What is Bloom syndrome?

Risk Factors

BS is rare, with only several hundred confirmed cases, but it is least rare among the Ashkenazi Jewish population. According to the Center for Jewish Genetics (2014), in this population, approximately 1 percent are carriers of BS. The US National Library of Medicine reports that roughly one out of three people with the disease have one or both parents of Ashkenazi Jewish descent.

Etiology and Genetics

BS was first described by David Bloom in 1954 and belongs to a class of human diseases called the chromosome breakage syndromes. A person affected with BS carries two mutant BLM genes, one inherited from each parent. When both parents carry the mutant BLM gene, there is a 25 percent chance for each pregnancy that the offspring will have BS. The BLM gene is on chromosome 15 and has been traced to band q26.1. The normal BLM gene encodes a protein belonging to the RecQ DNA helicase family. DNA helicases are enzymes that unwind the two complementary spiral strands comprising a DNA molecule. These enzymes are crucial for unwinding before DNA can be replicated in cell division. However, BLM gene mutations lead to changes in helicase enzyme activity, affecting the unwinding and copying of DNA as it is replicated.

During normal replication, each chromosome—made up of tightly coiled DNA as well as proteins—makes two identical DNA structures, called sister chromatids. Sister chromatids normally exchange some small sections of DNA during replication in a process called sister chromatid exchange (SCE). When the BLM gene is mutated, more errors occur during replication. In BS, there is an increased level of spontaneous SCEs—as many as ten times the amount of SCEs seen in normal cells. In addition to excessive amounts of SCEs, increased breaks and rearrangements between nonhomologous chromosomes (chromosomes that are not of the same pair) are also observed. This chromosome instability and hyperrecombination is thought to contribute to the increased risk of cancer and other features of BS, although the mechanisms linking chromosomes and cancer are not fully understood.

According to the US National Library of Medicine, more than seventy BS-causing mutations in the BLM gene have been identified. However, one particular mutation causes almost all cases of BS among those of Ashkenazi Jewish descent. This founder deletion/insertion mutation, referred to as blm

Ash
, has reached a carrier frequency of roughly 1 percent in the Ashkenazi Jewish population.

Symptoms

BS is physically characterized by proportional, but unusually small prenatal and postnatal size (although the brain and head are disproportionately small) and sun-sensitive skin lesions that are limited to the face and the back of the hands and forearms. The other most important clinical characteristic, which is not physically observable, is a striking predisposition to cancer. Tumors can be benign or malignant. They may arise at an early age, and with great frequency in a large variety of body locations and cell types. Leukemias, lymphomas, and carcinomas are particularly common. Individuals with BS also usually experience decreased fertility (males are infertile), increased predisposition to multiple infections because of a compromised immune system, and sometimes diabetes.

Screening and Diagnosis

Diagnosis can be presumed based on clinical features associated with BS and is confirmed or ruled out by chromosome analysis. Cells from patients will show a significant (up to tenfold) increase in SCEs compared with cells from normal individuals, as well as increased chromosome breakage and rearrangements, and increased presence of chromosome structures called quadriradicals.

The identification of the BLM gene and the specific BLM gene mutation responsible for BS in Ashkenazi Jews have made carrier testing possible for this population. Prenatal diagnosis of BS is also available for couples who carry BLM gene mutations that have already been identified.

Treatment and Therapy

There is no direct effective treatment for BS. Mutations will continue to arise in excess, but the life span of affected individuals may be maximized by early diagnosis and systematic management. Avoiding the sun (especially in infancy and youth), treating bacterial infections promptly, treating diabetes if it arises, and avoiding environmental exposures or therapies that may further damage chromosomes (such as X rays) are all measures that may increase life span and improve the quality of life of affected individuals. Most important, those with BS should be in close communication with an experienced physician, who can develop a cancer surveillance program.

Prevention and Outcomes

There is no effective means of prevention for BS. Genetic counseling should be available for parents of an affected child, and prenatal screening is an option for parents who are carriers. The Bloom's Syndrome Registry comprises the files of 265 people with BS and shows cancer as the most common cause of death. Within the registry, data from 2009 show that the mean age at death was 26 years, with a range of less than 1 to 49.

Bibliography

"Bloom Syndrome." Genetics Home Reference. National Institutes of Health, 21 July 2014. Web. 28 July 2014.

"Bloom's Syndrome." Center for Jewish Genetics. Center for Jewish Genetics, 2014. Web. 28 July 2014.

"Data from the Bloom's Syndrome Registry." Bloom's Syndrome Registry. Weill Cornell Medical College, 2009. Web. 29 July 2014.

Klug, William S., Michael R. Cummings, Charlotte Spencer, and Michael A. Palladino. Concepts of Genetics. 10th ed. San Francisco: Benjamin Cummings, 2012. Print..

Parker, Philip M. Bloom Syndrome: A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers. San Diego: ICON Group International, 2007. Print.

Victor Center. "Ashkenazi Jewish Genetic Diseases." Jewish Virtual Library. American-Israeli Cooperative Enterprise, 2014. Web. 31 July 2014.