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 A putto (; plural putti ) is a figure in a work of art depicted as a chubby male child, usually naked and sometimes winged. Originally limited to profane passions in symbolism,Dempsey, Charles. ''Inventing the Renaissance Putto''. University of ...

, the chubby-faced infants featured in

Renaissance painting Renaissance art (1350 – 1620 AD) is the painting, sculpture, and decorative arts of the period of European history known as the Renaissance, which emerged as a distinct style in Italy in about AD 1400, in parallel with developments which occ ...

s, which were often mistakenly described as

cherub A cherub (; plural cherubim; he, כְּרוּב ''kərūḇ'', pl. ''kərūḇīm'', likely borrowed from a derived form of akk, 𒅗𒊏𒁍 ''karabu'' "to bless" such as ''karibu'', "one who blesses", a name for the lamassu) is one of the u ...

Signs and symptoms

The appearance of people with the disorder is caused by a loss of bone in the

mandible In anatomy, the mandible, lower jaw or jawbone is the largest, strongest and lowest bone in the human facial skeleton. It forms the lower jaw and holds the lower tooth, teeth in place. The mandible sits beneath the maxilla. It is the only movabl ...

which the body replaces with excessive amounts of

fibrous tissue Fiber or fibre (from la, fibra, links=no) is a natural or artificial substance that is significantly longer than it is wide. Fibers are often used in the manufacture of other materials. The strongest engineering materials often incorporate ...

. In most cases, the condition fades as the child grows, but in rare cases the condition continues to deform the affected person's face. Cherubism also causes premature loss of the

primary teeth Deciduous teeth or primary teeth, also informally known as baby teeth, milk teeth, or temporary teeth,Illustrated Dental Embryology, Histology, and Anatomy, Bath-Balogh and Fehrenbach, Elsevier, 2011, page 255 are the first set of teeth in the ...

and lack of eruption and or displacement of the

permanent teeth Permanent teeth or adult teeth are the second set of teeth formed in diphyodont mammals. In humans and old world simians, there are thirty-two permanent teeth, consisting of six maxillary and six mandibular molars, four maxillary and four mandibul ...

. Cherubism is a rare

autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

disease of the

maxilla The maxilla (plural: ''maxillae'' ) in vertebrates is the upper fixed (not fixed in Neopterygii) bone of the jaw formed from the fusion of two maxillary bones. In humans, the upper jaw includes the hard palate in the front of the mouth. The t ...

and mandible. Approximately 200 cases have been reported by medical journals with the majority being males. Cherubism is usually first diagnosed around age seven and continues through puberty and may or may not continue to advance with age. Degrees of cherubism vary from mild to severe.

Osteoclast An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated pro ...

ic and

osteoblastic Osteoblasts (from the Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts function ...

remodeling contributes to the change of normal bone to fibrous tissue and

cyst A cyst is a closed sac, having a distinct envelope and cell division, division compared with the nearby Biological tissue, tissue. Hence, it is a cluster of Cell (biology), cells that have grouped together to form a sac (like the manner in which ...

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 condition 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 In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...

of the SH3BP2 gene from chromosome 4p16.3. While the condition 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 condition 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 A trabecula (plural trabeculae, from Latin for "small beam") is a small, often microscopic, tissue element in the form of a small beam, strut or rod that supports or anchors a framework of parts within a body or organ. A trabecula generally ha ...

of the Coronoid process, the ramus of mandible, the

body of mandible In anatomy, the mandible, lower jaw or jawbone is the largest, strongest and lowest bone in the human facial skeleton. It forms the lower jaw and holds the lower tooth, teeth in place. The mandible sits beneath the maxilla. It is the only movabl ...

and the maxilla regions. The maxilla will be affected up to and including the

orbits In celestial mechanics, an orbit is the curved trajectory of an object such as the trajectory of a planet around a star, or of a natural satellite around a planet, or of an artificial satellite around an object or position in space such as a p ...

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

ly linked. Cherubism has also been found from the random mutation of a gene in an individual having no family history of the condition. However it is not well understood why males tend to express the disease more frequently. Children with cherubism vary in severity in their maxilla and mandible bony

lesions A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals. Types There is no designated classifi ...

. The disease is expressed at a rate of 80 to 100% of all affected. Studies of multiple generations of families with the gene found that all boys developed cherubism, but 30–50% of girls show no symptoms. The cause of cherubism is believed to be from a

of gene of SH3BP2. Cherubism has also been found combined with other genetic disorders including

Noonan syndrome Noonan syndrome (NS) is a genetic disorder that may present with mildly unusual facial features, short height, congenital heart disease, bleeding problems, and skeletal malformations. Facial features include widely spaced eyes, light-colored ...

