Case 99 – Summary

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This week we have been looking at Diamond Blackfan anaemia (DBA). This is a rare, genetically and clinically heterogeneous, inherited red cell aplasia. It is one of the Inherited Bone Marrow Failure Syndromes (IBMFS), and probably the second most common IBMFS after Fanconi Anaemia. It has a prevalence of 5 to 7 cases per million live births.

  1. Most “Classical” cases present with anaemia in the neonatal period or in infancy, but not at birth, and hydrops fetalis has rarely been reported. 95% are diagnosed before the age of 2. Initial clinical features are an isolated anaemia, with symptoms such as pallor, shortness of breath while suckling, failure to thrive, systolic murmur. There is no organomegaly.
  2. However, non classical cases with less distinctive phenotypes can present in older children and adults. In fact more and more adults are being diagnosed with DBA.
  3. Cases are sporadic in 75% cases, with an equal sex ratio
  4. 10-25% have a positive family history
  1. It is a cancer pre-disposition syndrome – there is a moderately increased risk of developing MDS, AML, but also ALL, lymphomas and Hodgkin’s disease, as well as solid tumours such as osteosarcoma and other carcinomas. However the risk is not as high as that in FA.

Haematological features:

  1. Macrocytic anaemia
  2. Reticulocytopenia
  3. Variable platelet count, but often elevated
  4. Normal neutrophils, occasionally neutropenia
  5. Elevated HbF
  6. Elevated eADA (erythrocyte adenosine deaminase) activity is found in 90% of DBA patients [in non-transfused sample]. eADA is a key enzyme in purine metabolism but its relevance to DBA pathophysiology remains unexplained. eADA > 1.70 nmol/min/mg haemoglobin is strongly suggestive of DBA, even though eADA is non-specific.
  7. Bone marrow smears – absence or paucity of erythroid precursors which are morphologically normal in appearance (=< 5% of nucleated cells). Cellularity is normal and other haemopoietic lineages are normal.

Non-haematological features:

Congenital anomalies are associated with the anaemia in 10-40% of DBA-affected patients. Intrauterine growth retardation (a low birth rate is reported in 25% cases) and faltering growth are common. Many patients have a small stature, which can often be made worse by long term steroid therapy and iron overload. Height below 3rd centile is described in 30% children.

Congenital anomalies can include:

  • Craniofacial anomalies (most common) – representing 50% of congenital anomalies reported.
    • Hypertelorism
    • Broad flat nasal bridge
    • Microcephaly
    • Cleft palate
    • High arched palate
    • Pierre Robin syndrome
  • Those affecting the upper limbs
    • Triphalangeal thumb
    • Thumb duplication or hypoplasia
    • Radial hypoplasia
  • Structural defects of the heart e.g. VSD, ASD, coarctation of the aorta, patent foramen ovale, tetralogyof Fallot etc.
  • Abnormalities of the kidneys & genitourinary system e.g. absent, horseshoe kidney, duplicated collecting systems, hypospadias
  • Bones and teeth (e.g. defective enamel formation)
  • Congenital glaucoma, strabismus, congenital cataract

Differential diagnosis

  1. In children, transient erythroblastopenia of childhood (TEC) should be the major consideration. This is often related to viral illness and is self limiting with spontaneous resolution.

2. Other differentials include:

  • Pearson syndrome,
  • parvovirus B19
  • human immunodeficiency virus (HIV) and other infections,
  • drugs and toxins
  • immune-medicated disease should be ruled out before the diagnosis of DBA can be established.
  • Other inherited bone marrow failure syndromes e.g. FA, SDS & DKC must be ruled out

Important Investigations

1. Before first transfusion

  • FBC
  • Reticulocyte
  • HbF
  • E-ADA
  • Serology for parvovirus, hep B, C, HIV

2. To confirm diagnosis

  • Bone marrow aspirate & trephine
  • Cytogenetics & FISH (should be negative)
  • Parvovirus PCR on BMB – should be negative
  • Mutation analysis

3. Others

  • Examine for congenital anomalies
  • USS abdomen
  • ECHO
  • Hearing test
  • Ophthalmology review

4. Hepatitis B vaccination ideally prior to starting transfusion

5. Immunology investigations

6. Check vaccination response. MMR & Chickenpox vaccine prior to starting high dose steroid

7. Check vaccination response

8. HLA typing for index case and siblings

9. Extended red cell phenotyping

Genetics:

The understanding of DBA & DBA genetics is evolving.

