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Cherubism is a rare genetic disorder that causes
prominence in the lower portion in the face. The name is
derived from the temporary chubby-cheeked resemblance
to, often confused with, in Renaissance paintings.
Presentation
The appearance of people with the disorder is caused by a
loss of bone in the mandible which the body replaces with
excessive amounts of fibrous tissue. In most cases, the
condition fades as the child grows, but in a few even rarer
cases the condition continues to deform the affected
person's face. Cherubism also causes premature loss of the
primary teeth and uneruption of the permanent teeth.
Facial appearance of 37 year old woman diagnosed with cherubism.
The disease Cherubism is a rare autosomal
dominant disease of the maxilla and mandible.
Approximately 200 cases have been reported by
medical journals with the majority being males. The
name originates from the chubby faced angels or
Cherubs of the renaissance era paintings.
Cherubism is usually first diagnosed around age 7
and continues through puberty and may or may
not continue to advance with age.[1] The degrees of
Cherubism vary from mild to severe. Osteoclastic
and osteoblastic remodeling contributes to the
change of normal bone to fibrous tissue and cyst
formation. As noted by the name, the patient's face becomes
enlarged and disproportionate due to the fibrous tissue and
atypical bone formation. The sponge-like bone formations
lead to early tooth loss and permanent tooth eruption
problems. The disease also affects the orbital area, creating an
upturned eye appearance. The cause of cherubism is believed
to be traced to a genetic defect resulting from a mutation of
the SH3BP2 gene from chromosome 4p16.3.[] While the
disease is rare and painless, the afflicted suffer the emotional
trauma of disfigurement. The effects of Cherubism may also
interfere with normal jaw motion and speech. Currently,
removal of the tissue and bone by surgery is the only
treatment available. This disease is also one of the few that
unexpectedly stops and regresses. Normal bone remodeling
activity may resume after puberty. Further research is needed
to understand the mechanisms responsible for Cherubism, as
well as potential
Anatomy
Cherubism is displayed with genetic conformation
and when excessive osteoclasts are found in the
affected areas of the mandible and Maxilla. Large
cysts will be present with excessive fibrous areas
inside the bone. The fibers and cysts will be found
among the trabecula of the Coronoid process, the
ramus of mandible, the body of mandible and the
maxilla regions. The maxilla will be affected up to
and including the orbits and sometimes inside the
lower orbits.[7] The maxilla and zygomatic bones are
depressed and eyes appear to gaze upward.[8] The
maxilla has been found to be more severely affected
in most cases than the mandible bone. Some patients
found with lower inner orbital growths and cysts
may lose vision.
Diagnosis
The disease is usually diagnosed when dental
abnormalities are found. These abnormalities
include premature deciduous teeth and abnormal
growth of permanent teeth due to displacement by
cysts and lesions. The only definite way to correctly
diagnose the disease is by sequence analysis of the
SH3BP2 gene. The gene has been found to have missense mutation in exon 9.[3] Initial study of the
patient is usually conducted using x-ray and CT
scans. Neurofibromatosis may resemble Cherubism
and may accompany the disease. Genetic testing is
the final diagnosis tool.
[History
Cherubism was first written about in 1933 by Dr. W.
A. Jones of Kingston, Ontario. All that was known at
the time was the characteristic swelling pattern and
the increase and then regress of bone lesions. It was
later found that this disease is autosomal dominantly
linked, meaning the displayed phenotype is
determined by the dominant allele while the normal
allele is recessive. One copy of the dominant allele is
enough to cause the disorder. Because the disease was
found to be dominant the diseased phenotype tends to
be seen in every generation at some level of severity.
Therefore
afflicted fathers or mothers of children with
Cherubism pass the phenotype to both daughters and
sons.[3] Cherubism has also been found from the
random mutation of a gene in an individual having
no family history of the disease. However it is not
well understood why males tend to express the
disease more frequently. The disease is expressed at a
rate of 80 to 100% of all affected. Yet children with
Cherubism vary in severity in their maxilla and
mandible bony lesions. The cause of Cherubism is
believed to be from a mutation of gene of SH3BP2.
