Bloom Syndrome

Bloom syndrome is a rare autosomal recessive chromosomal instability disorder caused by biallelic BLM variants, with proportionate short stature, sun sensitive facial erythema, immunodeficiency and a very high risk of cancer at young ages. The founder variant blmAsh is frequent in people of Ashkenazi Jewish descent.

Pathophysiology. BLM encodes a RecQ helicase that stabilises DNA replication and resolves recombination intermediates. Its loss causes a marked increase in sister chromatid exchange and chromosomal breakage, and cancer from many tissues.

Intrauterine growth restriction is the rule, and postnatal growth remains slow.

Cancer is the leading cause of death, with leukaemia, lymphoma and epithelial cancers appearing at younger ages than in the general population.

• Intrauterine growth restriction and proportionate short stature
• Sun sensitive telangiectatic erythema of the cheeks, nose and dorsal hands, in a butterfly distribution
• Narrow face, prominent nose, malar hypoplasia
• Recurrent respiratory and ear infections with low immunoglobulins
• Cancers: leukaemia, lymphoma, and carcinomas of the breast, colon, skin and others, at young ages
• Type 2 diabetes mellitus and insulin resistance in young adults
• Subfertility, with azoospermia in men and premature menopause in women
• Café-au-lait macules, hypo- and hyperpigmented areas
• Mild learning difficulties in some

• Cytogenetic testing: greatly increased sister chromatid exchange (often over 50 in each metaphase) on cultured blood lymphocytes, with quadriradial chromosomes.
• Genetic testing of BLM with deletion and duplication analysis, and targeted testing for the blmAsh variant in at risk populations.
• Immunological assessment: immunoglobulins, vaccine responses and lymphocyte subsets.
• Metabolic screening: fasting glucose or glucose tolerance test, and HbA1c.
• Carrier testing of relatives and prenatal diagnosis options.

Differential diagnosis.

• Rothmund-Thomson syndrome
• Systemic lupus erythematosus (facial rash)
• Silver-Russell syndrome and other causes of growth restriction
• Fanconi anaemia and Nijmegen breakage syndrome
• Ataxia telangiectasia
• Xeroderma pigmentosum and other photosensitivity disorders

• Sun protection: sun protection factor 50 or more, protective clothing, avoidance of midday sun. This reduces facial erythema and skin damage.
• Radiation avoidance: minimise diagnostic X-ray and CT exposure, use MRI or ultrasound, and avoid radiotherapy where alternatives exist.
• Immunodeficiency: immunoglobulin replacement 0.4 to 0.6 g/kg intravenously every 3 to 4 weeks (or subcutaneous weekly equivalent) in patients with hypogammaglobulinaemia and recurrent infection. Treat infections promptly.
• Cancer surveillance: whole body MRI yearly from childhood, colonoscopy every 1 to 2 years from about 10 years of age (adults every year), breast MRI yearly from 25 years, and full blood count with clinical review every 3 to 6 months.
• Cancer treatment: use reduced doses of chemotherapy (particularly alkylating agents, anthracyclines and topoisomerase inhibitors) because of toxicity and secondary cancer risk, and avoid radiotherapy if possible.
• Diabetes: yearly glucose tolerance test or HbA1c from 10 years. Treat with metformin 500 mg once daily increased to 1000 mg twice daily (maximum 2000 mg daily), reducing the dose at eGFR under 45 mL/min.
• Growth: growth hormone does not correct the short stature and carries cancer concerns, so it is not used routinely.
• Fertility and endocrine: fertility preservation counselling, hormone replacement for ovarian insufficiency, and testosterone assessment.
• Genetic counselling: each sibling has a 25% chance of being affected.

Special groups.

• Pregnancy: women have reduced fertility, and there is a high risk of foetal growth restriction and complications; plan specialist obstetric care.

Monitoring. Clinical review every 3 to 6 months, with a full cancer surveillance plan, annual glucose testing, and immunoglobulin levels yearly.

Referral and escalation. Refer to clinical genetics, haematology oncology and immunology. Urgent for persistent fever, new lumps, bleeding, weight loss or bone pain.