Handbook of Genetic Counseling/Bloom Syndrome-1

Bloom Syndrome

Genetics

• Mutation of BLM gene at chromosome 15q26.1
• Common Ashkenazi Jewish mutation- blmASH (2281del6ins7)
• Abnormalities in DNA repair and chromosomal structure
  • increased chromosome breakage
  • increased rate of homologous chromosome exchange
  • formation of quadriradial (QR) configuration in mitosis
  • increased rate of sister chromatid exchanges (SCEs)
  • unique to Bloom Syndrome

Incidence

• Ashkenazi Jewish population
• Carrier frequency 1 in 107
• Incidence 1/160,000
• Very rare in Non-Ashkenazi Jewish populations

Diagnosis

• Characteristic clinical features
• Demonstration of symmetric QR interchange configuration and increased number

of SCEs

• Demonstration of mutations in both BLM genes

Clinical Features

• Predominant features
  • Small body size
    • Mean birth weight 1906 g in males and 1810 g in females
    • Mean adult height 147.5 cm in males and 138.6 cm in females
  • Predisposition to cancer- of all cell types and at all sites
• Additional features which may or may not be present
  • Characteristic facies- keel-shaped face, dolicocephaly, narrow cranium, malar hypoplasia, nasal prominence, small mandible, and prominent ears.
  • Hypersensitivity to sunlight- formation of sun-sensitive erythema (telangiectasia) on face and possible hands/forearms
  • Areas of hyper- and hypo- pigmented skin- café-au-lait spots
  • High-pitched and somewhat squeaky voice
  • Vomiting and diarrhea during infancy
  • Diabetes mellitus- generally with onset in the second or third decade
  • Failure of spermatogenesis in males
  • Early cessation of menstruation and reduced fertility in females
  • General immunodeficiency- often associated with ottitis media and pneumonia
  • Slightly increased incidence of minor anatomic anomalies including anomalous digits, pilonidal dimples, wedges of altered color of the irides, and obstructing anomalies of the urethra
  • Restricted intellectual ability- generally average to low-average intelligence but can be more severe

Natural History

• Intrauterine Growth Deficiency
• full-term infants tend to have low birth weight
• Onset of facial skin lesion usually in first or second summer, can be later
• Cancer predisposition throughout life- always higher than age-associated risk
• Mean age of cancer diagnosis 24.7 (range of 2 to 48 years)
• Mean age of death is 23.6 years (range from <1 to 49)
• Cancer is the most common cause of death

Inheritance

• Autosomal Recessive

Testing

• Cytogenetic analysis
• Increased in number or chromatid gaps, breaks, and interchanges
• Increase in the number of sister-chromatid exchanges (SCEs)
• Can be performed on any cell which can be brought into mitosis
• Molecular Genetic Analysis
• Clinical testing for common Ashkenazi Jewish mutation- blmASH
• 98% detection for Ashkenazi Jewish Bloom syndrome patients
• Research testing - full gene screening for affected individuals
• Memorial Sloan-Kettering Cancer Center
• Prenatal diagnosis
• Sister chromatid exchange assay via amnio or CVS
• Amnio or CVS for known familial mutation

Management & Treatment

• No treatment for growth deficiency
• Protection from the sun decreases severity of skin lesion
• Careful monitoring for cancer
• Cancer treatment must consider hypersensitivity to DNA-damaging chemicals

Differential Diagnosis

• Other syndromes associated with sun sensitivity and telangiectasias:
• Erythropoietic protoporphyria
• Rothmund-Thomson syndrome
• Cockayne syndomre
• Hereditary hemorrhagic telangiectasia
• Ataxia telangiectasia

Psychosocial Issues

• Physical appearance may affect self-image, confidence
• Reduced life expectancy
• High probability of malignancy

Patient Resources

• Bloom's Syndrome Registry

NY Blood Center

310 East 67th Street

New York, NY 10021

Phone: (212) 570-3075

• National Foundation for Jewish Genetic Diseases, Inc. (NFJGD)

250 Park Ave, Suite 1000

New York, NY 10177

Phone: (212) 371-1030

Web

• Xeroderma Pigmentosum Society, Inc.

Box 4759

Poughkeepsie, NY 12602

Phone: (518) 851-2612

Web

E-mail: xps@xps.org

Case Specifics

• See attached

References

• Byarlay, J. and Goldsmith, L. (1997) Other Genetic Disorders of the Skin. In Rimoin, D, Connor, J, and Pueritz, R ed. Principles and Practice of Medical Genetics. Churchill Livingstone: New York. 1309-1310.
• German, J. and Ellis, N. (2001). Bloom Syndrome. In Scriver, C., Beaudet, A., Sly, W., and Velle, D. ed. Metabolic and Molecular Bases of Inherited Disease. McGraw Hill: New York. 733-751.
• Goodman, R. (1979) Genetic Disorders among the Jewish People. Johns Hopkins

University Press: Baltimore. 73-79.

Notes

The information in this outline was last updated in March 2003.