Bloom syndrome (ORPHA:125)
Bloom syndrome is a rare disorder associated with pre- and postnatal growth deficiency, a telangiectatic erythematous rash of the face and other sun-exposed areas, insulin resistance and predisposition to early onset and recurrent cancer of multiple organ systems.
Epidemiology
Bloom syndrome (BSyn) overall prevalence is unknown, but in the Ashkenazi Jewish population it is estimated at approximately 1/ 48,000 births. A founder mutation, known as BLMash is present in approximately 1 in 100 persons of Ashkenazi Jewish background. There are also founder mutations in the Slavic and Hispanic populations.
Clinical description
Individuals with BSyn show proportionate growth deficiency of prenatal onset (average birth weight 1757 g) and continuing throughout life (average adult height of 149 cm for men and 138 cm for women). Dolichocephaly, narrow face, prominent nose and ears, and malar and mandibular hypoplasia can be observed. Subcutaneous adipose tissue is sparse. Telangiectatic erythema appears during the first 1-2 years of life on the face (in particular the cheek), dorsum of the hands and other sun-exposed areas. Café-au-lait macules and hypopigmented skin lesions are common. Children with BSyn characteristically feed slowly, have a decreased appetite and eat a limited variety of foods. Despite nutritional interventions, weight gain is modest and children are rarely in the normal range for growth. One major feature of Bsyn is a greatly increased predisposition to cancers in a distribution corresponding to the general population but occurring at a much younger age. Survivors of a first cancer may have multiple cancers in their lifetime. Most men with BSyn have azoospermia or severe oligospermia, while women are often fertile but may begin menopause prematurely.
Etiology
Bloom syndrome is inherited as an autosomal recessive trait. The BLM gene codes for a RecQ helicase that forms a complex with two other proteins, DNA topoisomerase IIIα and RMI.BLM heterozygotes are healthy and without any clinical features of the disorder.
Diagnostic methods
The diagnosis of BSyn is suspected clinically by identification of characteristic features and is confirmed by identification of biallelic pathogenic variants of the BLM gene on molecular genetic testing.
Differential diagnosis
The differential diagnosis of Bloom syndrome includes Fanconi anemia, Silver-Russell syndrome, Rothmund-Thomson syndrome, ataxia-telangiectasia, and Nijmegen breakage syndrome. Three other disorders also may be of interest in a differential diagnosis. RECQ-mediated genome instability 1, RECQ-mediated genome instability 2, Microcephaly, growth restriction, & increased sister-chromatid exchange 2.
Antenatal diagnosis
Prenatal diagnosis of at-risk pregnancies is possible by cytogenetic (SCE) or molecular genetic testing (BLM sequencing and deletion/duplication) of fetal cells obtained by amniocentesis or chorionic villus sampling. Molecular genetic testing is preferred.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Management is symptomatic. Increased calorie density formulas and foods may promote weight gain and increased growth. Although growth hormone treatment may improve linear growth, many clinicians caution against its use because of reports of early onset of cancer in some treated children. Standard antibiotic regimens are used to treat infections. If the serum levels of immunoglobulins are low and the patient is experiencing repeated infections, some have been treated with intravenous or subcutaneous immunoglobulins. Skin protection, including covering exposed skin and use of a broad-spectrum sunscreen with at least 30 SPF is crucial to reduce the sun-sensitive skin rash. Health supervision recommendations for persons with Bloom syndrome have been published, including recommendations for cancer surveillance. Due to hypersensitivity of patients to chemotherapy, reduced dosage and/or duration of therapy is recommended, usually beginning with 50% of the weight-based dosage. Caution should be exercised with use of ionizing radiation or alkylating agents, particularly busulfan, cyclophosphamide or melphalan.
Prognosis
The high occurrence of cancer reduces life expectancy. The median overall life expectancy is approximately 30 years, with cancer and related complications as the leading cause of death.

                            Last update: 
                            June 2019


                            - Expert reviewer(s): 
                            Dr Christopher CUNNIFF  -  Maeve FLANAGAN