Cherubism: Symptoms, Types, Causes and Treatment

Cherubism is a rare genetic disorder that affects the bones of the face, most notably the jaws, leading to distinctive facial changes in children. Despite its dramatic appearance, cherubism is typically benign and often regresses with age. Understanding its symptoms, types, causes, and treatment options is essential for patients, families, and clinicians navigating this complex condition.

Symptoms of Cherubism

Cherubism is best known for its striking facial features, especially in children. However, the presentation and severity can vary significantly between individuals. Early recognition of the symptoms is essential for diagnosis and management, as well as for providing reassurance and support to affected families.

Symptom	Onset/Age	Key Feature	Source(s)
Jaw Swelling	2–10 years	Bilateral, painless, symmetrical	1, 4, 5, 11
"Cherubic" Face	Childhood	Full cheeks, eyes-upwards appearance	1, 5, 11
Dental Issues	Childhood	Malocclusion, displaced/abnormal teeth	1, 4, 11
Eye Signs	Advanced cases	Sclera visible below pupils ("eyes-to-heaven")	1, 11

Table 1: Key Symptoms of Cherubism

Onset and Early Presentation

• Age of Onset: Most children appear normal at birth. The first signs usually emerge between ages 2 and 10, with swelling of the lower face being the most noticeable change 1, 4, 5, 11.
• Initial Symptoms: Painless, symmetrical swelling of both jaws is the classic first sign. This swelling is often noticed by family members or dentists.

Facial and Ocular Features

• Cherubic Appearance: The jaw swelling leads to full, rounded cheeks and, in some cases, an upward tilting of the eyes, exposing the sclera beneath the iris. This gives the child an angelic or "cherubic" look, reminiscent of Renaissance paintings 1, 5, 11.
• Eye Involvement: When the maxilla (upper jaw) is affected, the eyes may appear pushed upwards, further enhancing the cherubic appearance 1, 11.

Oral and Dental Manifestations

• Dental Abnormalities: The jaw lesions can cause malocclusion (misalignment of teeth), displacement of teeth, and delayed or abnormal eruption. Dental arches may be expanded, and teeth may be missing, impacted, or malformed 1, 4, 11.
• Difficulty in Chewing: In severe cases, dental and skeletal changes may interfere with chewing or speech.

Other Features

• Painless Lesions: Unlike many other jaw conditions, cherubism does not typically cause pain 1, 4, 5, 11.
• Progression and Regression: The swelling tends to increase until puberty, after which it often stabilizes or gradually regresses into adulthood 5, 11.

Types of Cherubism

Cherubism is not a one-size-fits-all disorder. Its severity, progression, and radiological appearance can differ widely. Understanding these types helps guide management and prognosis.

Type	Age/Stage	Key Traits	Source(s)
Quiescent	Older children/adults	Stable, little/no growth	5
Non-Aggressive	Teenagers	Slow/moderate growth, some dental impact	5, 6
Aggressive	Young children	Rapid growth, extensive bone changes	5, 6, 13
Familial	Any age	Inherited, often multiple family members	1, 2, 8
Sporadic	Any age	No family history, isolated cases	1, 11

Table 2: Types and Classifications of Cherubism

Clinical Behavior-Based Types

• Quiescent Cherubism:

  • Seen in older children and adults.
  • Lesions are stable and show little to no growth.
  • Minimal impact on function or appearance 5.

• Non-Aggressive Cherubism:

  • Most common in teenagers.
  • Lesions grow slowly or moderately.
  • Dental and skeletal changes can occur, but are less severe 5, 6.

• Aggressive Cherubism:

  • Usually affects younger children.
  • Characterized by rapid expansion of lesions, significant jaw deformation, tooth displacement, and sometimes thinning or perforation of the jaw bones.
  • May require early intervention 5, 6, 13.

Genetic and Inheritance-Based Types

• Familial Cherubism:

  • Inherited, often following an autosomal dominant pattern (one affected parent can pass it on to children).
  • Multiple family members may be affected, sometimes with variable severity 1, 2, 8.

• Sporadic Cherubism:

  • Occurs without a family history.
  • May result from a new (de novo) mutation in the affected individual 1, 11.

Radiological and Histopathological Classification

• Lesions can also be categorized based on radiographic appearance (well-defined, multilocular radiolucencies) and histological features (presence of multinucleated giant cells within a fibrous stroma) 1, 6.

Causes of Cherubism

Cherubism is fundamentally a genetic disorder, but its unique jaw-specific and age-related features are shaped by complex molecular and environmental interactions.

Cause/Mechanism	Description	Impact	Source(s)
SH3BP2 Mutations	Dominant mutations in SH3BP2 gene	Drives disease, inherited	5, 8, 9
Inheritance	Usually autosomal dominant, rare recessive	Familial clustering	2, 5, 8
Cellular Effects	Hyperactive osteoclasts, inflammation	Bone resorption, swelling	7, 9, 10
TNF-α Overproduction	Inflammatory cytokine excess	Bone destruction, symptoms	3, 7, 10
TLR/MYD88 Pathway	Enhanced innate immune signaling	Jaw-specific lesions	10

Table 3: Key Causes and Mechanisms in Cherubism

Genetic Mutations: SH3BP2

• SH3BP2 Gene: Cherubism is primarily caused by dominant mutations in the SH3BP2 gene located on chromosome 4p16.3 5, 8, 9. These mutations result in a gain of function of the SH3BP2 protein.
• Inheritance: Most cases follow an autosomal dominant inheritance pattern—meaning one copy of the mutated gene is enough to cause the disorder. However, rare cases of autosomal recessive inheritance have been described 2, 5, 8.

