Bloom Syndrome

Epidemiology and Etiology:

· Rare (100 living cases)

· Ashkenazic Jews often

· Autosomal recessive

· BLM mutations

· Protein product is a recQ DNA helicase

· Monitors DNA integrity during S phase

· involved in unwinding DNA during replication

· Other mutations

Common sites:

·

Gross features:

· Growth retardation

· Low-birthweight

· Continues post-natally

· Erythematous rash

· Cheeks

· Bridge of nose

· Exacerbated by sunlight

· Appears during infancy

· Hyper- and hypopigmentation (spotty)

· Distinctive facies

· Long and thin

· Clinodactyly common

· Polydactyly maybe

· Syndactyly maybe

Histologic features:

·

Immunophenotype:

Marker:

Sensitivity:

Specificity:

Molecular features:

· Gene mutation at 15q26.1

· Other mutations

· Workup:

· Analyze 20 metaphases for SCE frequency

· If negative, analyze 50 solid-stained mets for chromosome breaks and rearrangements

· Analyze 5 G-banded mets for a constitutional karyotype

· Cytogenetic characteristics

· Spontaneous sister chromatid exchange

· Secondary to replication defect

· Majority occur in second cell cycle in culture

· Normal cells have same SCE rate for first and second cell cycle

· Measurement of these events is most rapid and reliable test for Bloom

· BrdU incorporation into cultured cells over 2 complete cycles

· Bloom patients will have SCE frequency of 60-100 per cell (normal < 10)

· Analyze 20 mets for SCE frequency

· Note that a minor population of cells with normal SCE level may be found

· (spontaneous correction of mutation by SCE)

· Post-second metaphase cells show distinctive small patches of dark staining on otherwise pale chromatids

· Note that Bloom positive cases will show slow growth rate

· Duplicate cultures are advised

· Spontaneous aberrations

· Isochromatid breaks

· Transverse breakage at the centromere

· Distinctive symmetrical quadriradial chromatid interchanges

· As many as 5% of cells

· If SCE frequency is negative (see above):

· Analyze 50 solid-stained mets for chromosome breaks and rearrangements

· Hypersensitivity to ethylating agents

· Ethyl methane sulphonate -> increased SCEs

Other features:

· Severe immune deficiency

· Particularly IgA and IgM

· Malignancies predisposition

· Acute leukemia particularly

· Wilms

· Carcinomas

· Many do not survive into adulthood

References:

· Rooney D. Human Cytogenetics: Malignancy and Acquired Abnormalities: A Practical Approach. 3rd ed. Oxford University Press; 2001.

· Gardner RJM, Sutherland GR. Chromosome abnormalities and genetic counseling. Oxford University Press; 2004.

· CCMG Cytogenetic Practice Guidelines, 2003