Are You Confident of the Diagnosis?

Bloom syndrome (BS) is characterized by severe growth deficiency of prenatal onset that persists into infancy, childhood and adulthood.

What you should be alert for in the history

The skin at birth and during early infancy is normal, but following sun exposure an erythematous rash in the butterfly area of the face appears leading to teleangiectatic lesions and hypo- and hyperpigmented areas. Gastroesophageal reflux (GER) is common and likely responsible for recurrent respiratory and gastrointestinal tract infections. Learning disabilities are frequently recorded. Features of adulthood are infertilty in males and subfertility in females, susceptibility to type II diabetes and most prominently predisposition to all types of cancers. A minority of BS are diagnosed for the first time following an early onset malignancy.

Characteristic findings on physical examination

The hallmark physical features are proportionate dwarfism, facial dysmorphisms including narrow face, small mandible, prominent nose and big ears and pigmentation, redness and dilated blood vessels in skin, and high-pitch voice. Subcutaneous fat tissue is characteristically sparse.

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Expected results of diagnostic studies

Based on the recurrent infections that may be clinical indicators of immunodeficiency, serologic tests are performed, often showing abnormally low levels of immunoglobulin A and M.

Cytogenetic analysis evidences a 10-fold increase of sister chromatid exchanges (SCEs), a pathognomonic sign of Bloom’s chromosomal instability. This instability has been used for diagnosis before the identification of the BLM gene, along with elevated rates of quadriradials composed of a pair of homologous chromosomes that have undergone a somatic crossing over. Both hallmarks attest hypercombination that primes chromosome rearrangements and loss of heterozygosity, a key mechanism for recessive tumorigenesis of oncosuppressor and caretaker genes.

Telomere instability, elevated mutation rate, abnormalities in DNA replication and hypersensitivity to replication inhiìbitors are other features of Bloom’s cells.The mutation test confirms the clinical diagnosis by evidencing biallelic mutations of the BLM gene. The BLM genetic test is provided following consistent clinical diagnosis.

Diagnosis confirmation

Differential diagnosis includes those disorders that feature small stature and evidence of sustained genomic instability, including Werner and Rothmund-Thomson, Fanconi anemia, ataxia-telangiectasia and AT-like syndromes. Silver-Russell syndrome, an imprinting defect characterized by pre- and postnatal growth retardation, can also be considered. Following molecular diagnosis of the patient, the test should be extended to both parents to detect their carrier status.

Who is at Risk for Developing this Disease?

BS is an extremely rare autosomal recessive (AR) disease with 265 cases reported in the 2009 Registry. It is more common in the Ashkenazi Jewish population where 1% are carriers of the defective gene, owing to high levels of inbreeding. Consanguineity should be inquired consistent with autosomal recessive transmission, especially in the Ashkenazi ethnic group. Couples with an affected child may be assumed to carry a mutation in BLM and thus have a recurrence risk of 25% for each subsequent child. Once a sib is known to be unaffected, the risk of being a carrier is 2 of 3.

Heterozygous carriers of a BS-causing mutation manifest none of the clinical signs of BS. However, evidence has been provided that BLMAsh healthy carriers have a higher risk of colon carcinoma, and the increased risk of breast cancer is considered for carriers of BLM mutations.

What is the Cause of the Disease?

Bloom syndrome is caused by biallelic inactivating mutations in the DNA RECQ3 BLM helicase gene, located in 15q26.1. About 70 different nonsense or frameshifts mutations leading to premature termination and missense mutations were detected in BS patients. The complex mutation corresponding to a 6bp deletion and a 7bp insertion at nucleotide 2207, known as the blm Ash mutation, is present in almost all BS patients of Ashkenazi Jewish ancestry, indicating a founder effect in this ethnic group.

Another 18 recurring mutations have been detected restricted to other populations and geographic areas, and 48 mutations are unique.

A recent report suggests an X-linked pattern of inheritance in a few male individuals, raising the possible BS locus heterogeneity.


The BLM protein is a cell-cycle-regulated RECQ helicase involved in the repair of double-strand breaks and homologous recombination, telomere stability and DNA replication, particularly in the repair of stalled replication forks. It acts through multiprotein complexes including the related RECQ2 (WRN) and RECQL4 helicases, the FANCJ gene product and the RAD51 recombinase, which has a central role in the process of homologous recombination.

The functional cooperation of BLM and RAD51 genes has been underlined by the finding that genetic variants of BLM interact with RAD51 to increase breast cancer susceptibility. The involvement of the BLM protein in many intersected DNA repair pathways accounts for the multisystem anomalies when the gene product is faulty or lacking. In addition, the chromosomal instability primed by the constitutive biallelic BLM mutations eventually results in cancer.

Systemic Implications and Complications

At infancy and childhood the prominent systemic implications are the feeding problems. Supplemental feeding by intubation does not improve linear growth but results in increased fat deposition. Growth hormone has not proven suitable to increase growth rate. Serious medical complications are the recurrent infections, especially otitis, and pneumonia, whose frequency does not seem related to the degree of immunodeficiency but more likely to the gastroesophageal reflux (GER); this is the reason why evaluation for GER and microaspirations into the lung of gastric content should be recommended.

The repeated infection bouts lead to chronic obstructive pulmonary disease and eventually pulmonary failure at an unusually early age. Other serious medical complications that are much more common than in the normal population and appear at a much earlier age are type II diabetes mellitus and cancer of a wide variety of types and anatomic sites. In the first decade the most common malignancies are Wilms and osteosarcoma; in the teens and twenties leukemia and lymphomas become more common and from the twenties onwards the risk of developing a carcinoma at any site is high. This lifelong increased risk of malignancy leads to a shortened life expectancy, and no patient with BS has yet been reported to have survived over the age of 50 owing to cancer and complications of the disease itself and to cancer treatments.

