Diamond–Blackfan anemia

Diamond–Blackfan anemia (DBA), also known as About 20–25% of DBA patients may be identified with a
Blackfan-Diamond anemia, inherited pure red cell genetic test for mutations in the RPS19 gene.
aplasia[1] and as inherited erythroblastopenia,[2] is
a congenital erythroid aplasia that usually presents
in infancy.[3] DBA causes low red blood cell counts
(anemia), without substantially affecting the other blood 3 History
components (the platelets and the white blood cells),
which are usually normal. This is in contrast to First noted by Hugh W. Josephs in 1936,[1]:485[5] the
Shwachman–Bodian–Diamond syndrome, in which the condition is however named for the pediatricians Louis
bone marrow defect results primarily in neutropenia, and K. Diamond and Kenneth Blackfan, who described
congenital hypoplastic anemia in 1938.[6] Responsive-
Fanconi anemia, where all cell lines are affected resulting
in pancytopenia. ness to corticosteroids was reported in 1951.[1]:485 In
1961, Diamond and colleagues presented longitudinal
A variety of other congenital abnormalities may also oc-
data on 30 patients and noted an association with skele-
cur in DBA.
tal abnormalities.[7] In 1997, a region on chromosome
19 was determined to carry a gene mutated in some
DBA.[8][9] In 1999, mutations in the ribosomal protein
1 Clinical features S19 gene (RPS19) were found to be associated with dis-
ease in 42 of 172 DBA patients.[10] In 2001, a second
DBA gene was localized to a region of chromosome 8,
Diamond–Blackfan anemia is characterized by and further genetic heterogeneity was inferred.[11] Addi-
normocytic or macrocytic anemia (low red blood tional genes were subsequently identified.[12]
cell counts) with decreased erythroid progenitor cells
in the bone marrow. This usually develops during the
neonatal period. About 47% of affected individuals also
have a variety of congenital abnormalities, including
3.1 Notable cases
craniofacial malformations, thumb or upper limb ab-
normalities, cardiac defects, urogenital malformations, A girl named Audrey Nethery of Louisville, Kentucky
and cleft palate. Low birth weight and generalized has a large online following from her singing and dancing
growth delay are sometimes observed. DBA patients videos and has brought public attention to the very rare
[13][14]
have a modest risk of developing leukemia and other disease. “The tiny dancer’s zest for the feel-happy,
malignancies. cool move packed, music pumping workout (Zumba)
has inspired millions of people to fall in love with her.
Subsequently, all the unexpected attention on Audrey
has given her family a great opportunity to raise much
2 Diagnosis needed awareness and funds for Diamond Blackfan Ane-
mia (DBA).”[15]
Typically, a diagnosis of DBA is made through a blood
count and a bone marrow biopsy.
A diagnosis of DBA is made on the basis of anemia, low 4 Genetics
reticulocyte (immature red blood cells) counts, and di-
minished erythroid precursors in bone marrow. Features Most pedigrees suggest an autosomal dominant mode of
that support a diagnosis of DBA include the presence inheritance[1] with incomplete penetrance.[16] Approxi-
of congenital abnormalities, macrocytosis, elevated fetal mately 10–25% of DBA occurs with a family history of
hemoglobin, and elevated adenosine deaminase levels in disease.
red blood cells.[4] With the exception of DBA rarely arising from mutation
Most patients are diagnosed in the first two years of life. of transcription factor GATA1 [17][18] DBA arises from
However, some mildly affected individuals only receive abnormal ribosomal protein genes.[1] The disease is char-
attention after a more severely affected family member is acterized by genetic heterogeneity, affecting different ri-
identified. bosomal gene loci:[12]

