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This is an exciting time in craniofacial research because
of the explosion of new information and opportunities created
by the human genome project, a worldwide scientific effort
to identify all human genes.
With the use of molecular technology and the participation
of families with craniofacial conditions, clinical and laboratory
researchers are identifying genes involved in craniofacial
development and disorders. Gaining such knowledge is important
for health professionals to improve their care and treatment
of patients affected by these conditions.
Five percent of all newborns in the United States each year
have a birth defect, and at least 1/800 newborns have a malformation
affecting the head, face or neck. Of the over 5,500 known
inherited conditions in man, over 700 involve malformations
of the craniofacial region, and over 300 have cleft lip with
or without cleft palate. This highly diverse group of disorders
is due to many different environmental and genetic causes
and their interactions with one another.
There are approximately 80,000 to 100,000 genes composed
of DNA (deoxyribonucleic acid) in every cell of our body.
These genes inform each cell how to function. For example,
some genes contain information so that a cell becomes a muscle,
nerve, or bone cell. These cells then use the information
from other genes to organize and become tissues, organs, and
the complex structures of the face and skull. We have several
thousands of genes organized into chains of genes which resemble
beads on a string. These "chains of genes" are called chromosomes.
There are a total of 23 pairs of chromosomes in each cell,
and one of those pairs of chromosomes, sex chromosomes (designated
by X and Y) determines whether an individual is a male or
a female. Because genes are on chromosomes, which are in pairs,
the genes also come in pairs, and each gene is located to
a specific pair of chromosomes. A human being is created when
the mother's egg with one copy of each chromosome, or 23 maternal
chromosomes, is fertilized by a sperm containing 23 paternal
chromosomes so that the first cell of a fetus contains 23
pairs of chromosomes. Each parent has contributed one chromosome
or one gene to each pair of the child's chromosomes or genes.
The first cell is then replicated until an entire human being
is formed and that same genetic information is in every cell
of his or her body.
An inherited condition can be passed through genes from either
the mother, the father, or both. Disorders which are called
"autosomal dominant" are common among craniofacial syndromes
and are caused by a change or "mutation" in only one copy
of a gene from one biological parent. Such a condition is
passed, on average, fifty percent of the time from one parent
to the child, and so on in subsequent generations. Examples
of these conditions are: The mandibulofacial dysostoses, which
include Treacher Collins syndrome, a condition characterized
by eye and ear anomalies and small cheekbones and chin; midfacial
dysostoses. which include Opitz syndrome, whose features are
widely spaced eyes and a broad nose, Waardenburg syndrome,
a disorder of widely spaced eyes, pigmentary changes, and
deafness; or the craniosynostoses, which include Crouzon,
Pfeiffer, Saethre-Chotzen, and Apert syndromes whose common
characteristic is premature fusion of bones of the head, resulting
in abnormal skull shape. Velocardiofacial syndrome, another
autosomal dominant condition, is associated with cleft palate.
Individuals with this condition may have a missing portion
of one copy of chromosome 22.
Conditions which are called "autosomal recessive" are less
common in craniofacial inherited conditions and are caused
by a mutation in both copies of a gene, one copy from both
the mother and father who are "carriers." In recessive disorders,
carriers are not affected, even though one copy of their genes
is mutated. If both parents are carriers for the same gene
mutation, they would have a 1 in 4 or 25% chance of having
a child affected with the condition.
For other conditions, it is unclear how they are inherited
because more than one family member may be affected, but transmission
directly from a parent or a relative to a child is not always
obvious. These conditions are considered multifactorial because
more than one gene in combination with environmental effects
are thought to be the cause, as in the case of cleft 1ip with
and without cleft palate. The recurrence risk for this anomaly
is 3-15%.
Sometimes, a child is born and is the first member of the
family with a condition because a gene from either the mother's
egg or father's sperm underwent a spontaneous change or new
mutation prior to fertilization. Such an individual is considered
the first case in a family, or a "sporadic" case. Most cases
of Moebius syndrome, a craniofacial condition with abnormalities
in the nerves of the face, or hemifacial microsomia with facial
asymmetry are sporadic. However, when that affected individual
has children, he or she has a chance of passing on the mutated
gene to their children.