Treatment Options

BS patients are more likely to suffer a range of complications of all treatments due to immunodeficiency.

The treatment for diabetes follows the standard protocol.

Hypersensitivity to DNA-damaging chemical and ionizing radiation requires a modified cancer treatment protocol, reducing both dosage and duration. The treatment outcomes, however, are frequently unsatisfactory in these patients owing to severe reactions including fatal bone marrow suppression, interstitial pneumonia, hepatitis, mucositis leading to intestinal hemorrhage, and neurologic toxicity.

Despite the fact that patient numbers are too small for any prospective trial in individual cancers, cancer surveillance should be initiated at a young age, particularly for the common cancers such as carcinoma of the breast and colon.

Patient Management

Facial sun exposure should be avoided in infancy and early childhood.

Surveillance for cancer is a lifelong issue. Under the age of 20 years leukemia is the main type of cancer, while later solid tumors are more frequent, especially colon cancer for which screening should be carried out regularly. Counselling regarding risk of cancer should be extended to the families owing to a reported increased risk of colon and breast cancer in the carriers.

Prenatal diagnosis by molecular genetic testing and preimplantation genetic diagnosis (PGD) for at-risk pregnancies need prior identification of the BLM-causing mutations in the family.

Optimal Therapeutic Approach for this Disease

As regards photosensitivity, sun exposure should be avoided because BS patients have been found to exhibit a specific sensitivity in the UV-B range approaching the UV-A range. Both UV-A and UV-B minimal erythema dose thresholds have been demonstrated to be reduced in a few patients.

As Bloom syndrome patients show hypersensitivity to ionizing agents and chemotherapeutic substances, protocols for anticancer treatments should be reduced in dosage and duration to avoid serious complications from treatment itself.

Unusual Clinical Scenarios to Consider in Patient Management

Concurrent autoimmune diseases have been observed in BS patients and should thus be considered in patient management. Recently a BS patient has been described with the most striking features of lupus-like skin lesions reported to date. Whether or not cutaneous lupus erythematosus exists concurrently in selected patients or lupus-like morphology is a clinical expression of BS remains open.

Although diabetic retinopathy and hemorrhagic leukemic retinopathy occur in BS patients, their systemic association as well as early macular drusen delineate an unusual clinical scenario. Only single examples of a tracheoesophageal fistula, a cardiac malformation, absence/malformation of the thumbs, and absence of a toe have been reported in the Bloom registry.

What is the Evidence?

Sanz , MN, German , J. “Bloom's syndrome”. Gene reviews. (This is an electronic review signed and updated by the leading scientists in the field.)

German , J, Sanz , MM, Ciocci , S, Ye , TZ, Ellis , NA. “Syndrome-causing mutations of the BLM gene in persons in the Bloom's Syndrome Registry”. Human Mutation. vol. 8. 2007. pp. 743-75. (This overview provides a detailed description of the mutations reported in the RECQ DNA BLM helicase and a discussion over the ethnic origins of the recurrent mutations and the founder effect of a few mutations.)

Gruber , SB, Ellis , NA, Karen , K, Scott , RA, Kolachana , P, Bonner , JD. “BLM heterozygosity and the risk of colorectal cancer”. Science . vol. 297. 2002. pp. 2013(This report provides data on the relative risk of colorectal carcinoma in the Ashkenazi population carrying the BLMAsh allele.)

Amor-Gueret , M, Dubois-d’Enghien , C, Laugé , A, Onclercq-Delic , R, Barakat , A, Chadli, E. “Three new BLM gene mutations associated with Bloom syndrome”. Genet Test . vol. 12. 2008. pp. 257(The authors describe a new method for the BLM gene mutation scan based on direct genomic DNA sequencing. They report four mutations in the BLM-gene, three of which have never been described.)

Aslan , D, Ezgu , FS. “The gene of Bloom's syndrome: an autosomal recessive disorder with male dominance”. Gene Test Mol Biomarkers. vol. 13. 2009. pp. 443-4. (The authors raise the possibility that BS might also be transmitted as an X-linked disorder. This would explain why some males affected with BS do not show mutations in the BLM gene.)

Ding , S, Yu J-, C, Chen S-, T, Hsu G-, C, Kuo S-, J, Lin , YH. “Genetic variants of BLM interact with RAD51 to increase breast cancer susceptibility”. Carcinogenesis. vol. 30. 2009. pp. 43-9. (This paper suggests that the interaction between the BLM and RAD51 proteins is critical for breast cancer risk, based on specific BLM and RAD51 diplotypes.)

McGowan , J, Maize , J, Cook , J. “Lupus-like histopathology in Bloom syndrome: reexamining the clinical and histological complication of photosensitivity”. Am. J. Dermatopatholol. vol. 31. 2008. pp. 786-91. (A prototypic detailed clinical report of a 16-year-old man: the histologic and immunologic features of the photo-exposed skin lesions in this BS patient underline features that are indistinguishable from cutaneous lupus erythematosus.)

Thomas , ERA, Shanley , S, Walker , L, Eeles , R. “Surveillance and treatment of malignancy in Bloom syndrome”. Clin Oncol. vol. 2. 2008. pp. 375-9. (A very detailed case report of an Ashkenazi descent case with a practical discussion of the pitfalls and problems encountered in the cancer management of Bloom patients.)

“Bloom's Syndrome Registry contact information”.

Bhisitkul , RB, Rizen , M. “Bloom syndrome: multiple retinopathies in a chromosome breakage disorder”. Br J Ophthalmol. vol. 88. 2004. pp. 354-(Case report of a 39-year-old BS man with a variety of concurrent ocular abnormalities.)