Cherubism has also been found
combined with other genetic disorders including Noonan
syndrome, Ramon syndrome, and Fragile X syndrome.[4]
Mutations of the SH3BP2 gene are only reported in 75% of
Cherubism cases.[2] The mutation of the SH3BP2 gene is
believed to increase production of over active proteins from
this gene. The SH3BP2 gene is found on the smaller arm of
chromosome 4 at position 16.3.[2] The SH3BP2 protein is
involved with chemical signaling to immune system cells
known as macrophages and B cells. Because osteoclasts are
also macrophages, this protein plays an active role in
production and activation of osteoclasts and bone
reabsorbtion. Osteoclasts also sense the increased
inflammation of the mandible and maxilla and are activated to
break down bone structures. Bone loss and inflammation lead
to increased fibrous tissue and cyst growth. The cyst growth
leads to the enlarged yet painless condition. The bone
reabsorbtion is performed by the osteoclast. The
osteoclast removes the mineralized matrix and collagen
by secreting enzymes. The osteoclast is one large cell
that has multiple nuclei and high concentration of
vesicles and vacuoles. A special membrane that
contacts the bone is called the ruffled border. This
border maintains the enzymes and increases the surface
area contacting the bone. The hydroxyapatite is the
mineral part of the bone that includes phosphate and
calcium ions which are absorbed by endocytosis and
released into the extracellular fluid. The formation of
osteoclasts is dependent on receptor activator of
nuclear factor kB (RANK Ligand) and macrophage
colony-stimulating factor (M-CSF).[5] The formation of
osteoclasts is directly dependent on their precursors
contact with membrane bound proteins.[5] When
osteoclasts are activated they travel by chemo taxis
throughout the bone. The ability of the osteoclast to attach is
enabled by specific motifs of Arg-Gly-Asp which hold
positive, neutral, and negative charges respectively.[5]
Cathepsin K is the major protease that degrades collagen
and noncollagenous proteins. Cathepsin B, C, D, E, G, and L
are also expressed. Matrix metalloproteinases (MMPs) are
also secreted and are believed to be important in osteoclast
migration.[5] Parathyroid hormone as well as growth factor
interleukin regulates osteoclasts by balancing the calcium
levels in blood and bone. Increased parathyroid hormone is
known to make osteoclasts break down and release more
calcium into the extracellular fluid. Osteoblast activity is
unable to keep up with the osteoclast activity and lesions are
formed.[6] Osteoblasts are unrelated to osteoclasts.[5]
Treatment
Because Cherubism changes and improves over time the treatment
should be individually determined. Generally moderate cases are
watched until they subside or progress into the more severe range.
Severe cases may require surgery to eliminate bulk cysts and fibrous
growth of the maxilla and mandible. Surgical bone grafting of the
cranial facial bones may be successful on some patients. Surgery is
preferred for patients ages 5 to 15.[1] Special consideration should
be taken when operating on the face to avoid the marginal
mandibular branch of the facial nerve as well as the zygomatic
branch of the facial nerve. Unintentional damage to these nerves can
decrease muscle strength in the face and mandible region.
Orthodontic treatment is generally required to avoid permanent
dental problems arising from malocclusive bite, misplaced, and
unerupted permanent teeth.[1] Orthodontic treatment may be used
to erupt permanent teeth that have been unable to descend due to
lesions and cysts being in their path of eruption. In patients with
orbital issues of diploia,
[Prevention
Since this disease is genetically linked genetic
counseling may be the only way to decrease
occurrences of Cherubism. The lack of severity of
symptoms of the parents may be cause for failure to
recognize the disorder. The optimal time to be tested
for mutations is prior to having children. The disease
results from a genetic mutation and this gene has
been found to spontaneously mutate. Therefore there
may be no prevention techniques available.
[Conclusion
The face displays emotions and is the major form of
communication method we use. The slightest amount of
disfigurement of the face is easily noticed. While the
Cherubism is not accompanied with pain the need to help
children and adults afflicted is apparent. Because this
disease is associated with the time of tooth eruption the
disease may be helpful in discovering what factors of
tooth eruption contribute to Cherubism. The disease is
also useful in defining roles of the genes involved in
disorganizing osteoclast activity. Further research of the
mechanisms responsible for Cherubism could lead to
discoveries and cures for many other bone diseases such
as osteoporosis.
[Genetics
Mutations in the gene have been identified in about 80 percent of people with
cherubism. In most of the remaining cases, the genetic cause of the condition is
unknown. The SH3BP2 gene provides instructions for making a protein whose
exact function is unclear. The protein plays a role in transmitting chemical signals
within cells, particularly cells involved in the replacement of old bone tissue with
new bone (bone remodeling) and certain zzcells.
Mutations in the SH3BP2 gene lead to the production of an overly active version of
this protein. The effects of SH3BP2 mutations are still under study, but researchers
believe that the abnormal protein disrupts critical signaling pathways in cells
associated with the maintenance of bone tissue and in some immune system cells.
The overactive protein likely causes inflammation in the jaw bones and triggers the
production of osteoclasts, which are cells that break down bone tissue during bone
remodeling. An excess of these bone-eating cells contributes to the destruction of
bone in the upper and lower jaws. A combination of bone loss and inflammation
likely underlies the cyst-like growths characteristic of cherubism.
This condition is inherited in an autosomal dominant pattern, which means one
copy of the altered gene in each cell is sufficient to cause the disorder.[9] In some
cases, an affected person inherits the mutation from one affected parent. Other
cases may result from new mutations in the gene. These cases occur in people with
no history of the disorder in their family.