, Ramon syndrome, and

fragile X syndrome Fragile X syndrome (FXS) is a genetic disorder characterized by mild-to-moderate intellectual disability. The average IQ in males with FXS is under 55, while about two thirds of affected females are intellectually disabled. Physical features may ...

. 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 The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...

cells known as

macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...

and

B cells B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted o ...

. 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 Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...

in the jaw bones and triggers the production of

osteoclasts An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and remodeling of bones of the vertebral skeleton. The osteoclast disassembles and digests the composite of hydrated prote ...

, which are cells that break down bone tissue during

bone remodeling Bone remodeling (or bone metabolism) is a lifelong process where mature bone tissue is removed from the skeleton (a process called ''bone resorption'') and new bone tissue is formed (a process called ''ossification'' or ''new bone formation''). ...

. 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

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

The chemical imbalance 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 condition is by

sequence analysis In bioinformatics, sequence analysis is the process of subjecting a DNA, RNA or peptide sequence to any of a wide range of analytical methods to understand its features, function, structure, or evolution. Methodologies used include sequence alig ...

of the SH3BP2 gene. The gene has been found to have

missense mutation In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense m ...

in exon 9. Initial study of the patient is usually conducted using

x-ray An X-ray, or, much less commonly, X-radiation, is a penetrating form of high-energy electromagnetic radiation. Most X-rays have a wavelength ranging from 10 picometers to 10 nanometers, corresponding to frequencies in the range 30&nb ...

and CT scans.

Neurofibromatosis Neurofibromatosis (NF) is a group of three conditions in which tumors grow in the nervous system. The three types are neurofibromatosis type I (NF1), neurofibromatosis type II Neurofibromatosis type II (also known as MISME syndrome – multi ...

may resemble cherubism and may accompany the condition. Genetic testing is the final diagnosis tool.

Prevention

Because this genetic anomaly 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 disorder results from a genetic mutation, and this gene has been found to spontaneously mutate. Therefore, there may be no prevention techniques available.

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 Bone grafting is a surgical procedure that replaces missing bone in order to repair bone fractures that are extremely complex, pose a significant health risk to the patient, or fail to heal properly. Some small or acute fractures can be cured wit ...

of the cranial facial bones may be successful on some patients. Surgery is preferred for patients aged 5 to 15. Special consideration should be taken when operating on the face to avoid the marginal mandibular branch 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 Orthodontics is a dentistry specialty that addresses the diagnosis, prevention, management, and correction of mal-positioned teeth and jaws, and misaligned bite patterns. It may also address the modification of facial growth, known as dentofacial ...

treatment is generally required to avoid permanent dental problems arising from malocclusive bite and misplaced permanent teeth that have not erupted. 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. Patients with orbital issues of

diplopia Diplopia is the simultaneous perception of two images of a single object that may be displaced horizontally or vertically in relation to each other. Also called double vision, it is a loss of visual focus under regular conditions, and is often v ...

eye proptosis Exophthalmos (also called exophthalmus, exophthalmia, proptosis, or exorbitism) is a bulging of the eye anteriorly out of the orbit. Exophthalmos can be either bilateral (as is often seen in Graves' disease) or unilateral (as is often seen in ...

, and visual loss will require

ophthalmologic Ophthalmology ( ) is a surgical subspecialty within medicine that deals with the diagnosis and treatment of eye disorders. An ophthalmologist is a physician who undergoes subspecialty training in medical and surgical eye care. Following a medic ...

treatment.

Prognosis

Due to the rarity of the condition, it is difficult to reliably estimate statistics. However, a 2006 study which followed 7 cases over an average of 8.5 years noted that "In general, cherubism does not have a poor prognosis. It has been noted that the condition does not progress beyond puberty. As the patient grows to adulthood, the jawbone lesions tend to resolve, and a progressively more normal jaw configuration is noted."

History

Cherubism was first documented and named in 1933 by Dr. W. A. Jones of

Kingston, Ontario Kingston is a city in Ontario, Canada. It is located on the north-eastern end of Lake Ontario, at the beginning of the St. Lawrence River and at the mouth of the Cataraqui River (south end of the Rideau Canal). The city is midway between Toro ...

, describing a case of three siblings of the same family of

Jewish Russian :''This List of Jews contains individuals who, in accordance with Wikipedia's verifiability and no original research policies, have been identified as Jews by reliable sources.'' The following is a list of Jews born in the territory of the for ...

heritage. All that was known at the time was the characteristic swelling pattern and the increase and then regress of bone

. By the time the children reached the ages of fifteen, sixteen, and seventeen, the facial deformity had become an obvious disfigurement 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. Yet, in some cases dysplasia recurred after surgery, necessitating additional surgeries.

References

External links

{{Deficiencies of intracellular signaling peptides and proteins 1930s neologisms Jaw disorders Deficiencies of intracellular signaling peptides and proteins Rare diseases Cherubim