A descriptive summary prepared by the Bloom’s Syndrome Registry for registered persons and their families.
Bloom’s syndrome (BS) is a rare disorder the two main features of which are the following:
(i) Unusually small size, both before and after birth. During infancy and early childhood, fat tissue is exceptionally sparse, an unusual and unexplained lack of interest in feeding doubtless contributing to this. Body proportions are approximately normal as is muscular development, often giving the affected child unusual agility and grace. When grown, men with BS are taller than women, occasionally reaching slightly over 5 feet.
(ii) A sun-sensitive, red, skin lesion affecting the face almost exclusively. It varies in severity from mild to severe. Sometimes the backs of the hands and forearms are affected mildly.
Although the general health is good, persons with BS are more likely than others to develop the following:
(i) Infections of the middle ear and lung (pneumonia), the latter sometimes progressing to bronchiectasis and chronic lung disease.
(ii) Diabetes, that in many respects resembles the standard adult-onset type but appearing earlier in life in BS than in the general population.
(iii) Neoplasms (tumors), both benign and malignant, of the standard types and sites that affect other people but in BS arising unusually early in life.
Regarding reproductive ability, puberty is at the usual age, and sexual interests and activity are normal. Several women with BS have had children, all normal. The menopause is unusually early. All men appropriately tested have been infertile.
Although mental deficiency is not a regular feature of BS, some affected persons have been retarded. Many have exhibited a poorly defined restriction on learning and the development of outside interests. However, most affected persons do obtain reasonably good educations, develop friendships, and integrate well in society. A few have excelled in school and obtained higher degrees.
BS is a genetic trait. The affected person has inherited from each of his/her parents a mutation in the Bloom’s syndrome gene, i.e., he/she has two mutant BS genes, no normal. The BS gene is named BLM. (Note. The designations for human genes are printed in italics, e.g., BLM, the proteins which they encode in roman typeface, e.g. BLM, which is the BS protein.) Persons who carry a mutated BLM in single “dose” – who in genetic terms are heterozygotes -- are healthy and of normal height. Once a couple has had a child with BS, thereby demonstrating that each partner is heterozygous for a mutated BLM, the risk of BS for each pregnancy is 1 in 4 (25%). Prenatal diagnosis is possible.
More than 60 different BS-causing mutations of BLM have been detected. They obviously have arisen at various times in the distant past and been transmitted through perfectly healthy people for untold numbers of generations. The great rarity of the syndrome itself is because very few people carry a mutation of BLM. In the Ashkenazi Jewish population, one particular BS-causing mutation, referred to as blmAsh, did reach a relatively high frequency because of the unusual population structure of Eastern European Jewry. Today approximately 1% of Ashkenazi persons carries blmAsh, which explains why BS is relatively less rare in that group than in any other identified so far.
What is known about BLM, the normal BS protein? It has DNA helicase activity; i.e., the ability to unwind – to “open up” -- the double helical structure of DNA. However, a large number of DNA helicases exist in human cells, and in exactly which DNA transaction(s) BLM is active remains the subject of investigation in several basic research laboratories. Nevertheless, it is obvious that this evolutionarily highly conserved protein plays a very important role in maintaining the stability of the genetic material itself, i.e., of the DNA, of preserving the fidelity of the genome; when a cell lacks BLM’s function (the situation in every cell of the person with BS), many more mutations arise than in other people. In the cells of persons with BS the chromosomes can be seen to break and rearrange more often than in cells of others; such microscopically visible chromosome mutations are of particular importance in relation to BS’s cancer proneness.
What is known about how/why the lack of a normal BLM results in clinical “Bloom’s syndrome”?
(i) The explanation is not yet known for the syndrome’s main feature, the unusually small size. Obviously the lack of BLM in some way results in there being proportionally fewer than normal cells in each tissue and organ of the body.
(ii) The proneness to serious middle ear and lung infections suggests that BLM is required for the optimum functioning of cell lineages that are concerned with immunity. However, gastro-esophageal reflus (see below) could also be responsible.
(iii) The reason diabetes appears more frequently and earlier in BS than in others is unknown. The striking sparseness of fat tissue early in life conceivably is in some way responsible.
