What
is the 11;22 translocation and the Supernumerary
der(22)Syndrome?
(renamed in 2004 to Emanel Syndrome)
By
Dr. Beverly Emanuel,
The Children's Hospital of Philadelphia
In order to talk
about the Supernumerary der(22) Syndrome, first we need to step
back and describe some terminology. This is so that everyone
reading this will begin on the same footing. As you may know, a
syndrome is really a collection of findings that has been seen
recurring over and over again in patients. For example, one
group of associated features actually includes: a heart problem;
malformed ears with pits or tags; small chin; and a high arched
or cleft palate. Syndromes are often named after the person or
persons who first described the collection of findings, although
this has not happened in this case. Once an underlying cause is
identified, the name may be changed to reflect the specific
chemical abnormality, chromosome difference, or gene change that
caused the problem. Here, in the case of the Supernumerary
der(22)t(11;22), the name reflects the chromosomal change.
Genes are made up
of a chemical called DNA and they are housed within larger
structures called chromosomes. Most people have 23 pairs of
chromosomes (46 total), with one of each pair coming from the
mother and the other from the father. Chromosomes are numbered 1
through 22; the 23rd pair are called sex chromosomes because
they determine a person's sex (male or female). The chromosomes
are found in every cell in the body. Cells are so small that
they, and the chromosomes they contain, can only be seen by
observation with a microscope.
Since genes are
housed inside the chromosomes, they themselves can't be seen at
the microscope, but they can be measured by using special
"molecular" tests. A good way to think about
chromosomes and genes is to compare them to a train. A train has
a number of box cars just as a chromosome has a number of
stripes or bands. We can see the box cars when we look at a
train, just as we can see the chromosomes and their band
patterns when we observe them at the microscope. We cannot,
however, see the packages inside the box car without first
opening the door. The same is true for a chromosome - the genes
are the packages inside.
When a baby is
conceived with either too much or too little chromosomal
material, birth problems or birth defects can occur. This may
include a whole extra chromosome, as in the Supernumerary
der(22)t(11;22) syndrome (an extra "derivative" 22
chromosome), a whole missing chromosome as in Turner syndrome (a
missing X), a piece of material missing or extra, or a complex
rearrangement of chromosomal material. When chromosomal material
is missing or extra, genes are generally missing or extra. Since
genes are the blueprint of the body, when they are deficient or
duplicated, the body's blueprint changes, frequently leading to
birth problems and learning differences.
So again you ask,
what is the 11;22 tranlsocation and the Supernumerary der(22)
Syndrome?
In 1980, working
at the Children's Hospital of Philadelphia in the U.S.A., we
(Dr. Elaine Zackai and I) described the 11;22 translocation. At
about the same time, the t(11;22) was also described by a
consortium of European scientists. People who carry the 11;22
translocation have a very small piece of chromosome 22 (22q11
-> qter) transferred to chromosome 11 and a small piece of
chromosome 11 (11q23 -> qter) transferred to 22 (thus, it is
called a translocation). Chromosomes are divided into two parts,
the top part being called the "p"or short arm and the
bottom part called the "q" or long arm. Thus, the
22q11 -> qter and 11q23 -> qter designation tells everyone
who works in genetics that the area transferred or translocated
starts at a very specific spot on the "q" arm of
chromosomes 11 and 22 and goes to the end ("ter" or
terminus) of the "q" arm. It is very important to know
the location of a moved piece of chromosomal material in order
to make some general comparisons between individuals. This is
because if two children have different parts of the same
chromosomes extra it would be like comparing "apples to
oranges" to compare them to one another. Most often when
there is a chromosomal rearrangement or translocation they are
not exactly alike.
However, with the
t(11;22), we suspect that the story is different. The 11;22
translocation is appears to be the only translocation which
seems to have recurred over and over again, creating numerous
carriers. The points of chromosome exchange appear to be at the
same spots on 11 and 22 in all instances. Several hundred
families with what appears to be the same rearrangement have
been described in the scientific literature. Carriers of the
t(11;22) are themselves normal, but come to the attention of the
geneticist or pediatrician subsequent to the birth of a child
affected with the +der(22) syndrome who has the derivative (22)
or rearranged chromosome 22 as an extra chromosome.
Occasionally, translocation carriers are discovered upon being
studied for multiple miscarriages or infertility. Patients with
the +der(22) syndrome (or the extra chromosome) have distinctive
features which can include tags or pits in front of their ears,
abnormally shaped ears, a cleft or high arched palate, a small
chin, a heart defect, mental retardation and sometimes genital
abnormalities in the male.
Geneticists have
long been interested in understanding the mechanisms and results
of chromosomal rearrangement. Chromosomal rearrangements or
translocations are the result of DNA rearrangements at the
molecular level. Translocations are one of the major categories
of structural chromosomal alterations. The mechanisms by which
they are generated are largely unknown. Balanced translocations,
i.e. those in which there is no microscopically visible loss of
genetic material are amongst the most common of these
rearrangements accounting for roughly 0.2% of structural
abnormalities. In general, the chromosomal change is presumed to
occur during the formation of either the egg or sperm which
created the first person with the rearrangement in a family.
Then, that person carries the change in every cell of his or her
body and is capable of passing the change to his/her children.
It can be transmitted either as a balanced rearrangement or as
an extra chromosome as in the Supernumerary der(22) Syndrome.
The cellular
events which end in chromosomal rearrangement or translocations,
especially those like the recurrent t(11;22), remain to be
elucidated. Understanding the molecular basis of this
translocation may serve as a model for understanding the
mechanisms involved in creating other translocations. Thus,
efforts to map the elusive constitutional t(11;22) translocation
breakpoint are progressing. For example, we have already
determined that a major portion of the DNA which surrounds the
region of the breakpoint on chromosome 22 is duplicated several
times on chromosome 22. This duplication which is normally
present on every chromosome 22 may make this chromosome more
prone to engage in rearrangements. The determination of the
exact size of the duplication, number of copies and their
location is currently under investigation. Further, the
relationship between having a translocation, especially an 11;22
translocation, and how chromosomes separate during formation of
egg and sperm, is not clear and has not been well studied. These
are some of the studies we are currently pursuing in our
laboratory research.
Further, our
research team includes several geneticists who specialize in
identifying genes, how they work, and why they cause problems
when they are extra or changed. We hope to provide the
scientific community with new information about the genes which
reside in the duplicated pieces of chromosomes 11 and 22. We
also try to understand how genes influence each other. When
there is a supernumerary der(22), many genes are extra but
probably not all of them play a role in causing the symptoms
associated with the duplication. Thus, additional studies will
be necessary to understand the role that each of the genes plays
in the cause of the complex and variable symptoms which are seen
in the children with the Supernumerary der(22) syndrome. Our
research studies will enable us to determine if these problems
are caused by the duplication of several genes, or by many
duplicated genes. Further, most individuals with the
Supernumerary der(22) syndrome have a duplication of the same
exact pieces of chromosomal material but they do not all have
the same symptoms. Perhaps other factors play a role in who
develops which symptoms. Much more work needs to be done and
this is our job for the future. We welcome your participation in
our research efforts and thank you for all of your interest.
TOGETHER, we will begin to understand the t(11;22) and the
Supernumerary der(22)t(11;22) syndrome.
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