Diamond-Blackfan anemia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Roghayeh Marandi[2]

Synonyms and keywords: Erythrogenesis imperfecta; congenital pure red cell aplasia, hereditary pure red cell aplasia, familial pure red cell aplasia

Overview

Diamond-Blackfan anemia (DBA) is a congenital erythroid aplasia that usually presents in infancy.The classic form is characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets. About half of the affected patients have congenital malformations and growth retardation in 30% of affected individuals. The symptoms and physical findings associated with DBA vary greatly from person to person. The hematologic complications occur in 90% of affected individuals during the first year of life.

Historical Perspective

  • Diamond and Blackfan described congenital hypoplastic anemia in 1938.
  • In 1951, responsiveness to corticosteroids was reported.
  • In 1961, Diamond and colleagues presented longitudinal data on 30 patients and noted an association with skeletal abnormalities.
  • In 1997 a region on chromosome 19 was determined to carry a gene mutated in DBA.
  • In 1999, mutations in the ribosomal protein S19 gene (RPS19) were found to be associated with disease in some of the patients.
  • In 2001, it was determined that a second DBA gene lies in a region of chromosome 8.
  • In 2007, Furthermore mutations in large ribosomal subunit-associated proteins rpl5, rpl11, and rpl35a, have been described.
  • In 2010, 10 additional DBA genes are identified.
  • Non-RP gene, GATA1, was identified in 2012.
  • The largest study to date, "The Genetic Landscape of Diamond-Blackfan Anemia" provides a genetic explanation for nearly 80 percent of patients.
  • Researchers still wants to know why steroids often work in DBA, find more mutations, and address some questions about Diamond-Blackfan anemia.

Pathophysiology

Mutations in ribosomal protein genes have been confirmed to be the direct cause of faulty erythropoiesis and anemia.. DBA has revealed itself as a "Ribosomapthy".

Ribosomal protein gene mutations---> Ribosomal protein Insufficiency ---> Imbalance of Ribosomal Assembly Intermediates ---> Free Ribosomal proteins bind to inhibitors of P53 and Stabilize P53 expression ---> P53 Activation ---> Cell Cycle Arrest

Researchers found Ribosomal protein gene mutations reduce the actual numbers of ribosomes in blood precursor cells. Without enough ribosomes, the precursors can’t produce enough GATA1, which is essential for precursor cells to differentiate into red blood cells, so mature red cells never form. Based on a documented pathogenetic hypothesis which has been named " ribosomal stress ", ultimately a defective ribosome biosynthesis leads to apoptosis in those defective erythroid progenitors which in turn is leading to erythroid failure. In ‘‘ribosomal stress, reduced RP synthesis activates p53 that induces the downstream events and leads to cell cycle termination or apoptosis. Finally, this phenomenon results in the DBA phenotype of anemia, deprived growth, and results in congenital abnormalities. Mutated RP genes in DBA encode ribosomal proteins which are involved in either the small (RPS) or large (RPL) subunits of these proteins and the scarcity of these proteins can result the development of the disease. Other blood cells — like platelets, T cells, and B cells — are not affected and can still develop since they’re not dependent on GATA1.

In the remaining 10-15% of DBA cases, no abnormal genes have yet been identified. It is likely that mutations are in a regulatory region including intronic regions and promoters in one of the known RP genes may account for the DBA phenotype.

Causes

  • in about 80-85% of cases Diamond-Blackfan anemia, a block in erythropoiesis occurs due to the ribosomal protein gene mutation. [1]
  • In the remaining 10-15% of DBA cases, no abnormal genes have yet been identified. It is likely that mutations are in a regulatory region including intronic regions and promoters in one of the known RP genes and may account for the DBA phenotype.
  • Ribosomal protein mutations are sprodaic(55%) or hereditary.
    • Sporadic mutation occurs in genes encoding several different ribosomal proteins.
    • Approximately 40-45 % DBA cases are inherited with an autosomal dominant inheritance. and they have a family history of the disease with varying phenotypes.[2], although some of cases (GATA1-related DBA and TSR2-related DBA) are inherited in an X-linked manner..Also, autosomal recessive inheritance, with a lesser frequency has been reported.Variable expressivity is seen in all RP gene mutations. Possible mechanisms underlying variable expressivity include an influence of modifier genes and environmental factors.
    • About 25% of patients have mutations in the ribosome protein S19 (RPS19) gene on chromosome 19 at cytogenetic position 19q13.2. RPS19 has an important role in 18S rRNA maturation in yeast and in human cells.
    • Other mutated genes have been found in RPL5, RPL11, RPL35A, RPS7, RPS10, RPS17, RPS24, and RPS26, and rarely in RPL15, RPL17, RPL19, RPL26, RPL27, RPL31, RPS15A, RPS20, RPS27, RPS28, RPS29, that result in small or large ribosomal subunit synthesis deficiencies in human cells[2]
    • Mutation of "Non-RP" genes such as TSR2 and GATA1, and EPO also were found.[2]TSR2 plays a role in ribosome biogenesis since it is involved in the pre-rRNA processing and binds to RPS26. GATA1 which is the major erythroid transcription factor as being essential for precursor cells to differentiate into red blood cells and plays a critical role in regulating normal erythroid differentiation by activating of other erythroid genes.

