Cherubism

Excerpt

Clinical characteristics: Cherubism is a childhood-onset autoinflammatory bone disease characterized by proliferative fibroosseous lesions limited to the mandible and maxilla. The phenotype ranges from no clinical manifestations to severe mandibular and maxillary bone lysis and cortical expansion with dental, orbital/ophthalmologic, respiratory, speech, and swallowing complications. In most affected persons, teeth are displaced, unerupted, hypoplastic, or absent, or they may appear to be floating in cyst-like spaces; malocclusion, premature exfoliation of deciduous teeth, and root resorption have also been reported. Respiratory manifestations can include obstructive sleep apnea and upper-airway obstruction. Orbital and ophthalmologic manifestations can occur with enlargement of the maxilla and orbital floor displacement. Intellect and development are typically normal. The course and duration of the active process of bone destruction varies between affected individuals; new lesions can occur until puberty, and rarely in adulthood. Regression of the lesions occurs as they become filled with bone and remodel during the second and third decade of life. By age 30 years, the facial abnormalities associated with cherubism are usually less obvious than during childhood.

Diagnosis/testing: Diagnosis is established in a proband with typical clinical, radiographic, histologic, and family history findings and/or a heterozygous gain-of-function pathogenic variant in SH3BP2 or biallelic loss-of-function pathogenic variants in OGFRL1 identified by molecular genetic testing.

Management: Treatment of manifestations: Management through a craniofacial clinic with pediatric experience; surgical interventions include curettage with or without bone grafting; speech and language therapy as needed; treatment of obstructive sleep apnea and upper-airway obstruction per ENT and/or sleep specialist; orthodontic treatment for malocclusive bite, premature loss of deciduous teeth, and widely spaced, misplaced, uninterrupted, or absent permanent teeth; treatment per ophthalmologist in those with ocular manifestations.

Surveillance: Clinical and radiographic assessment of jaw lesions annually during cyst development and growth and then every two to three years or as needed after cyst growth stops; assess for feeding issues and jaw pain at each visit; assess for upper-airway obstruction and obstructive sleep apnea as needed; assess dental eruption and for displacement and dental anomalies every six months; ophthalmology evaluation annually or as needed.

Evaluation of relatives at risk: If the pathogenic variant(s) in the proband are known, molecular genetic testing can be used to clarify genetic status of at-risk family members; if the pathogenic variant(s) are not known, relatives at risk should be evaluated for clinical and radiographic manifestations of cherubism.

Genetic counseling: Cherubism can be inherited in an autosomal dominant (most commonly) or an autosomal recessive (rarely) manner. Approximately 80% of affected individuals have the disorder as the result of a heterozygous gain-of-function pathogenic variant in SH3BP2. In two families reported to date, cherubism is caused by biallelic loss-of-function pathogenic variants in OGFRL1 and inherited in an autosomal recessive manner.

Autosomal dominant inheritance: Most individuals diagnosed with cherubism represent simplex cases (i.e., a single occurrence in a family) and are presumed to have the disorder as the result of a de novo pathogenic variant. Each child of an individual with autosomal dominant cherubism has a 50% risk of inheriting the pathogenic variant.

Autosomal recessive inheritance: If both parents are known to be heterozygous for an OGFRL1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives requires prior identification of the OGFRL1 pathogenic variants in the family.

If the cherubism-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.