Bloom syndrome, also called Bloom-Torre-Machacek syndrome or congenital telangiectatic erythema (MIM 210900), is a rare autosomal recessive inherited disorder characterized by genomic instability and predisposition to the development all types of cancer. Bloom syndrome is due to mutations in the BLM gene inducing the formation of an abnormal DNA helicase protein. The most prominent features include growth deficiency of prenatal onset, mild immunodeficiency, excessive photosensitivity with facial lupus-like skin lesions, type 2 diabetes mellitus and hypogonadism. The increased risk of malignancy in Bloom syndrome leads to a shortened life expectancy and alters the quality of life of affected persons.
Bloom syndrome is a rare genodermatosis inherited in the autosomal recessive mode. It is due to mutations in the BLM or RECQL3 gene located on chromosome 15 (15q26.1). The parents of a patient with Bloom syndrome may be asymptomatic. The BLM gene encodes a BLM helicase which forms a complex with two other proteins, DNA topoisomerase IIIα and RMI. DNA helicases are involved in the replication and repair of DNA. Thus, the mutation in BLM gene generates errors during the DNA replication process and leads to more numerous chromosomal rearrangements and breakages. Individuals with Bloom syndrome are at high risk of cancer due to the genomic instability. A person with Bloom syndrome might develop up to five independent primary cancers.
Bloom syndrome is an extremely uncommon disorder in most populations, although its frequency has not been precisely measured. It has been most commonly described in the Ashkenazi Jewish population who account for about one-third of affected individuals worldwide (approximately 1% of Ashkenazi Jews are carriers of the BLMAsh mutation). About 170 cases have been reported in the United States of America. Males are four-fold more affected by Bloom syndrome than females.
Mutations in the BLM or RECQL3 gene located on chromosome 15 which encodes a DNA helicase in the RecQ family cause Bloom syndrome. The RecQ family is highly conserved and plays crucial roles as genome caretakers. In humans, mutations in three RecQ genes BLM, RECQL4, and WRN, are responsible for Bloom syndrome, Rothmund-Thomson syndrome, and Werner syndrome, respectively. The protein product of BLM is important in maintaining the stability of the DNA during the replication process. It is involved in the detection, transmission, and resolution of damaged DNA. The lack of BLM protein may cause a change in the divergent epigenetic and genetic anomalies that induce tumor formation.
Persons with Bloom syndrome are characterized by severe prenatal and postnatal growth retardation characterized by proportionate small stature with microcephaly, a characteristic facial morphology including a long, narrow face; a small lower jaw; and prominent nose and ears. A high-pitched voice is also frequently noticed in Bloom syndrome.
They can also present mild immunodeficiency leading to recurrent infections affecting the ears, trachea, bronchi, and lungs during infancy, chronic obstructive pulmonary disease, increased reflux, with vomiting, and diarrhea, type 2 diabetes mellitus, and hypogonadism with azoospermia and infertility in males, and sub-fertility in females.
Cutaneous features include photosensitive erythema on the face in a butterfly distribution over the cheeks similar clinically and histologically to the rash seen in systemic lupus erythematosus. Telangiectasia and poikiloderma occur early in the first or second year of life in response to sun exposure. Similar skin lesions can also present on other areas typically exposed to the sun, such as the forearms and the back of the hands. Also, small clusters of telangiectases often appear in the rash; telangiectases can also affect the eyes. Other skin features include mouth fissures, as well as café-au-lait spots and areas of hypopigmentation which appear on parts of the skin not exposed to the sun, and their development is not in relation with the rashes.
Unlike the Rothmund-Thomson syndrome and Werner syndrome, in which there are cataracts and hair abnormalities, there are no abnormalities of the eyes or hair in Bloom syndrome. There are also no major skeletal or anatomic abnormalities in Bloom syndrome.
Bloom syndrome patients suffer from almost all the major types of cancer, which are characterized by three facts: (1) for each cancer type, tumor development occurs on average at an earlier age than normal, (2) possible occurrence of multiple independent primary cancers, and (3) the types and localization of cancer is very broad. Thus, the mean age of cancer diagnosis is 24 years, and death occurs before 30 years of age. Up to 50% of Bloom syndrome patients will develop cancer, 15% of which are leukemias, 15% lymphomas that occur 150 to 300 times more frequently than in normal individuals. Leukemias may be myeloid or lymphoid malignancies. The median age for leukemia and lymphoma diagnoses is 20 years. Furthermore, 10% of patients will develop a second malignancy. Thus, many types of cancer have been described in Bloom syndromes, such as carcinomas of the respiratory tract, gastrointestinal tract, especially colorectal cancer, breast, liver, skin, connective tissue sarcoma; retinoblastoma and brain tumor. Skin cancers, mainly basal cell carcinoma and squamous cell carcinoma, are also common.
If suspected clinically, the diagnosis of Bloom syndrome should be established by the DNA sequencing which identifies biallelic pathogenic variants in BLM on molecular genetic testing. If the latter is not contributive, specialized cytogenetic studies may highlight an increased frequency of sister chromatid exchange. Genetic and prenatal testing is recommended for high-risk carrier populations.
A multidisciplinary approach is required to manage patients with Bloom syndrome. Supplemental feeding does not in improve linear growth. Growth hormone administration to children with Bloom syndrome seems ineffective to increase growth rate or adult height. Furthermore, it may increase the risk to develop tumors. Antibiotic prophylaxis and therapy may control the infections. The treatments used in general population also manage diabetes mellitus. Dermatologic recommendations include frequent skin screenings and avoidance of sun exposure.
For the treatment of cancers, the hypersensitivity of cells to both DNA-damaging chemicals and ionizing radiation requires reduction of both dosages and durations to avoid serious complications.
A close oncologic following to diagnose early signs of neoplasm is imperative. The tools and the rhythm of supervision are not, however, well codified. Unexplained symptoms may indicate a malignancy, and appropriate investigations should be achieved. Screening for colon and breast cancer earlier and more frequently than in general population is also advised.