Differentiating Diamond-Blackfan anemia from other Diseases

  • Aplastic anemia
  • Fanconi anemia is a bone marrow failure syndrome, present with pancytopenia, and physical abnormalities usually present within the first decade of life.
  • Transient Erythroblastopenia of Childhood is anacquired anemia usually (over 80%) presents at one year of age, while DBA usually (90%) presents before one year of age.
  • Shwachman-Diamond syndrome (SDS) is a clinical syndrome characterized by exocrine pancreatic dysfunction with malabsorption, single or multi-lineage cytopenia, growth failure, bone abnormality, and susceptibility to myelodysplastic syndrome, and AML
  • Pearson syndrome is an inherited mDNA mutation characterized by sideroblastic anemia of childhood, exocrine pancreatic failure, liver failure, renal tubular defects, and pancytopenia. Death generally occurs in infancy due to liver failure.
  • Dyskeratosis congenita (DC) is an inheretied disorder with the classic triad of lacy reticular pigmentation of the upper chest and/or neck, dysplastic nails, and oral leukoplakia. These patients have an increased risk of MDS, BMF, or AML.
  • Cartilage-hair hypoplasia (CHH)It is an autosomal recessive inherited disorder characterized by anemia, macrocytosis, defective T cell-mediated immune response, short tubular bone, and fine sparse blond hair.
  • Congenital amegakaryocytic thrombocytopenia (CAMT) usually presents at birth or in infancy with severe thrombocytopenia, petechiae, and/or intracranial or intestinal mucosal bleeding. In childhood, these patients may develop pancytopenia, MDS, or leukemia.
  • Infections: Parvovirus B19, HIV, Viral hepatitis
  • Drugs and toxins (eg. antileptic drugs, azathioprine)
  • Immune-mediated disorders( eg Thymoma, Myasthenia Gravis, SLE)

Epidemiology and Demographics

  • Incidence

Incidence of Classical Diamond-Blackfan anemia (DBA) is about seven per million live births per year. Thus in the United States, with 4 million live births per year, each year approximately 25-35 new patients will be diagnosed.

  • Prevalence of DBA

It is approximately 5000 cases worldwide.

  • Age

DBA is usually first diagnosed in infancy. The average age of presenting with anemia is two months and the average age of diagnosis with DBA is 3-4 months.

  • Race

There is no racial predilection to DBA.

  • Gender

DBA affects men and women equally.

Risk Factors

  • Positive family history of DBA
  • Have a known genetic cause
  • The cause cannot be detected, in some cases

Natural History, Complications and Prognosis

Natural history

The severity of Diamond-Blackfan anemia may vary, even within the same family.

  • Classic DBA:
    • Symptoms of anemia include fatigue, weakness, and an abnormally pale appearance (pallor).
    • The symptomatic onset of Diamond black-fan anemia becomes apparent during the first year of life
  • Approximately half of DBA cases have Congenital malformations, in particular craniofacial, upper-limb, heart, and genitourinary malformations:(observed in ~30%-50%):
  • All diagnostic criteria are met.
  • Non-classic DBA:
    • presents with mild or absent anemia with only subtle indications of erythroid abnormalities such as macrocytosis, elevated ADA, and/or elevated HbF concentration
    • Have mild anemia beginning later in childhood or in adulthood, while others have some of the physical features but no bone marrow problems.
    • Minimal or no evidence of congenital anomalies or short stature[3]

Complications

  • Common complications of Diamond black-fan include:
  • Physical abnormalities
  • higher-than-average chance of developing myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) bone cancer (osteosarcoma), colon cancer
  • Eye problems such as cataracts, glaucoma, or strabismus
  • kidney abnormalities
  • hypospadias
  • Secondary complications due to standard therapies( Corticosteroids treatment, Red cell transfusion, Bone marroe transplantation):
    • Transfusion iron overload
      • Cirrhosis or fibrosis of the liver
      • Cardiac arrythmias
      • Diabetes
      • Reproductive organ failure
      • Growth stunting
      • Endocrine failure affecting the thyroid and adrenal
    • Side effects of corticosteroids
    • Stem cell transplantation
      • Graft vs. Host Disease (GVHD)
      • Rejection