DBA belongs to a group of disorders known as ribosomopathies. Inheritance are autosomal dominant, with heterozygous mutation in the ribosomal protein genes. The first identified DBA gene, also the most commonly mutated, is RPS19. It accounts for 25% DBA cases. RPS19 codes for a ribosomal protein located at chromosome 19q13.2. RPS19 protein haplo-insufficiency i.e. where the protein produced by a single copy of a normal gene is not sufficient to produce normal function. About 50% DBA patients have a single mutation in a gene encoding a ribosomal protein. More and more gene mutations as well as deletions are being identified. Recently mutations in GATA1, the first non-ribosomal protein gene, have been identified in some DBA families.

Ribosomal protein genes known to be affected include:

  • RPL5, RPL11, RPL35A
  • RPS7, RPS10, RPS17, RPS19, RPS24 and RPS26

These genes are responsible for the production of approximately 80 different ribosomal proteins, which are components for ribosomes.

Each ribosome is made up of two subunits – the large and small subunits.

RPL5, RPL11, RPL35A are found in the large subunits whereas RPS7, RPS10, RPS17, RPS19, RPS24 and RPS26 are found in the small subunits.

The specific functions of each ribosomal protein within these subunits are unclear. However, it is thought that the perturbed ribosomal biogenesis leads to an accumulation of p53 which has a role in initiating apoptosis in the DBA erythroid precursor.

Family screening

  • Inheritance is autosomal dominant with variable penetrance and expressivity
  • Parents and siblings should be screened to search for mild or asymptomatic carriers.
  • A complete family history including a history of congenital anomalies, any persistent or intermittent anaemia and history of macrocytosis or presumed pernicious anaemia.
  • Tests should include: FBC, reticulocyte count, HbF, eADA
  • If a genotype is identified in the index case, then genotyping is performed in the parents
  • Genotyping in the sibling and other family members if applicable
  • Other possibly affected family members should also be evaluated even if not currently anaemic, as anaemia may present in the future and advice should be given to seek help should symptoms develop
  • In vitro fertilisation with pre-implantation genetic diagnosis may be available for families with known genetic mutations allowing for the selection of unaffected embryos. This is often done simultaneously for the selection of an HLA-identical donor for the DBA patient.

Treatment options

Spontaneous remission is achieved in 20% of patients. However, the majority of patients require treatment. Some patients can also achieve remission after having a period of treatment.

1. Red cell transfusion

  • Transfusion should be used in those below 1 year of age
  • In those who are steroid non-responsive (about 20%)
  • Or those having growth difficulties with steroid
  • Transfusion is individualised, given usually every 3 to 4 weeks according to growth and exercise tolerance,
  • Extended red cell phenotyping should be carried out to minimise allo-immunisation

2. Corticosteroid therapy

  • Steroids have a profound effect on linear growth as well as neurocognitive development in infants, therefore it should be delayed until after 1 year of age
  • However, in areas where there is difficulty obtaining safe blood products or difficulty with venous access, sometimes steroids may be started earlier
  • Approximately 80% of patients will respond to steroid. Those who fail to respond to steroid initially may respond on re-challenge.
  • About 35%-40% of DBA patients on the international registry use steroids to maintain transfusion independence
  • Start a Trial of prednisolone 2mg/kg daily for maximum of 4 weeks, commencing 1-2 weeks after a transfusion when Hb is 90-100g/L
  • If steroid responsive (Hb maintained > 90g/L without the need for transfusion), then steroid should be tapered to a maintenance dose of <0.5mg/kg/day, ideally on an alternate day regime e.g. 1mg/kg alt days. Some treatment centres aim for <0.5mg/kg alt days if achievable as it is felt that the long term steroid toxicity and impact on growth is minimised at this dosing regime
  • Steroid taper should be over a couple of months initially to around 1mg/kg/day (some centres prefer weaning alternate days to achieve 2mg/kg alternate days over 8 weeks), then a much slower taper after that. This is so that a patient can come off the high dose regime relatively quickly to minimise side effects from high dose therapy, and the slow wean thereafter to prevent the lost of steroid response
  • Steroid response usually occurs in 10-15 days with a rise in reticulocyte count
  • If steroid unresponsive after 4 weeks, it should be quickly weaned off over 2 weeks and a transfusion programme should be commenced.
  • A steroid re-trial can be attempted after 12-18 months, as some children may become steroid responsive subsequently