1
2 8
In 1997, a patient was identified who carried a rare bal-
anced chromosomal translocation involving chromosome
19 and the X chromosome. This suggested that the af-
fected gene might lie in one of the two regions that were
disrupted by this cytogenetic anomaly. Linkage analy-
sis in affected families also implicated this region in dis-
ease, and led to the cloning of the first DBA gene. About
20–25% of DBA cases are caused by mutations in the
ribosome protein S19 (RPS19) gene on chromosome 19
at cytogenetic position 19q13.2. Some previously undi-
agnosed relatives of DBA patients were found to carry
mutations, and also had increased adenosine deaminase
levels in their red blood cells, but had no other overt signs
of disease.
A subsequent study of families with no evidence of
RPS19 mutations determined that 18 of 38 families
showed evidence for involvement of an unknown gene on
chromosome 8 at 8p23.3-8p22.[28] The precise genetic
defect in these families has not yet been delineated.
Malformations are seen more frequently with DBA6
RPL5 and DBA7 RPL11 mutations.[16]
The genetic abnormalities underpinning the com-
bination of DBA with Treacher Collins syndrome
(TCS)/mandibulofacial dysostosis (MFD) phenotypes
are heterogeneous, including RPS26 (the known DBA10
gene), TSR2 which encodes a direct binding partner of
RPS26, and RPS28.[27]
DBA Mutation Database.
5 Molecular basis
The phenotype of DBA patients suggests a hematological
stem cell defect specifically affecting the erythroid pro-
genitor population. Loss of ribosomal function might be
predicted to affect translation and protein biosynthesis
broadly and impact many tissues. However, DBA is char-
acterized by dominant inheritance, and arises from partial
loss of ribosomal function, so it is possible that erythroid
progenitors are more sensitive to this decreased function,
while most other tissues are less affected.
6 Treatment
Corticosteroids can be used to treat anemia in DBA. In
a large study of 225 patients, 82% initially responded to
this therapy, although many side effects were noted.[29]
Some patients remained responsive to steroids, while
efficacy waned in others. Blood transfusions can also be
used to treat severe anemia in DBA. Periods of remission
may occur, during which transfusions and steroid treat-
ments are not required. Bone marrow transplanta-
tion (BMT) can cure hematological aspects of DBA.
This option may be considered when patients become
transfusion-dependent because frequent transfusions can
REFERENCES
lead to iron overloading and organ damage. However,
adverse events from BMTs may exceed those from iron
overloading.[30]
A 2007 study[31] showed the efficacy of leucine and
isoleucine supplementation in one patient. Larger stud-
ies are being conducted.
7 See also
• List of hematologic conditions
• Pure red cell aplasia
8 References
[1] Kaushansky, K; Lichtman, M; Beutler, E; Kipps, T; Pr-
chal, J; Seligsohn, U. (2010). “35”. Williams Hematology
(8th ed.). McGraw-Hill. ISBN 978-0071621519.
[2] Tchernia, Gilbert; Delauney, J (June 2000). “Diamond–
Blackfan anemia” (PDF). Orpha.net. Retrieved 1 January
2010.
[3] Cmejla R, Cmejlova J, Handrkova H, et al. (February
2009). “Identification of mutations in the ribosomal pro-
tein L5 (RPL5) and ribosomal protein L11 (RPL11) genes
in Czech patients with Diamond–Blackfan anemia”. Hum.
Mutat. 30 (3): n/a. doi:10.1002/humu.20874. PMID
19191325.
[4] Williamson, MA; Snyder, LM. (2015). “Chapter 9”. Wal-