Cellular and Molecular Mechanisms

• Osteoclast Overactivity: The mutated SH3BP2 gene causes signaling changes in myeloid cells, leading to hyperactive osteoclasts (bone-resorbing cells) 7, 9.
  • This results in excessive bone breakdown in the jaws and replacement with fibrous tissue 7, 9.
• Inflammatory Pathways: The mutations also drive increased production of inflammatory molecules, especially tumor necrosis factor alpha (TNF-α) 7, 10.
• TLR/MYD88 Pathway: Mutant cells are hyperresponsive to signals from toll-like receptors (TLRs), leading to excessive inflammatory signaling and further bone resorption 10.
  • This mechanism helps explain why lesions are restricted to the jaws, where there is increased exposure to oral bacteria and tissue remodeling 10.

Environmental and Age-Related Factors

• Jaw-Specificity: The abundance of TLR ligands (from oral bacteria and damaged tissue during jaw remodeling) likely triggers the jaw-specific development of lesions 10.
• Regression with Age: When jaw growth slows after puberty, the stimulus for lesion formation decreases. This leads to spontaneous regression of the lesions in most individuals 5, 10, 11.

Treatment of Cherubism

Treatment for cherubism is highly individualized, focusing on the severity of symptoms, risk of complications, and psychosocial impact. In many cases, conservative management is appropriate, while surgery or experimental therapies may be needed for aggressive disease.

Treatment	Indication	Outcome/Goal	Source(s)
Observation	Most cases, mild disease	Monitors for progression, avoids overtreatment	2, 5, 11
Surgery	Functional/aesthetic issues, aggressive lesions	Immediate correction, stops progression, bone regeneration	1, 4, 12, 13
Curettage	Rapidly growing/large lesions	Reduces mass, preserves teeth	1, 12, 13
Segmental Resection	Severe, risk of fracture	Reconstruction, prevents complications	1, 13
Medical Therapy	Experimental/active disease	Potential to modulate inflammation	3, 6

Table 4: Main Treatment Approaches in Cherubism

Observation and Conservative Management

• Watchful Waiting: Since cherubism is self-limiting in most cases, observation with regular follow-up is recommended, especially in mild or quiescent cases 2, 5, 11.
• Monitoring: Patients are monitored for progression, dental development, and potential psychosocial impacts.

Indications for Surgery

• Functional or Emotional Disturbance: Surgery is considered when jaw swelling impairs chewing, breathing, speech, or causes significant emotional distress due to facial appearance 1, 2, 4, 5, 11.
• Aesthetic Concerns: Cosmetic correction may be performed for social or psychological reasons, often after puberty when lesions have stabilized 2, 4, 11.

Surgical Techniques

• Curettage and Contouring: Most commonly used during the active growth phase to remove fibrous tissue and reshape the jaws. This can arrest lesion growth and stimulate bone regeneration 1, 12, 13.
• Segmental Resection and Reconstruction: Reserved for very extensive lesions or where there is a risk of pathological fractures. Reconstruction may involve bone grafts or other techniques 1, 13.
• Timing: Surgery is usually delayed until after puberty unless there are severe functional or psychological issues 4, 5, 11, 12.

Medical and Experimental Therapies

• Targeted Therapies: Recent research in mouse models suggests that drugs targeting key pathways (e.g., SYK inhibitors, TNF-α blockers, calcineurin inhibitors) may help control inflammation and bone loss in aggressive or progressive cases 3, 6.
  • SYK Inhibitors: Have shown promise in reducing established lesions and inflammation in experimental models 3.
  • Anticalcineurin Agents: May be beneficial for aggressive cases based on histological markers 6.
• Clinical Application: These medical therapies remain largely experimental and are not yet established as standard treatments for humans.

Long-Term Follow-Up

• Regression: Most lesions regress spontaneously by adulthood, and follow-up is essential to monitor for complications or recurrence 11.
• Dental Management: Orthodontic and dental care may be needed to address malocclusion or tooth abnormalities.

Conclusion

Cherubism is a rare, genetically driven disorder with a dramatic yet often self-limiting impact on facial structure and dental health. Advances in understanding its genetic and cellular basis are opening new avenues for future therapies.

Key Takeaways:

• Early symptoms include painless, symmetrical jaw swelling, "cherubic" facial appearance, and dental abnormalities 1, 4, 5, 11.
• Types range from quiescent to aggressive, and can be familial or sporadic 5, 6, 8, 11.
• Caused by mutations in the SH3BP2 gene, leading to aberrant bone resorption and inflammation in the jaws 5, 7, 8, 9, 10.
• Treatment is tailored to the individual, with most cases managed conservatively. Surgery is reserved for functional or aesthetic needs, while experimental therapies targeting inflammation are under investigation 1, 2, 3, 4, 5, 6, 11, 12, 13.

Cherubism, while rare and potentially distressing in childhood, is usually benign and self-resolving. With careful monitoring and individualized care, most affected individuals can expect a favorable long-term outcome.