Prognosis

  • Prognosis is relatively good,Overall actuarial survival is 75% at age 40 years, but complications related to treatment may alter the quality of life of the affected individuals. Severe complications as a result of treatment or the development of cancer may reduce life expectancy.
  • Hematopoietic stem cell transplant (HSCT) is the sole curative option, but carries significant morbidity and is generally restricted to those with a matched related donor.
  • Ultimately, 40% of case subjects remain dependent upon corticosteroids which increase the risk of heart disease, osteoporosis, and severe infections.
  • Another 40% become dependent upon red cell transfusions which require regular chelation to prevent iron overload and increases the risk of alloimmunization and transfusion reactions, and can cause severe co-morbidities.

Diagnosis

History and Symptoms | Physical Examination | Laboratory Findings | Electrocardiogram | Chest X Ray | CT | MRI | Echocardiography or Ultrasound | Other Imaging Findings | Other Diagnostic Studies

Diagnosis

  • Diagnosing DBA is usually hard due to its partial phenotypes and the wide inconsistency of clinical expressions. the International Clinical Consensus Conference stated diagnostic and supporting criteria for the diagnosis of DBA.
  • Diagnostic criteria
  • Major supporting criteria
    • Gene mutation described in ‘‘classical’’ DBA
    • Positive family history
  • Minor supporting criteria
    • Elevated erythrocyte adenosine deaminase activity
    • Congenital anomalies described in ‘‘classical’’ DBA
    • Elevated HbF
    • No evidence of another inherited bone marrow failure syndrome


Classical DBA

All diagnostic criteria are met


Probable DBA

3 Diagnostic criteria + positive family history

OR

2 Diagnostic criteria + 3 minor criteria

OR

3 Minor criteria + positive family history


Non-classical DBA

DBA associated gene mutation without sufficient diagnostic criteria

History and symptoms

History

  • DBA typically presents in infancy, most commonly with pallor and lethargy, median age at presentation is 8 weeks. Hydrops fetalis in some cases have been seen.

Symptoms

Physical exam

Appearance of the Patient

  • Congenital malformations( observed in approximately 50% of affected individuals):
    • 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
    • Growth
      • Low birth weight (in 25% of affected infants)
      • Growth retardation9in 30%.Growth retardation can be influenced by other factors including steroid treatment


Following Initial Diagnosis, patients should be evaluated by:

  • a hematologist
  • a clinical geneticist for congenital malformations and to obtain a detailed family history
  • an ophthalmologist for glaucoma and cataract for individuals on steroid therapy
  • an Orthopedic evaluation for individuals with clinical findings suggestive of Klippel-Feil anomaly or Sprengel deformity
  • Orthopedic for individuals with upper-limb and/or thumb anomalies
  • Ultrasound examination of the kidney and urinary tract
  • a nephrologist and a urologist, as appropriate
  • a cardiologist including echocardiography
  • Developmental assessment

Laboratory findings

Blood tests:

  • Increased red-cell mean corpuscular volume (MCV)
  • Reticulocytopenia
  • Elevated erythrocyte adenosine deaminase activity(eADA)
    • DBA is associated with an increased ADA activity 30– 33%. ADA is a critical enzyme of the purine salvage pathway, which enables the deamination of adenosine in inosine and 2'-deoxyadenosine deamination in deoxyinosine. It is also increased in some leukemias, lymphomas, and immune system disorders.
  • Elevated hemoglobin F (HbF) concentration

Genetic tests

1. A sequence analysis of RPS19 is performed first.

2. If no pathogenic variant in RPS19 is found, perform sequence analysis of the remaining pathologic variants which are known to cause DBA or other gene mutations.[3]

Bone marrow aspirate

Other tests

  • Additional blood tests or genetic tests such as exome sequencing, genome sequencing, and mitochondrial sequencing may be ordered to rule out other types of anemia or other disorders.
  • Diagnosis of related-therapies complications:
    • Monitoring Transfusional Iron Overload with serum ferritin and Iron level. Here is a list of recommended labs to monitor and prevent the devastating effects of iron overload in the thyroid, heart, and the effects of diabetes:
      • Total T3
      • Total T4
      • TSH
      • T3 uptake (instead of free T4)
      • IGF-1(monitors acute fluctuations in insulin action and determines inadequate insulin treatment or poor control of dietary intake)
      • NT-proBNP (aids in the diagnosis of left ventricular dysfunction in heart failure)
      • Antithyroid Abs (Antithyroglobulin and AntiThyroperoxidase)
      • Fructosamine (useful in situations where the A1C cannot be reliably measured – as with transfused persons)
      • Vitamin D