The chromosome location of over 60 genes for craniofacial
conditions have been found. Over 70 genes and their mutations
have been found for specific craniofacial conditions. Examples
of some of these genes are listed in the table. A disease-causing
gene is identified by first locating it to a specific chromosome,
and then tracking the presence of a mutation in that gene
in each affected member of a family. The proof that the gene
causes the disorder is the presence of a mutation in affected
members and the absence of a mutation in unaffected members
of the families and the general population. This scientific
method requires the participation of many affected and unaffected
family members and is most easily applied to the study of
autosomal dominant and recessive disorders.
We have found that these "craniofacial disease-causing" genes
contain the information to make different proteins. For instance,
these genes contain the information for: 1) transcription
factor proteins which regulate the activities of other genes;
2) homeobox proteins that are important in the organization
and patterning of the human body; and 3) fibroblast growth
factor receptors which are involved in many processes of human
development, growth, and health maintenance. Finding the genes
has taught us several unexpected things: 1) Some disorders
originally thought to be distinct may be related and represent
different degrees of severity of the same disorder such as
Crouzon and Pfeiffer syndrome; 2) The same conditions can
be caused by mutations in different genes. A patient with
Pfeiffer syndrome can either have a mutation in Fibroblast
Growth Factor Receptor 1 or Fibroblast Growth Factor Receptor
2, which suggests these genes may have similar functions;
and 3) Different mutations in the same gene can result in
two completely distinct conditions. Different mutations in
Fibroblast Growth Factor Receptor 3 can result in Crouzon
syndrome or achondroplasia, the most common form of dwarfism
in man. This suggests different mutations cause distinctly
different functional changes to the gene. We will continue
to learn an immense amount, especially because it is predicted
that the human genome project will complete the DNA sequence
of all the genes by the year 2005.
Knowledge of the genes involved in craniofacial development
and mutations in these genes causing craniofacial abnormalities
will be useful in clinical practice to help diagnostic work-ups
and determine recurrence risks in families. Finding a disease
gene is the first step in a scientist's journey toward understanding
why a craniofacial condition occurs. With the information
of the genes, we can begin to understand the function of the
gene.
Understanding the properties of the protein and how a mutation
alters its normal function will eventually fuel strategies
to prevent and alleviate genetic abnormalities, either by
the use of gene or drug therapies. Although many of these
discoveries were initiated by geneticists, a multidisciplinary
approach to research in craniofacial conditions is necessary.
Anatomists, cell biologists, developmental biologists, biochemists,
protein chemists, statisticians, epidemiologists, and clinical
researchers are necessary to further elucidate the products
and functions of these genes.
At our Center for Craniofacial Development and Disorders,
based at Johns Hopkins University and in collaboration with
many other international and national institutions, we have
incorporated basic, applied, behavioral, and social scientific
approaches toward solving the mysteries of why some individuals
have craniofacial conditions. Why are some individuals, even
within the same family, more mildly or more severely affected,
physically and emotionally? What can we do to prevent these
conditions?
We are also studying craniofacial disorders in other organisms
such as fish and mice because much can be learned from other
systems especially very early in development. We believe it
is important to educate other health professionals, teachers,
students, and families about our discoveries and to learn
how to apply this knowledge in the thoughtful and responsible
care of patients. At Johns Hopkins, we are also using the
multidisciplinary approach to providing care to patients.
Clinical specialists such as plastic, reconstructive, and
maxillofacial surgeons, otolaryngologists, ophthalmologists,
dentists, hearing and speech pathologists, pediatricians,
internists, geneticists, psychologists, and social workers,
and counselors in a variety of subspecialties will assist
in clinical decision making. With the recent gene discoveries,
we have made advances and hope to learn much more in the future
with the encouragement, support and participation from families
such as yours. Thank you.
Newsletter:
FACES: The National Craniofacial Association
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