Bloom syndrome
Bloom-Torre-Machacek syndrome (older); congenital telangiectatic erythema and stunted growth
Bloom syndrome is a rare autosomal recessive chromosome-instability syndrome caused by biallelic loss-of-function mutations of the BLM gene on chromosome 15q26.1, which encodes the BLM (RecQL3) helicase essential for homologous-recombination DNA repair and stalled replication-fork resolution. The cardinal features are severe prenatal-onset proportionate growth retardation, a strikingly characteristic photosensitive facial "butterfly" telangiectatic erythema developing in infancy, immunodeficiency, type 2 diabetes, infertility (men) / subfertility (women) and a markedly elevated lifetime risk of essentially all common cancers (cumulative risk >80%) at unusually young ages — particularly leukaemia and lymphoma in childhood, and carcinomas of the head/neck, breast, gastrointestinal tract, urological and gynaecological organs in adulthood. The disease is over-represented in Ashkenazi Jewish populations (BLM Ash founder mutation). The diagnostic hallmark is markedly elevated sister chromatid exchange (SCE) on cytogenetic analysis. The dermatologist often recognises the photosensitive facial erythema and growth phenotype, prompting referral to clinical genetics.
Genetics
- Biallelic loss-of-function mutations of BLM on chromosome 15q26.1 — encodes the BLM (RecQL3) helicase, a member of the RecQ helicase family essential for homologous-recombination DNA repair, dissolution of double Holliday junctions and resolution of stalled replication forks.
- Autosomal recessive.
- Founder mutation BLMAsh (c.2207_2212delinsTAGATTC) in ~1 in 100 Ashkenazi Jews; targeted preconception carrier screening available.
- Diagnosis confirmed by markedly elevated sister chromatid exchange (SCE) frequency on cytogenetic analysis of cultured lymphocytes (10× higher than control) — the historical gold standard, now supplemented by germline BLM sequencing.
Clinical features
- Growth — severe proportionate prenatal-onset growth retardation; affected adults typically <150 cm in height; weight proportionate.
- Cutaneous:
- Photosensitive facial telangiectatic erythema in a "butterfly" malar / bridge-of-nose distribution, developing in the first 1–2 years of life and triggered by sun exposure; lupus-like.
- Café-au-lait macules and hypopigmented patches.
- Photo-distributed bullae and crusting in some.
- Head and face — narrow face with prominent nose and ears; high-pitched voice; dolichocephaly.
- Endocrine — impaired glucose tolerance / type 2 diabetes; growth hormone deficiency in some.
- Reproductive — male infertility (azoospermia); female subfertility with early menopause.
- Immunological — combined humoral / cellular immunodeficiency; recurrent respiratory and ear infections; chronic lung disease.
- Cancer — see next section.
- Other — gastrointestinal (chronic diarrhoea), pulmonary, mild intellectual impairment.
Cancer risk
- Cumulative cancer risk >80% by age 50; many patients develop multiple primaries.
- Median age at first cancer ~26; substantially younger than the general population.
- Childhood and adolescence:
- Acute lymphoblastic leukaemia (ALL).
- Acute myeloid leukaemia (AML).
- Lymphoma (Hodgkin and non-Hodgkin).
- Adulthood:
- Squamous cell carcinoma of the head and neck (oral cavity, pharynx, larynx, oesophagus).
- Cutaneous squamous cell carcinoma — particularly on photo-exposed skin.
- Cutaneous and other basal cell carcinoma.
- Breast carcinoma.
- Colorectal carcinoma.
- Genitourinary carcinoma (bladder, kidney, cervix).
- Lung carcinoma.
- Cancer mortality is the leading cause of death in Bloom syndrome.
Surveillance
- Multidisciplinary care — paediatric / adult haematology, oncology, dermatology, ENT / oral medicine, gynaecology, endocrinology, immunology, clinical genetics; lifelong.
- Skin — annual full skin examination; lifelong photoprotection (broad-spectrum SPF 50+, sun-protective clothing).
- Oral cavity — annual ENT / oral medicine assessment from adolescence; biopsy any white / red lesion.
- Breast — annual mammography / MRI from age 25 in women.
- Colorectum — colonoscopy from age 25, more frequent if symptoms.
- GU — annual urinalysis; cervical screening up to date.
- Haematology — annual FBC; peripheral blood film if symptomatic.
- Diabetes — annual screening for type 2 diabetes from adolescence.
- Immunology — immunoglobulins, vaccination history; consider IVIg if recurrent infections.
Management of cancers
- Markedly enhanced normal-tissue radiosensitivity and chemotherapy toxicity due to defective DNA repair — radiotherapy and DNA-damaging chemotherapy agents (especially alkylating agents) must be used cautiously, with reduced doses, increased surveillance for second malignancies, and specialist input.
- Surgical resection is the cornerstone for solid tumours.
- Anti-PD-1 immunotherapy (cemiplimab, pembrolizumab) — emerging option for advanced cSCC / head-and-neck SCC.
- Allogeneic transplantation for haematological malignancy is associated with substantial conditioning toxicity in Bloom syndrome — reduced-intensity protocols.
- Genetic counselling and cascade testing of relatives.
References
- Cunniff C et al. Bloom's syndrome — clinical spectrum, molecular pathogenesis and cancer predisposition. Mol Syndromol; 2017.
- de Voer RM et al. Germline mutations in the spindle assembly checkpoint genes BUB1 and BUB3 are risk factors for colorectal cancer. Gastroenterology; 2013 (related context).
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