3. HSCT

  • The only curative treatment for DBA
  • An HLA-identical sibling donor should be used for a patient who requires regular transfusion
  • HSCT can restore erythropoiesis in about 90% of cases
  • Familial cord blood can also be used
  • Matched unrelated donors are increasingly used where there is no Sibling donor, and outcome have greatly improved in recent years
  • Careful evaluation of a family donor must be carried out, especially in the absence of a genetic mutation, the sibling must have a full evaluation including eADA to ensure the donor does not have a phenotypically milder DBA
  • HSCT complications are reduced in those with the least co-morbidities e.g. iron overload. Hence iron loading needs to be evaluated and iron chelation optimised
  • MUD HSCT seems to have higher rates of lung GvHD and gut toxicity from case reports
  • In general conditioning should include serotherapy to reduce GvHD

Steroid toxicity, monitoring & management

  • DBA is one disease where a patient may be on life-long steroid.
  • Even at low doses, there may be significant side effects and toxicity
  • Live vaccines e.g. MMR & chickenpox vaccines given prior to starting high dose steroid (or VZV status determined)
  • Ensure all other vaccinations are completed
  • Pneumocystis jirovecii (PCP) prophylaxis should be started after the first month of high dose steroid, and continued until the patient is on low dose alternate day therapy
  • Gastric protection should be used until patient is on low dose therapy, using a PPI or H2 antagonist
  • Stress steroid dose may be required in acute illness or surgery
  • Side effects such as pathological fractures, cataracts, avascular necrosis have been noted in high rates in DBA patients
  • DEXA should be performed periodically e.g. every 5 years, with a baseline carried out usually at age 5
  • Ophthalmology and audiology review annually
  • An accurate growth chart must be maintained for each patient
  • Steroid therapy needs to be reviewed if there are growth concerns or other toxicity
  • Endocrine review from 10 years of age until end of pubertal development (or earlier if issues with growth)
  • Dental review
  • Vitamin D supplementation, screen for impaired glucose tolerance, monitoring of blood films and periodic bone marrow biopsy
  • Ferriscan/MRI T2*

Transfusion, iron chelation and monitoring for iron overload

  • Long term transfusion necessitates iron chelation
  • Other than transplant related mortality, transfusion-associated iron overload is the leading cause of death in DBA patients
  • Chelation should be started after 10-20 transfusions at 10-15ml/kg per transfusion
  • Serum ferritin is used as a surrogate marker for total body iron burden, but is an unreliable measure, even though ferritin trend may be helpful over time
  • Multiple parameters are required to assess iron burden e.g. T2*MRI of liver and heart, ferriscan in some centres and liver biopsy
  • Liver iron concentration (LIC) of < 3mg/g dry weight is considered normal
  • LIC >15mg/g dry weight is associated with clinically significant cardiac iron overload and risk of cardiac death in Thalassaemia patients
  • However, hepatic iron appears to be a poor surrogate for cardiac iron burden in general and particularly in DBA patients
  • Cardiac MRI T2* < 20 ms associated with decreased ejection fraction
  • Cardiac MRI T2* < 10 ms is associated with heart failure, and is an indication of severe iron loading and requires urgent iron chelation. Cardiac siderosis can result in toxic cardiomyopathy or fatal arrhythmia and has been the cause of death in DBA patients in registries
  • Liver biopsy is invasive but has the advantage of identifying fibrosis and cirrhosis
  • Iron chelation:
    • Oral deferasirox – needs to monitor for GI bleeding and liver toxicity
    • Subcutaneous or IV desferrioxamine
    • Deferiprone – but associated with cytopenias and only reserved in extreme cases of cardiac iron overload and congestive cardiomyopathy
    • Oral deferasirox & desferrioxamine maybe used in combination
  • Patients require
    • Regular ophthalmology, audiology, endocrine review
    • Cardiology review annually with ECG & ECHO
    • Refer to endocrinologist by 5 years of age to monitor for growth and diabetes, as well as thyroid and parathyroid problems

Gene therapy

  • This is currently under development targeting RPS19 mutation

Reproductive choices

  • Pregnancies should be planned as far as possible
  • Intensification of iron chelation should be performed before conception
  • Genetic testing as discussed above, inheritance is autosomal dominant
  • Full evaluation should be carried out in terms of blood-borne infections, iron overload, diabetes mellitus, hypothyroidism, cardiomyopathy and any other DBA or treatment related comorbidities. Pregnancy should be managed as high risk
  • Complications of pregnancy include
    • Fetal loss
    • Pre-eclampsia
    • Preterm delivery
    • Intra-uterine death
    • Intra-uterine growth retardation
    • Congenital abnormalities
  • The cause of pregnancy complication is an area of debate but is likely to be multi-factorial, to do with DBA itself, anaemia and treatment complications/toxicities

The science and the understanding of DBA is rapidly evolving. Therefore DBA management is also likely to evolve with time.

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