SUMMARY
1. Bloom syndrome is an autosomal recessive chromosomal breakage syndrome associated with immunodeficiency.
2. Bloom syndrome patients are characterized by the following clinical features:
- Short stature (with normal proportions)
- Bird-like facies (sloping forehead, receding chin/micrognathia and long nose)
- Hypogammaglobulinemia
- Erythematous facial rash on sun exposed areas (resembling an SLE butterfly rash)
- Skin hyperpigmentation or hypopigmentation
- Markedly increased risk for developing malignancy (approximately 50% by age 25)
- Infertility
- Predisposition to develop Type 2 diabetes later in life
3. The immunodeficiency in Bloom syndrome is mainly characterized by hypogammaglobulinemia and impaired specific antibody responses. Patients commonly suffer from upper respiratory or gastrointestinal infections.
4. Bloom syndrome is caused by mutations in the BLM gene, which encodes for a RecQ helicase called the Bloom syndrome protein. – This protein helps to maintain the stability of DNA when the double helix is unwound during recombination repair and replication.
5. The diagnosis of Bloom syndrome is suggested by the presence of classic clinical features as well as the finding of increased sister chromatid exchanges on karyotype following incubation with BUdR (a thymidine analog).
6. Sequencing of the BLM gene can confirm the diagnosis.
7. Supportive therapies for immunodeficiency include immunoglobulin therapy and prophylactic antibiotics. Radiotherapy should be avoided as patients have increased radiation sensitivity and high risk for malignancy. There is no curative therapy for this disease.
OVERVIEW
Bloom syndrome is an autosomal recessive chromosomal breakage syndrome associated with immunodeficiency. Bloom syndrome patients are characterized by the following clinical features:
- Short stature (with normal proportions)
- Bird-like facies (sloping forehead, receding chin/micrognathia and long nose)
- Hypogammaglobulinemia
- Erythematous facial rash on sun exposed areas (resembling an SLE butterfly rash; this rash may be disfiguring in severe cases)
- Skin hyperpigmentation or hypopigmentation
- Markedly Increased risk for developing malignancy (approximately 50% by age 25)
- Infertility
- Predisposition to develop Type 2 diabetes later in life
The immunodeficiency in Bloom syndrome is mainly characterized by hypogammaglobulinemia and occasionally impaired specific antibody responses. Patients commonly suffer from upper respiratory of gastrointestinal infections. These abnormalities may be due to defective V(D)J recombination.
Bloom syndrome is caused by mutations in the BLM gene, which encodes for a RecQ helicase called the Bloom syndrome protein – this protein helps to maintain the stability of DNA when the double helix is unwound during recombination repair and replication.
EVALUATION
The diagnosis of Bloom syndrome is suggested by the presence of classic clinical features such as short stature, bird-like facies, facial rash, skin hyper/hypopigmentation, and hypogammaglobulinemia.
Step 1: Immune Evaluation
- Quantitative immunoglobulins (IgG, IgM, IgA)
- Antibody titers to vaccine antigens
- Flow cytometry for B cell, T cell, and NK cell enumeration
- T cell proliferation to mitogens
-Patients commonly have low quantitative immunoglobulin levels
- Protein (Tetanus, Diphtheria) and polysaccharide (Pneumococcus) vaccine antibody response should be evaluated. Patients may have reduced specific antibody response.
- Lymphocyte subset values (B cells, T cells, NK cells) are typically normal in Bloom syndrome
- Most patients have normal proliferative responses to T cell mitogens such as phytohemagglutinin A (PHA). However, responses to a T cell-dependent B cell mitogen such as pokeweed mitogen may be decreased.
Step 2: Karyotype
- Excessive numbers of sister-chromatid exchanges can be detected on karyotype following incubation with BUdR (a thymidine analog) and is suggestive of this diagnosis.
Step 3: Gene Sequencing
- BLM Gene Sequencing
- BLM gene sequencing is commercially available through Gene Dx.
MANAGEMENT
Supportive therapies for immunodeficiency include immunoglobulin replacement therapy and prophylactic antibiotics.
Typical IVIG replacement is started with 400-600mg/kg of every 4 weeks. Trough levels should be maintained above 800mg/dl. The total dose or dosing frequency may be increased to achieve desired troughs and clinical response.
The addition of prophylactic antibiotics can be considered in certain patients who continue to have infections despite appropriate immunoglobulin replacement. Two sample prophylaxis regimens are outlined below:
- Amoxicillin 20mg/kg divided twice daily. Maximum of 500mg twice daily.
- Azithromycin 10mg/kg once weekly. Maximum of 1 gram once weekly.
Radiotherapy should be avoided as patients have increased radiation sensitivity and markedly increased risk for malignancy. There is no curative therapy for this disease.
RESOURCES
Diagnostic Resources
1. Gene Dx : Gene Sequencing - BLM
Literature Resources
1. Kaneko 2004
Clinical features of Bloom Syndrome