A
37-year-old woman exhibiting symptoms of mild cherubism (Credit: wikipedia.org)
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 putti, often
confused with cherubs,
in Renaissance paintings.
History
"Cherubism" was first coined and documented in
1933 by Dr. W. A. Jones of Kingston,
Ontario, describing a case of three siblings of the same family of Jewish
Russian heritage. All that was known at the time was the characteristic
swelling pattern and the increase and then regress of bone lesions. By the
time the children reached the ages of fifteen, sixteen, and seventeen, the
facial deformity had become "grotesque", and in 1943, the children
were operated on by the Jones medical team, reducing the hard swelling of their
jaws. Four years following the surgeries, there was no reappearance of the
swellings.
Presentation
Cherubism in
a 10-year-old boy (Credit: wikipedia.org)
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.
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. Cherubism is usually first diagnosed around age 7 and
continues through puberty and may or may not continue to advance with age.
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.
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. The
maxilla and zygomatic bones are depressed and eyes appear to gaze upward. 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.
Causes
Cherubism 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. 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. Mutations
of the SH3BP2 gene are only reported in 75% of Cherubism cases. 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. The
SH3BP2 protein is involved with chemical signaling to immune
system cells known as macrophages and B cells.
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. Osteoclasts also sense the increased inflammation of the
mandible and maxilla and are further activated to break down bone structures. Bone
loss and inflammation lead to increased fibrous
tissue and cyst growth. 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.
Diagnosis
Three-dimensional
computed tomography of a 41-year-old Chinese woman diagnosed with cherubism
shows a remarkable expansion of the mandible, which can lead to a soap bubble
appearance and the bilateral bulges of the maxilla (Credit: wikipedia.org)
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. 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.
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. 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. 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 diplopia, eye
proptosis, and visual loss will require ophthalmologic treatment.
Prevention
Because this disease is genetically linked, genetic counseling may be the only way to
decrease occurrences of Cherubism. The lack of severe symptoms in the parents
may be the cause of failure in recognizing 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.
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