lach’s Interpretation of Diagnostic Tests (10th ed.). Lip-
pincott Williams & Wilkins. ISBN 9781451191769.
[5] Hugh W. Josephs (1936). “Anaemia of infancy and
early childhood”. Medicine (Baltimore). 15: 307–451.
doi:10.1097/00005792-193615030-00001.
[6] Diamond LK, Blackfan, KD (1938). “Hypoplastic ane-
mia.”. Am. J. Dis. Child. 56: 464–467.
[7] Diamond LK, Allen DW, Magill FB (1961). “Con-
genital (erythroid) hypoplastic anemia: a 25 year
study.”. Am. J. Dis. Child. 102 (3): 403–415.
doi:10.1001/archpedi.1961.02080010405019. PMID
13722603.
[8] Gustavsson P, Willing TN, van Haeringen A, Tchernia
G, Dianzani I, Donner M, Elinder G, Henter JI, Nils-
son PG, Gordon L, Skeppner G, van't Veer-Korthof L,
Kreuger A, Dahl N (1997). “Diamond–Blackfan anaemia:
genetic homogeneity for a gene on chromosome 19q13
restricted to 1.8 Mb.”. Nat. Genet. 16 (4): 368–71.
doi:10.1038/ng0897-368. PMID 9241274.
[9] Gustavsson P, Skeppner G, Johansson B, Berg T, Gor-
don L, Kreuger A, Dahl N (1997). “Diamond–Blackfan
anaemia in a girl with a de novo balanced reciprocal
X;19 translocation.”. J. Med. Genet. 34 (9): 779–
82. doi:10.1136/jmg.34.9.779. PMC 1051068 . PMID
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[10] Draptchinskaia N, Gustavsson P, Andersson B, Petters-
son M, Willig TN, Dianzani I, Ball S, Tchernia G, Klar
J, Matsson H, Tentler D, Mohandas N, Carlsson B, Dahl
N (1999). “The gene encoding ribosomal protein S19 is
mutated in Diamond–Blackfan anaemia.”. Nat. Genet. 21
(2): 168–75. doi:10.1038/5951. PMID 9988267.
[11] Gazda H, Lipton JM, Willig TN, Ball S, Niemeyer CM,
Tchernia G, Mohandas N, Daly MJ, Ploszynska A, Or-
fali KA, Vlachos A, Glader BE, Rokicka-Milewska R,
Ohara A, Baker D, Pospisilova D, Webber A, Viskochil
DH, Nathan DG, Beggs AH, Sieff CA (2001). “Evidence
for linkage of familial Diamond–Blackfan anemia to chro-
mosome 8p23.3-p22 and for non-19q non-8p disease.”.
Blood. 97 (7): 2145–50. doi:10.1182/blood.V97.7.2145.
PMID 11264183.
[12] Online Mendelian Inheritance in Man. Diamond-
Blackfan anemia. Johns Hopkins University.
[13] https://www.youtube.com/channel/
UCfCq-0GqaJQuZGcuGtnNgLQ
[14] http://www.womenyoushouldknow.net/
6-year-old-audrey-nethery-puts-her-rare-blood-disorder-in-spotlight-with-awesome-zumba-moves-sets-sights-ellen-show/
[15] http://www.cosmopolitan.com/
health-fitness/news/a45231/
this-little-girl-is-better-at-zumba-than-youll-ever-be/
[16] Boria, I; Garelli, E; Gazda, H. T.; Aspesi, A; Quarello,
P; Pavesi, E; Ferrante, D; Meerpohl, J. J.; Kartal, M; Da
Costa, L; Proust, A; Leblanc, T; Simansour, M; Dahl, N;
Fröjmark, A. S.; Pospisilova, D; Cmejla, R; Beggs, A. H.;
Sheen, M. R.; Landowski, M; Buros, C. M.; Clinton, C.
M.; Dobson, L. J.; Vlachos, A; Atsidaftos, E; Lipton, J.
M.; Ellis, S. R.; Ramenghi, U; Dianzani, I (2010). “The
ribosomal basis of Diamond-Blackfan Anemia: Mutation
and database update”. Human Mutation. 31 (12): 1269–
79. doi:10.1002/humu.21383. PMID 20960466.
[17] Sankaran, Vijay G.; Ghazvinian, Roxanne; Do, Ron;
Thiru, Prathapan; Vergilio, Jo-Anne; Beggs, Alan H.;
Sieff, Colin A.; Orkin, Stuart H.; Nathan, David G.
(2012-07-02). “Exome sequencing identifies GATA1 mu-
tations resulting in Diamond-Blackfan anemia”. Jour-
nal of Clinical Investigation. 122 (7): 2439–2443.
doi:10.1172/jci63597.
[18] Parrella, Sara; Aspesi, Anna; Quarello, Paola; Garelli,
Emanuela; Pavesi, Elisa; Carando, Adriana; Nardi,
