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.