(iv) In contrast, the cancer predisposition of BS is explained: the increased number of mutations that are arising spontaneously in the various cells of the body is responsible. When a mutation occurs in one of the classes of genes known as growth-suppressors and proto-oncogenes, whose important normal functions are to regulate how often a cell will divide or determine how long it will live, normal control over those important matters is lost; and, the consequence is an abnormal degree of proliferation of that cell and its progeny – neoplasia. (If the resulting neoplasm threatens the life of the person in whom it arises, it is said to be malignant – a cancer.)
(Note. The reader of the preceding section will note, possibly with surprise, that of the four major features/complications of BS, the basis for only the fourth is understood to any significant degree. Those 238 persons with BS, and their families, who have participated in the over-four-decades-long program to define and understand BS – the Bloom’s Syndrome Registry – have understood two important things, first, that rare BS is a valuable model from which clinical investigators and basic scientists can learn about important health matters such as the determination of size and immunity, and about important diseases such as cancer, diabetes, and chronic lung disease; and, second, that with the gradual accrual of such understanding, they themselves may benefit directly-- and often do.)
(i) No treatment is available to stabilize the genome in the cells of persons with BS – i.e., that will correct the tendency for excessive numbers of mutations to arise.
(ii) Medical intervention aimed at improving growth in BS has been unsuccessful. Growth hormone production is normal in BS, and its administration has had little if any effect. Infants and young children with BS are notoriously poor eaters; sometimes a condition known as gastro-esophageal reflux has been shown to be responsible. If demonstrable, management of the reflux can be attempted. Non-volitional feeding (as, for example, by the surgical placement of a tube into the upper intestinal tract for supplementary nocturnal feeding) can increase fat deposits in infants with BS; however, an effect of such treatment on linear growth (height) is minimal or absent.
(iii) The facial skin lesion demands protection from the sun by the avoidance of sunlight whenever possible, and the use of suitable head covering, and the application of sun-blocking creams.
(iv) With respect to the proneness to middle ear infection and pneumonia, prompt treatment of respiratory tract infections with antibiotics is advisable to prevent permanent damage to the lungs (which in several cases has led to chronic and disabling lung disease).
(v) The diabetes in BS is treated in standard ways, to avoid or delay that diseases’s own set of serious complications.
(vi) With respect to the cancer proneness: Although as mentioned in (i), above] its cause, the genomic instability, cannot be corrected, programs for cancer surveillance can be devised and carried out with the help of a family physician knowledgeable about BS. (The Registry, when asked, will provide physicians with information about BS.) During childhood, when leukemia is the main neoplasm arising, no special surveillance is indicated, at least at present. In adulthood, however, extra attention is to be paid to seemingly unimportant symptoms that might permit early diagnosis of so-called solid tumors, those cancers that, for cure, usually depend on their prompt surgical removal. Procedures in general use for early diagnosis of cancer such as mammography, Pap smears, and colonoscopy may be begun earlier in life than usual. Because bone marrow transplantation sometimes is useful in treating cancer of certain types, early identification of a genetically compatible sib as a potential marrow donor can be attempted; also, if future non-BS pregnancies occur, stem cells can be harvested from the placental blood and stored frozen. In theory, storage frozen of the affected person’s own bone marrow, withdrawn when he/she is healthy, could be useful (and in one case has been); however, its secure storage for many years presents major problems.
(vii) Many of those with BS require varying degrees of family protection throughout their lives as result of a combination of factors foremost of which is the significant handicap of small size, but also the facial skin lesion when severe, chronic lung disease if present, and the poorly understood learning disability.
The Bloom’s Syndrome Registry
James L. German III, M.D1, Registrar
Maureen Sanz, Ph.D.2, Co-Registrar
Eberhard Passarge, M.D.3, Co-Registrar
1Department of Pediatrics, Weill Medical College of Cornell University, 1300 York Avenue, New York, N.Y. 10021. Tel. 212/746-3956 or 212/866-2330; Email: firstname.lastname@example.org
2Department of Pediatrics, Weill Medical College of Cornell University, 1300 York Avenue, New York, N.Y. 10021. Tel. 212/746-3956; and Biology Department, Molloy College, 1000 Hempstead Avenue, Rockville Centre, NY 06217. Tel. 516/678-5000, ext. 6217 or 201/768-7432; Email: email@example.com
3Institute of Human Genetics, University Clinic, University of Essen, Hufelandstrasse 55, 45122 Essen, Germany. Tel. 49-201-723-4560 or 49-2324-41603; Email: firstname.lastname@example.org