Treatment

Medical Therapy | Surgery | Cost-Effectiveness of Therapy | Future or Investigational Therapies

  • Red cell transfusions
    • Transfusions are usually the mainstay of treatment for the first year of life for the anemia of DBA. Also, Red blood transfusions are used for those patients who do not respond to corticosteroid treatment
  • Corticosteroid therapy
    • after the first year patients are started on a course of treatment with corticosteroids and it remains the mainstay of treatment after the original report of their efficacy. In a large study of 225 patients, 82% initially responded to this therapy, although many side effects were noted. Treatment with corticosteroids can improve the anemia in 80% of patients, but individuals often become intolerant to long-term corticosteroid therapy and turn to regular red blood cell transfusions, which is the only available standard therapy for the anemia. [1]
    • Chronic glucocorticoid therapy predisposes patients to iatrogenic Cushing syndrome and adrenal insufficiency.
    • Chronic blood transfusions place patients at risk for the iron overload of the liver, heart, and endocrine organs. Growth failure, osteopenia, diabetes mellitus, and failure of the thyroid, parathyroids, adrenals, gonads, and pituitary gland, may be related to therapy.
  • Bone marrow transplantation (BMT)
    • It is the only curative treatment for the anemia of DBA. This option may be considered when patients become transfusion-dependent because frequent transfusions can lead to iron overloading and organ damage. This can be done using an unaffected sibling or an unrelated donor.

Remission

  • Periods of remission may occur, during which transfusions and steroid treatments are not required. Remission defined as an adequate Hemoglobin level without any treatment, lasting 6 months, independent of prior therapy. 72% of patients experience remission during the first decade of life. Some of them have more than one remission in their life. Relapses usually occur after a viral illness.
  • Some patients who have such mild signs and symptoms do not require treatment.[3]
  • Cancer treatment

Prevention of secondary complications

  • Iron chelation
    • usually started after ten to 12 transfusions (170-200 mL/kg of packed red blood cells), when serum ferritin concentration reaches 1,000-1,500 µg/L, or when the hepatic iron concentration reaches 6-7 mg/g of dry weight liver tissue
      • Deferasirox is recommended in individuals age two years or older.
      • Desferrioxamine
  • Corticosteroids side effects:
    • One of the critical side effects of corticosteroids is growth retardation. If growth is severely impaired, corticosteroids should be stopped.[3]

Further or investigational therapies

  • Investigations of several other agents showed these drugs appear to be largely ineffective and there is currently no evidence that any of these has a major role in the management of DBA [4]
  • Researchers still wants to know why steroids often work in DBA, find more mutations, and address some questions about Diamond-Blackfan anemia.[1]

Case Studies

Case #1

External Links

Template:Hematology


de:Diamond-Blackfan-Syndrom

Template:WikiDoc Sources

  1. ↑ 1.0 1.1 1.2 Ulirsch JC, Verboon JM, Kazerounian S, Guo MH, Yuan D, Ludwig LS, Handsaker RE, Abdulhay NJ, Fiorini C, Genovese G, Lim ET, Cheng A, Cummings BB, Chao KR, Beggs AH, Genetti CA, Sieff CA, Newburger PE, Niewiadomska E, Matysiak M, Vlachos A, Lipton JM, Atsidaftos E, Glader B, Narla A, Gleizes PE, O'Donohue MF, Montel-Lehry N, Amor DJ, McCarroll SA, O'Donnell-Luria AH, Gupta N, Gabriel SB, MacArthur DG, Lander ES, Lek M, Da Costa L, Nathan DG, Korostelev AA, Do R, Sankaran VG, Gazda HT (December 2018). "The Genetic Landscape of Diamond-Blackfan Anemia". Am. J. Hum. Genet. 103 (6): 930–947. doi:10.1016/j.ajhg.2018.10.027. PMC 6288280. PMID 30503522.
  2. ↑ 2.0 2.1 2.2 2.3 Da Costa L, Narla A, Mohandas N (2018). "An update on the pathogenesis and diagnosis of Diamond-Blackfan anemia". F1000Res. 7. doi:10.12688/f1000research.15542.1. PMC 6117846. PMID 30228860.
  3. ↑ 3.0 3.1 3.2 3.3 Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean L, Stephens K, Amemiya A, Clinton C, Gazda HT. PMID 20301769. Vancouver style error: initials (help); Missing or empty |title= (help)
  4. ↑ 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 (September 2008). "Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference". Br. J. Haematol. 142 (6): 859–76. doi:10.1111/j.1365-2141.2008.07269.x. PMC 2654478. PMID 18671700.
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