Definition

Bloom syndrome (OMIM #210900) is a rare hereditary disease associated with increased chromosome breakage. The number of spontaneous mutations is elevated, thereby explaining the increased cancer risk. The most distinctive symptom is significant growth restriction.

Key Data

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Synonyms BS, BSyn
Gene BLM
Gene product BLM DNA RecQ 3′-5′ helicase
Function Part of the RECQ helicases that unwind the DNA double helix. BLM maintains genomic stability during the process of DNA replication by limiting sister chromatin exchange (SCE).
Heredity Autosomal recessive
Prevalence Unknown
1:48.000 in Ashkenazi Jews; 0.5% heterozygosity for the blmAsh mutation
Genotype-phenotype correlation Homozygous and compound heterozygous carriers of one of the 60 pathogenic variants of the BLM gene exhibit a similar phenotype.
Penetrance Unknown
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Diagnosis

Indicative Findings

  • Unexplained severe intrauterine growth restriction that persists throughout infancy and childhood until adolescence.

  • Significant growth deficit and erythematous skin changes in the face after exposure to sunlight (butterfly rash)

  • Significant growth deficit and tumor diagnosis

Confirming the Diagnosis

The diagnosis of “Bloom syndrome” is confirmed by molecular genetic evidence of a biallelic/homozygous pathogenic variant of the BLM gene and/or, if the molecular genetics are inconclusive, by the identification of an increased frequency of sister chromatid exchanges (SCE) by specific cytogenetic studies.

  • Single-gene testing
    In individuals of Ashkenazi-Jewish descent, it is helpful to start with a specific analysis of the most frequent pathogenic variant: c.2207_2212delinsTAGATTC (blmAsh) (97% of all pathogenic variants are blmAsh).

  • Multiple-gene panel

  • Exome/genome/mitochondrial sequencing

Differential Diagnoses

  • Russell-Silver syndrome

  • Fanconi anemia

  • Ataxia telangiectasia

  • Ataxia telangiectasia-like syndrome

  • Werner syndrome

  • Nijmegen breakage syndrome

Clinical Presentation

Clinical Presentation

  • Prenatal and postnatal growth restriction

  • Reduction of subcutaneous fatty tissue

  • Dwarfism

  • Hypersensitivity to sunlight, tendency towards facial erythema

  • Immunodeficiency

  • Gastroesophageal reflux

  • Recurring infections, especially in the upper airways

  • Learning disorders / low intelligence (not universal)

  • Premature ovarian insufficiency in women

  • Reduced fertility / infertility in men

  • Urinary tract obstruction in men

  • Insulin resistance (type II diabetes mellitus)

  • Chronically obstructive airway diseases

Predisposition to Cancer (Entities):

  • ALL

  • AML

  • Lymphomas

  • Gastrointestinal tumors (colorectal carcinomas)

  • Germ cell tumors

  • Genital tumors

  • Tumors of the urinary tract

  • Sarcomas

  • Mammary carcinoma

  • Nephroblastomas

  • Medulloblastomas

  • Retinoblastomas

Multiple tumors develop with the same distribution pattern as in the healthy population but with an earlier onset.

Therapeutic Considerations

  • Avoid exposing face to sunlight

  • MRI and ultrasound preferred for diagnosis over X-ray and CT

  • Hypersensitivity to ionizing radiation and DNA-damaging cytostatics also requires a reduction in doses or a shortening of the duration of therapy.

Surveillance Recommendations

Surveillance Recommendations

Evidence-based standards are lacking for early detection, particularly during childhood. The AACR consensus recommendations are listed below.

  • Hematology-oncology:

    • Medical history and clinical examination
    • Avoid exposure to radiation
    • Blood count every 3-4 months
    • Breast MRI and ultrasound as of age 18
    • Annual colonoscopy as of age 10-12
    • Stool test every 6 months
    • Renal ultrasound every 3 months after diagnosis until age 8 (screening for nephroblastoma)
    • HPV vaccination

  • Dermatology:

    • Annual skin examination
    • Limit exposure to sunlight!

  • Pulmonology:

    • Pulmonary function testing according to clinical need
    • Aggressive antibiotic treatment after an antibiogram

  • Gastroenterology/Nutrition:

    • Basic examination
    • Swallowing tests as needed
    • Dietary supplementation

  • Endocrinology:

    • Annual TSH, T3, T4
    • Annual glucose test on an empty stomach and a lipid profile from 10 years of age

  • Orthopedics:

    • Annual scoliosis examination

  • Dental:

    • Six-monthly checkups