Margherita; Ellis, Steven R.; Ramenghi, Ugo (2014-07-
01). “Loss of GATA-1 full length as a cause of Diamond– [31] Pospisilova D, Cmejlova J, Hak J, Adam T, Cmejla R
Blackfan anemia phenotype”. Pediatric Blood & Cancer.
61 (7): 1319–1321. doi:10.1002/pbc.24944. ISSN 1545-
5017.
[19] Hoffbrand, AV; Moss PAH. (2011). Essential Haematol-
ogy (6th ed.). Wiley-Blackwell. ISBN 978-1-4051-9890-
5.
[20] Gazda HT, Grabowska A, Merida-Long LB, et al. (De-
cember 2006). “Ribosomal protein S24 gene is mutated in
Diamond–Blackfan anemia”. Am. J. Hum. Genet. 79 (6):
1110–8. doi:10.1086/510020. PMC 1698708 . PMID
17186470.
3
[21] Cmejla R, Cmejlova J, Handrkova H, Petrak J,
Pospisilova D (December 2007). “Ribosomal pro-
tein S17 gene (RPS17) is mutated in Diamond–
Blackfan anemia”. Hum. Mutat. 28 (12): 1178–82.
doi:10.1002/humu.20608. PMID 17647292.
[22] Farrar JE, Nater M, Caywood E, et al. (September 2008).
“Abnormalities of the large ribosomal subunit protein,
Rpl35a, in Diamond–Blackfan anemia”. Blood. 112 (5):
1582–92. doi:10.1182/blood-2008-02-140012. PMC
2518874 . PMID 18535205.
[23] Gazda H. T.; Sheen M. R.; Vlachos A; et al.
(2008). “Ribosomal protein L5 and L11 mutations
are associated with cleft palate and abnormal thumbs
in Diamond-Blackfan anemia patients”. The Amer-
ican Journal of Human Genetics. 83 (6): 769–
80. doi:10.1016/j.ajhg.2008.11.004. PMC 2668101 .
PMID 19061985.
[24] Online 'Mendelian Inheritance in Man' (OMIM) 603632
[25] Online 'Mendelian Inheritance in Man' (OMIM) 603701
[26] Online 'Mendelian Inheritance in Man' (OMIM) 604174
[27] Gripp K. W., Curry C, Olney A. H., Sandoval C, Fisher
J, Chong J. X., UW , Genomics Mendelian, Pilchman
L, Sahraoui R, Stabley D. L., Sol-Church K (2014).
“Diamond-Blackfan anemia with mandibulofacial dys-
tostosis is heterogeneous, including the novel DBA genes
TSR2 and RPS28”. American Journal of Medical Genet-
ics. 164A (9): 2240–9. doi:10.1002/ajmg.a.36633. PMC
4149220 . PMID 24942156.
[28] Gazda H, Lipton JM, Willig TN, et al. (April
2001). “Evidence for linkage of familial Diamond–
Blackfan anemia to chromosome 8p23.3-p22 and for
non-19q non-8p disease”. Blood. 97 (7): 2145–50.
doi:10.1182/blood.V97.7.2145. PMID 11264183.
[29] Vlachos A, Klein GW, Lipton JM (2001). “The Di-
amond Blackfan Anemia Registry: tool for investigat-
ing the epidemiology and biology of Diamond–Blackfan
anemia.”. J. Pediatr. Hematol. Oncol. 23 (6): 377–
82. doi:10.1097/00043426-200108000-00015. PMID
11563775.
[30] Saunders, E. F.; Olivieri, N; Freedman, M. H. (1993).
“Unexpected complications after bone marrow transplan-
tation in transfusion-dependent children”. Bone marrow
transplantation. 12 Suppl 1: 88–90. PMID 8374573.
(2007). “Successful treatment of a Diamond–Blackfan
anemia patient with amino acid leucine.”. Haematolog-
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17562599.
9 External links
• Diamond Blackfan Anemia Foundation (USA)
• Daniella Maria Arturi Foundation Research For The
Cure (USA)
4 9 EXTERNAL LINKS

• GeneReviews/NCBI/NIH/UW entry on Diamond–

Blackfan Anemia
• OMIM entries on Diamond–Blackfan Anemia

• Diamond–Blackfan Anemia research study of In-

herited Bone Marrow Failure Syndromes (IBMFS)

• UK Diamond Blackfan Anaemia Charity

• Diamond Blackfan Anæmia International Support

Group

• Diamond Blackfan Anemia Registry of North

America (DBAR)

• Diamond–Blackfan anemia Genetics Home Refer-

ence
 5

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