported DBA patients with RPS19 mutations and associated malformations (p = 9.745 x 10(-7)). In addition, mutations in RPL5 appeared to cause a more severe phenotype compared to mutations in RPL11 or RPS19, with RPL11 mutations being predominantly associated with thumb abnormalities.

Population Genetics
In France, Willig et al. (1999) estimated the incidence of DBA to be 7.3 cases per million live births.

Landowski et al. (2013) stated that the incidence of DBA is estimated to be 5 to 7 per million live births, equally distributed between genders.

History
Mentzer (2003) provided a biographic sketch of Louis Diamond (1902-1999) and a review of his contributions to pediatric hematology. Diamond and Blackfan (1938) described ‘their’ syndrome in an article on hypoplastic anemia. They reported 4 children with hypoplastic anemia beginning in infancy and requiring red cell transfusions at regular intervals. Similar cases had been reported earlier by Josephs (1936) at Johns Hopkins. Diamond’s name is also associated with that of Shwachman in the syndrome of pancreatic insufficiency and bone marrow dysfunction, Shwachman-Diamond syndrome (260400).

‘Congenital (erythroid) hypoplastic anemia’ was the term used by Diamond et al. (1961) for the disorder subsequently called Diamond-Blackfan anemia. Confusingly, Estren and Dameshek (1947) had used the designation ‘familial hypoplastic anemia’ for the disorder in 2 families that were later shown to have Fanconi anemia (FA; 227650) (Li and Potter, 1978).

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