A proportional small body size is one of the cardinal pictures of the syndrome. Yet, we do not have a scientific explanation of why the body is small. Because the cells in a person with Bloom's syndrome appear to be the same size as the cells in other persons, the simplest explanation is that there are altogether fewer cells. This explanation begs the question why are there fewer cells?
The question of why are there fewer cells in persons with Bloom's syndrome is difficult to answer because the development of a person from conception to birth is a process that takes many months and that is largely hidden from sight. Persons with Bloom's syndrome are born smaller than normal and, although there is growth, they never catch up to normal size. In order to learn about mechanisms of growth, scientists turn to model organisms to try to answer these questions, because it is possible to perturb systems and measure outcomes. But model organisms have the limitation that many details of the processes that mold human development are different from those in other animals. As an example, the mouse is a commonly used model organism because it can be genetically manipulated. The experimentally derived mouse with a deleted mouse Bloom's syndrome gene dies at an early embryonic stage; it does not live to birth. Here, we have substituted one mystery for another: why is the human with a deleted Bloom's syndrome gene alive and the mouse not?
From ultra-sound probing, we do know that the size of the Bloom's syndrome fetus is smaller than the size of the normal fetus at the same developmental stage; however, we do no know when this difference first becomes apparent. Is it from conception or does the developmental lag begin at a later stage?
During development in the uterus, the fetus grows in size. Much of this growth comes from cells dividing. When a cell divides, two daughter cells are generated. Daughter cells have several possible fates: they could continue to divide; they could stop dividing and live on (to divide later or never to divide again); or they could die. Moreover, the fate of one daughter cell can be different from the fate of the other. For example, one daughter cell could go on to divide and the other could die. In Bloom's syndrome, we do not know whether the explanation for the small size is a deficit in cell proliferation, an increase in overall cell death, or some combination of the two mechanisms. There are data from the study of model organisms and of human Bloom's cells put into culture that support the idea that the explanation lies in some combination of the two mechanisms. Bloom's syndrome cells do take longer to divide in cell culture than normal cells. On the other hand, an increase in cell death has been documented in the hematopoietic cell development of a Bloom's syndrome mutant mouse.
Bloom's syndrome cells may proliferate more slowly because the cells encounter various problems when they try to replicate their DNA, but the mechanistic details of how these problems arise and why it takes longer for Bloom's syndrome cells to handle them are presently poorly defined.
While there is an enormous amount of cell proliferation in the fetus, cell division and proliferation is also important in the adult. Cells in many organs die over time, and these cells are replenished by a class of cells referred to as stem cells. For example, the skin, immune system, and gut are all maintained through stem cell populations that divide and produce daughters that can themselves proliferate. Stem cells have two key properties. (1) They are able to self renew. When they divide, at least one of the daughter cells is a stem cell--able to divide again. (2) They are multi-potent. Multipotency is the capacity to differentiate into given specialized cell types. The stem cells replenish the body but they age too. Over time, we all lose stem cells and the ability to maintain the tissues slowly dissipates. Given the problems Bloom's cells have in proliferation, it is reasonable to ask do the stem cell populations in Bloom's syndrome have the same capacity to divide and to produce progeny as normal stem cell populations? Are there the same numbers of stem cells? It is worth asking how many of the features and complications of Bloom's syndrome trace to a problem with the stem cells.